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EP4634220A2 - Antigen-binding molecules that bind to aav particles and uses - Google Patents

Antigen-binding molecules that bind to aav particles and uses

Info

Publication number
EP4634220A2
EP4634220A2 EP23847703.8A EP23847703A EP4634220A2 EP 4634220 A2 EP4634220 A2 EP 4634220A2 EP 23847703 A EP23847703 A EP 23847703A EP 4634220 A2 EP4634220 A2 EP 4634220A2
Authority
EP
European Patent Office
Prior art keywords
seq
amino acid
acid sequence
hcvr
lcvr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23847703.8A
Other languages
German (de)
French (fr)
Inventor
Christos Kyratsous
Andrew J. Murphy
Sven MOLLER-TANK
Yang Shen
Tri Nguyen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Regeneron Pharmaceuticals Inc
Original Assignee
Regeneron Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Regeneron Pharmaceuticals Inc filed Critical Regeneron Pharmaceuticals Inc
Publication of EP4634220A2 publication Critical patent/EP4634220A2/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
    • C07K16/084—Papovaviridae, e.g. papillomavirus, polyomavirus, SV40, BK virus, JC virus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2851—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2881—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD71
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/35—Valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/524—CH2 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present disclosure relates to antigen-binding molecules, including antibodies or antigen-binding fragments thereof, that bind to a capsid of an adeno-associated virus (AAV) particle.
  • AAV adeno-associated virus
  • the disclosure provides multispecific antigen-binding molecules such as multispecific antibodies, e.g., bispecific antibodies, or antigen-binding fragments thereof, that bind to a capsid of an AAV and/or a molecule on a cell surface, as well as related molecular complexes and pharmaceutical compositions.
  • Methods for using the antibodies (e.g., multispecific antibodies) disclosed herein, molecular complexes and/or pharmaceutical composition are also provided.
  • Viral particles have emerged as vectors for gene therapy and the treatment of disease.
  • Viral vectors such as those based on the genome of adeno-associated virus (AAV)
  • AAV adeno-associated virus
  • retargeted AAV as a gene delivery vehicle remains less than ideal, at least in part, due to limited success from the efforts to redirect vector tropism.
  • the efficiency of AAV vector-mediated gene delivery to different cell types also varies greatly.
  • One possible mechanism for inefficient AAV transduction of certain cells may be a lack of cellular receptor(s) to mediate virus binding and entry.
  • the present disclosure provides antibodies that bind to a capsid of an adeno-associated virus (AAV) particle, and multispecific antibodies such as, for example, bispecific antibodies, which can bind both to the capsid of an AAV particle and a molecule (i.e., a target molecule) on a cell surface, and methods of use thereof.
  • AAV adeno-associated virus
  • multispecific antibodies such as, for example, bispecific antibodies, which can bind both to the capsid of an AAV particle and a molecule (i.e., a target molecule) on a cell surface
  • the antibodies described herein can bridge the virus to target cell surfaces that are not naturally targeted by the virus, thereby redirecting virus delivery and transduction.
  • an antibody, or an antigen-binding fragment thereof wherein said antibody, or said antigen-binding fragment thereof, binds to a capsid of an adeno- associated virus (AAV) particle, and wherein said antibody, or said antigen-binding fragment thereof, comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1
  • HCVR2 a heavy chain variable region
  • said antibody, or said antigen-binding fragment thereof comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:
  • said antibody, or said antigen-binding fragment thereof comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a HCVR comprising the amino acid sequence of S
  • an antibody, or an antigen-binding fragment thereof wherein said antibody, or said antigen-binding fragment thereof, binds to a capsid of an adeno-associated virus (AAV) particle, wherein said antibody, or said antigen-binding fragment thereof, binds to one or more residues in one or more viral protein 3 (VP3) polypeptides in said capsid, wherein said one or more residues are selected from the residues listed in Tables 18-26.
  • AAV adeno-associated virus
  • said antibody, or said antigen-binding fragment thereof binds to a capsid of an AAV2 particle comprising amino acid substitutions R585A and R588A, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): a) S264, A266, N268, H271 , N382, S384, Q385, G512, R487, D494, K527, D529, K532, L538, D533, E555, N705, K706, V708, T450, Q457, and R459; b) S264, G265, A266, S267, N268, H271 , N382, G383, S384, R487, K527, D528, E530, E574, Q575, K706, and S707; c) N254, L256, K258, I260, S261 , Q263, Y272,
  • said antibody, or said antigen-binding fragment thereof binds to a capsid of an AAV8 particle, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): a) N255, L257, K259, 1261 , S262, N263, S266, A269, Y275, E325, V326, T327, Q328, A658, N670, S671 , F672, I673, T674, Q548, N549, A550, A551 , D559, E720, and T663; and/or b) N255, L257, S266, E325, V326, T327, Q328, N670, S671 , F672, I673, T674, N549, T719, and E720.
  • said antibody, or said antigen-binding fragment thereof binds to a capsid of an AAV9 particle, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): a) N254, I260, N262, Y274, E324, V325, T326, D327, N328, R550, D665, N668, S669, F670, 1671 , T672, Q546, G547, G549, E718, and A661 ; and/or b) N254, L256, I260, N262, E324, V325, T326, D551 , N668, S669, F670, T672, G330, and E718.
  • said antibody, or said antigen-binding fragment thereof comprises:
  • HCVR heavy chain variable region
  • HCDR2 heavy chain variable region
  • LCVR light chain variable region
  • HCVR heavy chain variable region
  • HCDR2 heavy chain variable region
  • LCVR light chain variable region
  • said antibody, or said antigen-binding fragment thereof comprises:
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
  • said antibody, or said antigen-binding fragment thereof comprises:
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 71
  • LCVR comprising the amino acid sequence of SEQ ID NO: 10
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 81
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
  • said antibody, or said antigen-binding fragment thereof is a humanized antibody or antigen binding fragment thereof, human antibody or antigen binding fragment thereof, murine antibody or antigen binding fragment thereof, chimeric antibody or antigen binding fragment thereof, Fab fragment, F(ab')2 fragment, F(ab)'3 fragments, single-chain fragment variable (scFv), bis-scFv, (scFv)2, diabody, minibody, nanobody, triabody, tetrabody, disulfide stabilized Fv protein (dsFv), single-domain antibody (sdAb), Ig NAR, single heavy chain antibody, bispecific antibody, trispecific antibody, or chemically modified derivatives thereof.
  • said antibody, or said antigen-binding fragment thereof comprises an IgG 1 , lgG2, lgG3, or lgG4 constant region, or a variant thereof. [0018] In some embodiments, said antibody, or said antigen-binding fragment thereof, comprises an IgG 1 constant region, or a variant thereof.
  • the IgG 1 constant region comprises the amino acid sequence of SEQ ID NO: 259 or 1 164.
  • said antibody, or said antigen-binding fragment thereof comprises an lgG4 constant region, or a variant thereof.
  • the lgG4 constant region comprises the amino acid sequence of SEQ ID NO: 261.
  • said antigen-binding fragment is a Fab fragment.
  • said antigen-binding fragment is an scFv fragment.
  • said antibody, or said antigen-binding fragment thereof binds to AAV2 with a dissociation constant (KD) of less than about 1.5 x 10 -6 M, as measured in a surface plasmon resonance assay.
  • KD dissociation constant
  • said antibody, or said antigen-binding fragment thereof binds to AAV2 with a dissociation constant (K D ) of less than about 20 nM, as measured in a surface plasmon resonance assay.
  • K D dissociation constant
  • said capsid comprises one or more wild-type AAV capsid polypeptides.
  • said capsid comprises one or more non-wild-type AAV capsid polypeptides.
  • rein binding of said antibody or antigen-binding fragment thereof to said AAV particle capsid does not neutralize said AAV particle.
  • an antibody or an antigen-binding fragment thereof, that competes for binding to a capsid of an adeno-associated virus (AAV) particle with any of the above-described antibodies or antigen-binding fragments.
  • AAV adeno-associated virus
  • composition comprising any of the above-described antibodies or antigen-binding fragments and a pharmaceutically acceptable carrier or excipient.
  • a multispecific antibody or a multispecific antigen-binding fragment thereof, comprising: i) a first antigen-binding domain that binds to a capsid of an adeno-associated virus (AAV) particle; and ii) a second antigen-binding arm that binds to a molecule on a cell surface
  • said first antigen-binding domain comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10;
  • a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 10
  • the first antigen-binding domain that binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO:
  • the first antigen-binding domain that binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or
  • a multispecific antibody or a multispecific antigen-binding fragment thereof, comprising: i) a first antigen-binding domain that binds to a capsid of an adeno-associated virus (AAV) particle, and ii) a second antigen-binding domain that binds to a molecule on a cell surface, wherein said first antigen-binding domain binds to one or more residues in one or more viral protein 3 (VP3) polypeptides in said capsid, wherein said one or more residues are selected from the residues listed in Tables 18-26.
  • AAV adeno-associated virus
  • said first antigen-binding domain binds to a capsid of an AAV2 particle comprising amino acid substitutions R585A and R588A, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): a) S264, A266, N268, H271 , N382, S384, Q385, G512, R487, D494, K527, K529, K532, L538, D533, E555, N705, K706, V708, T450, Q457, and R459; b) S264, G265, A266, S267, N268, H271 , N382, G383, S384, R487, K527, D528, E530, Q574, Q575, K706, and S707; c) N254, L256, K258, I260, S261 , Q263, Y272, E322, V323,
  • said first antigen-binding domain binds to a capsid of an AAV8 particle, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): e) N255, L257, K259, 1261 , S262, N263, S266, A269, Y275, E325, V326, T327, Q328, A658, N670, S671 , F672, I673, T674, Q548, N549, A550, A551 , D559, E720, and T663; and/or f) N255, L257, S266, E325, V326, T327, Q328, N670, S671 , F672, I673, T674, N549, T719, and E720.
  • said first antigen-binding domain binds to a capsid of an AAV9 particle, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): g) N254, I260, N262, Y274, E324, V325, T326, D327, N328, R550, D665, N668, S669, F670, 1671 , T672, Q546, G547, G549, E718, and A661 ; and/or h) N254, L256, I260, N262, E324, V325, T326, D551 , N668, S669, F670, T672, G330, and E718.
  • said first antigen-binding domain that binds to a capsid of an AAV particle comprises:
  • HCVR heavy chain variable region
  • HCDR2 heavy chain variable region
  • LCVR light chain variable region
  • HCVR heavy chain variable region
  • HCDR2 heavy chain variable region
  • LCVR light chain variable region
  • HCVR heavy chain variable region
  • HCDR2 heavy chain variable region
  • LCVR light chain variable region
  • HCVR heavy chain variable region
  • HCDR2 HCDR2
  • HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81
  • LCVR light chain variable region
  • said first antigen-binding domain that binds to a capsid of an AAV particle comprises :
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; 3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
  • said first antigen-binding domain that binds to a capsid of an AAV particle comprises:
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1 159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 81
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
  • the molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
  • ASGR1 asialoglycoprotein receptor 1
  • TfR transferrin receptor
  • CACNG1 calcium voltage-gated channel auxiliary subunit gamma 1
  • the molecule on the cell surface is ASGR1 .
  • the second antigen-binding domain that binds to ASGR1 comprises: a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
  • said second antigen-binding domain that binds to ASGR1 comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO:
  • said second antigen-binding domain that binds to ASGR1 comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
  • the molecule on the cell surface is TfR.
  • the second antigen-binding domain that binds to TfR comprises:
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271
  • a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516; 24) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
  • said second antigen-binding domain that binds to TfR comprises:
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 327
  • a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328
  • a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329
  • a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333
  • a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334
  • a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 611 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
  • the second antigen-binding domain that binds to TfR comprises:
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 276
  • HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 361
  • LCVR comprising the amino acid sequence of SEQ ID NO: 366
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 501
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 506
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 511
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 516
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 521
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 526
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536; 26) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 1 119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1 127.
  • the molecule on the cell surface is CACNG1 .
  • the antigen-binding domain that binds to CACNG1 comprises:
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
  • the second antigen-binding domain that binds to CACNG1 comprises:
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949; 18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803; 1 1) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 1 181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
  • a multispecific antibody or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1”); and c) a third polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); wherein ABD1 or ABD2 binds to a capsid of an adeno-associated virus (AAV) particle, and the other of ABD1 or ABD2 binds to
  • ABD1 binds to a capsid of an adeno-associated virus (AAV) particle and ABD2 binds to a molecule on the cell surface.
  • AAV adeno-associated virus
  • ABD2 binds to a capsid of an adeno-associated virus (AAV) particle and ABD1 binds to a molecule on the cell surface.
  • AAV adeno-associated virus
  • the first heavy chain region is linked to the second heavy chain region via a linker.
  • a multispecific antibody or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) an Fc domain; b) a second polypeptide chain, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an Fc domain; and c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); wherein ABD1 or ABD2 binds to a capsid of an adeno-associated virus (AAV) particle, and the other of ABD1 or ABD2 binds to
  • ABD1 binds to a capsid of an adeno-associated virus (AAV) particle and ABD2 binds to a molecule on the cell surface.
  • AAV adeno-associated virus
  • ABD2 binds to a capsid of an adeno-associated virus (AAV) particle and ABD1 binds to a molecule on the cell surface.
  • AAV adeno-associated virus
  • the first scFv and/or the first heavy chain region is linked to the Fc domain via a linker.
  • the ABD1 or ABD2 which binds to a capsid of an AAV particle comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCVR that comprises a HCVR
  • the ABD1 or ABD2 which binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO:
  • the ABD1 or ABD2 which binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1 159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10
  • the molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
  • ASGR1 asialoglycoprotein receptor 1
  • TfR transferrin receptor
  • CACNG1 calcium voltage-gated channel auxiliary subunit gamma 1
  • the molecule on the cell surface is ASGR1 .
  • the other of ABD1 or ABD2 which binds to ASGR1 comprises: a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
  • the other of ABD1 or ABD2 which binds to ASGR1 comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of
  • the other of ABD1 or ABD2 which binds to ASGR1 comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
  • the molecule on the cell surface is TfR.
  • the other of ABD1 or ABD2 which binds to TfR comprises:
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271
  • a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 11 19, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
  • the other of ABD1 or ABD2 which binds to TfR comprises:
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 327
  • a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328
  • a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329
  • a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333
  • a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334
  • a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580; 30) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 611 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
  • the other of ABD1 or ABD2 which binds to TfR comprises:
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 276
  • HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356; 9) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 501
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 506
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 511
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 516
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 521
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 526
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 531
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 536
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 1 119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1 127.
  • the molecule on the cell surface is CACNG1 .
  • the other of ABD1 or ABD2 which binds to CACNG1 comprises:
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
  • the other of ABD1 or ABD2 which binds to CACNG1 comprises:
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809; 11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1211 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.
  • the other of ABD1 or ABD2 which binds to CACNG1 comprises:
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823; 12) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 1 181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1 189; or
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
  • a multispecific antibody or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) an scFv comprising a first antigen-binding domain (“ABD1 ”) operably linked to (ii) a first heavy chain region of a first Fab (“Fab1”), said first heavy chain region operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain
  • two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
  • ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
  • ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
  • the scFv is linked to the first heavy chain region via a linker.
  • a multispecific antibody or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) an scFv comprising a first antigen-binding domain (“ABD1”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that
  • two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
  • ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
  • ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
  • the scFv is linked to the Fc domain via a linker.
  • a multispecific antibody or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”), said second heavy chain region of Fab2 operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (“Fab3”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1 ”); d) a fourth polypeptide chain comprising a second light chain that pairs with
  • two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
  • ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
  • ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
  • the first heavy chain region is linked to the second heavy chain region via a linker.
  • a multispecific antibody or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (“Fab3”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1 ”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain
  • two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
  • ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
  • ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
  • the second heavy chain region is linked to the Fc domain via a linker.
  • a multispecific antibody, or a multispecific antigen-binding fragment thereof comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an scFv comprising a first antigen-binding domain (“ABD1 ”), said scFv operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen
  • two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
  • ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
  • ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
  • the scFv is linked to the first heavy chain region via a linker.
  • a multispecific antibody, or a multispecific antigen-binding fragment thereof comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) an scFv comprising a first antigen-binding domain (“ABD1 ”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain
  • two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
  • ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
  • ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
  • the second heavy chain region is linked to the Fc domain via a linker.
  • a multispecific antibody or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”), said second heavy chain region operably linked to (iii) a third heavy chain region of a third Fab (“Fab3”); b) a second polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1”); and c) a third polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); d) a fourth polypeptide chain comprising a third light chain
  • two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
  • ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
  • ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
  • the first heavy chain region is operably linked to the second heavy chain region and/or the second heavy chain region is operably linked to the third heavy chain region via a linker.
  • the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a
  • the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the
  • the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid
  • said molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
  • ASGR1 asialoglycoprotein receptor 1
  • TfR transferrin receptor
  • CACNG1 calcium voltage-gated channel auxiliary subunit gamma 1
  • said molecule on the cell surface is ASGR1.
  • the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises: a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
  • the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR
  • the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
  • the molecule on the cell surface is TfR.
  • the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises:
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271
  • a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557; 28) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 11 19, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
  • the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises:
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 327
  • a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328
  • a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329
  • a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333
  • a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334
  • a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455; 18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 4
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 611 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1 131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
  • the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises:
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 276
  • HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 361
  • LCVR comprising the amino acid sequence of SEQ ID NO: 366
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 501
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 506
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 51 1
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 516
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 521
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 526
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 531
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 536
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 1 119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1 127.
  • the molecule on the cell surface is CACNG1 .
  • the other(s) of ABD1 , ABD2 and ABD3 which binds to CACNG1 comprises:
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
  • the other(s) of ABD1 , ABD2 and ABD3 which binds to CACNG1 comprises:
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1 193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 121 1 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.
  • the other(s) of ABD1 , ABD2 and ABD3 which binds to
  • CACNG1 comprises:
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 1 181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1 189; or
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
  • a multispecific antibody or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first scFv comprising a first antigen-binding domain (“ABD1 ”) operably linked to (ii) a first heavy chain region of a first Fab (“Fab1 ”), said first heavy chain region of Fab1 operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second scFv comprising a second antigen-binding domain (“ABD2”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”), said second heavy chain region of Fab2 operably linked to (iii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the
  • two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface.
  • ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 and ABD4 binds to a molecule on a cell surface.
  • ABD3 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD2 binds to a molecule on a cell surface.
  • the first scFv is linked to the first heavy chain region and/or the second scFv is linked to the second heavy chain region via a linker.
  • a multispecific antibody or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ’’) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a first scFv comprising a first antigen-binding domain (“ABD1 ”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a second scFv comprising a second antigen-binding domain (“ABD2”); c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab
  • two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface.
  • ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 and ABD4 binds to a molecule on a cell surface.
  • ABD3 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD2 binds to a molecule on a cell surface.
  • the first scFv and/or second scFv is linked to the Fc domain via a linker.
  • a multispecific antibody or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”) operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (“Fab3) operable liked to (ii) a fourth heavy chain region of a fourth Fab (“Fab4”) operably linked to (iii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1 ”); d) a fourth antigen-binding domain
  • two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface.
  • ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 and ABD4 binds to a molecule on a cell surface.
  • ABD2 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD3 binds to a molecule on a cell surface.
  • the first heavy chain region is linked to the second heavy chain region and/or the third heavy chain region is linked to fourth heavy chain region via a linker.
  • the at least one of ABD1 , ABD2, ABD3, and ABD4 which binds to a capsid of an AAV particle comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises
  • the at least one of ABD1 , ABD2, ABD3, and ABD4 which binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2
  • the at least one of ABD1 , ABD2, ABD3, and ABD4 which binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising
  • said molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
  • ASGR1 asialoglycoprotein receptor 1
  • TfR transferrin receptor
  • CACNG1 calcium voltage-gated channel auxiliary subunit gamma 1
  • said molecule on the cell surface is ASGR1 .
  • the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to ASGR1 comprises: a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
  • the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to ASGR1 comprises a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a
  • the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to ASGR1 comprises a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
  • said molecule on the cell surface is TfR.
  • the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to TfR comprises:
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271
  • a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526; 25) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
  • the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to TfR comprises:
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 327
  • a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328
  • a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329
  • a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333
  • a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334
  • a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509; 23) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 5
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 61 1 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
  • the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to TfR comprises:
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 276
  • HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 361
  • LCVR comprising the amino acid sequence of SEQ ID NO: 366
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 501
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 506
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 511
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 516
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 521
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 526
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 531
  • a LCVR comprising the amino acid sequence of SEQ ID NO: 536
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557; 28) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ;
  • said molecule on the cell surface is CACNG1 .
  • the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to CACNG1 comprises:
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
  • a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
  • HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1 193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
  • a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 121 1 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.
  • the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to CACNG1 comprises:
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
  • HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 1 181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1 189; or
  • a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
  • the linker is:
  • the linker is:
  • the linker is:
  • the linker is:
  • the linker is 5 amino acids to 25 amino acids in length.
  • the linker is 25 to 35 amino acids in length.
  • the linker is or comprises a multimer of G n S (SEQ ID NO:
  • n is an integer from 1 to 10.
  • the linker is or comprises a multimer of G 4 S (SEQ ID NO: 242).
  • the linker is or comprises two consecutive glycines (2Gly), three consecutive glycines (3Gly), four consecutive glycines (4Gly (SEQ ID NO: 243)), five consecutive glycines (5Gly (SEQ ID NO: 244)), six consecutive glycines (6Gly (SEQ ID NO: 245)), seven consecutive glycines (7Gly (SEQ ID NO: 246)), eight consecutive glycines (8Gly (SEQ ID NO: 247)) or nine consecutive glycines (9Gly (SEQ ID NO: 248)).
  • one or more light chains are universal light chains.
  • a light chain constant region (CL) and a first heavy chain constant region (CH1) of one or more Fabs are in a CrossmAb arrangement.
  • the multispecific antibodies or multispecific antigenbinding fragments comprise an Fc heterodimer.
  • one Fc domain in the Fc heterodimer comprises amino acid substitutions S354C and T366W (according to EU numbering) as compared to a wild-type Fc domain
  • the other Fc domain in the Fc heterodimer comprises amino acid substitutions Y349C, T366S, L368A, and Y407V (according to EU numbering) as compared to a wild-type Fc domain.
  • At least one Fc domain in the Fc heterodimer comprises a star mutation as compared to a wild-type Fc domain.
  • one Fc domain in the Fc heterodimer comprises amino acid mutations H435R and/or Y436F (according to EU numbering) as compared to a wild-type Fc domain.
  • said capsid comprises one or more wild-type AAV capsid polypeptides.
  • said capsid comprises one or more non-wild-type AAV capsid polypeptides.
  • the multispecific antibodies or multispecific antigen-binding fragments can be a bispecific antibody or bispecific antigen-binding fragment thereof.
  • composition comprising a multispecific antibody or multispecific antigen-binding fragment described herein, and a pharmaceutically acceptable carrier or excipient.
  • a molecular complex comprising an AAV particle bound to one or more antibodies and/or antigen-binding fragments described herein.
  • said AAV particle comprises one or more mutations in one or more AAV capsid proteins inhibiting the natural tropism of said AAV particle.
  • composition comprising a molecular complex described herein and a pharmaceutically acceptable carrier or excipient.
  • a method of preparing the molecular complex described herein comprising incubating said AAV particle in the presence of said one or more antibodies and/or antigen-binding fragments under conditions allowing specific binding of said one or more antibodies and/or antigen-binding fragments to said AAV particle capsid.
  • a molecular complex comprising an AAV particle bound to one or more multispecific antibodies and/or multispecific antigen-binding fragments described herein.
  • said AAV particle comprises one or more mutations in one or more AAV capsid proteins inhibiting the natural tropism of said AAV particle.
  • composition comprising a molecular complex described herein and a pharmaceutically acceptable carrier or excipient.
  • a method of preparing a molecular complex described herein comprising incubating said AAV particle in the presence of said one or more multispecific antibodies and/or multispecific antigen-binding fragments under conditions allowing specific binding of said one or more multispecific antibodies and/or multispecific antigen-binding fragments to said AAV particle capsid.
  • a method for targeting an AAV particle to a cell expressing a molecule on the cell surface comprising contacting the cell with a molecular complex described herein or a pharmaceutical composition described herein, wherein said molecular complex comprises one or more multispecific antibodies and/or multispecific antigen-binding fragments which bind to said molecule on the cell surface.
  • a method for delivering a polynucleotide to a cell expressing a molecule on the cell surface comprising contacting the cell with a molecular complex described herein or a pharmaceutical composition described herein, wherein said molecular complex comprises the AAV particle comprising said polynucleotide and bound to one or more multispecific antibodies and/or multispecific antigen-binding fragments which bind to said molecule on the cell surface.
  • said cell is in a subject and said molecular complex is administered to the subject.
  • said AAV particle does not target said cell in the absence of said one or more multispecific antibodies and/or multispecific antigen-binding fragments.
  • any of the features or components of embodiments discussed above or herein may be combined, and such combinations are encompassed within the scope of the present disclosure. Any specific value discussed above or herein may be combined with another related value discussed above or herein to recite a range with the values representing the upper and lower ends of the range, and such ranges are encompassed within the scope of the present disclosure.
  • Figures 1A-1L depict graphs of binding activities of the anti-adeno-associated virus (AAV) antibodies described herein to various adeno-associated virus (AAV) serotypes. RLU, relative light units.
  • Figures 2A-2J depict graphs showing immunoglobulin gamma Fc receptor I (FcGR- 1) AAV retargeting by anti-AAV antibodies derived using next-generation sequencing (NGS)Zmass spectrometry (MS) methods ( Figures 2A-2F) and by anti-AAV antibodies derived from hybridoma ( Figures 2G-2J) described herein for various AAV serotypes.
  • FcGR- 1 immunoglobulin gamma Fc receptor I
  • NGS next-generation sequencing
  • MS mass spectrometry
  • FIG 3 shows a schematic representation of alternative format antibody designs for bispecific antibodies of the present disclosure.
  • Exemplary bispecific antibodies target AAV and Asialoglycoprotein Receptor 1 (ASGR1).
  • Star mutations are depicted with an asterisk (*) and knob-in-hole (KiH) mutations are depicted with a triangle (e.g., ⁇ ).
  • Figure 4 displays a description of alternative format bispecific antibody molecules described herein.
  • FIGs 7A-7B illustrate that bispecific antibodies can effectively retarget adeno- associated virus (AAV) to the central nervous system (CNS).
  • a schematic representation of anti-transferrin receptor (TfR) x anti-AAV bispecific antibody retargeting of AAV to the CNS is depicted in Figure 7A.
  • a comparison of wild-type (WT) AAV9, covalent-platform control and bispecific platform retargeting of AAV to cerebellum, cortex, and hippocampus is shown in Figure 7B.
  • BBB blood-brain barrier.
  • FIGs 8A-8B demonstrate that liver detargeting can be controlled by modulating antibody concentration [Ab] and/or use of a detargeting capsid.
  • a comparison of transduction efficiency between the covalent platform and the bispecific platform evaluated using cDNA quantitation is shown in Figure 8A.
  • a comparison between detargeted AAV9 and WT AA9 using the bispecific platform in cerebellum and liver is shown in Figure 8B.
  • IHC immunohistochemistry.
  • FIG. 10 shows flow cytometry data illustrating co-incubation of AAV9 W503A with AF70 (top two rows) and AF71 (bottom two rows) resulted in improved transduction efficiency over control AAV without antibody on HEK 293 cells overexpressing mouse CACNG1 (mCACNGI). Transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody (AAV:Ab ratio 1 :1) and 1 AAV to 9 antibodies (AAV:Ab ratio 1 :9) as assessed by percent (%) GFP positive cells.
  • FIG 11 depicts line graphs showing co-incubation of AAV9 W503A with AF70 (top) and AF71 (bottom) resulted in improved transduction efficiency over control AAV without antibody on HEK 293 cells overexpressing mouse CACNG1 (mCACNGI). Transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody (AAV:Ab ratio 1 :1) and 1 AAV to 9 antibodies (AAV:Ab ratio 1 :9) as assessed by mean fluorescence intensity (MFI).
  • MFI mean fluorescence intensity
  • FIG. 12 shows flow cytometry data illustrating co-incubation of AAV9 W503A with AF70 (top two rows) and AF71 (bottom two rows) resulted in improved AAV transduction efficiency over control AAV without antibody on HEK 293 cells overexpressing human CACNG1 (hCACNGI). Transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody (AAV:Ab ratio 1 :1) and 1 AAV to 9 antibodies (AAV:Ab ratio 1 :9) as assessed by percent (%) GFP positive cells.
  • Figure 13 depicts line graphs showing co-incubation of AAV9 W503A with AF70 (top) and AF71 (bottom) resulted in improved AAV transduction efficiency over control AAV without antibody on HEK 293 cells overexpressing human CACNG1 (hCACNGI). Transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody (AAV:Ab ratio 1 :1) and 1 AAV to 9 antibodies (AAV:Ab ratio 1 :9) as assessed by mean fluorescence intensity (MFI).
  • MFI mean fluorescence intensity
  • Figure 14 shows immunohistochemical staining of differentiated C2C12 myotubes for Myosin Heavy Chain (MyHC) and demonstration that incubation of AAV with AF70 and AF71 enhanced transduction into the myotubes as determined by GFP fluorescence.
  • MyHC Myosin Heavy Chain
  • Figure 15 shows immunohistochemical staining of differentiated human myotubes for Myosin Heavy Chain (MyHC) and demonstration that incubation of AAV with AF70 and AF71 enhanced transduction into the myotubes as determined by GFP fluorescence.
  • Human myotubes were most efficiently transduced with AAV complexed with AF71 at molar ratio 1 :3 and 1 :9.
  • Figures 16A-16D demonstrate incubation of AAV with AF70 and AF71 enhanced transduction into differentiated C2C12 myotubes as determined by quantification of GFP positive cells.
  • Figures 18A-18B show non-limiting examples of AAVx mTfR alternative format (AF) antibodies described herein.
  • Star mutations are depicted with an asterisk (*) and knob-in-hole (KiH) mutations are depicted with a triangle (e.g., ⁇ ).
  • Figure 19 shows an example experimental setup used to test alternative format antibodies binding to AAV9W503A virus by ELISA.
  • Figure 20 depicts ELISA data for AAV x mTfR alternative format antibodies binding to AAV9W503A.
  • Figure 21 shows a schematic diagram of a FLuc assay protocol used to test retargeting of AAV9W503A using mTfR alternative format antibodies on 293T cells expressing mTfR receptor.
  • Figure 22 shows a line graph of data generated in experiments testing AAV9W503A retargeting using AAVxmTfR alternative format antibodies on mTfR293T cells.
  • Figures 23A-23C illustrate a retargeting assay using AAV9 scCBH.eGFP.
  • Figures 24A-24B show in vitro test infection results for in vivo injection samples.
  • Figures 25A-25F depict AAV x mTfR liver and brain (hippocampus, cortex, and cerebellum) green fluorescent protein (GFP) staining for control groups (Figure 25A) and alternative format designs, AAV x mTfR AF1 (Figure 25B), AAV x mTfR AF3 ( Figure 25C), AAV x mTfR AF5 ( Figure 25D), AAV x mTfR AF7 ( Figure 25E), and AAV x mTfR AF9 ( Figure 25F).
  • GFP green fluorescent protein
  • Figure 26 shows relative RNA expression of GFP in liver samples as determined by RT-qPCR.
  • Figure 27 shows RNA expression of GFP in brain samples as determined by RT- qPCR.
  • Figures 28A-28D depict GFP staining in brain, heart and liver tissues from mice receiving AAV9 ( Figures 28A-28B) or AAV9W503A ( Figures 28C and 28D) complexed with AAV x mTfR alternative format AF7 at AAV vector genome (VG) to antibody (Ab) ratios (VG:Ab ratios) of 1 :9 and 1 :3.
  • AAV9 Figures 28A-28B
  • AAV9W503A Figures 28C and 28D
  • Figures 29A-29I depict AAV x mTfR alternative format designs AF3 and AF7.
  • Figure 29A provides a description of AAV x mTfR alternative format designs AF3 and AF7.
  • Star mutations are depicted with an asterisk (*) and knob-in-hole (KiH) mutations are depicted with a triangle (e.g., ⁇ ).
  • Figures 29B-29E show examples of AAV x mTfR AF3 amino acid sequences ( Figure 29B) and corresponding nucleotide sequences ( Figures 29C-29E).
  • Figures 29F-29I show examples of AAV x mTfR AF7 amino acid sequences (Figure 29F) and corresponding nucleotide sequences ( Figures 29G-29I).
  • Figures 30A-30G depict AAV x CACNGI alternative format designs AF70 and AF71.
  • Figure 30A provides a description of AAV x CACNG1 alternative format designs AF70 and AF71.
  • Figures 30B-30G show examples of AAV x mTfR AF70 amino acid sequences (Figure 30B) and corresponding nucleotide sequences ( Figures 30C-30D).
  • Figures 30E-30G show examples of AAV x mTfR AF71 amino acid sequences ( Figure 30E) and corresponding nucleotide sequences (Figures 30F-30G).
  • Figure 31 illustrates AAV x CACNG1 bispecific antibody enhancement of transduction into CACNG1 overexpressing 293 cells. GFP expression was assessed by flow cytometry and is shown as % GFP positive cells (top panels) or MFI of GFP expressing cells (bottom panels).
  • Figure 32 depicts an example of a study design for testing Hu37 complexed with anti-AAV x CACNG1 2x2 antibodies in D2.MDX mice.
  • Figure 33 shows in vitro transduction in HEK293-hCACNG1 of complexes prepared for in vivo study.
  • Figures 34A-34C illustrate improved Hu37 transduction in muscle tissues when complexed with an 2x2 anti-CACNG1xAAV alternative format antibody.
  • Figures 35A-35B illustrate bispecific antibody enhancement of Hu37 transduction into skeletal muscle.
  • Figure 38 depicts IVIS data that demonstrate retargeting of multiple serotypes to liver with AF30.
  • Figures 39A-39D depict IVIS & PK qPCR data that demonstrate retargeting to liver with antibodies comprised of either one or two anti-AAV binding arms.
  • Figures 40A-40C depict IVIS, PK qPCR, & ELISA data that demonstrate antibody can effectively retarget AAV when dosed prior to AAV administration.
  • Figures 41A-41B depict IVIS & PK qPCR data that demonstrate retargeting of REGN16199 with and without Fc.
  • Figures 42A-42F depict IVIS, PK qPCR, & RNA Taqman data that demonstrate successful targeting with linear Fab formats.
  • Figure 43 depicts PK qPCR data of serum samples 24 hours after administration of various antibody formats complexed with AAV.
  • Figure 44 depicts IVIS data that demonstrate retargeting of AAV with a variety of different antibody formats.
  • Figure 45 depicts IVIS data that demonstrate retargeting of AAV with antibody comprised of one anti-AAV arm and one anti-ASGR1 arm.
  • Figures 46A-46I depict AAV x ASGR alternative format designs AF1 , AF5, and AF9.
  • Figures 46A-46C show examples of AAV x ASGR AF1 amino acid sequences ( Figure 46A) and corresponding nucleotide sequences ( Figures 46B-46C).
  • Figures 46D-46F show examples of AAV x ASGR AF5 amino acid sequences ( Figure 46D) and corresponding nucleotide sequences ( Figures 46E-46F).
  • Figures 46G-46I show examples of AAV x ASGR AF9 amino acid sequences (Figure 46G) and corresponding nucleotide sequences ( Figures 46H-46I).
  • Figures 47A-47I depict AAV x mTfR alternative format designs AF1 , AF5, and AF9.
  • Figures 47A-47C show examples of AAV x mTfR AF1 amino acid sequences ( Figure 47A) and corresponding nucleotide sequences ( Figures 47B-47C).
  • Figures 47D-47F show examples of AAV x mTfR AF5 amino acid sequences ( Figure 47D) and corresponding nucleotide sequences ( Figures 47E-47F).
  • Figures 47G-47I show examples of AAV x mTfR AF9 amino acid sequences (Figure 47G) and corresponding nucleotide sequences ( Figures 47H-47I).
  • Figure discloses “3xG4S” as SEQ ID NO: 1115 and “4xG4S” as SEQ ID NO: 1161.
  • antigen encompasses any agent (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleotide, portions thereof, or combinations thereof) that, when introduced into an immunocompetent host is recognized by the immune system of the host and is capable of eliciting an immune response by the host.
  • agent e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleotide, portions thereof, or combinations thereof
  • epitope can refer to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule known as a paratope.
  • a single antigen may have more than one epitope.
  • different antibodies may bind to different areas on an antigen and may have different biological effects.
  • Epitopes may be either conformational or linear.
  • a conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain.
  • a linear epitope is one produced by adjacent amino acid residues in a polypeptide chain.
  • an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen.
  • Epitopes may also be defined as structural or functional. Functional epitopes are generally a subset of structural epitopes and are defined as those residues that directly contribute to the affinity of the interaction between a major histocompatibility complex (MHC) molecule and the antigen.
  • MHC major histocompatibility complex
  • antigen-binding molecule refers in its broadest sense to a molecule that specifically binds to an antigen.
  • an antigen-binding molecule is an antibody or an antigen-binding fragment of an antibody, including, e.g., multispecific antibodies such as bispecific antibodies or fragments thereof.
  • multispecific antigen-binding molecule or “multispecific binding molecule” or “MBM” includes molecules (e.g., antibodies and antigen-binding fragments of antibodies) that bind two or more (e.g., three or four) different epitopes or antigens.
  • the multispecific antigen-binding molecules are bispecific (e.g., bispecific antibodies).
  • the multispecific antigen-binding molecules are trispecific.
  • the multispecific antigen-binding molecules are tetraspecific.
  • the present disclosure includes multispecific (e.g., bispecific) antigen-binding molecules (e.g., antibodies) that specifically bind a capsid of an AAV particle and a molecule of a cell surface.
  • antigen-binding molecules may be referred to herein as, e.g., “anti- AAV x anti-cell surface molecule” or other similar terminology (e.g., anti-AAV/anti-cell surface molecule).
  • a multispecific antigen-binding molecule of the disclosure may comprise a first ABD (“ABD1”), a second ABD (“ABD2”), a third ABD (“ABD3”), and/or a fourth ABD (“ABD4”), each of which may be part of, e.g., an scFv or a Fab.
  • antibody means any antigen-binding molecule or molecular complex comprising at least one complementarity determining region (CDR) that specifically binds to or interacts with a particular antigen.
  • CDR complementarity determining region
  • antibody includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM).
  • IgM multimers thereof
  • antibody also includes immunoglobulin molecules consisting of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
  • the heavy chain constant region comprises three domains, CH1 , CH2 and CH3.
  • Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and a light chain constant region.
  • the light chain constant region comprises one domain (C L 1).
  • the V H and V L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • Each V H and V L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.
  • the FRs of the anti-AAV antibody or anti-cell surface molecule antibody may be identical to the human germline sequences or may be naturally or artificially modified.
  • An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.
  • antibody also includes antigen-binding fragments of full antibody molecules.
  • antigen-binding fragment of an antibody, “antigen-binding portion” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex.
  • Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains.
  • DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized.
  • the DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.
  • Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3- CDR3-FR4 peptide.
  • CDR complementarity determining region
  • engineered molecules such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigenbinding fragment," as used herein.
  • SMIPs small modular immunopharmaceuticals
  • An antigen-binding fragment of an antibody will typically comprise at least one variable domain.
  • the variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences.
  • the V H and L domains may be situated relative to one another in any suitable arrangement.
  • the variable region may be dimeric and contain V H -V H , V H -V L or L-VL dimers.
  • the antigen-binding fragment of an antibody may contain a monomeric V H or V L domain.
  • an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain.
  • variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present disclosure include: (i) VH-CH1 ; (ii) VH- C H 2; (iii) V H -C H 3; (iv) VH-C H 1-C H 2; (V) VH-C H 1 -CH2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L ; (viii) V L - C H 1 ; (ix) VL-C H 2; (X) V L -C H 3; (xi) VL-C H 1 -C H 2; (xii) VL-C H 1 -C H 2-CH3; (xiii) V L -C H 2-C H 3; and (xiv)
  • variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region.
  • a hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule.
  • an antigen-binding fragment of an antibody of the present disclosure may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non- covalent association with one another and/or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)).
  • antigen-binding fragments may be monospecific or multispecific (e.g., bispecific).
  • a bispecific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen.
  • Any multispecific antibody format including the non-limiting example formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present disclosure using routine techniques available in the art.
  • CDR complementarity determining region
  • Exemplary conventions that can be used to identify the boundaries of CDRs include, e.g., the Kabat definition, the Chothia definition, the ABS definition and the IMGT definition. See, e.g., Kabat, 1991 , “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (Kabat numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol. 273:927-948 (Chothia numbering scheme); Martin et al., 1989, Proc. Natl. Acad. Sci. USA 86:9268-9272 (ABS numbering scheme); and Lefranc et ai, 2003, Dev. Comp. Immunol. 27:55-77 (IMGT numbering scheme). Public databases are also available for identifying CDR sequences within an antibody.
  • single chain Fv or “scFv” as used herein can refer to a polypeptide chain comprising the V H and V L domains of an antibody, where these domains are present in a single polypeptide chain.
  • Fab can refer to a pair of polypeptide chains, the first polypeptide chain comprising a variable heavy (VH) domain of an antibody N- terminal to a first constant domain (referred to herein as C1), and the second polypeptide chain comprising a variable light (VL) domain of an antibody N-terminal to a second constant domain (referred to herein as C2) capable of pairing with the first constant domain.
  • VH variable heavy
  • VL variable light domain of an antibody N-terminal to a second constant domain
  • the VH is N- terminal to the first constant domain (CH1) of the heavy chain
  • V L is N- terminal to the constant domain of the light chain (CL).
  • the Fabs of the disclosure can be arranged according to the native orientation or include domain substitutions or swaps on that facilitate correct VH and VL pairings, particularly where the antigen-binding molecules of the disclosure comprise non-identical Fabs.
  • correct chain pairing can be achieved by the use of universal light chains that can pair with both variable regions of a heterodimeric antigen-binding molecules of the disclosure.
  • universal light chain as used herein in the context of an antigen-binding molecule described herein can refer to a light chain polypeptide capable of pairing with the heavy chain region of a first Fab to form the first Fab and capable of pairing with the heavy chain region of a second Fab to form the second Fab. Universal light chains are also known as “common light chains.”
  • Fc domain can refer to a portion of the heavy chain that pairs with the corresponding portion of another heavy chain.
  • Fc region can refer to the region of antibody-based binding molecules formed by association of two heavy chain Fc domains. The two Fc domains within the Fc region may be the same or different from one another. In a native antibody the Fc domains are typically identical, but for the purpose of producing the antigen-binding molecules of the disclosure, one or both Fc domains might advantageously be modified to allow for heterodimerization.
  • the term “derived from” indicates a relationship between a first and a second molecule. It generally can refer to structural similarity between the first molecule and a second molecule and does not connote or include a process or source limitation on a first molecule that is derived from a second molecule.
  • the term “specifically binds” as used herein means that an antigen-binding molecule forms a complex with a target antigen that is relatively stable under physiologic
  • Specific binding can be characterized by a K D of about 5x10 -2 M or less (e.g., less than 5x10 -2 M, less than 10 -2 M, less than 5x10 2 M, less than 10 -3 M, less than 5x10 -4 M, less than 10 -4 M, less than 5x10 5 M, less than 10 5 M, less than 5x10 -6 M, less than 10 -6 M, less than 5x10 7 M, less than 10 7 M, less than 5x10 -8 M, less than 10 -8 M, less than 5x10 9 M, less than 10' 9 M, or less than 10 -1 ° M).
  • K D of about 5x10 -2 M or less (e.g., less than 5x10 -2 M, less than 10 -2 M, less than 5x10 2 M, less than 10 -3 M, less than 5x10 -4 M, less than 10 -4 M, less than 5x10 5 M, less than 10 5 M, less than 5x10 -6 M, less than 10 -6
  • an antigen-binding molecule or antigen-binding domain e.g., an antigen-binding molecule or antigen-binding domain
  • Methods for determining the binding affinity of an antibody or an antibody fragment, e.g., an antigen-binding molecule or antigen-binding domain, to a target antigen include, for example, equilibrium dialysis, surface plasmon resonance (e.g., Biacore assays), fluorescent-activated cell sorting (FACS) binding assays and the like.
  • An antigen-binding molecule that specifically binds to a target antigen from one species can, however, have cross-reactivity to the target antigen from one or more other species.
  • operably linked can refer to a functional relationship between two or more regions of a polypeptide chain in which the two or more regions are linked so as to produce a functional polypeptide.
  • nucleic acid or fragment thereof indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 90%, and more preferably at least about 95%, 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well- known algorithm of sequence identity, such as FASTA, BLAST or Gap, as discussed below.
  • a nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in certain instances, encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.
  • the term “substantial similarity” or “substantially similar” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 95% sequence identity, even more preferably at least 98% or 99% sequence identity.
  • residue positions which are not identical differ by conservative amino acid substitutions.
  • a “conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein.
  • the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331 , herein incorporated by reference.
  • Examples of groups of amino acids that have side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartate and glutamate, and (7) sulfur-containing side chains are cysteine and methionine.
  • Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalaninetyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine.
  • a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 1443-1445, herein incorporated by reference.
  • a "moderately conservative" replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.
  • Sequence similarity for polypeptides is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions.
  • GCG software contains programs such as Gap and Bestfit which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1 . Polypeptide sequences also can be compared using FASTA using default or recommended parameters, a program in GCG Version 6.1.
  • FASTA e.g., FASTA2 and FASTA3
  • FASTA2 and FASTA3 provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra).
  • Another preferred algorithm when comparing a sequence of the disclosure to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402, each herein incorporated by reference.
  • subject or "patient” as used herein includes all members of the animal kingdom including non-human primates and humans.
  • antibodies and antigen-binding fragments thereof that bind a capsid of an AAV particle also known as “anti-AAV antibodies” herein.
  • the capsid comprises any of various wild-type and/or non-wild-type AAV capsid protein(s) described herein.
  • the antibodies and/or antigenbinding fragments thereof bind an epitope on a capsid described herein.
  • the anti-AAV antibodies provided herein, or antigen-binding portions thereof may be included as part of a multispecific antigen-binding molecule, e.g., a multispecific antibody or multispecific antigenbinding fragment thereof, described herein.
  • AAV is an abbreviation for adeno-associated virus and may be used to refer to the virus itself or derivatives thereof.
  • AAVs are members of the Parvovirus family of small, nonenveloped, single-stranded DNA viruses.
  • ITR inverted terminal repeats
  • ORFs open reading frames
  • the wildtype rep reading frame encodes four proteins of molecular weight 78 kD (“Rep78”), 68 kD (“Rep68”), 52 kD (“Rep52”) and 40 kD (“Rep 40”).
  • Rep78 and Rep68 are transcribed from the p5 promoter, and Rep52 and Rep40 are transcribed from the p19 promoter. These proteins function mainly in regulating the transcription and replication of the AAV genome.
  • the wildtype cap reading frame encodes three structural (capsid) viral proteins (VPs) having molecular weights of 83-85 kD (VP1), 72-73 kD (VP2) and 61-62 kD (VP3). More than 80% of total proteins in an AAV virion (capsid) comprise VP3; in mature virions VP1 , VP2 and VP3 are found at relative abundance of approximately 1 :1 :10, although ratios of 1 :1 :8 have been reported. Padron et al. (2005) J. Virology 79:5047-58.
  • AAV encompasses all subtypes and both naturally occurring and modified forms (e.g., recombinant forms), except where stated otherwise.
  • AAV includes primate AAV (e.g., AAV type 1 (AAV1), primate AAV type 2 (AAV2), primate AAV type 3 (AAV3), primate AAV3B, primate AAV type 4 (AAV4), primate AAV type 5 (AAV5), primate AAV type 6 (AAV6), primate AAV6.2, primate AAV type 7 (AAV7), primate AAV type 8 (AAV8), primate AAV type 9 (AAV9), AAV10, AAV type hu11 (AAV hu11), AAV11, AAV12, AAV13, AAVDJ, Anc80L65, AAV2G9, AAVLK03, AAV type rh32.33 (AAVrh.32.33), AAV retro (AAV retro), AAV PHP.B, AAV PHP.eB
  • capsid protein includes a protein that is part of the capsid of the virus.
  • the capsid proteins are generally referred to as VP1 , VP2 and/or VP3, and may be encoded by the single cap gene.
  • the three AAV capsid proteins can be produced in nature an overlapping fashion from the cap ORF alternative translational start codon usage, although all three proteins use a common stop codon.
  • the ORF of a wildtype cap gene encodes from 5’ to 3’ three alternative start codons: ‘‘the VP1 start codon,” “the VP2 start codon,” and “the VP3 start codon”; and one “common stop codon”.
  • VP1 The largest viral protein, VP1 , is generally encoded from the VP1 start codon to the “common stop codon.”
  • VP2 is generally encoded from the VP2 start codon to the common stop codon.
  • VP3 is generally encoded from the VP3 start codon to the common stop codon.
  • VP1 comprises at its N-terminus sequence that it does not share with the VP2 or VP3, referred to as the VP1-unique region (VP1-u).
  • the VP1-u region is generally encoded by the sequence of a wildtype cap gene starting from the VP1 start codon to the “VP2 start codon.”
  • VP1-u comprises a phospholipase A2 domain (PLA2), which may be important for infection, as well as nuclear localization signals which may aid the virus in targeting to the nucleus for uncoating and genome release.
  • PHA2 phospholipase A2 domain
  • the VP1 , VP2, and VP3 capsid proteins share the same C-terminal sequence that makes up the entirety of VP3, which may also be referred to herein as the VP3 region.
  • the VP3 region is encoded from the VP3 start codon to the common stop codon.
  • VP2 has an additional ⁇ 60 amino acids that it shares with the VP1 .
  • an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described may bind to an epitope on the capsid.
  • the antibody may comprise any of the antibodies, e.g., multispecific antibodies, such as bispecific antibodies, which bind to the capsid of an AAV particle disclosed herein.
  • a multispecific antibody disclosed herein may comprise, for example, comprise a first binding domain that binds to a capsid of an AAV particle.
  • the first binding domain binds to an epitope on the capsid of the AAV particle.
  • the AAV particle capsid may comprise wild-type and/or non-wildtype AAV capsid proteins.
  • the epitope may comprise any of various serotypespecific or serotype-non-specific (i.e., “universal”) epitopes understood by one of ordinary skill in the art.
  • the epitope may comprise, e.g., any amino acid residues set forth in Tables 19-26, or variants of variants, derivatives or epitopes combinations thereof.
  • an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described herein may bind to an epitope on the capsid which is comprised of any amino acid residues of a capsid protein VP1 , VP2 or VP3, or a combination thereof.
  • the AAV particle can be derived from any AAV serotype described herein.
  • an antibody, or an antigen-binding fragment thereof can bind to any amino acid residue, or any combination thereof, of any variable region of a capsid, or any combination thereof, e.g., a variable region comprised of a capsid protein VP1 , VP2 or VP3, or a combination thereof (e.g., variable region I, II, III, IV, V, VI, VII, VIII, IX, or a combination thereof, as described in Emmanuel, et al., Journal of Virology, 2022, 96, 3).
  • an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described herein may bind to an epitope of an AAV1 capsid comprised of any amino acid residue or combination thereof of a variable region I, II, III, IV, V, VI, VII, VIII, IX, or combination thereof.
  • the antibody, or an antigen-binding fragment thereof may bind to AAV1 at any of residues 456-459, 492-499, 582, 583, 588- 591 , 593-595, 597, or any combination thereof, as described in Tseng, et al., Front Immunol. 2014, 5: 9.
  • an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described herein may bind to an epitope of an AAV2 capsid comprised of any amino acid residue or combination thereof of a variable region I, II, III, IV, V, VI, VII, VIII, IX, or combination thereof.
  • the antibody, or an antigen-binding fragment thereof may bind to AAV2 at any of residues 253, 254, 258, 261-264, 272-281, 369-378, 381 , 384, 385, 474-483, 492-502, 534, 548, 556, 560-573, 585-589, 601-610, 658-660, 708, 717, or any combination thereof, as described in Tseng, et al., Front Immunol. 2014, 5: 9.
  • an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described herein may bind to an epitope of an AAV5 capsid comprised of any amino acid residue or combination thereof of a variable region I, II, III, IV, V, VI, VII, VIII, IX, or combination thereof.
  • the antibody, or an antigen-binding fragment thereof may bind to AAV5 at any of residues 246, 254-261 , 374, 375, 483, 485- 492, 494, 496, 499-501 , 530, 532-538, 653, 654, 656, 657, 704-708, or any combination thereof as described in Tseng, et al., Front Immunol. 2014, 5: 9.
  • an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described herein may bind to an epitope of an AAV8 capsid comprised of any amino acid residue or combination thereof of a variable region I, II, III, IV, V, VI, VII, VIII, IX, or combination thereof.
  • the antibody, or an antigen-binding fragment thereof may bind to AAV8 at any of residues 586-591 or any combination thereof as described in Tseng, et al., Front Immunol. 2014, 5: 9.
  • an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described herein may bind to an epitope of an AAV9 capsid comprised of any amino acid residue or combination thereof of a variable region I, II, III, IV, V, VI, VII, VIII, IX, or combination thereof.
  • the antibody, or an antigen-binding fragment thereof may bind to AAV9 at any of residues 221 , 228, 246-248, 250-256, 258- 260, any of residues 262-273 of variable region I, any of residues 274, 275, 278, 291 , 293, 324, 325, any of residues 327-333 of variable region II, any of residues 334, 335, 338, 341 , 363-365, 369-373, 375, 376, any of residues 382-387, 389, 391 of variable region III, any of residues 438-441 , 443, any of residues 446, 448, 449, 451-460, 462, 464-473 of variable region IV, any of residues 488, 491-501 , 503-506, 510-515 of variable region V, any of residues 528-534, 545 of variable region VI, any of residues 547-560 of variable region VII, residue 572, any of residues 579, 584, 5
  • ITR inverted terminal repeat
  • the phrase “inverted terminal repeat” or “ITR” includes symmetrical nucleic acid sequences in the genome of adeno-associated viruses required for efficient replication. ITR sequences are located at each end of the AAV DNA genome. The ITRs serve as the origins of replication for viral DNA synthesis and are essential cis components for generating AAV particles, e.g., packaging into AAV particles.
  • AAV ITR comprise recognition sites for replication proteins Rep78 or Rep68.
  • a "D" region of the ITR comprises the DNA nick site where DNA replication initiates and provides directionality to the nucleic acid replication step.
  • An AAV replicating in a mammalian cell typically comprises two ITR sequences.
  • a single ITR may be engineered with Rep binding sites on both strands of the “A” regions and two symmetrical D regions on each side of the ITR palindrome.
  • Such an engineered construct on a double-stranded circular DNA template allows Rep78 or Rep68 initiated nucleic acid replication that proceeds in both directions.
  • a single ITR is sufficient for AAV replication of a circular particle.
  • the rep encoding sequence encodes a Rep protein or Rep protein equivalent that is capable of binding an ITR comprised on the transfer plasmid.
  • the Cap proteins of the disclosure when expressed with appropriate Rep proteins by a packaging cell, may encapsidate a transfer plasmid comprising a nucleotide of interest and an even number of two or more ITR sequences.
  • a transfer plasmid comprises one ITR sequence.
  • a transfer plasmid comprises two ITR sequences.
  • Rep proteins may be expressed from more than one ORF comprising nucleotide sequence encoding any combination of Rep78, Rep68, Rep 52 and/or Rep40 by use of separate nucleotide sequences operably linked to at least one expression control sequence for expression in a viral replication cell, each producing one or more of Rep78, Rep68, Rep 52 and/or Rep40 Rep proteins.
  • Rep proteins may be expressed individually from an ORF comprising a nucleotide sequence encoding any one of Rep78, Rep68, Rep 52, or Rep40 by use of separate nucleotide sequences operably linked to one expression control sequence for expression in a packaging cell, each producing only one Rep78, Rep68, Rep 52, or Rep40 Rep protein.
  • Rep proteins may be expressed from one ORF comprising nucleotide sequences encoding Rep78 and Rep52 Rep proteins operably linked to at least one expression control sequence for expression in a viral replication cell each producing Rep78 and Rep52 Rep protein.
  • a “chimeric AAV capsid protein” includes an AAV capsid protein that comprises amino acid sequences, e.g., portions, from two or more different AAV and that is capable of forming and/or forms an AAV viral capsid/viral particle.
  • a chimeric AAV capsid protein is encoded by a chimeric AAV capsid gene, e.g., a chimeric nucleotide comprising a plurality, e.g., at least two, nucleic acid sequences, each of which plurality is identical to a portion of a capsid gene encoding a capsid protein of distinct AAV, and which plurality together encodes a functional chimeric AAV capsid protein.
  • a chimeric capsid protein comprises one or more portions from a capsid protein of that AAV and one or more portions from a capsid protein of a different AAV.
  • a chimeric AAV2 capsid protein includes a capsid protein comprising one or more portions of a VP1 , VP2, and/or VP3 capsid protein of AAV2 and one or more portions of a VP1 , VP2, and/or VP3 capsid protein of a different AAV.
  • Table 1 sets forth the amino acid sequence identifiers of the heavy chain variable regions (HCVRs) and light chain variable regions (LCVRs), heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3), and light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3), as well as heavy chain (HC) and light chain (LC) of the exemplary anti-AAV antibodies and antigenbinding fragments.
  • HCVRs heavy chain variable regions
  • LCVRs light chain variable regions
  • HCDR1 , HCDR2 and HCDR3 heavy chain complementarity determining regions
  • LCDR1 , LCDR2 and LCDR3 light chain complementarity determining regions
  • Table 2 sets forth the sequence identifiers of the nucleic acid molecules encoding the HCVRs, LCVRs, HCDR1 , HCDR2, HCDR3, LCDR1 , LCDR2 LCDR3, HC and LC of the exemplary anti-AAV antibodies and antigen-binding fragments described herein.
  • Corresponding Fab and “standard mAb” i.e., mAb comprising a constant region derived from lgG4 subclass
  • Non-limiting examples of amino acid sequences and nucleotide sequences of the anti-AAV antibodies are also listed below.

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Abstract

Provided herein are anti-adeno-associated virus (AAV) antibodies and antigen fragments thereof, as well as multispecific antibodies (e.g., bispecific antibodies) that bind to both a capsid of an AAV particle and a molecule on a cell surface, related molecular complexes, affinity matrices, and pharmaceutical compositions, and methods of use thereof.

Description

ANTIGEN-BINDING MOLECULES THAT BIND TO AAV PARTICLES AND USES
THEREOF
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No. 63/387,876, filed December 16, 2022, U.S. Provisional Application No. 63/494,203, filed April 4, 2023, U.S. Provisional Application No. 63/520,508, filed August 18, 2023, and U.S. Provisional Application No. 63/578,925, filed August 25, 2023, the disclosure of each of which is herein incorporated by reference in its entirety.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on December 1 1 , 2023, is named 250298_000568_SL.xml and is 1 ,328,800 bytes in size.
FIELD OF THE DISCLOSURE
[0003] The present disclosure relates to antigen-binding molecules, including antibodies or antigen-binding fragments thereof, that bind to a capsid of an adeno-associated virus (AAV) particle. In particular, the disclosure provides multispecific antigen-binding molecules such as multispecific antibodies, e.g., bispecific antibodies, or antigen-binding fragments thereof, that bind to a capsid of an AAV and/or a molecule on a cell surface, as well as related molecular complexes and pharmaceutical compositions. Methods for using the antibodies (e.g., multispecific antibodies) disclosed herein, molecular complexes and/or pharmaceutical composition are also provided.
BACKGROUND
[0004] Viral particles have emerged as vectors for gene therapy and the treatment of disease. Viral vectors, such as those based on the genome of adeno-associated virus (AAV), offer promising platforms for gene delivery. Despite advances providing the ability to direct AAV infection, retargeted AAV as a gene delivery vehicle remains less than ideal, at least in part, due to limited success from the efforts to redirect vector tropism. The efficiency of AAV vector-mediated gene delivery to different cell types also varies greatly. One possible mechanism for inefficient AAV transduction of certain cells may be a lack of cellular receptor(s) to mediate virus binding and entry. There remains a need for selective and restrictive targeting of AAVs with enhanced cellular binding and transduction capabilities. SUMMARY OF THE DISCLOSURE
[0005] In general, the present disclosure provides antibodies that bind to a capsid of an adeno-associated virus (AAV) particle, and multispecific antibodies such as, for example, bispecific antibodies, which can bind both to the capsid of an AAV particle and a molecule (i.e., a target molecule) on a cell surface, and methods of use thereof. By binding to both a capsid of an AAV and a target cell surface molecule, the antibodies described herein can bridge the virus to target cell surfaces that are not naturally targeted by the virus, thereby redirecting virus delivery and transduction.
[0006] In one aspect, provided herein is an antibody, or an antigen-binding fragment thereof, wherein said antibody, or said antigen-binding fragment thereof, binds to a capsid of an adeno- associated virus (AAV) particle, and wherein said antibody, or said antigen-binding fragment thereof, comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1 159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0007] In some embodiments, said antibody, or said antigen-binding fragment thereof, comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[0008] In some embodiments, said antibody, or said antigen-binding fragment thereof, comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0009] In another aspect, provided herein is an antibody, or an antigen-binding fragment thereof, wherein said antibody, or said antigen-binding fragment thereof, binds to a capsid of an adeno-associated virus (AAV) particle, wherein said antibody, or said antigen-binding fragment thereof, binds to one or more residues in one or more viral protein 3 (VP3) polypeptides in said capsid, wherein said one or more residues are selected from the residues listed in Tables 18-26.
[0010] In some embodiments, said antibody, or said antigen-binding fragment thereof, binds to a capsid of an AAV2 particle comprising amino acid substitutions R585A and R588A, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): a) S264, A266, N268, H271 , N382, S384, Q385, G512, R487, D494, K527, D529, K532, L538, D533, E555, N705, K706, V708, T450, Q457, and R459; b) S264, G265, A266, S267, N268, H271 , N382, G383, S384, R487, K527, D528, E530, E574, Q575, K706, and S707; c) N254, L256, K258, I260, S261 , Q263, Y272, E322, V323, T324, Q325, A655, A667, S668, F669, I670, T671 , I332, Q545, G546, S547, E548, K556, N717, V719, T660, and F661 ; and/or d) N254, L256, Q263, S264, V323, T324, Q325, S655, A667, S668, F669, I670, T671 , G328, G546, E548, T716, and N717.
[0011] In some embodiments, said antibody, or said antigen-binding fragment thereof, binds to a capsid of an AAV8 particle, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): a) N255, L257, K259, 1261 , S262, N263, S266, A269, Y275, E325, V326, T327, Q328, A658, N670, S671 , F672, I673, T674, Q548, N549, A550, A551 , D559, E720, and T663; and/or b) N255, L257, S266, E325, V326, T327, Q328, N670, S671 , F672, I673, T674, N549, T719, and E720.
[0012] In some embodiments, said antibody, or said antigen-binding fragment thereof, binds to a capsid of an AAV9 particle, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): a) N254, I260, N262, Y274, E324, V325, T326, D327, N328, R550, D665, N668, S669, F670, 1671 , T672, Q546, G547, G549, E718, and A661 ; and/or b) N254, L256, I260, N262, E324, V325, T326, D551 , N668, S669, F670, T672, G330, and E718.
[0013] In some embodiments, said antibody, or said antigen-binding fragment thereof, comprises:
1) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10;
2) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1 159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157;
3) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or
4) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0014] In some embodiments, said antibody, or said antigen-binding fragment thereof, comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[0015] In some embodiments, said antibody, or said antigen-binding fragment thereof, comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0016] In some embodiments of any of the above-described antibodies or antigen-binding fragments, said antibody, or said antigen-binding fragment thereof, is a humanized antibody or antigen binding fragment thereof, human antibody or antigen binding fragment thereof, murine antibody or antigen binding fragment thereof, chimeric antibody or antigen binding fragment thereof, Fab fragment, F(ab')2 fragment, F(ab)'3 fragments, single-chain fragment variable (scFv), bis-scFv, (scFv)2, diabody, minibody, nanobody, triabody, tetrabody, disulfide stabilized Fv protein (dsFv), single-domain antibody (sdAb), Ig NAR, single heavy chain antibody, bispecific antibody, trispecific antibody, or chemically modified derivatives thereof.
[0017] In some embodiments, said antibody, or said antigen-binding fragment thereof, comprises an IgG 1 , lgG2, lgG3, or lgG4 constant region, or a variant thereof. [0018] In some embodiments, said antibody, or said antigen-binding fragment thereof, comprises an IgG 1 constant region, or a variant thereof.
[0019] In some embodiments, the IgG 1 constant region comprises the amino acid sequence of SEQ ID NO: 259 or 1 164.
[0020] In some embodiments, said antibody, or said antigen-binding fragment thereof, comprises an lgG4 constant region, or a variant thereof.
[0021] In some embodiments, the lgG4 variant comprises a hinge domain modified to reduce binding to Fey receptors.
[0022] In some embodiments, the lgG4 constant region comprises the amino acid sequence of SEQ ID NO: 261.
[0023] In some embodiments, said antigen-binding fragment is a Fab fragment.
[0024] In some embodiments, said antigen-binding fragment is an scFv fragment.
[0025] In some embodiments of any of the above-described antibodies or antigen-binding fragments, said antibody, or said antigen-binding fragment thereof, binds to AAV2 with a dissociation constant (KD) of less than about 1.5 x 10-6 M, as measured in a surface plasmon resonance assay.
[0026] In some embodiments, said antibody, or said antigen-binding fragment thereof, binds to AAV2 with a dissociation constant (KD) of less than about 20 nM, as measured in a surface plasmon resonance assay.
[0027] In some embodiments, said capsid comprises one or more wild-type AAV capsid polypeptides.
[0028] In some embodiments, said capsid comprises one or more non-wild-type AAV capsid polypeptides.
[0029] In some embodiments, rein binding of said antibody or antigen-binding fragment thereof to said AAV particle capsid does not neutralize said AAV particle.
[0030] In another aspect, provided herein is an antibody, or an antigen-binding fragment thereof, that binds to the same epitope(s) as any of the above-described antibodies or antigenbinding fragments.
[0031] In another aspect, provided herein is an antibody, or an antigen-binding fragment thereof, that competes for binding to a capsid of an adeno-associated virus (AAV) particle with any of the above-described antibodies or antigen-binding fragments.
[0032] In another aspect, provided herein is a pharmaceutical composition comprising any of the above-described antibodies or antigen-binding fragments and a pharmaceutically acceptable carrier or excipient.
[0033] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: i) a first antigen-binding domain that binds to a capsid of an adeno-associated virus (AAV) particle; and ii) a second antigen-binding arm that binds to a molecule on a cell surface, wherein said first antigen-binding domain comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0034] In some embodiments, the first antigen-binding domain that binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[0035] In some embodiments, the first antigen-binding domain that binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0036] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: i) a first antigen-binding domain that binds to a capsid of an adeno-associated virus (AAV) particle, and ii) a second antigen-binding domain that binds to a molecule on a cell surface, wherein said first antigen-binding domain binds to one or more residues in one or more viral protein 3 (VP3) polypeptides in said capsid, wherein said one or more residues are selected from the residues listed in Tables 18-26.
[0037] In some embodiment, said first antigen-binding domain binds to a capsid of an AAV2 particle comprising amino acid substitutions R585A and R588A, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): a) S264, A266, N268, H271 , N382, S384, Q385, G512, R487, D494, K527, K529, K532, L538, D533, E555, N705, K706, V708, T450, Q457, and R459; b) S264, G265, A266, S267, N268, H271 , N382, G383, S384, R487, K527, D528, E530, Q574, Q575, K706, and S707; c) N254, L256, K258, I260, S261 , Q263, Y272, E322, V323, T324, Q325, A655, A667, S668, F669, I670, T671 , I332, Q545, G546, S547, E548, K556, N717, V719, T660, and F661 ; and/or d) N254, L256, Q263, S264, V323, T324, Q325, S655, A667, S668, F669, I670, T671 , G328, G546, E548, T716, and N717.
[0038] In some embodiments, said first antigen-binding domain binds to a capsid of an AAV8 particle, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): e) N255, L257, K259, 1261 , S262, N263, S266, A269, Y275, E325, V326, T327, Q328, A658, N670, S671 , F672, I673, T674, Q548, N549, A550, A551 , D559, E720, and T663; and/or f) N255, L257, S266, E325, V326, T327, Q328, N670, S671 , F672, I673, T674, N549, T719, and E720.
[0039] In some embodiments, said first antigen-binding domain binds to a capsid of an AAV9 particle, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): g) N254, I260, N262, Y274, E324, V325, T326, D327, N328, R550, D665, N668, S669, F670, 1671 , T672, Q546, G547, G549, E718, and A661 ; and/or h) N254, L256, I260, N262, E324, V325, T326, D551 , N668, S669, F670, T672, G330, and E718.
[0040] In some embodiments, said first antigen-binding domain that binds to a capsid of an AAV particle comprises:
1) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10;
2) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1 159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157;
3) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or
4) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0041] In some embodiments, said first antigen-binding domain that binds to a capsid of an AAV particle comprises :
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; 3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[0042] In some embodiments, said first antigen-binding domain that binds to a capsid of an AAV particle comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1 159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0043] In some embodiments of any of the above-described multispecific antibodies or multispecific antigen-binding fragments, the molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
[0044] In some embodiments, the molecule on the cell surface is ASGR1 .
[0045] In some embodiments, the second antigen-binding domain that binds to ASGR1 comprises: a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0046] In some embodiments, said second antigen-binding domain that binds to ASGR1 comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[0047] In some embodiments, said second antigen-binding domain that binds to ASGR1 comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0048] In some embodiments, the molecule on the cell surface is TfR.
[0049] In some embodiments, the second antigen-binding domain that binds to TfR comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
1 1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516; 24) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
[0050] In some embodiments, said second antigen-binding domain that binds to TfR comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
21) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
22) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
23) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
24) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
25) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
26) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
27) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
28) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
29) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
30) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
31) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
32) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 611 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
33) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
[0051] In some embodiments, the second antigen-binding domain that binds to TfR comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536; 26) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR comprising the amino acid sequence of SEQ ID NO: 1 119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1 127.
[0052] In some embodiments, the molecule on the cell surface is CACNG1 .
[0053] In some embodiments, the antigen-binding domain that binds to CACNG1 comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
1 1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883; 15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[0054] In some embodiments, the second antigen-binding domain that binds to CACNG1 comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949; 18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1211 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.
[0055] In some embodiments, the second antigen-binding domain that binds to CACNG1 comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803; 1 1) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 1 181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[0056] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1”); and c) a third polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); wherein ABD1 or ABD2 binds to a capsid of an adeno-associated virus (AAV) particle, and the other of ABD1 or ABD2 binds to a molecule on a cell surface.
[0057] In some embodiments, ABD1 binds to a capsid of an adeno-associated virus (AAV) particle and ABD2 binds to a molecule on the cell surface.
[0058] In some embodiments, ABD2 binds to a capsid of an adeno-associated virus (AAV) particle and ABD1 binds to a molecule on the cell surface.
[0059] In some embodiments, the first heavy chain region is linked to the second heavy chain region via a linker.
[0060] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) an Fc domain; b) a second polypeptide chain, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an Fc domain; and c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); wherein ABD1 or ABD2 binds to a capsid of an adeno-associated virus (AAV) particle, and the other of ABD1 or ABD2 binds to a molecule on a cell surface.
[0061] In some embodiments, ABD1 binds to a capsid of an adeno-associated virus (AAV) particle and ABD2 binds to a molecule on the cell surface.
[0062] In some embodiments, ABD2 binds to a capsid of an adeno-associated virus (AAV) particle and ABD1 binds to a molecule on the cell surface.
[0063] In some embodiments, the first scFv and/or the first heavy chain region is linked to the Fc domain via a linker.
[0064] In some embodiments, the ABD1 or ABD2 which binds to a capsid of an AAV particle comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0065] In some embodiments, the ABD1 or ABD2 which binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; and/or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[0066] In some embodiments, the ABD1 or ABD2 which binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1 159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0067] In some embodiments, the molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
[0068] In some embodiments, the molecule on the cell surface is ASGR1 .
[0069] In some embodiments, the other of ABD1 or ABD2 which binds to ASGR1 comprises: a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0070] In some embodiments, the other of ABD1 or ABD2 which binds to ASGR1 comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[0071] In some embodiments, the other of ABD1 or ABD2 which binds to ASGR1 comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[0072] In some embodiments, the molecule on the cell surface is TfR.
[0073] In some embodiments, the other of ABD1 or ABD2 which binds to TfR comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
1 1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419; 15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 11 19, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
[0074] In some embodiments, the other of ABD1 or ABD2 which binds to TfR comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
21) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
22) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
23) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
24) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
25) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
26) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
27) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
28) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
29) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580; 30) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
31) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
32) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 611 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
33) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
[0075] In some embodiments, the other of ABD1 or ABD2 which binds to TfR comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356; 9) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ;
32) a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR comprising the amino acid sequence of SEQ ID NO: 1 119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1 127.
[0076] In some embodiments, the molecule on the cell surface is CACNG1 .
[0077] In some embodiments, the other of ABD1 or ABD2 which binds to CACNG1 comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
1 1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[0078] In some embodiments, the other of ABD1 or ABD2 which binds to CACNG1 comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809; 11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1211 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.
[0079] In some embodiments, the other of ABD1 or ABD2 which binds to CACNG1 comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823; 12) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 1 181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1 189; or
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[0080] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) an scFv comprising a first antigen-binding domain (“ABD1 ”) operably linked to (ii) a first heavy chain region of a first Fab (“Fab1”), said first heavy chain region operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface. [0081] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[0082] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [0083] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
[0084] In some embodiments, the scFv is linked to the first heavy chain region via a linker.
[0085] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) an scFv comprising a first antigen-binding domain (“ABD1”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface. [0086] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[0087] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[0088] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[0089] In some embodiments, the scFv is linked to the Fc domain via a linker.
[0090] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”), said second heavy chain region of Fab2 operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (“Fab3”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1 ”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); and e) a fifth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface. [0091] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[0092] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[0093] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
[0094] In some embodiments, the first heavy chain region is linked to the second heavy chain region via a linker.
[0095] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (“Fab3”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1 ”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); and e) a fifth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface. [0096] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[0097] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
[0098] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[0099] In some embodiments, the second heavy chain region is linked to the Fc domain via a linker. [00100] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an scFv comprising a first antigen-binding domain (“ABD1 ”), said scFv operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00101] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00102] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00103] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[00104] In some embodiments, the scFv is linked to the first heavy chain region via a linker. [00105] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) an scFv comprising a first antigen-binding domain (“ABD1 ”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00106] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00107] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00108] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[00109] In some embodiments, the second heavy chain region is linked to the Fc domain via a linker.
[00110] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”), said second heavy chain region operably linked to (iii) a third heavy chain region of a third Fab (“Fab3”); b) a second polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1”); and c) a third polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); d) a fourth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2, and ABD3 binds to a capsid of an adeno- associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00111] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00112] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00113] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
[00114] In some embodiments, the first heavy chain region is operably linked to the second heavy chain region and/or the second heavy chain region is operably linked to the third heavy chain region via a linker.
[00115] In some embodiments, the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00116] In some embodiments, the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; and/or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[00117] In some embodiments, the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00118] In some embodiments, said molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
[00119] In some embodiments, said molecule on the cell surface is ASGR1.
[00120] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises: a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00121] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[00122] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10. [00123] In some embodiments, the molecule on the cell surface is TfR.
[00124] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
1 1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557; 28) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 11 19, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
[00125] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455; 18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
21) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
22) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
23) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
24) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
25) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
26) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
27) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
28) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
29) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
30) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
31) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
32) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 611 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
33) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1 131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
[00126] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
1 1) a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR comprising the amino acid sequence of SEQ ID NO: 51 1 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ;
32) a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR comprising the amino acid sequence of SEQ ID NO: 1 119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1 127. [00127] In some embodiments, the molecule on the cell surface is CACNG1 .
[00128] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to CACNG1 comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[00129] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to CACNG1 comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1 193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 121 1 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219. [00130] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to
CACNG1 comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 1 181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1 189; or
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[00131] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first scFv comprising a first antigen-binding domain (“ABD1 ”) operably linked to (ii) a first heavy chain region of a first Fab (“Fab1 ”), said first heavy chain region of Fab1 operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second scFv comprising a second antigen-binding domain (“ABD2”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”), said second heavy chain region of Fab2 operably linked to (iii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a third antigen-binding domain (“ABD3”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a fourth antigen-binding domain (“ABD4”); wherein at least one of ABD1 , ABD2, ABD3 and ABD4 binds to a capsid of an adeno- associated virus (AAV) particle, and the other(s) of ABD1 , ABD2, ABD3, and ABD4 bind to a molecule on a cell surface.
[00132] In some embodiments, two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface. [00133] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 and ABD4 binds to a molecule on a cell surface.
[00134] In some embodiments, ABD3 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD2 binds to a molecule on a cell surface.
[00135] In some embodiments, the first scFv is linked to the first heavy chain region and/or the second scFv is linked to the second heavy chain region via a linker.
[00136] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ’’) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a first scFv comprising a first antigen-binding domain (“ABD1 ”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a second scFv comprising a second antigen-binding domain (“ABD2”); c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a third antigen-binding domain (“ABD3”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a fourth antigen-binding domain (“ABD4”); wherein at least one of ABD1 , ABD2, ABD3 and ABD4 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2, ABD3, and ABD4 bind to a molecule on a cell surface.
[00137] In some embodiments, two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface. [00138] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 and ABD4 binds to a molecule on a cell surface.
[00139] In some embodiments, ABD3 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD2 binds to a molecule on a cell surface.
[00140] In some embodiments, the first scFv and/or second scFv is linked to the Fc domain via a linker.
[00141] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”) operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (“Fab3) operable liked to (ii) a fourth heavy chain region of a fourth Fab (“Fab4”) operably linked to (iii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1 ”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ADB2”); e) a fifth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); and f) a sixth polypeptide chain comprising a fourth light chain that pairs with the fourth heavy chain region to form Fab4, wherein Fab 4 comprises a fourth antigen-binding domain (“ABD4”); wherein at least one of ABD1 , ABD2, ABD3 and ABD4 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2, ABD3, and ABD4 bind to a molecule on a cell surface.
[00142] In some embodiments, two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface. [00143] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 and ABD4 binds to a molecule on a cell surface.
[00144] In some embodiments, ABD2 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD3 binds to a molecule on a cell surface.
[00145] In some embodiments, the first heavy chain region is linked to the second heavy chain region and/or the third heavy chain region is linked to fourth heavy chain region via a linker.
[00146] In some embodiments, the at least one of ABD1 , ABD2, ABD3, and ABD4 which binds to a capsid of an AAV particle comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00147] In some embodiments, the at least one of ABD1 , ABD2, ABD3, and ABD4 which binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; and/or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[00148] In some embodiments, the at least one of ABD1 , ABD2, ABD3, and ABD4 which binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00149] In some embodiments, said molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
[00150] In some embodiments, said molecule on the cell surface is ASGR1 .
[00151] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to ASGR1 comprises: a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00152] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to ASGR1 comprises a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[00153] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to ASGR1 comprises a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00154] In some embodiments, said molecule on the cell surface is TfR.
[00155] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to TfR comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
11) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526; 25) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
[00156] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to TfR comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
21) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
22) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509; 23) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
24) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
25) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
26) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
27) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
28) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
29) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
30) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
31) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
32) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 61 1 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
33) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1 131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
[00157] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to TfR comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557; 28) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ;
32) a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR comprising the amino acid sequence of SEQ ID NO: 1 119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1 127.
[00158] In some embodiments, said molecule on the cell surface is CACNG1 .
[00159] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to CACNG1 comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[00160] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to CACNG1 comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1 193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 121 1 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.
[00161] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to CACNG1 comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
1 1) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 1 181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1 189; or
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[00162] In some embodiments, the linker is:
(a) at least 5 amino acids, at least 6 amino acids or at least 7 amino acids in length; and optionally
(b) up to 30 amino acids, up to 40 amino acids, up to 50 amino acids or up to 60 amino acids in length.
[00163] In some embodiments, the linker is:
(a) 5 amino acids to 50 amino acids in length;
(b) 5 amino acids to 45 amino acids in length;
(c) 5 amino acids to 40 amino acids in length;
(d) 5 amino acids to 35 amino acids in length;
(e) 5 amino acids to 30 amino acids in length;
(f) 5 amino acids to 25 amino acids in length; or
(g) 5 amino acids to 20 amino acids in length.
[00164] In some embodiments, the linker is:
(a) 6 amino acids to 50 amino acids in length;
(b) 6 amino acids to 45 amino acids in length;
(c) 6 amino acids to 40 amino acids in length;
(d) 6 amino acids to 35 amino acids in length;
(e) 6 amino acids to 30 amino acids in length;
(f) 6 amino acids to 25 amino acids in length; or (g) 6 amino acids to 20 amino acids in length.
[00165] In some embodiments, the linker is:
(a) 7 amino acids to 40 amino acids in length;
(b) 7 amino acids to 35 amino acids in length;
(c) 7 amino acids to 30 amino acids in length;
(d) 7 amino acids to 25 amino acids in length;
(e) 7 amino acids to 20 amino acids in length.
[00166] In some embodiments, the linker is 5 amino acids to 25 amino acids in length.
[00167] In some embodiments, the linker is 10 amino acids to 60 amino acids in length.
[00168] In some embodiments, the linker is 20 amino acids to 50 amino acids in length.
[00169] In some embodiments, the linker is 25 to 35 amino acids in length.
[00170] In some embodiments, the linker is or comprises a multimer of GnS (SEQ ID NO:
239) or SGn (SEQ ID NO: 240), where n is an integer from 1 to 10.
[00171] In some embodiments, the linker is or comprises a multimer of G4S (SEQ ID NO: 242).
[00172] In some embodiments, the linker is or comprises two consecutive glycines (2Gly), three consecutive glycines (3Gly), four consecutive glycines (4Gly (SEQ ID NO: 243)), five consecutive glycines (5Gly (SEQ ID NO: 244)), six consecutive glycines (6Gly (SEQ ID NO: 245)), seven consecutive glycines (7Gly (SEQ ID NO: 246)), eight consecutive glycines (8Gly (SEQ ID NO: 247)) or nine consecutive glycines (9Gly (SEQ ID NO: 248)).
[00173] In some embodiments, one or more light chains are universal light chains.
[00174] In some embodiments, a light chain constant region (CL) and a first heavy chain constant region (CH1) of one or more Fabs are in a CrossmAb arrangement.
[00175] In some embodiments of any of the above-described multispecific antibodies or multispecific antigen-binding fragments, the multispecific antibodies or multispecific antigenbinding fragments comprise an Fc heterodimer.
[00176] In some embodiments, the Fc domains in the Fc heterodimer comprise knob-in-hole mutations as compared to a wild-type Fc domain.
[00177] In some embodiments, one Fc domain in the Fc heterodimer comprises amino acid substitutions S354C and T366W (according to EU numbering) as compared to a wild-type Fc domain, and the other Fc domain in the Fc heterodimer comprises amino acid substitutions Y349C, T366S, L368A, and Y407V (according to EU numbering) as compared to a wild-type Fc domain.
[00178] In some embodiments, at least one Fc domain in the Fc heterodimer comprises a star mutation as compared to a wild-type Fc domain.
[00179] In some embodiments, one Fc domain in the Fc heterodimer comprises amino acid mutations H435R and/or Y436F (according to EU numbering) as compared to a wild-type Fc domain.
[00180] In some embodiments, said capsid comprises one or more wild-type AAV capsid polypeptides.
[00181] In some embodiments, said capsid comprises one or more non-wild-type AAV capsid polypeptides.
[00182] In some embodiments of any of the above-described multispecific antibodies or multispecific antibody fragments, the multispecific antibodies or multispecific antigen-binding fragments can be a bispecific antibody or bispecific antigen-binding fragment thereof.
[00183] In another aspect, provided herein is a pharmaceutical composition comprising a multispecific antibody or multispecific antigen-binding fragment described herein, and a pharmaceutically acceptable carrier or excipient.
[00184] In another aspect, provided herein is a molecular complex comprising an AAV particle bound to one or more antibodies and/or antigen-binding fragments described herein.
[00185] In some embodiments, said AAV particle comprises one or more mutations in one or more AAV capsid proteins inhibiting the natural tropism of said AAV particle.
[00186] In another aspect, provided herein is a pharmaceutical composition comprising a molecular complex described herein and a pharmaceutically acceptable carrier or excipient.
[00187] In another aspect, provided herein is a method of preparing the molecular complex described herein, comprising incubating said AAV particle in the presence of said one or more antibodies and/or antigen-binding fragments under conditions allowing specific binding of said one or more antibodies and/or antigen-binding fragments to said AAV particle capsid.
[00188] In another aspect, provided herein is a molecular complex comprising an AAV particle bound to one or more multispecific antibodies and/or multispecific antigen-binding fragments described herein.
[00189] In some embodiments, said AAV particle comprises one or more mutations in one or more AAV capsid proteins inhibiting the natural tropism of said AAV particle.
[00190] In another aspect, provided herein is a pharmaceutical composition comprising a molecular complex described herein and a pharmaceutically acceptable carrier or excipient.
[00191] In another aspect, provided herein is a method of preparing a molecular complex described herein, comprising incubating said AAV particle in the presence of said one or more multispecific antibodies and/or multispecific antigen-binding fragments under conditions allowing specific binding of said one or more multispecific antibodies and/or multispecific antigen-binding fragments to said AAV particle capsid.
[00192] In another aspect, provided herein is a method for targeting an AAV particle to a cell expressing a molecule on the cell surface, comprising contacting the cell with a molecular complex described herein or a pharmaceutical composition described herein, wherein said molecular complex comprises one or more multispecific antibodies and/or multispecific antigen-binding fragments which bind to said molecule on the cell surface.
[00193] In another aspect, provided herein is a method for delivering a polynucleotide to a cell expressing a molecule on the cell surface, comprising contacting the cell with a molecular complex described herein or a pharmaceutical composition described herein, wherein said molecular complex comprises the AAV particle comprising said polynucleotide and bound to one or more multispecific antibodies and/or multispecific antigen-binding fragments which bind to said molecule on the cell surface.
[00194] In some embodiments, said cell is in a subject and said molecular complex is administered to the subject.
[00195] In some embodiments, said AAV particle does not target said cell in the absence of said one or more multispecific antibodies and/or multispecific antigen-binding fragments.
[00196] In various embodiments, any of the features or components of embodiments discussed above or herein may be combined, and such combinations are encompassed within the scope of the present disclosure. Any specific value discussed above or herein may be combined with another related value discussed above or herein to recite a range with the values representing the upper and lower ends of the range, and such ranges are encompassed within the scope of the present disclosure.
[00197] Other embodiments will become apparent from a review of the ensuing detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[00198] Figures 1A-1L depict graphs of binding activities of the anti-adeno-associated virus (AAV) antibodies described herein to various adeno-associated virus (AAV) serotypes. RLU, relative light units.
[00199] Figures 2A-2J depict graphs showing immunoglobulin gamma Fc receptor I (FcGR- 1) AAV retargeting by anti-AAV antibodies derived using next-generation sequencing (NGS)Zmass spectrometry (MS) methods (Figures 2A-2F) and by anti-AAV antibodies derived from hybridoma (Figures 2G-2J) described herein for various AAV serotypes.
[00200] Figure 3 shows a schematic representation of alternative format antibody designs for bispecific antibodies of the present disclosure. Exemplary bispecific antibodies target AAV and Asialoglycoprotein Receptor 1 (ASGR1). Star mutations are depicted with an asterisk (*) and knob-in-hole (KiH) mutations are depicted with a triangle (e.g., ◄).
[00201] Figure 4 displays a description of alternative format bispecific antibody molecules described herein.
[00202] Figure 5 illustrates an example rationale for anti-AAV antibody selection.
[00203] Figures 6A-6J depict graphs of binding affinities of alternative format antibodies described herein (e.g., anti-AAV-ASGR1 bispecific antibodies) to an AAV2 heparin binding mutant (HBM) serotype. The AAV2-HBM serotype contains R585A R588A mutations. RLU, relative light units.
[00204] Figures 7A-7B illustrate that bispecific antibodies can effectively retarget adeno- associated virus (AAV) to the central nervous system (CNS). A schematic representation of anti-transferrin receptor (TfR) x anti-AAV bispecific antibody retargeting of AAV to the CNS is depicted in Figure 7A. A comparison of wild-type (WT) AAV9, covalent-platform control and bispecific platform retargeting of AAV to cerebellum, cortex, and hippocampus is shown in Figure 7B. BBB, blood-brain barrier.
[00205] Figures 8A-8B demonstrate that liver detargeting can be controlled by modulating antibody concentration [Ab] and/or use of a detargeting capsid. A comparison of transduction efficiency between the covalent platform and the bispecific platform evaluated using cDNA quantitation is shown in Figure 8A. A comparison between detargeted AAV9 and WT AA9 using the bispecific platform in cerebellum and liver is shown in Figure 8B. IHC, immunohistochemistry.
[00206] Figure 9 shows a schematic representation of AAV x CACNG1 alternative format (AF) antibodies AF70 and AF71. AF70 comprises anti-AAV#70 scFv fused to the N-terminus of anti-CACNG1 REGN10717 hlgG1 N297G antibody. AF71 comprises anti-AAV#70 scFv fused to the C-terminus of anti-CACNG1 REGN10717 hlgG1 N297G antibody. Disulfide bonds are indicated by S-S.
[00207] Figure 10 shows flow cytometry data illustrating co-incubation of AAV9 W503A with AF70 (top two rows) and AF71 (bottom two rows) resulted in improved transduction efficiency over control AAV without antibody on HEK 293 cells overexpressing mouse CACNG1 (mCACNGI). Transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody (AAV:Ab ratio 1 :1) and 1 AAV to 9 antibodies (AAV:Ab ratio 1 :9) as assessed by percent (%) GFP positive cells.
[00208] Figure 11 depicts line graphs showing co-incubation of AAV9 W503A with AF70 (top) and AF71 (bottom) resulted in improved transduction efficiency over control AAV without antibody on HEK 293 cells overexpressing mouse CACNG1 (mCACNGI). Transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody (AAV:Ab ratio 1 :1) and 1 AAV to 9 antibodies (AAV:Ab ratio 1 :9) as assessed by mean fluorescence intensity (MFI).
[00209] Figure 12 shows flow cytometry data illustrating co-incubation of AAV9 W503A with AF70 (top two rows) and AF71 (bottom two rows) resulted in improved AAV transduction efficiency over control AAV without antibody on HEK 293 cells overexpressing human CACNG1 (hCACNGI). Transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody (AAV:Ab ratio 1 :1) and 1 AAV to 9 antibodies (AAV:Ab ratio 1 :9) as assessed by percent (%) GFP positive cells.
[00210] Figure 13 depicts line graphs showing co-incubation of AAV9 W503A with AF70 (top) and AF71 (bottom) resulted in improved AAV transduction efficiency over control AAV without antibody on HEK 293 cells overexpressing human CACNG1 (hCACNGI). Transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody (AAV:Ab ratio 1 :1) and 1 AAV to 9 antibodies (AAV:Ab ratio 1 :9) as assessed by mean fluorescence intensity (MFI).
[00211] Figure 14 shows immunohistochemical staining of differentiated C2C12 myotubes for Myosin Heavy Chain (MyHC) and demonstration that incubation of AAV with AF70 and AF71 enhanced transduction into the myotubes as determined by GFP fluorescence.
[00212] Figure 15 shows immunohistochemical staining of differentiated human myotubes for Myosin Heavy Chain (MyHC) and demonstration that incubation of AAV with AF70 and AF71 enhanced transduction into the myotubes as determined by GFP fluorescence. Human myotubes were most efficiently transduced with AAV complexed with AF71 at molar ratio 1 :3 and 1 :9.
[00213] Figures 16A-16D demonstrate incubation of AAV with AF70 and AF71 enhanced transduction into differentiated C2C12 myotubes as determined by quantification of GFP positive cells.
[00214] Figures 17A-17D demonstrate incubation of AAV with AF70 and AF71 enhanced transduction into differentiated human myotubes as determined by quantification of GFP positive cells.
[00215] Figures 18A-18B show non-limiting examples of AAVx mTfR alternative format (AF) antibodies described herein. Star mutations are depicted with an asterisk (*) and knob-in-hole (KiH) mutations are depicted with a triangle (e.g., ◄).
[00216] Figure 19 shows an example experimental setup used to test alternative format antibodies binding to AAV9W503A virus by ELISA.
[00217] Figure 20 depicts ELISA data for AAV x mTfR alternative format antibodies binding to AAV9W503A.
[00218] Figure 21 shows a schematic diagram of a FLuc assay protocol used to test retargeting of AAV9W503A using mTfR alternative format antibodies on 293T cells expressing mTfR receptor.
[00219] Figure 22 shows a line graph of data generated in experiments testing AAV9W503A retargeting using AAVxmTfR alternative format antibodies on mTfR293T cells.
[00220] Figures 23A-23C illustrate a retargeting assay using AAV9 scCBH.eGFP.
[00221] Figures 24A-24B show in vitro test infection results for in vivo injection samples.
[00222] Figures 25A-25F depict AAV x mTfR liver and brain (hippocampus, cortex, and cerebellum) green fluorescent protein (GFP) staining for control groups (Figure 25A) and alternative format designs, AAV x mTfR AF1 (Figure 25B), AAV x mTfR AF3 (Figure 25C), AAV x mTfR AF5 (Figure 25D), AAV x mTfR AF7 (Figure 25E), and AAV x mTfR AF9 (Figure 25F).
[00223] Figure 26 shows relative RNA expression of GFP in liver samples as determined by RT-qPCR.
[00224] Figure 27 shows RNA expression of GFP in brain samples as determined by RT- qPCR.
[00225] Figures 28A-28D depict GFP staining in brain, heart and liver tissues from mice receiving AAV9 (Figures 28A-28B) or AAV9W503A (Figures 28C and 28D) complexed with AAV x mTfR alternative format AF7 at AAV vector genome (VG) to antibody (Ab) ratios (VG:Ab ratios) of 1 :9 and 1 :3.
[00226] Figures 29A-29I depict AAV x mTfR alternative format designs AF3 and AF7. Figure 29A provides a description of AAV x mTfR alternative format designs AF3 and AF7. Star mutations are depicted with an asterisk (*) and knob-in-hole (KiH) mutations are depicted with a triangle (e.g., ◄). Figures 29B-29E show examples of AAV x mTfR AF3 amino acid sequences (Figure 29B) and corresponding nucleotide sequences (Figures 29C-29E). Figures 29F-29I show examples of AAV x mTfR AF7 amino acid sequences (Figure 29F) and corresponding nucleotide sequences (Figures 29G-29I). Figure discloses “3xG4S” as SEQ ID NO: 1 1 15.
[00227] Figures 30A-30G depict AAV x CACNGI alternative format designs AF70 and AF71. Figure 30A provides a description of AAV x CACNG1 alternative format designs AF70 and AF71. Figures 30B-30G show examples of AAV x mTfR AF70 amino acid sequences (Figure 30B) and corresponding nucleotide sequences (Figures 30C-30D). Figures 30E-30G show examples of AAV x mTfR AF71 amino acid sequences (Figure 30E) and corresponding nucleotide sequences (Figures 30F-30G). Figure discloses “3xG4S” as SEQ ID NO: 1 1 15 and “4xG4S” as SEQ ID NO: 1 161.
[00228] Figure 31 illustrates AAV x CACNG1 bispecific antibody enhancement of transduction into CACNG1 overexpressing 293 cells. GFP expression was assessed by flow cytometry and is shown as % GFP positive cells (top panels) or MFI of GFP expressing cells (bottom panels).
[00229] Figure 32 depicts an example of a study design for testing Hu37 complexed with anti-AAV x CACNG1 2x2 antibodies in D2.MDX mice.
[00230] Figure 33 shows in vitro transduction in HEK293-hCACNG1 of complexes prepared for in vivo study.
[00231] Figures 34A-34C illustrate improved Hu37 transduction in muscle tissues when complexed with an 2x2 anti-CACNG1xAAV alternative format antibody.
[00232] Figures 35A-35B illustrate bispecific antibody enhancement of Hu37 transduction into skeletal muscle.
[00233] Figures 36A-36B depict AAV x ASGR alternative format designs AF21 (REGN16199), AF22 (REGN16200), AF29, AF30 (REGN16204), AF32 (REGN16202), AF37, AF41 , AF60A, AF61A, AF62, and AF63. Figure 36A provides a description of AAV x ASGR alternative format designs AF21 (REGN16199), AF22 (REGN16200), AF29, AF30 (REGN16204), and AF32 (REGN16202). Figure 36B provides a description of AAV x ASGR alternative format designs AF37, AF41 , AF60A, AF61A, AF62, and AF63. Figure discloses “3xG4S” as SEQ ID NO: 1115 and “4xG4S” as SEQ ID NO: 1161.
[00234] Figures 37A-37B depict IVIS (In Vivo Imaging Instrument, Perkin Elmer) data illustrating retargeting of AAV to liver with AF30 and AF32.
[00235] Figure 38 depicts IVIS data that demonstrate retargeting of multiple serotypes to liver with AF30.
[00236] Figures 39A-39D depict IVIS & PK qPCR data that demonstrate retargeting to liver with antibodies comprised of either one or two anti-AAV binding arms.
[00237] Figures 40A-40C depict IVIS, PK qPCR, & ELISA data that demonstrate antibody can effectively retarget AAV when dosed prior to AAV administration.
[00238] Figures 41A-41B depict IVIS & PK qPCR data that demonstrate retargeting of REGN16199 with and without Fc.
[00239] Figures 42A-42F depict IVIS, PK qPCR, & RNA Taqman data that demonstrate successful targeting with linear Fab formats.
[00240] Figure 43 depicts PK qPCR data of serum samples 24 hours after administration of various antibody formats complexed with AAV.
[00241] Figure 44 depicts IVIS data that demonstrate retargeting of AAV with a variety of different antibody formats.
[00242] Figure 45 depicts IVIS data that demonstrate retargeting of AAV with antibody comprised of one anti-AAV arm and one anti-ASGR1 arm.
[00243] Figures 46A-46I depict AAV x ASGR alternative format designs AF1 , AF5, and AF9. Figures 46A-46C show examples of AAV x ASGR AF1 amino acid sequences (Figure 46A) and corresponding nucleotide sequences (Figures 46B-46C). Figures 46D-46F show examples of AAV x ASGR AF5 amino acid sequences (Figure 46D) and corresponding nucleotide sequences (Figures 46E-46F). Figures 46G-46I show examples of AAV x ASGR AF9 amino acid sequences (Figure 46G) and corresponding nucleotide sequences (Figures 46H-46I). Figure discloses “3xG4S” as SEQ ID NO: 1115 and “4xG4S” as SEQ ID NO: 1161. [00244] Figures 47A-47I depict AAV x mTfR alternative format designs AF1 , AF5, and AF9. Figures 47A-47C show examples of AAV x mTfR AF1 amino acid sequences (Figure 47A) and corresponding nucleotide sequences (Figures 47B-47C). Figures 47D-47F show examples of AAV x mTfR AF5 amino acid sequences (Figure 47D) and corresponding nucleotide sequences (Figures 47E-47F). Figures 47G-47I show examples of AAV x mTfR AF9 amino acid sequences (Figure 47G) and corresponding nucleotide sequences (Figures 47H-47I). Figure discloses “3xG4S” as SEQ ID NO: 1115 and “4xG4S” as SEQ ID NO: 1161.
DETAILED DESCRIPTION
[00245] Before the present disclosure is described, it is to be understood that this disclosure is not limited to particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.
[00246] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All patents, applications and non-patent publications mentioned in this specification are incorporated herein by reference in their entireties.
Definitions
[00247] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1 , 99.2, 99.3, 99.4, etc.).
[00248] The term “antigen” encompasses any agent (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleotide, portions thereof, or combinations thereof) that, when introduced into an immunocompetent host is recognized by the immune system of the host and is capable of eliciting an immune response by the host.
[00249] The term "epitope" can refer to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstance, an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen. Epitopes may also be defined as structural or functional. Functional epitopes are generally a subset of structural epitopes and are defined as those residues that directly contribute to the affinity of the interaction between a major histocompatibility complex (MHC) molecule and the antigen. [00250] The term "antigen-binding molecule" refers in its broadest sense to a molecule that specifically binds to an antigen. In certain embodiments, an antigen-binding molecule is an antibody or an antigen-binding fragment of an antibody, including, e.g., multispecific antibodies such as bispecific antibodies or fragments thereof.
[00251] The term "multispecific antigen-binding molecule" or “multispecific binding molecule” or “MBM” includes molecules (e.g., antibodies and antigen-binding fragments of antibodies) that bind two or more (e.g., three or four) different epitopes or antigens. In some cases, the multispecific antigen-binding molecules are bispecific (e.g., bispecific antibodies). In some cases, the multispecific antigen-binding molecules are trispecific. In some cases, the multispecific antigen-binding molecules are tetraspecific. According to certain exemplary embodiments, the present disclosure includes multispecific (e.g., bispecific) antigen-binding molecules (e.g., antibodies) that specifically bind a capsid of an AAV particle and a molecule of a cell surface. Such antigen-binding molecules may be referred to herein as, e.g., “anti- AAV x anti-cell surface molecule” or other similar terminology (e.g., anti-AAV/anti-cell surface molecule).
[00252] The term “antigen-binding domain” or “ABD” as used herein can refer to the portion of an antigen-binding molecule that is capable of specific binding to an antigen. In certain embodiments, without limitation, a multispecific antigen-binding molecule of the disclosure may comprise a first ABD (“ABD1”), a second ABD (“ABD2”), a third ABD (“ABD3”), and/or a fourth ABD (“ABD4”), each of which may be part of, e.g., an scFv or a Fab.
[00253] The term "antibody", as used herein, means any antigen-binding molecule or molecular complex comprising at least one complementarity determining region (CDR) that specifically binds to or interacts with a particular antigen. The term "antibody" includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM). The term “antibody” also includes immunoglobulin molecules consisting of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1 , CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the disclosure, the FRs of the anti-AAV antibody or anti-cell surface molecule antibody (or antigen-binding portion thereof) may be identical to the human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.
[00254] The term "antibody", as used herein, also includes antigen-binding fragments of full antibody molecules. The terms "antigen-binding fragment" of an antibody, "antigen-binding portion" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.
[00255] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3- CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigenbinding fragment," as used herein.
[00256] An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and L domains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain VH-VH, VH-VL or L-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain. [00257] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present disclosure include: (i) VH-CH1 ; (ii) VH- CH2; (iii) VH-CH3; (iv) VH-CH1-CH2; (V) VH-CH1 -CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL- CH1 ; (ix) VL-CH2; (X) VL-CH3; (xi) VL-CH1 -CH2; (xii) VL-CH1 -CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody of the present disclosure may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non- covalent association with one another and/or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)).
[00258] As with full antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). A bispecific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format, including the non-limiting example formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present disclosure using routine techniques available in the art.
[00259] The terms “complementarity determining region” or “CDR,” as used herein, can refer to the sequences of amino acids within antibody variable regions which confer antigen specificity and binding affinity. In general, there are three CDRs in each heavy chain variable region (HCDR1 , HCDR2, HCDR3) and three CDRs in each light chain variable region (LCDR1 , LCDR2, LCDR3).
[00260] Exemplary conventions that can be used to identify the boundaries of CDRs include, e.g., the Kabat definition, the Chothia definition, the ABS definition and the IMGT definition. See, e.g., Kabat, 1991 , “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (Kabat numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol. 273:927-948 (Chothia numbering scheme); Martin et al., 1989, Proc. Natl. Acad. Sci. USA 86:9268-9272 (ABS numbering scheme); and Lefranc et ai, 2003, Dev. Comp. Immunol. 27:55-77 (IMGT numbering scheme). Public databases are also available for identifying CDR sequences within an antibody.
[00261] The term “single chain Fv” or “scFv” as used herein can refer to a polypeptide chain comprising the VH and VL domains of an antibody, where these domains are present in a single polypeptide chain.
[00262] The term “Fab” can refer to a pair of polypeptide chains, the first polypeptide chain comprising a variable heavy (VH) domain of an antibody N- terminal to a first constant domain (referred to herein as C1), and the second polypeptide chain comprising a variable light (VL) domain of an antibody N-terminal to a second constant domain (referred to herein as C2) capable of pairing with the first constant domain. In a native antibody, the VH is N- terminal to the first constant domain (CH1) of the heavy chain and the VL is N- terminal to the constant domain of the light chain (CL). The Fabs of the disclosure can be arranged according to the native orientation or include domain substitutions or swaps on that facilitate correct VH and VL pairings, particularly where the antigen-binding molecules of the disclosure comprise non-identical Fabs. For example, it is possible to replace the CH1 and CL domain pair in a Fab with a CH3-domain pair to facilitate correct modified Fab-chain pairing in heterodimeric antigen-binding molecules. It is also possible to reverse CH1 and CL, so that the CH1 is attached to V_ and CL is attached to the VH, a configuration generally known as Crossmab. Alternatively, or in addition to, the use of substituted or swapped constant domains, correct chain pairing can be achieved by the use of universal light chains that can pair with both variable regions of a heterodimeric antigen-binding molecules of the disclosure.
[00263] The term “universal light chain” as used herein in the context of an antigen-binding molecule described herein can refer to a light chain polypeptide capable of pairing with the heavy chain region of a first Fab to form the first Fab and capable of pairing with the heavy chain region of a second Fab to form the second Fab. Universal light chains are also known as “common light chains.”
[00264] The term “Fc domain” can refer to a portion of the heavy chain that pairs with the corresponding portion of another heavy chain. The term “Fc region” can refer to the region of antibody-based binding molecules formed by association of two heavy chain Fc domains. The two Fc domains within the Fc region may be the same or different from one another. In a native antibody the Fc domains are typically identical, but for the purpose of producing the antigen-binding molecules of the disclosure, one or both Fc domains might advantageously be modified to allow for heterodimerization.
[00265] As used herein, the term “derived from” indicates a relationship between a first and a second molecule. It generally can refer to structural similarity between the first molecule and a second molecule and does not connote or include a process or source limitation on a first molecule that is derived from a second molecule.
[00266] The term “specifically binds” as used herein means that an antigen-binding molecule forms a complex with a target antigen that is relatively stable under physiologic
Ill conditions. Specific binding can be characterized by a KD of about 5x10-2 M or less (e.g., less than 5x10-2 M, less than 10-2 M, less than 5x102M, less than 10-3 M, less than 5x10-4 M, less than 10-4M, less than 5x10 5M, less than 105M, less than 5x10-6M, less than 10-6 M, less than 5x107M, less than 107M, less than 5x10-8M, less than 10-8M, less than 5x10 9M, less than 10'9M, or less than 10-1° M). Methods for determining the binding affinity of an antibody or an antibody fragment, e.g., an antigen-binding molecule or antigen-binding domain, to a target antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance (e.g., Biacore assays), fluorescent-activated cell sorting (FACS) binding assays and the like. An antigen-binding molecule that specifically binds to a target antigen from one species can, however, have cross-reactivity to the target antigen from one or more other species.
[00267] The term “operably linked” as used herein can refer to a functional relationship between two or more regions of a polypeptide chain in which the two or more regions are linked so as to produce a functional polypeptide.
[00268] The term "substantial identity" or "substantially identical," when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 90%, and more preferably at least about 95%, 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well- known algorithm of sequence identity, such as FASTA, BLAST or Gap, as discussed below. A nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in certain instances, encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.
[00269] As applied to polypeptides, the term "substantial similarity" or "substantially similar" means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 95% sequence identity, even more preferably at least 98% or 99% sequence identity. Preferably, residue positions which are not identical differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331 , herein incorporated by reference. Examples of groups of amino acids that have side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartate and glutamate, and (7) sulfur-containing side chains are cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalaninetyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 1443-1445, herein incorporated by reference. A "moderately conservative" replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.
[00270] Sequence similarity for polypeptides, which is also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG software contains programs such as Gap and Bestfit which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1 . Polypeptide sequences also can be compared using FASTA using default or recommended parameters, a program in GCG Version 6.1. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence of the disclosure to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402, each herein incorporated by reference.
[00271] The term "subject" or "patient" as used herein includes all members of the animal kingdom including non-human primates and humans.
Anti-AAV Antibodies and Antigen-Binding Fragments Thereof
[00272] in a one aspect, provided herein are antibodies and antigen-binding fragments thereof that bind a capsid of an AAV particle (also known as “anti-AAV antibodies” herein). In some embodiments, the capsid comprises any of various wild-type and/or non-wild-type AAV capsid protein(s) described herein. In some embodiments, the antibodies and/or antigenbinding fragments thereof bind an epitope on a capsid described herein. The anti-AAV antibodies provided herein, or antigen-binding portions thereof, may be included as part of a multispecific antigen-binding molecule, e.g., a multispecific antibody or multispecific antigenbinding fragment thereof, described herein.
[00273] "AAV" is an abbreviation for adeno-associated virus and may be used to refer to the virus itself or derivatives thereof. AAVs are members of the Parvovirus family of small, nonenveloped, single-stranded DNA viruses. Generally, a wildtype AAV genome is 4.7 kb and is characterized by two inverted terminal repeats (ITR) and two open reading frames (ORFs), rep and cap. The wildtype rep reading frame encodes four proteins of molecular weight 78 kD (“Rep78”), 68 kD (“Rep68”), 52 kD (“Rep52”) and 40 kD (“Rep 40”). Rep78 and Rep68 are transcribed from the p5 promoter, and Rep52 and Rep40 are transcribed from the p19 promoter. These proteins function mainly in regulating the transcription and replication of the AAV genome. The wildtype cap reading frame encodes three structural (capsid) viral proteins (VPs) having molecular weights of 83-85 kD (VP1), 72-73 kD (VP2) and 61-62 kD (VP3). More than 80% of total proteins in an AAV virion (capsid) comprise VP3; in mature virions VP1 , VP2 and VP3 are found at relative abundance of approximately 1 :1 :10, although ratios of 1 :1 :8 have been reported. Padron et al. (2005) J. Virology 79:5047-58.
[00274] The genomic sequences of various serotypes of AAV, as well as the sequences of the native inverted terminal repeats (ITRs), Rep proteins, and capsid subunits are known in the art. Such sequences may be found in the literature or in public databases such as GenBank. See, e.g., GenBank Accession Numbers NC_002077 (AAV1), AF063497 (AAV1), NC001401 (AAV-2), AF043303 (AAV2), NC_001729 (AAV3), NC_001829 (AAV4), U89790 (AAV4), NC_006152 (AAV5), AF513851 (AAV7), AF513852 (AAV8), and NC_006261 (AAV8); the disclosures of which are incorporated by reference herein for teaching AAV nucleic acid and amino acid sequences. See also, e.g., Srivistava et al. (1983) J. Virology 45:555; Chiorini et al. (1998) J. Virology 71 :6823; Chiorini et al. (1999) J. Virology 73: 1309; Bantel-Schaal et al. (1999) J. Virology 73:939; Xiao et al. (1999) J. Virology 73:3994; Muramatsu et al. (1996) Virology 221 :208; Shade et al . , (1986) J. Virol. 58:921 ; Gao et al. (2002) Proc. Nat. Acad. Sci. USA 99: 11854; Moris et al. (2004) Virology 33:375-383; US Patent Publication 20170130245; international patent publications WO 00/28061 , WO 99/61601 , WO 98/11244; and U.S. Pat. No. 6,156,303, each of which is incorporated by reference in its entirety by reference.
[00275] “AAV” encompasses all subtypes and both naturally occurring and modified forms (e.g., recombinant forms), except where stated otherwise. AAV includes primate AAV (e.g., AAV type 1 (AAV1), primate AAV type 2 (AAV2), primate AAV type 3 (AAV3), primate AAV3B, primate AAV type 4 (AAV4), primate AAV type 5 (AAV5), primate AAV type 6 (AAV6), primate AAV6.2, primate AAV type 7 (AAV7), primate AAV type 8 (AAV8), primate AAV type 9 (AAV9), AAV10, AAV type hu11 (AAV hu11), AAV11, AAV12, AAV13, AAVDJ, Anc80L65, AAV2G9, AAVLK03, AAV type rh32.33 (AAVrh.32.33), AAV retro (AAV retro), AAV PHP.B, AAV PHP.eB, AAV PHP.S, AAVrh.64R1 , AAVhu.37, AAVrh.8, AAV2/8, etc.; non-primate animal AAV (e.g., avian AAV (AAAV)) and other non-primate animal AAV such as mammalian AAV (e.g., bat AAV, sea lion AAV, bovine AAV, canine AAV, equine AAV, caprine AAV, and ovine AAV etc.), squamate AAV (e.g., snake AAV, bearded dragon AAV), etc., "Primate AAV" can refer to AAV generally isolated from primates. Similarly, "non- primate animal AAV" can refer to AAV isolated from non-primate animals.
[00276] The term "capsid protein,” "Cap protein” and the like, includes a protein that is part of the capsid of the virus. For adeno-associated viruses, the capsid proteins are generally referred to as VP1 , VP2 and/or VP3, and may be encoded by the single cap gene. The three AAV capsid proteins can be produced in nature an overlapping fashion from the cap ORF alternative translational start codon usage, although all three proteins use a common stop codon. The ORF of a wildtype cap gene encodes from 5’ to 3’ three alternative start codons: ‘‘the VP1 start codon,” “the VP2 start codon,” and “the VP3 start codon”; and one “common stop codon”. The largest viral protein, VP1 , is generally encoded from the VP1 start codon to the “common stop codon.” VP2 is generally encoded from the VP2 start codon to the common stop codon. VP3 is generally encoded from the VP3 start codon to the common stop codon. Accordingly, VP1 comprises at its N-terminus sequence that it does not share with the VP2 or VP3, referred to as the VP1-unique region (VP1-u). The VP1-u region is generally encoded by the sequence of a wildtype cap gene starting from the VP1 start codon to the “VP2 start codon.” VP1-u comprises a phospholipase A2 domain (PLA2), which may be important for infection, as well as nuclear localization signals which may aid the virus in targeting to the nucleus for uncoating and genome release. The VP1 , VP2, and VP3 capsid proteins share the same C-terminal sequence that makes up the entirety of VP3, which may also be referred to herein as the VP3 region. The VP3 region is encoded from the VP3 start codon to the common stop codon. VP2 has an additional ~ 60 amino acids that it shares with the VP1 . This region is called the VP1/VP2 common region. [00277] In some embodiments, an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described may bind to an epitope on the capsid. In some embodiments, the antibody may comprise any of the antibodies, e.g., multispecific antibodies, such as bispecific antibodies, which bind to the capsid of an AAV particle disclosed herein. In some embodiments, a multispecific antibody disclosed herein may comprise, for example, comprise a first binding domain that binds to a capsid of an AAV particle. In some embodiments, the first binding domain binds to an epitope on the capsid of the AAV particle. The AAV particle capsid may comprise wild-type and/or non-wildtype AAV capsid proteins. In some embodiments, the epitope may comprise any of various serotypespecific or serotype-non-specific (i.e., “universal”) epitopes understood by one of ordinary skill in the art. In some embodiments, the epitope may comprise, e.g., any amino acid residues set forth in Tables 19-26, or variants of variants, derivatives or epitopes combinations thereof.
[00278] In some embodiments, an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described herein may bind to an epitope on the capsid which is comprised of any amino acid residues of a capsid protein VP1 , VP2 or VP3, or a combination thereof. The AAV particle can be derived from any AAV serotype described herein. In some embodiments, an antibody, or an antigen-binding fragment thereof can bind to any amino acid residue, or any combination thereof, of any variable region of a capsid, or any combination thereof, e.g., a variable region comprised of a capsid protein VP1 , VP2 or VP3, or a combination thereof (e.g., variable region I, II, III, IV, V, VI, VII, VIII, IX, or a combination thereof, as described in Emmanuel, et al., Journal of Virology, 2022, 96, 3).
[00279] As a non-limiting example, an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described herein may bind to an epitope of an AAV1 capsid comprised of any amino acid residue or combination thereof of a variable region I, II, III, IV, V, VI, VII, VIII, IX, or combination thereof. The antibody, or an antigen-binding fragment thereof may bind to AAV1 at any of residues 456-459, 492-499, 582, 583, 588- 591 , 593-595, 597, or any combination thereof, as described in Tseng, et al., Front Immunol. 2014, 5: 9.
[00280] As a non-limiting example, an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described herein may bind to an epitope of an AAV2 capsid comprised of any amino acid residue or combination thereof of a variable region I, II, III, IV, V, VI, VII, VIII, IX, or combination thereof. The antibody, or an antigen-binding fragment thereof may bind to AAV2 at any of residues 253, 254, 258, 261-264, 272-281, 369-378, 381 , 384, 385, 474-483, 492-502, 534, 548, 556, 560-573, 585-589, 601-610, 658-660, 708, 717, or any combination thereof, as described in Tseng, et al., Front Immunol. 2014, 5: 9.
[00281] As a non-limiting example, an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described herein may bind to an epitope of an AAV5 capsid comprised of any amino acid residue or combination thereof of a variable region I, II, III, IV, V, VI, VII, VIII, IX, or combination thereof. The antibody, or an antigen-binding fragment thereof may bind to AAV5 at any of residues 246, 254-261 , 374, 375, 483, 485- 492, 494, 496, 499-501 , 530, 532-538, 653, 654, 656, 657, 704-708, or any combination thereof as described in Tseng, et al., Front Immunol. 2014, 5: 9.
[00282] As a non-limiting example, an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described herein may bind to an epitope of an AAV8 capsid comprised of any amino acid residue or combination thereof of a variable region I, II, III, IV, V, VI, VII, VIII, IX, or combination thereof. The antibody, or an antigen-binding fragment thereof may bind to AAV8 at any of residues 586-591 or any combination thereof as described in Tseng, et al., Front Immunol. 2014, 5: 9.
[00283] As a non-limiting example, an antibody, or an antigen-binding fragment thereof that binds to a capsid of an AAV particle described herein may bind to an epitope of an AAV9 capsid comprised of any amino acid residue or combination thereof of a variable region I, II, III, IV, V, VI, VII, VIII, IX, or combination thereof. The antibody, or an antigen-binding fragment thereof may bind to AAV9 at any of residues 221 , 228, 246-248, 250-256, 258- 260, any of residues 262-273 of variable region I, any of residues 274, 275, 278, 291 , 293, 324, 325, any of residues 327-333 of variable region II, any of residues 334, 335, 338, 341 , 363-365, 369-373, 375, 376, any of residues 382-387, 389, 391 of variable region III, any of residues 438-441 , 443, any of residues 446, 448, 449, 451-460, 462, 464-473 of variable region IV, any of residues 488, 491-501 , 503-506, 510-515 of variable region V, any of residues 528-534, 545 of variable region VI, any of residues 547-560 of variable region VII, residue 572, any of residues 579, 584, 587-590 of variable region VIII, any of residues 651 - 653, 655-676, 678, any of residues 701-720, 722, 724-728 of variable region IX, or any of residues 730, 731 , or any combination thereof, as described in Emmanuel, et al., Journal of Virology, 2022, 96, 3.
[00284] The phrase “inverted terminal repeat” or “ITR” includes symmetrical nucleic acid sequences in the genome of adeno-associated viruses required for efficient replication. ITR sequences are located at each end of the AAV DNA genome. The ITRs serve as the origins of replication for viral DNA synthesis and are essential cis components for generating AAV particles, e.g., packaging into AAV particles.
[00285] AAV ITR comprise recognition sites for replication proteins Rep78 or Rep68. A "D" region of the ITR comprises the DNA nick site where DNA replication initiates and provides directionality to the nucleic acid replication step. An AAV replicating in a mammalian cell typically comprises two ITR sequences.
[00286] A single ITR may be engineered with Rep binding sites on both strands of the “A” regions and two symmetrical D regions on each side of the ITR palindrome. Such an engineered construct on a double-stranded circular DNA template allows Rep78 or Rep68 initiated nucleic acid replication that proceeds in both directions. A single ITR is sufficient for AAV replication of a circular particle. In methods of producing an AAV viral particle of the disclosure, the rep encoding sequence encodes a Rep protein or Rep protein equivalent that is capable of binding an ITR comprised on the transfer plasmid.
[00287] The Cap proteins of the disclosure, when expressed with appropriate Rep proteins by a packaging cell, may encapsidate a transfer plasmid comprising a nucleotide of interest and an even number of two or more ITR sequences. In some embodiments, a transfer plasmid comprises one ITR sequence. In some embodiments, a transfer plasmid comprises two ITR sequences.
[00288] Either Rep78 and/or Rep68 bind to unique and known sites on the sequence of the ITR hairpin, and act to break and unwind the hairpin structures on the end of an AAV genome, thereby providing access to replication machinery of the viral replication cell. As is well-known, Rep proteins may be expressed from more than one ORF comprising nucleotide sequence encoding any combination of Rep78, Rep68, Rep 52 and/or Rep40 by use of separate nucleotide sequences operably linked to at least one expression control sequence for expression in a viral replication cell, each producing one or more of Rep78, Rep68, Rep 52 and/or Rep40 Rep proteins. Alternatively, Rep proteins may be expressed individually from an ORF comprising a nucleotide sequence encoding any one of Rep78, Rep68, Rep 52, or Rep40 by use of separate nucleotide sequences operably linked to one expression control sequence for expression in a packaging cell, each producing only one Rep78, Rep68, Rep 52, or Rep40 Rep protein. In another embodiment, Rep proteins may be expressed from one ORF comprising nucleotide sequences encoding Rep78 and Rep52 Rep proteins operably linked to at least one expression control sequence for expression in a viral replication cell each producing Rep78 and Rep52 Rep protein.
[00289] A “chimeric AAV capsid protein” includes an AAV capsid protein that comprises amino acid sequences, e.g., portions, from two or more different AAV and that is capable of forming and/or forms an AAV viral capsid/viral particle. A chimeric AAV capsid protein is encoded by a chimeric AAV capsid gene, e.g., a chimeric nucleotide comprising a plurality, e.g., at least two, nucleic acid sequences, each of which plurality is identical to a portion of a capsid gene encoding a capsid protein of distinct AAV, and which plurality together encodes a functional chimeric AAV capsid protein. Association of a chimeric capsid protein to a specific AAV indicates that the capsid protein comprises one or more portions from a capsid protein of that AAV and one or more portions from a capsid protein of a different AAV. For example, a chimeric AAV2 capsid protein includes a capsid protein comprising one or more portions of a VP1 , VP2, and/or VP3 capsid protein of AAV2 and one or more portions of a VP1 , VP2, and/or VP3 capsid protein of a different AAV.
[00290] Sequence identifiers corresponding to exemplary anti-AAV antibodies provided herein are listed in Table 1 and Table 2. Table 1 sets forth the amino acid sequence identifiers of the heavy chain variable regions (HCVRs) and light chain variable regions (LCVRs), heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3), and light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3), as well as heavy chain (HC) and light chain (LC) of the exemplary anti-AAV antibodies and antigenbinding fragments. Table 2 sets forth the sequence identifiers of the nucleic acid molecules encoding the HCVRs, LCVRs, HCDR1 , HCDR2, HCDR3, LCDR1 , LCDR2 LCDR3, HC and LC of the exemplary anti-AAV antibodies and antigen-binding fragments described herein. Corresponding Fab and “standard mAb” (i.e., mAb comprising a constant region derived from lgG4 subclass) pairs are listed consecutively within Table 1 and Table 2. Non-limiting examples of amino acid sequences and nucleotide sequences of the anti-AAV antibodies are also listed below.
Table 1. Amino Acid Sequence Identifiers for Anti-AAV Antibodies Table 2. Nucleic Acid Sequence Identifiers for Anti-AAV Antibodies
REGN13876
HCVR DNA Sequence CAGGTGCACCTGCAAGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCTCCTGCACTGTCTCTGGTGATTCCATCAGAAGTGGTGGTTACTACTGGAGTTGGAT CCG CCAG CAG CCAG G AAG G G G CCTG G AATGG ATTGGTTTC ATCC ATC AG AGTG ACAG GTCCTACTATAACCCGTCCCTCATGAATCGACTCACCATGTCAGTAGACACGTCTAAGA ATCAATTCTCCCTGAAACTGACCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGT GCGAGAGATCGGGACACCATGGTTCGGGGAAGCATTACAACTTCCGGCCACTTCATTG ACTACTGGGGCCAGGGAACCCTGATCACCGTCTCCTCA
(SEQ ID NO: 1)
HCVR Amino Acid Sequence
QVHLQESGPGLVKPSQTLSLSCTVSGDSIRSGGYYWSWIRQQPGRGLEWIGFIHQSDRSY YNPSLMNRLTMSVDTSKNQFSLKLTSVTAADTAVYYCARDRDTMVRGSITTSGHFIDYWGQ GTLITVSS
(SEQ ID NO: 2)
HCDR1 DNA Sequence
GGTGATTCCATCAGAAGTGGTGGTTACTAC
(SEQ ID NO: 3)
HCDR1 Amino Acid Sequence
GDSIRSGGYY
(SEQ ID NO: 4)
HCDR2 DNA Sequence
ATCCATCAGAGTGACAGGTCC
(SEQ ID NO: 5)
HCDR2 Amino Acid Sequence
IHQSDRS
(SEQ ID NO: 6)
HCDR3 DNA Sequence
GCGAGAGATCGGGACACCATGGTTCGGGGAAGCATTACAACTTCCGGCCACTTCATTG ACTAC
(SEQ ID NO: 7)
HCDR3 Amino Acid Sequence
ARDRDTMVRGSITTSGHFIDY
(SEQ ID NO: 8) LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 9)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 10)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 11)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 12)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 13)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 14)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 15)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 16)
HC DNA Sequence
CAGGTGCACCTGCAAGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC
CTCTCCTGCACTGTCTCTGGTGATTCCATCAGAAGTGGTGGTTACTACTGGAGTTGGAT CCG CCAG CAG CCAG G AAG G G G CCTG G AATGG ATTGGTTTC ATCC ATC AG AGTG ACAG GTCCTACTATAACCCGTCCCTCATGAATCGACTCACCATGTCAGTAGACACGTCTAAGA ATCAATTCTCCCTGAAACTGACCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGT GCGAGAGATCGGGACACCATGGTTCGGGGAAGCATTACAACTTCCGGCCACTTCATTG ACTACTGGGGCCAGGGAACCCTGATCACCGTCTCCTCAGCCTCCACCAAGGGCCCATC GGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGG CTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC CCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGC AACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATG GTCCCCCATGA
(SEQ ID NO: 17)
HC Amino Acid Sequence
QVHLQESGPGLVKPSQTLSLSCTVSGDSIRSGGYYWSWIRQQPGRGLEWIGFIHQSDRSY YNPSLMNRLTMSVDTSKNQFSLKLTSVTAADTAVYYCARDRDTMVRGSITTSGHFIDYWGQ GTLITVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP*
(SEQ ID NO: 18)
LG DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 19)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 20)
REGN13877 (NAC67604) HCVR DNA Sequence
CAGGTGCAGCTGCAGGAGTCGGGCCCAGTACTGGTGAAGCCTTCGGAGACCCTGTCC CTCACCTGCACTGTCTCTGGTGACTCCATCAGTAATTACTACTGGAGCTGGATCCGGCA GTCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCTATTACAGTGGCGGCACCAAC
TACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAATAGACACGTCCAAGCGCCACTT CTCCCTGAAGCTGAACTCTGTGATCGCAGCGGACACGGCCGTATATTACTGTGCGAGA GCCCCTGTCACCATGGTTCGGGGAGTCATTACTTACAACTACCACTACGCTATGGACGT
CTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
(SEQ ID NO: 21)
HCVR Amino Acid Sequence
QVQLQESGPVLVKPSETLSLTCTVSGDSISNYYWSWIRQSPGKGLEWIGYIYYSGGTNYNP SLKSRVTISIDTSKRHFSLKLNSVIAADTAVYYCARAPVTMVRGVITYNYHYAMDVWGQGTT VTVSS
(SEQ ID NO: 22)
HCDR1 DNA Sequence
GGTGACTCCATCAGTAATTACTAC
(SEQ ID NO: 23)
HCDR1 Amino Acid Sequence
GDSISNYY
(SEQ ID NO: 24)
HCDR2 DNA Sequence
ATCT ATTAC AG TG G CG G CACC
(SEQ ID NO: 25)
HCDR2 Amino Acid Sequence
IYYSGGT
(SEQ ID NO: 26)
HCDR3 DNA Sequence
GCGAGAGCCCCTGTCACCATGGTTCGGGGAGTCATTACTTACAACTACCACTACGCTAT GGACGTC
(SEQ ID NO: 27)
HCDR3 Amino Acid Sequence
ARAPVTMVRGVITYNYHYAMDV
(SEQ ID NO: 28) LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 9)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 10)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 11)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 12)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 13)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 14)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 15)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 16)
HC DNA Sequence CAGGTGCAGCTGCAGGAGTCGGGCCCAGTACTGGTGAAGCCTTCGGAGACCCTGTCC CTCACCTGCACTGTCTCTGGTGACTCCATCAGTAATTACTACTGGAGCTGGATCCGGCA GTCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCTATTACAGTGGCGGCACCAAC TACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAATAGACACGTCCAAGCGCCACTT CTCCCTGAAGCTGAACTCTGTGATCGCAGCGGACACGGCCGTATATTACTGTGCGAGA GCCCCTGTCACCATGGTTCGGGGAGTCATTACTTACAACTACCACTACGCTATGGACGT CTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGT CTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAAC GTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTC CCCCATGA
(SEQ ID NO: 29)
HC Annino Acid Sequence
QVQLQESGPVLVKPSETLSLTCTVSGDSISNYYWSWIRQSPGKGLEWIGYIYYSGGTNYNP SLKSRVTISIDTSKRHFSLKLNSVIAADTAVYYCARAPVTMVRGVITYNYHYAMDVWGQGTT VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP*
(SEQ ID NO: 30)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG CATTAG C AG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 19)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 20) REGN13878
HCVR DNA Sequence
CAATTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
CTCTCATGTGCCGCCTCTGGATTCAGTTTCAGTAGTTATGGCATGCACTGGGTCCGCCA
GACTCCAGGCAAGGGACTGGAGTGGGTGACATTTATATCATATGACGGAAGTTATGATT
ACTATTTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACATTTCCAAGAACACA
TTGTATTTGCAAATGAACAGCCTGAGAATTGAGGACACGGCTGTCTATTACTGTGCGAG
CGGCCTCACTGGCCCTACGAGGTGGTATTTCGATCTCTGGGGCCGTGGCACCCTGGT
CACTGTCTCCTCC
(SEQ ID NO: 31)
HCVR Amino Acid Sequence
Q LQ LVESG G G WQ PG RSLRLSCAASG FSFSS YG M H WVRQTPG KG LEWVTF I SYDG SYDY
YLDSVKGRFTISRDISKNTLYLQMNSLRIEDTAVYYCASGLTGPTRWYFDLWGRGTLVTVSS
(SEQ ID NO: 32)
HCDR1 DNA Sequence
GGATTCAGTTTCAGTAGTTATGGC
(SEQ ID NO: 33)
HCDR1 Amino Acid Sequence
GFSFSSYG
(SEQ ID NO: 34)
HCDR2 DNA Sequence
ATATCATATG ACG G AAGTTATG AT
(SEQ ID NO: 35)
HCDR2 Amino Acid Sequence
ISYDGSYD
(SEQ ID NO: 36)
HCDR3 DNA Sequence
GCGAGCGGCCTCACTGGCCCTACGAGGTGGTATTTCGATCTC
(SEQ ID NO: 37)
HCDR3 Amino Acid Sequence
ASGLTGPTRWYFDL
(SEQ ID NO: 38) LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 9)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 10)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 11)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 12)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 13)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 14)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 15)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 16)
HC DNA Sequence CAATTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA CTCTCATGTGCCGCCTCTGGATTCAGTTTCAGTAGTTATGGCATGCACTGGGTCCGCCA GACTCCAGGCAAGGGACTGGAGTGGGTGACATTTATATCATATGACGGAAGTTATGATT ACTATTTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACATTTCCAAGAACACA TTGTATTTGCAAATGAACAGCCTGAGAATTGAGGACACGGCTGTCTATTACTGTGCGAG CGGCCTCACTGGCCCTACGAGGTGGTATTTCGATCTCTGGGGCCGTGGCACCCTGGT CACTGTCTCCTCCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC GAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTC CCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCT CCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACAC CAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGA
(SEQ ID NO: 39)
HC Amino Acid Sequence
Q LQ LVESG G G WQPG RSLRLSCAASG FSFSS YG M H WVRQTPG KG LEWVTF I SYDG SYDY YLDSVKGRFTISRDISKNTLYLQMNSLRIEDTAVYYCASGLTGPTRWYFDLWGRGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEP TVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP*
(SEQ ID NO: 40)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 19)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 20)
REGN13879 HCVR DNA Sequence
GAGGTGCAGTTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGA CTCTCCTGTGCAGTCTCTGGATTCACCTTTAGCAACTATGCCATGAGTTGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGGTTTTAGTGGAAGTGGTGGTAGCAC
ATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATACCAAGAAC ACGCTGTATCTGCAAATGAACATCCTGAGAGGCGAGGACACGGCCGTATATTATTGTG CGAAAAATCGGGTACGTGGATATAGTGGCCACCATCTTGACTACTGGGGCCAGGGAAC
CCCGGTCACCGTCTCCTCA
(SEQ ID NO: 41)
HCVR Amino Acid Sequence
EVQLLESGGGLVQPGGSLRLSCAVSGFTFSNYAMSWVRQAPGKGLEWVSGFSGSGGSTY YADSVKGRFTISRDNTKNTLYLQMNILRGEDTAVYYCAKNRVRGYSGHHLDYWGQGTPVT VSS
(SEQ ID NO: 42)
HCDR1 DNA Sequence
GGATTCACCTTTAGCAACTATGCC
(SEQ ID NO: 43)
HCDR1 Amino Acid Sequence
GFTFSNYA
(SEQ ID NO: 44)
HCDR2 DNA Sequence
TTTAGTGGAAGTGGTGGTAGCACA
(SEQ ID NO: 45)
HCDR2 Amino Acid Sequence
FSGSGGST
(SEQ ID NO: 46)
HCDR3 DNA Sequence
GCGAAAAATCGGGTACGTGGATATAGTGGCCACCATCTTGACTAC
(SEQ ID NO: 47)
HCDR3 Amino Acid Sequence
AKNRVRGYSGHHLDY
(SEQ ID NO: 48) LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 9)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 10)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 11)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 12)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 13)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 14)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 15)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 16)
HC DNA Sequence GAGGTGCAGTTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGA CTCTCCTGTGCAGTCTCTGGATTCACCTTTAGCAACTATGCCATGAGTTGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGGTTTTAGTGGAAGTGGTGGTAGCAC ATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATACCAAGAAC ACGCTGTATCTGCAAATGAACATCCTGAGAGGCGAGGACACGGCCGTATATTATTGTG CGAAAAATCGGGTACGTGGATATAGTGGCCACCATCTTGACTACTGGGGCCAGGGAAC CCCGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCC CTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTA CTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCA CACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACC GTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCA GCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGA
(SEQ ID NO: 49)
HC Amino Acid Sequence
EVQLLESGGGLVQPGGSLRLSCAVSGFTFSNYAMSWVRQAPGKGLEWVSGFSGSGGSTY YADSVKGRFTISRDNTKNTLYLQMNILRGEDTAVYYCAKNRVRGYSGHHLDYWGQGTPVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP*
(SEQ ID NO: 50)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC AC AAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 19)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 20)
REGN13880 (NAC67600) HCVR DNA Sequence
CAGGTACACCTGCAGGAGTCGGGCCCAGGACTGGTGATGCCTTCACAGATCCTGTCCC TCTCCTGCGTTATTTCTGGTGACTCCATCAGAAATGGCGGCTATTATTGGACCTGGACC CGCCAGCAACCAGGGAAGGGCCTGGAGTGGATCGGTCACATCCACTATAGTGAAAGG ACCTCCCACAATCCGTCCCTCCAGAGTCGCGTTATTATGTCAATAGACACGTCTGAGAA TAAGTTCTCCCTGAAACTGACCTCAGTGACTGTCGCGGACACGGCCATATATTATTGTG
CGCGAGGTCGGGACACCATGGTTCGGGGATCCATTACAACTTCCGGCCACTTCATTGA CTCCTGGGGTCAGGGAGCCCTGGTCACCGTCTCCTCA
(SEQ ID NO: 51), or
CAGGTACACCTCCAGGAGTCGGGCCCAGGACTGGTGATGCCTTCACAGATCCTGTCCC TCTCCTGCGTTATTTCTGGTGACTCCATCAGAAATGGCGGCTATTATTGGACCTGGACC CGCCAGCAACCAGGGAAGGGCCTGGAGTGGATCGGTCACATCCACTATAGTGAAAGG ACCTCCCACAATCCGTCCCTCCAGAGTCGCGTTATTATGTCAATAGACACGTCTGAGAA TAAGTTCTCCCTGAAACTGACCTCAGTGACTGTCGCGGACACGGCCATATATTATTGTG
CGCGAGGTCGGGACACCATGGTTCGGGGATCCATTACAACTTCCGGCCACTTCATTGA CTCCTGGGGTCAGGGAGCCCTGGTCACCGTCTCCTCA
(SEQ ID NO: 1109) (silent mutation underlined in sequence above), or
CAGGTACACCTGCAGGAGTCGGGCCCAGGACTGGTGATGCCTTCACAGATCCTGTCCC TCTCCTGCGTTATTTCTGGTGACTCCATCAGAAATGGCGGCTATTATTGGACCTGGACC CGCCAGCAACCAGGGAAGTGTCTGGAGTGGATCGGTCACATCCACTATAGTGAAAGGA CCTCCCACAATCCGTCCCTCCAGAGTCGCGTTATTATGTCAATAGACACGTCTGAGAAT AAGTTCTCCCTGAAACTGACCTCAGTGACTGTCGCGGACACGGCCATATATTATTGTGC
GCGAGGTCGGGACACCATGGTTCGGGGATCCATTACAACTTCCGGCCACTTCATTGAC TCCTGGGGTCAGGGAGCCCTGGTCACCGTCTCCTCA
(SEQ ID NO: 1158) (Cys mutation underlined in sequence above), or
CAGGTACACCTCCAGGAGTCGGGCCCAGGACTGGTGATGCCTTCACAGATCCTGTCCC TCTCCTGCGTTATTTCTGGTGACTCCATCAGAAATGGCGGCTATTATTGGACCTGGACC CGCCAGCAACCAGGGAAGTGCCTGGAGTGGATCGGTCACATCCACTATAGTGAAAGGA CCTCCCACAATCCGTCCCTCCAGAGTCGCGTTATTATGTCAATAGACACGTCTGAGAAT AAGTTCTCCCTGAAACTGACCTCAGTGACTGTCGCGGACACGGCCATATATTATTGTGC
GCGAGGTCGGGACACCATGGTTCGGGGATCCATTACAACTTCCGGCCACTTCATTGAC TCCTGGGGTCAGGGAGCCCTGGTCACCGTCTCCTCA
(SEQ ID NO: 1275) (2 silent mutations underlined in sequence above)
HCVR Amino Acid Sequence
QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSS
(SEQ ID NO: 52), or QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSS
(SEQ ID NO: 1159) (Cys mutation underlined in sequence above)
HCDR1 DNA Sequence
G GTG ACTCCATCAG AAATG G CG G CT ATT AT
(SEQ ID NO: 53)
HCDR1 Amino Acid Sequence
GDSIRNGGYY
(SEQ ID NO: 54)
HCDR2 DNA Sequence
ATCCACTATAGTGAAAGGACC
(SEQ ID NO: 55)
HCDR2 Amino Acid Sequence
IHYSERT
(SEQ ID NO: 56)
HCDR3 DNA Sequence
GCGCGAGGTCGGGACACCATGGTTCGGGGATCCATTACAACTTCCGGCCACTTCATTG ACTCC
(SEQ ID NO: 57)
HCDR3 Amino Acid Sequence
ARGRDTMVRGSITTSGHFIDS
(SEQ ID NO: 58)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CO ATCACTTG COG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 9), or GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCTGTGGGACACGACTGGAGATTAAA
(SEQ ID NO: 1156) (Cys mutation underlined in sequence above)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 10), or
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIK
(SEQ ID NO: 1157) (Cys mutation underlined in sequence above)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 11)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 12)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 13)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 14)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 15)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 16) HC DNA Sequence
CAGGTACACCTGCAGGAGTCGGGCCCAGGACTGGTGATGCCTTCACAGATCCTGTCCC TCTCCTGCGTTATTTCTGGTGACTCCATCAGAAATGGCGGCTATTATTGGACCTGGACC CGCCAGCAACCAGGGAAGGGCCTGGAGTGGATCGGTCACATCCACTATAGTGAAAGG ACCTCCCACAATCCGTCCCTCCAGAGTCGCGTTATTATGTCAATAGACACGTCTGAGAA
TAAGTTCTCCCTGAAACTGACCTCAGTGACTGTCGCGGACACGGCCATATATTATTGTG CGCGAGGTCGGGACACCATGGTTCGGGGATCCATTACAACTTCCGGCCACTTCATTGA CTCCTGGGGTCAGGGAGCCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATC GGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGG
CTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC CCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGC AACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATG
GTCCCCCATGA
(SEQ ID NO: 59), or
CAGGTACACCTCCAGGAGTCGGGCCCAGGACTGGTGATGCCTTCACAGATCCTGTCCC TCTCCTGCGTTATTTCTGGTGACTCCATCAGAAATGGCGGCTATTATTGGACCTGGACC CGCCAGCAACCAGGGAAGGGCCTGGAGTGGATCGGTCACATCCACTATAGTGAAAGG ACCTCCCACAATCCGTCCCTCCAGAGTCGCGTTATTATGTCAATAGACACGTCTGAGAA
TAAGTTCTCCCTGAAACTGACCTCAGTGACTGTCGCGGACACGGCCATATATTATTGTG CGCGAGGTCGGGACACCATGGTTCGGGGATCCATTACAACTTCCGGCCACTTCATTGA CTCCTGGGGTCAGGGAGCCCTGGTCACCGTCTCCTCAGCCTCAACCAAGGGACCGTC CGTGTTTCCCCTCGCTCCTTCATCAAAATCAACTTCCGGCGGAACCGCAGCGCTGGGC
TGCCTCGTGAAGGATTACTTCCCCGAGCCTGTGACCGTGTCCTGGAACTCGGGCGCCC TGACCTCCGGTGTCCACACGTTCCCCGCGGTCCTTCAGTCCTCCGGCTTGTATTCCCT GTCGTCCGTCGTGACCGTCCCGAGCAGCAGCCTGGGAACTCAGACCTACATCTGCAAC GTGAACCACAAGCCGTCGAACACCAAGGTCGATAAGAAAGTGGAGCCGAAGTCGTGC
GACAAAACTCATACA
(SEQ ID NO: 1107) (silent mutation underlined in sequence above)
HC Amino Acid Sequence
QVHLQESG PG LVMPSQ I LSLSCVISG DSI RNGG YYWTWTRQQ PG KG LEWIG HI HYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP*
(SEQ ID NO: 60), or
QVHLQESG PG LVMPSQ I LSLSCVISG DSI RNGG YYWTWTRQQ PG KG LEWIG HI HYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT
(SEQ ID NO: 1108) LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 19), or
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAACACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGT
(SEQ ID NO: 1 145)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 20)
REGN13881
HCVR DNA Sequence
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCTCCTGCACTGTCTCTCGTGGCTCCATCAGCAGTGGTGGTTACTATTGGAGCTGGAT CCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGATACATCCATTATAGTGAGAG GACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATGTCAGTTGACACGTCTAAGA ACCAGTTCTCCCTGAAGCTGACCTCTGTGACTGCCGCGGACACGGCCGTGTATTATTG
TGCGAGAGATCGGGACACCATGGTTCGGGGAGTCATTACAACTTCCGGCCACTTCATT
GACGACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
(SEQ ID NO: 61)
HCVR Amino Acid Sequence
QVQLQESGPGLVKPSQTLSLSCTVSRGSISSGGYYWSWIRQHPGKGLEWIGYIHYSERTYY NPSLKSRVTMSVDTSKNQFSLKLTSVTAADTAVYYCARDRDTMVRGVITTSGHFIDDWGQ GTLVTVSS
(SEQ ID NO: 62)
HCDR1 DNA Sequence
CGTGGCTCCATCAGCAGTGGTGGTTACTAT
(SEQ ID NO: 63)
HCDR1 Amino Acid Sequence
RGSISSGGYY
(SEQ ID NO: 64)
HCDR2 DNA Sequence
ATCCATTATAGTGAGAGGACC
(SEQ ID NO: 65)
HCDR2 Amino Acid Sequence
IHYSERT
(SEQ ID NO: 56)
HCDR3 DNA Sequence
GCGAGAGATCGGGACACCATGGTTCGGGGAGTCATTACAACTTCCGGCCACTTCATTG ACGAC
(SEQ ID NO: 66)
HCDR3 Amino Acid Sequence
ARDRDTMVRGVITTSGHFIDD
(SEQ ID NO: 67)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CO ATCACTTG COG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGO AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 9)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 10)
LCDR1 DNA Sequence
C AG AG CATTAG C AG CTAT
(SEQ ID NO: 11)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 12)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 13)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 14)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 15)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 16)
HC DNA Sequence
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCTCCTGCACTGTCTCTCGTGGCTCCATCAGCAGTGGTGGTTACTATTGGAGCTGGAT CCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGATACATCCATTATAGTGAGAG
GACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATGTCAGTTGACACGTCTAAGA ACCAGTTCTCCCTGAAGCTGACCTCTGTGACTGCCGCGGACACGGCCGTGTATTATTG TGCGAGAGATCGGGACACCATGGTTCGGGGAGTCATTACAACTTCCGGCCACTTCATT GACGACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCA TCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCT GCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATA TGGTCCCCCATGA
(SEQ ID NO: 68)
HC Amino Acid Sequence
QVQLQESGPGLVKPSQTLSLSCTVSRGSISSGGYYWSWIRQHPGKGLEWIGYIHYSERTYY NPSLKSRVTMSVDTSKNQFSLKLTSVTAADTAVYYCARDRDTMVRGVITTSGHFIDDWGQ GTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP*
(SEQ ID NO: 69)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT
CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC
TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA
ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAACACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 19)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 20)
REGN13882
HCVR DNA Sequence
GAGGTGCACTTATTGGACTCTGGCGGAGGCTTGGTTCAGTCGGGGGAGTCCCTGAGA
CTCTCCTGTACAGTCTCTGGAGTCACTTTTGAAAACCTTGTCATGAACTGGGTCCGGCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCGCAAGTGTTGGAGGTCGTTATACTGGCGC
GGTCTTCGCAGACTCAGTGAGGGGCCGGTTCACGATCTCCAGAGACCATTCCGAGAAT
ACGCTCTTTCTGCACATGAGCAGCCTGAGAGCCGAGGACACGGCCGTTTATTTTTGTAC GAAAGATTCCTCTGTCCTGATTCGGGGAGTCATTAGTACAAACTACTTCTATAGTATGGA CGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
(SEQ ID NO: 70)
HCVR Amino Acid Sequence
EVH LLDSG G G LVQSG ESLRLSCTVSG VTF ENLVM N WVRQ APG KG LEWVASVG G RYTG AV FADSVRGRFTISRDHSENTLFLHMSSLRAEDTAVYFCTKDSSVLIRGVISTNYFYSMDVWG QGTTVTVSS
(SEQ ID NO: 71)
HCDR1 DNA Sequence
GGAGTCACTTTTGAAAACCTTGTC
(SEQ ID NO: 72)
HCDR1 Amino Acid Sequence
GVTFENLV
(SEQ ID NO: 73)
HCDR2 DNA Sequence
GTTGGAGGTCGTTATACTGGCGCG
(SEQ ID NO: 74)
HCDR2 Amino Acid Sequence
VGGRYTGA
(SEQ ID NO: 75)
HCDR3 DNA Sequence
ACGAAAGATTCCTCTGTCCTGATTCGGGGAGTCATTAGTACAAACTACTTCTATAGTATG GACGTC
(SEQ ID NO: 76)
HCDR3 Amino Acid Sequence
TKDSSVLIRGVISTNYFYSMDV
(SEQ ID NO: 77)
LCVR DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 9)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 10)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 11)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 12)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 13)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 14)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 15)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 16)
HC DNA Sequence
GAGGTGCACTTATTGGACTCTGGCGGAGGCTTGGTTCAGTCGGGGGAGTCCCTGAGA
CTCTCCTGTACAGTCTCTGGAGTCACTTTTGAAAACCTTGTCATGAACTGGGTCCGGCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCGCAAGTGTTGGAGGTCGTTATACTGGCGC GGTCTTCGCAGACTCAGTGAGGGGCCGGTTCACGATCTCCAGAGACCATTCCGAGAAT ACGCTCTTTCTGCACATGAGCAGCCTGAGAGCCGAGGACACGGCCGTTTATTTTTGTAC GAAAGATTCCTCTGTCCTGATTCGGGGAGTCATTAGTACAAACTACTTCTATAGTATGGA CGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATC GGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGG CTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC CCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGC AACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATG GTCCCCCATGA
(SEQ ID NO: 78)
HC Amino Acid Sequence
EVH LLDSG G G LVQSG ESLRLSCTVSG VTF ENLVM N WVRQ APG KG LEWVASVG G RYTG AV FADSVRGRFTISRDHSENTLFLHMSSLRAEDTAVYFCTKDSSVLIRGVISTNYFYSMDVWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP*
(SEQ ID NO: 79)
LG DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 19)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 20)
REGN13883 HCVR DNA Sequence
CAGGAGCAACTACAACAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCC CTCACCTGCGCTGTCCATGGTGGGTCATTCAGTGGTTACTACTGGAGTTGGATCCGCC AGCCCCCCGGGAAGGGGCTGGAGTGGATTGGGGAAATCTATCCTAGTGGAGGCACCA
ACCAAAATCCGTCCCTCAAGAGTCGAGTCACCATATCACTAGACATGTCCCAGAACCAG TTCTCCCTGAGGCTGAACTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGA G ACG G AATTGG G ACGG ATACTTTG ACTTCTG G GG CCAGG G AATTAAG GTCACTGTCTC
CTCA
(SEQ ID NO: 80)
HCVR Amino Acid Sequence
QEQLQQWGAGLLKPSETLSLTCAVHGGSFSGYYWSWIRQPPGKGLEWIGEIYPSGGTNQ NPSLKSRVTISLDMSQNQFSLRLNSVTAADTAVYYCARRNWDGYFDFWGQGIKVTVSS
(SEQ ID NO: 81)
HCDR1 DNA Sequence
GGTGGGTCATTCAGTGGTTACTAC
(SEQ ID NO: 82)
HCDR1 Amino Acid Sequence
GGSFSGYY
(SEQ ID NO: 83)
HCDR2 DNA Sequence
ATCTATCCTAGTGGAGGCACC
(SEQ ID NO: 84)
HCDR2 Amino Acid Sequence
IYPSGGT
(SEQ ID NO: 85)
HCDR3 DNA Sequence
GCGAGACGGAATTGGGACGGATACTTTGACTTC
(SEQ ID NO: 86)
HCDR3 Amino Acid Sequence
ARRNWDGYFDF
(SEQ ID NO: 87)
LCVR DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 9)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 10)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 11)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 12)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 13)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 14)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 15)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 16)
HC DNA Sequence
CAGGAGCAACTACAACAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCC
CTCACCTGCGCTGTCCATGGTGGGTCATTCAGTGGTTACTACTGGAGTTGGATCCGCC AGCCCCCCGGGAAGGGGCTGGAGTGGATTGGGGAAATCTATCCTAGTGGAGGCACCA ACCAAAATCCGTCCCTCAAGAGTCGAGTCACCATATCACTAGACATGTCCCAGAACCAG TTCTCCCTGAGGCTGAACTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGA GACGGAATTGGGACGGATACTTTGACTTCTGGGGCCAGGGAATTAAGGTCACTGTCTC CTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCAC CTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGT GACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGT CCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTG G G CACG AAG ACCTACACCTG CAACGTAG ATCACAAG CCC AG CAACACCAAGGTGG ACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGA
(SEQ ID NO: 88)
HC Amino Acid Sequence
QEQLQQWGAGLLKPSETLSLTCAVHGGSFSGYYWSWIRQPPGKGLEWIGEIYPSGGTNQ NPSLKSRVTISLDMSQNQFSLRLNSVTAADTAVYYCARRNWDGYFDFWGQGIKVTVSSAS TKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP*
(SEQ ID NO: 89)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CO ATCACTTG COG G GCAAGTCAG AG CATTAG C AG CTATTTAAATTG GTATC AGO AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 19)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 20)
REGN13884
HCVR DNA Sequence CAGGTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA CTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATACACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCACTTATATGGTATGATGGAAGTAATAA
ATACTATACAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAAGACACGGCTGTGTATTACTGTGC GAGAGATAGAGTGCGATCGTATAGCTGGAACTACTTTGACTACTGGGGCCAGGGAACC
CTGGTCACCGTCTCCTCA
(SEQ ID NO: 90)
HCVR Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVALIWYDGSNKY YTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRVRSYSWNYFDYWGQGTLVT VSS
(SEQ ID NO: 91)
HCDR1 DNA Sequence
GGATTCACCTTCAGTAGCTATGGC
(SEQ ID NO: 92)
HCDR1 Amino Acid Sequence
GFTFSSYG
(SEQ ID NO: 93)
HCDR2 DNA Sequence
ATATG GTATG ATG G AAGTAATAAA
(SEQ ID NO: 94)
HCDR2 Amino Acid Sequence
IWYDGSNK
(SEQ ID NO: 95)
HCDR3 DNA Sequence
GCGAGAGATAGAGTGCGATCGTATAGCTGGAACTACTTTGACTAC
(SEQ ID NO: 96)
HCDR3 Amino Acid Sequence
ARDRVRSYSWNYFDY
(SEQ ID NO: 97)
LCVR DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 9)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 10)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 11)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 12)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 13)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 14)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 15)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 16)
HC DNA Sequence
CAGGTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
CTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATACACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCACTTATATGGTATGATGGAAGTAATAA ATACTATACAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAAGACACGGCTGTGTATTACTGTGC GAGAGATAGAGTGCGATCGTATAGCTGGAACTACTTTGACTACTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCT GCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA CCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGT G CCCTCCAG CAG CTTGG G CACG AAG ACCTACACCTG CAACGTAG ATCACAAG CCCAG C AACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGA
(SEQ ID NO: 98)
HC Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVALIWYDGSNKY YTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRVRSYSWNYFDYWGQGTLVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP*
(SEQ ID NO: 99)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CO ATCACTTG COG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC AC AAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 19)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 20)
REGN13885
HCVR DNA Sequence GAGGTGCAACTGGTGGAATCTGGAGGAGGCTTGGTCCAGCCTGGGGGTTCCCTGAGA CTCTCCTGTGCAGCCTCTGGGTTCATCGTCAGTAACAACTATATGAGATGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCGGTCATTTATAGTGGTGGTGGCACATA CTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGACACAATTCCAAGAACACG ATATATCTTCAAATGAACAGCCTGCGAATTGAGGACACGGCCGTGTATTATTGTGCGAG AGAAGATAGCCACTCGTCGGAAAGTTATGACTACTTCTACGGCATGGACGTCTGGGGC CAAGGGACCACGGTCACCGTCTCCCCA
(SEQ ID NO: 100)
HCVR Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCAASG F I SN N YM RWVRQ APG KG LE WVSVI YSGGGTYY ADSVKGRFTISRHNSKNTIYLQMNSLRIEDTAVYYCAREDSHSSESYDYFYGMDVWGQGTT VTVSP
(SEQ ID NO: 101)
HCDR1 DNA Sequence
GGGTTCATCGTCAGTAACAACTAT
(SEQ ID NO: 102)
HCDR1 Amino Acid Sequence
GFIVSNNY
(SEQ ID NO: 103)
HCDR2 DNA Sequence
ATTTATAGTGGTGGTGGCACA
(SEQ ID NO: 104)
HCDR2 Amino Acid Sequence
IYSGGGT
(SEQ ID NO: 105)
HCDR3 DNA Sequence
GCGAGAGAAGATAGCCACTCGTCGGAAAGTTATGACTACTTCTACGGCATGGACGTC
(SEQ ID NO: 106)
HCDR3 Amino Acid Sequence
AREDSHSSESYDYFYGMDV
(SEQ ID NO: 107)
LCVR DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 9)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 10)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 11)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 12)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 13)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 14)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 15)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 16)
HC DNA Sequence
GAGGTGCAACTGGTGGAATCTGGAGGAGGCTTGGTCCAGCCTGGGGGTTCCCTGAGA CTCTCCTGTGCAGCCTCTGGGTTCATCGTCAGTAACAACTATATGAGATGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCGGTCATTTATAGTGGTGGTGGCACATA CTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGACACAATTCCAAGAACACG ATATATCTTCAAATGAACAGCCTGCGAATTGAGGACACGGCCGTGTATTATTGTGCGAG AGAAGATAGCCACTCGTCGGAAAGTTATGACTACTTCTACGGCATGGACGTCTGGGGC CAAGGGACCACGGTCACCGTCTCCCCAGCCTCCACCAAGGGCCCATCGGTCTTCCCC CTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTC AAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCG TGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCA CAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGA
(SEQ ID NO: 108)
HC Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCAASG F I SN N YM RWVRQ APG KG LE WVSVI YSGGGTYY ADSVKGRFTISRHNSKNTIYLQMNSLRIEDTAVYYCAREDSHSSESYDYFYGMDVWGQGTT VTVSPASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP*
(SEQ ID NO: 109)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 19)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 20)
REGN13070
HCVR DNA Sequence CAATTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
CTCTCATGTGCCGCCTCTGGATTCAGTTTCAGTAGTTATGGCATGCACTGGGTCCGCCA
GACTCCAGGCAAGGGACTGGAGTGGGTGACATTTATATCATATGACGGAAGTTATGATT
ACTATTTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACATTTCCAAGAACACA
TTGTATTTGCAAATGAACAGCCTGAGAATTGAGGACACGGCTGTCTATTACTGTGCGAG CGGCCTCACTGGCCCTACGAGGTGGTATTTCGATCTCTGGGGCCGTGGCACCCTGGT CACTGTCTCCTCC
(SEQ ID NO: 110)
HCVR Amino Acid Sequence
Q LQ LVESG G G WQPG RSLRLSCAASG FSFSS YG M H WVRQTPG KG LEWVTF I SYDG SYDY YLDSVKGRFTISRDISKNTLYLQMNSLRIEDTAVYYCASGLTGPTRWYFDLWGRGTLVTVSS
(SEQ ID NO: 11 1)
HCDR1 DNA Sequence
GGATTCAGTTTCAGTAGTTATGGC
(SEQ ID NO: 112)
HCDR1 Amino Acid Sequence
GFSFSSYG
(SEQ ID NO: 113)
HCDR2 DNA Sequence
ATATCATATG ACG G AAGTTATG AT
(SEQ ID NO: 114)
HCDR2 Amino Acid Sequence
ISYDGSYD
(SEQ ID NO: 115)
HCDR3 DNA Sequence
GCGAGCGGCCTCACTGGCCCTACGAGGTGGTATTTCGATCTC
(SEQ ID NO: 116)
HCDR3 Amino Acid Sequence
ASGLTGPTRWYFDL
(SEQ ID NO: 117)
LCVR DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 118)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 119)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 120)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 121)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 122)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 123)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 124)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 125)
HC DNA Sequence
CAATTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
CTCTCATGTGCCGCCTCTGGATTCAGTTTCAGTAGTTATGGCATGCACTGGGTCCGCCA GACTCCAGGCAAGGGACTGGAGTGGGTGACATTTATATCATATGACGGAAGTTATGATT ACTATTTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACATTTCCAAGAACACA TTGTATTTGCAAATGAACAGCCTGAGAATTGAGGACACGGCTGTCTATTACTGTGCGAG CGGCCTCACTGGCCCTACGAGGTGGTATTTCGATCTCTGGGGCCGTGGCACCCTGGT CACTGTCTCCTCCGCCTCTACAAAGGGACCTTCTGTGTTTCCTCTGGCTCCTTGTTCTA GATCTACATCTGAATCTACAGCTGCTCTGGGATGTCTGGTGAAGGATTATTTTCCTGAA CCTGTGACAGTGTCTTGGAATTCTGGAGCTCTGACATCTGGAGTGCATACATTTCCTGC TGTGCTGCAGTCTTCTGGACTGTATTCTCTGTCTTCTGTGGTGACAGTGCCTTCTTCTTC TCTGG G AACAAAG ACATATACATGTAATG TGG ATCATAAG CCTTCTAATACAAAG GTG G ATAAGAGAGTGGAATCTAAGTATGGACCTCCTTGTCCTCCTTGTCCTGCTCCTGGCGGT GGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAGCCTAAGGATACACTGATGATCTCTAG AACACCTGAAGTGACATGTGTGGTGGTGGATGTGTCTCAGGAAGATCCTGAAGTGCAG TTTAATTGGTATGTGGATGGAGTGGAAGTGCATAATGCTAAGACAAAGCCTAGAGAAGA ACAGTTTAATTCTACATATAGAGTGGTGTCTGTGCTGACAGTGCTGCATCAGGATTGGC
TGAATGGAAAGGAATATAAGTGTAAGGTGTCTAATAAGGGACTGCCTTCTTCTATCGAA AAGACAATCTCTAAGGCTAAGGGACAGCCTAGAGAACCTCAGGTGTATACACTGCCTC CTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTCTGACATGTCTGGTGAAGGGATTT TATCCTTCTGATATCGCTGTGGAATGGGAATCTAATGGACAGCCTGAAAATAATTATAAG ACAACACCTCCTGTGCTGGATTCTGATGGATCTTTTTTTCTGTATTCTAGACTGACAGTG GATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTTGTTCTGTGATGCATGAAGCTCT GCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTCCTGGAAAGTAG
(SEQ ID NO: 126)
HC Amino Acid Sequence
Q LQ LVESG G GWQPG RSLRLSCAASG FSFSS YG M H WVRQTPG KG LEWVTF I SYDG SYDY YLDSVKGRFTISRDISKNTLYLQMNSLRIEDTAVYYCASGLTGPTRWYFDLWGRGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPSVFLF PPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRW SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSVMHEALHNRFTQKSLSLSPGK*
(SEQ ID NO: 127)
LG DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA
GAGTGTTAG
(SEQ ID NO: 128)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 129)
REGN13071
HCVR DNA Sequence
CAGGAGCAACTACAACAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCC CTCACCTGCGCTGTCCATGGTGGGTCATTCAGTGGTTACTACTGGAGTTGGATCCGCC AGCCCCCCGGGAAGGGGCTGGAGTGGATTGGGGAAATCTATCCTAGTGGAGGCACCA
ACCAAAATCCGTCCCTCAAGAGTCGAGTCACCATATCACTAGACATGTCCCAGAACCAG TTCTCCCTGAGGCTGAACTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGA GACGGAATTGGGACGGATACTTTGACTTCTGGGGCCAGGGAATTAAGGTCACTGTCTC
CTCA
(SEQ ID NO: 130)
HCVR Amino Acid Sequence
QEQLQQWGAGLLKPSETLSLTCAVHGGSFSGYYWSWIRQPPGKGLEWIGEIYPSGGTNQ NPSLKSRVTISLDMSQNQFSLRLNSVTAADTAVYYCARRNWDGYFDFWGQGIKVTVSS
(SEQ ID NO: 131)
HCDR1 DNA Sequence
GGTGGGTCATTCAGTGGTTACTAC
(SEQ ID NO: 132)
HCDR1 Amino Acid Sequence
GGSFSGYY
(SEQ ID NO: 133)
HCDR2 DNA Sequence
ATCTATCCTAGTGGAGGCACC
(SEQ ID NO: 134)
HCDR2 Amino Acid Sequence IYPSGGT
(SEQ ID NO: 135)
HCDR3 DNA Sequence
GCGAGACGGAATTGGGACGGATACTTTGACTTC
(SEQ ID NO: 136)
HCDR3 Amino Acid Sequence
ARRNWDGYFDF
(SEQ ID NO: 137)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 118)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 119)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 120)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 121)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 122)
LCDR2 Amino Acid Sequence
AAS (SEQ ID NO: 123)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 124)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 125)
HC DNA Sequence
CAGGAGCAACTACAACAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCC CTCACCTGCGCTGTCCATGGTGGGTCATTCAGTGGTTACTACTGGAGTTGGATCCGCC AGCCCCCCGGGAAGGGGCTGGAGTGGATTGGGGAAATCTATCCTAGTGGAGGCACCA
ACCAAAATCCGTCCCTCAAGAGTCGAGTCACCATATCACTAGACATGTCCCAGAACCAG TTCTCCCTGAGGCTGAACTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGA GACGGAATTGGGACGGATACTTTGACTTCTGGGGCCAGGGAATTAAGGTCACTGTCTC CTCAGCCTCTACAAAGGGACCTTCTGTGTTTCCTCTGGCTCCTTGTTCTAGATCTACATC TGAATCTACAGCTGCTCTGGGATGTCTGGTGAAGGATTATTTTCCTGAACCTGTGACAG
TGTCTTGGAATTCTGGAGCTCTGACATCTGGAGTGCATACATTTCCTGCTGTGCTGCAG TCTTCTGGACTGTATTCTCTGTCTTCTGTGGTGACAGTGCCTTCTTCTTCTCTGGGAACA AAGACATATACATGTAATGTGGATCATAAGCCTTCTAATACAAAGGTGGATAAGAGAGT GGAATCTAAGTATGGACCTCCTTGTCCTCCTTGTCCTGCTCCTGGCGGTGGCGGACCT TCTGTGTTTCTGTTTCCTCCTAAGCCTAAGGATACACTGATGATCTCTAGAACACCTGAA
GTGACATGTGTGGTGGTGGATGTGTCTCAGGAAGATCCTGAAGTGCAGTTTAATTGGTA TGTGGATGGAGTGGAAGTGCATAATGCTAAGACAAAGCCTAGAGAAGAACAGTTTAATT CTACATATAGAGTGGTGTCTGTGCTGACAGTGCTGCATCAGGATTGGCTGAATGGAAA GGAATATAAGTGTAAGGTGTCTAATAAGGGACTGCCTTCTTCTATCGAAAAGACAATCT CTAAGGCTAAGGGACAGCCTAGAGAACCTCAGGTGTATACACTGCCTCCTTCTCAGGA
AGAAATGACAAAGAATCAGGTGTCTCTGACATGTCTGGTGAAGGGATTTTATCCTTCTG ATATCGCTG TG GAATG G G AATCTAATGG ACAG CCTG AAAATAATTATAAG ACAAC ACCT CCTGTGCTGGATTCTGATGGATCTTTTTTTCTGTATTCTAGACTGACAGTGGATAAGTCT AGATGGCAGGAAGGAAATGTGTTTTCTTGTTCTGTGATGCATGAAGCTCTGCATAATAG ATTTACACAGAAGTCTCTGTCTCTGTCTCCTGGAAAGTAG
(SEQ ID NO: 138)
HC Amino Acid Sequence
QEQLQQWGAGLLKPSETLSLTCAVHGGSFSGYYWSWIRQPPGKGLEWIGEIYPSGGTNQ NPSLKSRVTISLDMSQNQFSLRLNSVTAADTAVYYCARRNWDGYFDFWGQGIKVTVSSAS TKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPSVFLFP PKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSC SVMHEALHNRFTQKSLSLSPGK* (SEQ ID NO: 139)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC
TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAACACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 128)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 129)
REGN13072
HCVR DNA Sequence
CAGGTACACCTGCAGGAGTCGGGCCCAGGACTGGTGATGCCTTCACAGATCCTGTCCC TCTCCTGCGTTATTTCTGGTGACTCCATCAGAAATGGCGGCTATTATTGGACCTGGACC CGCCAGCAACCAGGGAAGGGCCTGGAGTGGATCGGTCACATCCACTATAGTGAAAGG ACCTCCCACAATCCGTCCCTCCAGAGTCGCGTTATTATGTCAATAGACACGTCTGAGAA TAAGTTCTCCCTGAAACTGACCTCAGTGACTGTCGCGGACACGGCCATATATTATTGTG CGCGAGGTCGGGACACCATGGTTCGGGGATCCATTACAACTTCCGGCCACTTCATTGA CTCCTGGGGTCAGGGAGCCCTGGTCACCGTCTCCTCA
(SEQ ID NO: 140)
HCVR Amino Acid Sequence
QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSS
(SEQ ID NO: 141)
HCDR1 DNA Sequence G GTG ACTCC ATCAGAAATG G CG G CT ATT AT
(SEQ ID NO: 142)
HCDR1 Amino Acid Sequence
GDSIRNGGYY
(SEQ ID NO: 143)
HCDR2 DNA Sequence
ATCCACTATAGTGAAAGGACC
(SEQ ID NO: 144)
HCDR2 Amino Acid Sequence
IHYSERT
(SEQ ID NO: 145)
HCDR3 DNA Sequence
GCGCGAGGTCGGGACACCATGGTTCGGGGATCCATTACAACTTCCGGCCACTTCATTG ACTCC
(SEQ ID NO: 146)
HCDR3 Amino Acid Sequence
ARGRDTMVRGSITTSGHFIDS
(SEQ ID NO: 147)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 118)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 119)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT (SEQ ID NO: 120)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 121)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 122)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 123)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 124)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 125)
HC DNA Sequence
CAGGTACACCTGCAGGAGTCGGGCCCAGGACTGGTGATGCCTTCACAGATCCTGTCCC TCTCCTGCGTTATTTCTGGTGACTCCATCAGAAATGGCGGCTATTATTGGACCTGGACC
CGCCAGCAACCAGGGAAGGGCCTGGAGTGGATCGGTCACATCCACTATAGTGAAAGG ACCTCCCACAATCCGTCCCTCCAGAGTCGCGTTATTATGTCAATAGACACGTCTGAGAA
TAAGTTCTCCCTGAAACTGACCTCAGTGACTGTCGCGGACACGGCCATATATTATTGTG CGCGAGGTCGGGACACCATGGTTCGGGGATCCATTACAACTTCCGGCCACTTCATTGA CTCCTGGGGTCAGGGAGCCCTGGTCACCGTCTCCTCAGCCTCTACAAAGGGACCTTCT GTGTTTCCTCTGGCTCCTTGTTCTAGATCTACATCTGAATCTACAGCTGCTCTGGGATGT
CTGGTGAAGGATTATTTTCCTGAACCTGTGACAGTGTCTTGGAATTCTGGAGCTCTGAC ATCTGGAGTGCATACATTTCCTGCTGTGCTGCAGTCTTCTGGACTGTATTCTCTGTCTTC TGTGGTGACAGTGCCTTCTTCTTCTCTGGGAACAAAGACATATACATGTAATGTGGATC ATAAGCCTTCTAATACAAAGGTGGATAAGAGAGTGGAATCTAAGTATGGACCTCCTTGT
CCTCCTTGTCCTGCTCCTGGCGGTGGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAGCC TAAGGATACACTGATGATCTCTAGAACACCTGAAGTGACATGTGTGGTGGTGGATGTGT CTCAGGAAGATCCTGAAGTGCAGTTTAATTGGTATGTGGATGGAGTGGAAGTGCATAAT
GCTAAGACAAAGCCTAGAGAAGAACAGTTTAATTCTACATATAGAGTGGTGTCTGTGCT G ACAGTG CTG CATC AG G ATTG G CTG AATG G AAAG G AATATAAGTGTAAG GTGTCTAATA AGGGACTGCCTTCTTCTATCGAAAAGACAATCTCTAAGGCTAAGGGACAGCCTAGAGAA CCTCAGGTGTATACACTGCCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTCT GACATGTCTGGTGAAGGGATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAATG GACAGCCTGAAAATAATTATAAGACAACACCTCCTGTGCTGGATTCTGATGGATCTTTTT TTCTGTATTCTAGACTGACAGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTT GTTCTGTGATGCATGAAGCTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTC CTGGAAAGTAG
(SEQ ID NO: 148)
HC Amino Acid Sequence
QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGG GPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNRFTQKSLSLSPGK*
(SEQ ID NO: 149)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 128)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 129)
REGN13073
HCVR DNA Sequence CAGGTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA CTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATACACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCACTTATATGGTATGATGGAAGTAATAA ATACTATACAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAAGACACGGCTGTGTATTACTGTGC GAGAGATAGAGTGCGATCGTATAGCTGGAACTACTTTGACTACTGGGGCCAGGGAACC
CTGGTCACCGTCTCCTCA
(SEQ ID NO: 150)
HCVR Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVALIWYDGSNKY YTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRVRSYSWNYFDYWGQGTLVT VSS
(SEQ ID NO: 151)
HCDR1 DNA Sequence
GGATTCACCTTCAGTAGCTATGGC
(SEQ ID NO: 152)
HCDR1 Amino Acid Sequence
GFTFSSYG
(SEQ ID NO: 153)
HCDR2 DNA Sequence
ATATG GTATG ATG G AAGTAATAAA
(SEQ ID NO: 154)
HCDR2 Amino Acid Sequence
IWYDGSNK
(SEQ ID NO: 155)
HCDR3 DNA Sequence
GCGAGAGATAGAGTGCGATCGTATAGCTGGAACTACTTTGACTAC
(SEQ ID NO: 156)
HCDR3 Amino Acid Sequence
ARDRVRSYSWNYFDY
(SEQ ID NO: 157)
LCVR DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 118)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 119)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 120)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 121)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 122)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 123)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 124)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 125)
HC DNA Sequence
CAGGTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
CTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATACACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCACTTATATGGTATGATGGAAGTAATAA ATACTATACAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAAGACACGGCTGTGTATTACTGTGC GAGAGATAGAGTGCGATCGTATAGCTGGAACTACTTTGACTACTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCAGCCTCTACAAAGGGACCTTCTGTGTTTCCTCTGGCTCCTTG TTCTAGATCTACATCTGAATCTACAGCTGCTCTGGGATGTCTGGTGAAGGATTATTTTCC TGAACCTGTGACAGTGTCTTGGAATTCTGGAGCTCTGACATCTGGAGTGCATACATTTC CTGCTGTGCTGCAGTCTTCTGGACTGTATTCTCTGTCTTCTGTGGTGACAGTGCCTTCT TCTTCTCTGGGAACAAAGACATATACATGTAATGTGGATCATAAGCCTTCTAATACAAAG GTGGATAAGAGAGTGGAATCTAAGTATGGACCTCCTTGTCCTCCTTGTCCTGCTCCTGG CGGTGGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAGCCTAAGGATACACTGATGATCT CTAGAACACCTGAAGTGACATGTGTGGTGGTGGATGTGTCTCAGGAAGATCCTGAAGT
GCAGTTTAATTGGTATGTGGATGGAGTGGAAGTGCATAATGCTAAGACAAAGCCTAGAG AAGAACAGTTTAATTCTACATATAGAGTGGTGTCTGTGCTGACAGTGCTGCATCAGGAT TGGCTGAATGGAAAGGAATATAAGTGTAAGGTGTCTAATAAGGGACTGCCTTCTTCTAT CGAAAAGACAATCTCTAAGGCTAAGGGACAGCCTAGAGAACCTCAGGTGTATACACTG CCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTCTGACATGTCTGGTGAAGGG ATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAATGGACAGCCTGAAAATAATTA TAAG ACAACACCTCCTGTG CTG G ATTCTG ATG G ATCTTTTTTTCTGTATTCTAG ACTG AC AGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTTGTTCTGTGATGCATGAAG CTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTCCTGGAAAGTAG
(SEQ ID NO: 158)
HC Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVALIWYDGSNKY YTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRVRSYSWNYFDYWGQGTLVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPS VFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNRFTQKSLSLSPGK*
(SEQ ID NO: 159)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA
GAGTGTTAG
(SEQ ID NO: 128)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 129)
REGN13074
HCVR DNA Sequence
GAGGTGCAGTTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGA CTCTCCTGTGCAGTCTCTGGATTCACCTTTAGCAACTATGCCATGAGTTGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGGTTTTAGTGGAAGTGGTGGTAGCAC
ATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATACCAAGAAC ACGCTGTATCTGCAAATGAACATCCTGAGAGGCGAGGACACGGCCGTATATTATTGTG CGAAAAATCGGGTACGTGGATATAGTGGCCACCATCTTGACTACTGGGGCCAGGGAAC
CCCGGTCACCGTCTCCTCA
(SEQ ID NO: 160)
HCVR Amino Acid Sequence
EVQLLESGGGLVQPGGSLRLSCAVSGFTFSNYAMSWVRQAPGKGLEWVSGFSGSGGSTY YADSVKGRFTISRDNTKNTLYLQMNILRGEDTAVYYCAKNRVRGYSGHHLDYWGQGTPVT VSS
(SEQ ID NO: 161)
HCDR1 DNA Sequence
GGATTCACCTTTAGCAACTATGCC
(SEQ ID NO: 162)
HCDR1 Amino Acid Sequence
GFTFSNYA
(SEQ ID NO: 163)
HCDR2 DNA Sequence
TTTAGTGGAAGTGGTGGTAGCACA
(SEQ ID NO: 164)
HCDR2 Amino Acid Sequence FSGSGGST
(SEQ ID NO: 165)
HCDR3 DNA Sequence
GCGAAAAATCGGGTACGTGGATATAGTGGCCACCATCTTGACTAC
(SEQ ID NO: 166)
HCDR3 Amino Acid Sequence
AKNRVRGYSGHHLDY
(SEQ ID NO: 167)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 118)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 119)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 120)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 121)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 122)
LCDR2 Amino Acid Sequence
AAS (SEQ ID NO: 123)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 124)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 125)
HC DNA Sequence
GAGGTGCAGTTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGA
CTCTCCTGTGCAGTCTCTGGATTCACCTTTAGCAACTATGCCATGAGTTGGGTCCGCCA
GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGGTTTTAGTGGAAGTGGTGGTAGCAC
ATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATACCAAGAAC ACGCTGTATCTGCAAATGAACATCCTGAGAGGCGAGGACACGGCCGTATATTATTGTG
CGAAAAATCGGGTACGTGGATATAGTGGCCACCATCTTGACTACTGGGGCCAGGGAAC CCCGGTCACCGTCTCCTCAGCCTCTACAAAGGGACCTTCTGTGTTTCCTCTGGCTCCTT
GTTCTAGATCTACATCTGAATCTACAGCTGCTCTGGGATGTCTGGTGAAGGATTATTTTC
CTGAACCTGTGACAGTGTCTTGGAATTCTGGAGCTCTGACATCTGGAGTGCATACATTT CCTGCTGTGCTGCAGTCTTCTGGACTGTATTCTCTGTCTTCTGTGGTGACAGTGCCTTC
TTCTTCTCTGGGAACAAAGACATATACATGTAATGTGGATCATAAGCCTTCTAATACAAA GGTGGATAAGAGAGTGGAATCTAAGTATGGACCTCCTTGTCCTCCTTGTCCTGCTCCTG
GCGGTGGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAGCCTAAGGATACACTGATGATC TCTAGAACACCTGAAGTGACATGTGTGGTGGTGGATGTGTCTCAGGAAGATCCTGAAG
TGCAGTTTAATTGGTATGTGGATGGAGTGGAAGTGCATAATGCTAAGACAAAGCCTAGA GAAGAACAGTTTAATTCTACATATAGAGTGGTGTCTGTGCTGACAGTGCTGCATCAGGA
TTGGCTGAATGGAAAGGAATATAAGTGTAAGGTGTCTAATAAGGGACTGCCTTCTTCTA TCGAAAAGACAATCTCTAAGGCTAAGGGACAGCCTAGAGAACCTCAGGTGTATACACTG
CCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTCTGACATGTCTGGTGAAGGG ATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAATGGACAGCCTGAAAATAATTA TAAG ACAACACCTCCTGTG CTG G ATTCTG ATG G ATCTTTTTTTCTGTATTCTAG ACTG AC AGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTTGTTCTGTGATGCATGAAG
CTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTCCTGGAAAGTAG
(SEQ ID NO: 168)
HC Amino Acid Sequence
EVQLLESGGGLVQPGGSLRLSCAVSGFTFSNYAMSWVRQAPGKGLEWVSGFSGSGGSTY
YADSVKGRFTISRDNTKNTLYLQMNILRGEDTAVYYCAKNRVRGYSGHHLDYWGQGTPVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPS VFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST
YRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNRFTQKSLSLSPGK* (SEQ ID NO: 169)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT
GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA
ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAACACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 128)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 129)
REGN13075
HCVR DNA Sequence
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCTCCTGCACTGTCTCTCGTGGCTCCATCAGCAGTGGTGGTTACTATTGGAGCTGGAT CCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGATACATCCATTATAGTGAGAG GACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATGTCAGTTGACACGTCTAAGA
ACCAGTTCTCCCTGAAGCTGACCTCTGTGACTGCCGCGGACACGGCCGTGTATTATTG TGCGAGAGATCGGGACACCATGGTTCGGGGAGTCATTACAACTTCCGGCCACTTCATT GACGACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
(SEQ ID NO: 170)
HCVR Amino Acid Sequence
QVQLQESGPGLVKPSQTLSLSCTVSRGSISSGGYYWSWIRQHPGKGLEWIGYIHYSERTYY NPSLKSRVTMSVDTSKNQFSLKLTSVTAADTAVYYCARDRDTMVRGVITTSGHFIDDWGQ GTLVTVSS
(SEQ ID NO: 171)
HCDR1 DNA Sequence CGTGGCTCCATCAGCAGTGGTGGTTACTAT
(SEQ ID NO: 172)
HCDR1 Amino Acid Sequence
RGSISSGGYY
(SEQ ID NO: 173)
HCDR2 DNA Sequence
ATCCATTATAGTGAGAGGACC
(SEQ ID NO: 174)
HCDR2 Amino Acid Sequence
IHYSERT
(SEQ ID NO: 145)
HCDR3 DNA Sequence
GCGAGAGATCGGGACACCATGGTTCGGGGAGTCATTACAACTTCCGGCCACTTCATTG ACGAC
(SEQ ID NO: 175)
HCDR3 Amino Acid Sequence
ARDRDTMVRGVITTSGHFIDD
(SEQ ID NO: 176)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 118)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 119)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT (SEQ ID NO: 120)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 121)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 122)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 123)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 124)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 125)
HC DNA Sequence
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCTCCTGCACTGTCTCTCGTGGCTCCATCAGCAGTGGTGGTTACTATTGGAGCTGGAT CCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGATACATCCATTATAGTGAGAG GACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATGTCAGTTGACACGTCTAAGA ACCAGTTCTCCCTGAAGCTGACCTCTGTGACTGCCGCGGACACGGCCGTGTATTATTG TGCGAGAGATCGGGACACCATGGTTCGGGGAGTCATTACAACTTCCGGCCACTTCATT GACGACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCTACAAAGGGACCTT CTGTGTTTCCTCTGG CTCCTTGTTCTAG ATCTACATCTG AATCTACAG CTG CTCTG G G AT GTCTGGTGAAGGATTATTTTCCTGAACCTGTGACAGTGTCTTGGAATTCTGGAGCTCTG ACATCTGGAGTGCATACATTTCCTGCTGTGCTGCAGTCTTCTGGACTGTATTCTCTGTCT TCTGTGGTGACAGTGCCTTCTTCTTCTCTGGGAACAAAGACATATACATGTAATGTGGA TCATAAG CCTTCTAATACAAAG GTG G ATAAG AG AGTG G AATCTAAGTATG G ACCTCCTT
GTCCTCCTTGTCCTGCTCCTGGCGGTGGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAG CCTAAGGATACACTGATGATCTCTAGAACACCTGAAGTGACATGTGTGGTGGTGGATGT GTCTCAGGAAGATCCTGAAGTGCAGTTTAATTGGTATGTGGATGGAGTGGAAGTGCATA ATGCTAAGACAAAGCCTAGAGAAGAACAGTTTAATTCTACATATAGAGTGGTGTCTGTG CTGACAGTGCTGCATCAGGATTGGCTGAATGGAAAGGAATATAAGTGTAAGGTGTCTAA TAAGGGACTGCCTTCTTCTATCGAAAAGACAATCTCTAAGGCTAAGGGACAGCCTAGAG AACCTCAGGTGTATACACTGCCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCT CTGACATGTCTGGTGAAGGGATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAA TGGACAGCCTGAAAATAATTATAAGACAACACCTCCTGTGCTGGATTCTGATGGATCTTT TTTTCTGTATTCTAGACTGACAGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTC TTGTTCTGTGATGCATGAAGCTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTC TCCTGGAAAGTAG
(SEQ ID NO: 177)
HC Amino Acid Sequence
QVQLQESGPGLVKPSQTLSLSCTVSRGSISSGGYYWSWIRQHPGKGLEWIGYIHYSERTYY NPSLKSRVTMSVDTSKNQFSLKLTSVTAADTAVYYCARDRDTMVRGVITTSGHFIDDWGQ GTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPG GGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE QFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNRFTQKSLSLSPGK*
(SEQ ID NO: 178)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 128)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 129)
REGN13076
HCVR DNA Sequence GAGGTGCACTTATTGGACTCTGGCGGAGGCTTGGTTCAGTCGGGGGAGTCCCTGAGA CTCTCCTGTACAGTCTCTGGAGTCACTTTTGAAAACCTTGTCATGAACTGGGTCCGGCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCGCAAGTGTTGGAGGTCGTTATACTGGCGC GGTCTTCGCAGACTCAGTGAGGGGCCGGTTCACGATCTCCAGAGACCATTCCGAGAAT ACGCTCTTTCTGCACATGAGCAGCCTGAGAGCCGAGGACACGGCCGTTTATTTTTGTAC GAAAGATTCCTCTGTCCTGATTCGGGGAGTCATTAGTACAAACTACTTCTATAGTATGGA CGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
(SEQ ID NO: 179)
HCVR Amino Acid Sequence
EVH LLDSG G G LVQSG ESLRLSCTVSG VTF ENLVM N WVRQ APG KG LEWVASVG G RYTG AV FADSVRGRFTISRDHSENTLFLHMSSLRAEDTAVYFCTKDSSVLIRGVISTNYFYSMDVWG QGTTVTVSS
(SEQ ID NO: 180)
HCDR1 DNA Sequence
GGAGTCACTTTTGAAAACCTTGTC
(SEQ ID NO: 181)
HCDR1 Amino Acid Sequence
GVTFENLV
(SEQ ID NO: 182)
HCDR2 DNA Sequence
GTTGGAGGTCGTTATACTGGCGCG
(SEQ ID NO: 183)
HCDR2 Amino Acid Sequence
VGGRYTGA
(SEQ ID NO: 184)
HCDR3 DNA Sequence
ACGAAAGATTCCTCTGTCCTGATTCGGGGAGTCATTAGTACAAACTACTTCTATAGTATG GACGTC
(SEQ ID NO: 185)
HCDR3 Amino Acid Sequence
TKDSSVLIRGVISTNYFYSMDV
(SEQ ID NO: 186) LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 118)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 119)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 120)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 121)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 122)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 123)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 124)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 125)
HC DNA Sequence GAGGTGCACTTATTGGACTCTGGCGGAGGCTTGGTTCAGTCGGGGGAGTCCCTGAGA CTCTCCTGTACAGTCTCTGGAGTCACTTTTGAAAACCTTGTCATGAACTGGGTCCGGCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCGCAAGTGTTGGAGGTCGTTATACTGGCGC GGTCTTCGCAGACTCAGTGAGGGGCCGGTTCACGATCTCCAGAGACCATTCCGAGAAT ACGCTCTTTCTGCACATGAGCAGCCTGAGAGCCGAGGACACGGCCGTTTATTTTTGTAC GAAAGATTCCTCTGTCCTGATTCGGGGAGTCATTAGTACAAACTACTTCTATAGTATGGA CGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCTACAAAGGGACCTTCT GTGTTTCCTCTGGCTCCTTGTTCTAGATCTACATCTGAATCTACAGCTGCTCTGGGATGT CTGGTGAAGGATTATTTTCCTGAACCTGTGACAGTGTCTTGGAATTCTGGAGCTCTGAC ATCTGGAGTGCATACATTTCCTGCTGTGCTGCAGTCTTCTGGACTGTATTCTCTGTCTTC TGTGGTGACAGTGCCTTCTTCTTCTCTGGGAACAAAGACATATACATGTAATGTGGATC ATAAGCCTTCTAATACAAAGGTGGATAAGAGAGTGGAATCTAAGTATGGACCTCCTTGT CCTCCTTGTCCTGCTCCTGGCGGTGGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAGCC TAAGGATACACTGATGATCTCTAGAACACCTGAAGTGACATGTGTGGTGGTGGATGTGT CTCAGGAAGATCCTGAAGTGCAGTTTAATTGGTATGTGGATGGAGTGGAAGTGCATAAT GCTAAGACAAAGCCTAGAGAAGAACAGTTTAATTCTACATATAGAGTGGTGTCTGTGCT G ACAGTG CTG CATC AG G ATTG G CTG AATG G AAAG G AATATAAGTGTAAG GTGTCTAATA AGGGACTGCCTTCTTCTATCGAAAAGACAATCTCTAAGGCTAAGGGACAGCCTAGAGAA CCTCAGGTGTATACACTGCCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTCT GACATGTCTGGTGAAGGGATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAATG GACAGCCTGAAAATAATTATAAGACAACACCTCCTGTGCTGGATTCTGATGGATCTTTTT TTCTGTATTCTAGACTGACAGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTT GTTCTGTGATGCATGAAGCTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTC CTGGAAAGTAG
(SEQ ID NO: 187)
HC Amino Acid Sequence
EVHLLDSGGGLVQSGESLRLSCTVSGVTFENLVMNWVRQAPGKGLEWVASVGGRYTGAV FADSVRGRFTISRDHSENTLFLHMSSLRAEDTAVYFCTKDSSVLIRGVISTNYFYSMDVWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPG GGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE QFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNRFTQKSLSLSPGK*
(SEQ ID NO: 188)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 128)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 129)
REGN13220
HCVR DNA Sequence
CAGGTGCACCTGCAAGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCTCCTGCACTGTCTCTGGTGATTCCATCAGAAGTGGTGGTTACTACTGGAGTTGGAT CCG CCAG CAG CCAG G AAG G G G CCTG G AATGG ATTGGTTTCATCC ATC AG AGTG ACAG GTCCTACTATAACCCGTCCCTCATGAATCGACTCACCATGTCAGTAGACACGTCTAAGA ATCAATTCTCCCTGAAACTGACCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGT GCGAGAGATCGGGACACCATGGTTCGGGGAAGCATTACAACTTCCGGCCACTTCATTG ACTACTGGGGCCAGGGAACCCTGATCACCGTCTCCTCA
(SEQ ID NO: 189)
HCVR Amino Acid Sequence
QVHLQESGPGLVKPSQTLSLSCTVSGDSIRSGGYYWSWIRQQPGRGLEWIGFIHQSDRSY YNPSLMNRLTMSVDTSKNQFSLKLTSVTAADTAVYYCARDRDTMVRGSITTSGHFIDYWGQ GTLITVSS
(SEQ ID NO: 190)
HCDR1 DNA Sequence
GGTGATTCCATCAGAAGTGGTGGTTACTAC
(SEQ ID NO: 191)
HCDR1 Amino Acid Sequence
GDSIRSGGYY
(SEQ ID NO: 192)
HCDR2 DNA Sequence
ATCCATCAGAGTGACAGGTCC (SEQ ID NO: 193)
HCDR2 Amino Acid Sequence
IHQSDRS
(SEQ ID NO: 194)
HCDR3 DNA Sequence
GCGAGAGATCGGGACACCATGGTTCGGGGAAGCATTACAACTTCCGGCCACTTCATTG ACTAC
(SEQ ID NO: 195)
HCDR3 Amino Acid Sequence
ARDRDTMVRGSITTSGHFIDY
(SEQ ID NO: 196)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG COG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGO AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 118)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 119)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 120)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 121)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 122) LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 123)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 124)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 125)
HC DNA Sequence
CAGGTGCACCTGCAAGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCTCCTGCACTGTCTCTGGTGATTCCATCAGAAGTGGTGGTTACTACTGGAGTTGGAT COG CCAG CAG CCAG G AAG G G G CCTG G AATGG ATTGGTTTC ATCC ATC AG AGTG ACAG GTCCTACTATAACCCGTCCCTCATGAATCGACTCACCATGTCAGTAGACACGTCTAAGA ATCAATTCTCCCTGAAACTGACCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGT GCGAGAGATCGGGACACCATGGTTCGGGGAAGCATTACAACTTCCGGCCACTTCATTG ACTACTGGGGCCAGGGAACCCTGATCACCGTCTCCTCAGCCTCTACAAAGGGACCTTC TGTGTTTCCTCTG G CTCCTTGTTCTAG ATCTACATCTG AATCTAC AG CTGCTCTG G G ATG TCTGGTGAAGGATTATTTTCCTGAACCTGTGACAGTGTCTTGGAATTCTGGAGCTCTGA CATCTGGAGTGCATACATTTCCTGCTGTGCTGCAGTCTTCTGGACTGTATTCTCTGTCTT CTGTGGTGACAGTGCCTTCTTCTTCTCTGGGAACAAAGACATATACATGTAATGTGGAT CATAAGCCTTCTAATACAAAGGTGGATAAGAGAGTGGAATCTAAGTATGGACCTCCTTG TCCTCCTTGTCCTGCTCCTGGCGGTGGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAGC CTAAGGATACACTGATGATCTCTAGAACACCTGAAGTGACATGTGTGGTGGTGGATGTG TCTCAGGAAGATCCTGAAGTGCAGTTTAATTGGTATGTGGATGGAGTGGAAGTGCATAA TGCTAAGACAAAGCCTAGAGAAGAACAGTTTAATTCTACATATAGAGTGGTGTCTGTGC TGACAGTGCTGCATCAGGATTGGCTGAATGGAAAGGAATATAAGTGTAAGGTGTCTAAT AAGGGACTGCCTTCTTCTATCGAAAAGACAATCTCTAAGGCTAAGGGACAGCCTAGAGA ACCTCAGGTGTATACACTGCCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTC TGACATGTCTGGTGAAGGGATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAAT GGACAGCCTGAAAATAATTATAAGACAACACCTCCTGTGCTGGATTCTGATGGATCTTTT TTTCTGTATTCTAGACTGACAGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCT TGTTCTGTGATGCATGAAGCTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCT CCTGGAAAGTAG
(SEQ ID NO: 197)
HC Amino Acid Sequence
QVHLQESGPGLVKPSQTLSLSCTVSGDSIRSGGYYWSWIRQQPGRGLEWIGFIHQSDRSY YNPSLMNRLTMSVDTSKNQFSLKLTSVTAADTAVYYCARDRDTMVRGSITTSGHFIDYWGQ GTLITVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGG GGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNRFTQKSLSLSPGK*
(SEQ ID NO: 198)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 128)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 129)
REGN13221
HCVR DNA Sequence
CAGGTGCAGCTGCAGGAGTCGGGCCCAGTACTGGTGAAGCCTTCGGAGACCCTGTCC CTCACCTGCACTGTCTCTGGTGACTCCATCAGTAATTACTACTGGAGCTGGATCCGGCA GTCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCTATTACAGTGGCGGCACCAAC TACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAATAGACACGTCCAAGCGCCACTT CTCCCTGAAGCTGAACTCTGTGATCGCAGCGGACACGGCCGTATATTACTGTGCGAGA GCCCCTGTCACCATGGTTCGGGGAGTCATTACTTACAACTACCACTACGCTATGGACGT CTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
(SEQ ID NO: 199)
HCVR Amino Acid Sequence
QVQLQESGPVLVKPSETLSLTCTVSGDSISNYYWSWIRQSPGKGLEWIGYIYYSGGTNYNP SLKSRVTISIDTSKRHFSLKLNSVIAADTAVYYCARAPVTMVRGVITYNYHYAMDVWGQGTT VTVSS (SEQ ID NO: 200)
HCDR1 DNA Sequence
GGTGACTCCATCAGTAATTACTAC
(SEQ ID NO: 201)
HCDR1 Amino Acid Sequence
GDSISNYY
(SEQ ID NO: 202)
HCDR2 DNA Sequence
ATCTATTACAGTGGCGGCACC
(SEQ ID NO: 203)
HCDR2 Amino Acid Sequence
IYYSGGT
(SEQ ID NO: 204)
HCDR3 DNA Sequence
GCGAGAGCCCCTGTCACCATGGTTCGGGGAGTCATTACTTACAACTACCACTACGCTAT GGACGTC
(SEQ ID NO: 205)
HCDR3 Amino Acid Sequence
ARAPVTMVRGVITYNYHYAMDV
(SEQ ID NO: 206)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG COG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGO AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 118)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 119)
LCDR1 DNA Sequence
C AG AG CATTAG C AG CTAT
(SEQ ID NO: 120)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 121)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 122)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 123)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 124)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 125)
HC DNA Sequence
CAGGTGCAGCTGCAGGAGTCGGGCCCAGTACTGGTGAAGCCTTCGGAGACCCTGTCC CTCACCTGCACTGTCTCTGGTGACTCCATCAGTAATTACTACTGGAGCTGGATCCGGCA GTCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCTATTACAGTGGCGGCACCAAC TACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAATAGACACGTCCAAGCGCCACTT CTCCCTGAAGCTGAACTCTGTGATCGCAGCGGACACGGCCGTATATTACTGTGCGAGA GCCCCTGTCACCATGGTTCGGGGAGTCATTACTTACAACTACCACTACGCTATGGACGT CTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCTACAAAGGGACCTTCTGTG TTTCCTCTG G CTCCTTGTTCTAG ATCTACATCTG AATCTAC AG CTG CTCTG G G ATGTCTG GTGAAGGATTATTTTCCTGAACCTGTGACAGTGTCTTGGAATTCTGGAGCTCTGACATC TG G AGTG C ATACATTTCCTG CTGTG CTG C AGTCTTCTG G ACTG TATTCTCTGTCTTCTGT G GTG ACAGTG CCTTCTTCTTCTCTG G G AACAAAG AC ATATACATGTAATGTG G ATCATA AGCCTTCTAATACAAAGGTGGATAAGAGAGTGGAATCTAAGTATGGACCTCCTTGTCCT CCTTGTCCTGCTCCTGGCGGTGGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAGCCTAA
GGATACACTGATGATCTCTAGAACACCTGAAGTGACATGTGTGGTGGTGGATGTGTCTC AGGAAGATCCTGAAGTGCAGTTTAATTGGTATGTGGATGGAGTGGAAGTGCATAATGCT AAGACAAAGCCTAGAGAAGAACAGTTTAATTCTACATATAGAGTGGTGTCTGTGCTGAC AGTGCTGCATCAGGATTGGCTGAATGGAAAGGAATATAAGTGTAAGGTGTCTAATAAGG G ACTG CCTTCTTCTATCG AAAAG ACAATCTCTAAG G CTAAGG G AC AG CCTAG AG AACCT CAGGTGTATACACTGCCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTCTGAC ATGTCTGGTGAAGGGATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAATGGAC AGCCTGAAAATAATTATAAGACAACACCTCCTGTGCTGGATTCTGATGGATCTTTTTTTC TGTATTCTAGACTGACAGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTTGT TCTGTGATGCATGAAGCTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTCCT GGAAAGTAG
(SEQ ID NO: 207)
HC Amino Acid Sequence
QVQLQESGPVLVKPSETLSLTCTVSGDSISNYYWSWIRQSPGKGLEWIGYIYYSGGTNYNP SLKSRVTISIDTSKRHFSLKLNSVIAADTAVYYCARAPVTMVRGVITYNYHYAMDVWGQGTT VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGG PSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNRFTQKSLSLSPGK*
(SEQ ID NO: 208)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG CATTAG C AG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC AC AAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 128)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 129) REGN13284
HCVR DNA Sequence
GAGGTGCAACTGGTGGAATCTGGAGGAGGCTTGGTCCAGCCTGGGGGTTCCCTGAGA
CTCTCCTGTGCAGCCTCTGGGTTCATCGTCAGTAACAACTATATGAGATGGGTCCGCCA
GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCGGTCATTTATAGTGGTGGTGGCACATA
CTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGACACAATTCCAAGAACACG
ATATATCTTCAAATGAACAGCCTGCGAATTGAGGACACGGCCGTGTATTATTGTGCGAG AGAAGATAGCCACTCGTCGGAAAGTTATGACTACTTCTACGGCATGGACGTCTGGGGC CAAGGGACCACGGTCACCGTCTCCCCA
(SEQ ID NO: 209)
HCVR Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCAASG F I SN N YM RWVRQ APG KG LE WVSVI YSGGGTYY ADSVKGRFTISRHNSKNTIYLQMNSLRIEDTAVYYCAREDSHSSESYDYFYGMDVWGQGTT VTVSP
(SEQ ID NO: 210)
HCDR1 DNA Sequence
GGGTTCATCGTCAGTAACAACTAT
(SEQ ID NO: 21 1)
HCDR1 Amino Acid Sequence
GFIVSNNY
(SEQ ID NO: 212)
HCDR2 DNA Sequence
ATTTATAGTGGTGGTGGCACA
(SEQ ID NO: 213)
HCDR2 Amino Acid Sequence
IYSGGGT
(SEQ ID NO: 214)
HCDR3 DNA Sequence
GCGAGAGAAGATAGCCACTCGTCGGAAAGTTATGACTACTTCTACGGCATGGACGTC
(SEQ ID NO: 215)
HCDR3 Amino Acid Sequence
AREDSHSSESYDYFYGMDV (SEQ ID NO: 216)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 118)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 119)
LCDR1 DNA Sequence
CAG AG CATTAG CAG CTAT
(SEQ ID NO: 120)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 121)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 122)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 123)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 124)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 125) HC DNA Sequence
GAGGTGCAACTGGTGGAATCTGGAGGAGGCTTGGTCCAGCCTGGGGGTTCCCTGAGA CTCTCCTGTGCAGCCTCTGGGTTCATCGTCAGTAACAACTATATGAGATGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCGGTCATTTATAGTGGTGGTGGCACATA CTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGACACAATTCCAAGAACACG ATATATCTTCAAATGAACAGCCTGCGAATTGAGGACACGGCCGTGTATTATTGTGCGAG AGAAGATAGCCACTCGTCGGAAAGTTATGACTACTTCTACGGCATGGACGTCTGGGGC CAAGGGACCACGGTCACCGTCTCCCCAGCCTCTACAAAGGGACCTTCTGTGTTTCCTC TG G CTCCTTGTTCTAG ATCTACATCTG AATCTACAGCTG CTCTGG G ATGTCTG GTG AAG GATTATTTTCCTGAACCTGTGACAGTGTCTTGGAATTCTGGAGCTCTGACATCTGGAGT GCATACATTTCCTGCTGTGCTGCAGTCTTCTGGACTGTATTCTCTGTCTTCTGTGGTGA CAGTGCCTTCTTCTTCTCTGGGAACAAAGACATATACATGTAATGTGGATCATAAGCCTT CTAATACAAAGGTGGATAAGAGAGTGGAATCTAAGTATGGACCTCCTTGTCCTCCTTGT CCTGCTCCTGGCGGTGGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAGCCTAAGGATAC ACTGATGATCTCTAGAACACCTGAAGTGACATGTGTGGTGGTGGATGTGTCTCAGGAA GATCCTGAAGTGCAGTTTAATTGGTATGTGGATGGAGTGGAAGTGCATAATGCTAAGAC AAAGCCTAGAGAAGAACAGTTTAATTCTACATATAGAGTGGTGTCTGTGCTGACAGTGC TGCATCAGGATTGGCTGAATGGAAAGGAATATAAGTGTAAGGTGTCTAATAAGGGACTG CCTTCTTCTATCGAAAAGACAATCTCTAAGGCTAAGGGACAGCCTAGAGAACCTCAGGT GTATACACTGCCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTCTGACATGTC TGGTGAAGGGATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAATGGACAGCCT
GAAAATAATTATAAGACAACACCTCCTGTGCTGGATTCTGATGGATCTTTTTTTCTGTATT CTAGACTGACAGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTTGTTCTGTG ATGCATGAAGCTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTCCTGGAAA GTAG
(SEQ ID NO: 217)
HC Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCAASG F I VSN N YM RWVRQ APG KG LE WVSVI YSGGGTYY ADSVKGRFTISRHNSKNTIYLQMNSLRIEDTAVYYCAREDSHSSESYDYFYGMDVWGQGTT VTVSPASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGG PSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNRFTQKSLSLSPGK*
(SEQ ID NO: 218)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 128)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 129)
[00291] Provided herein are anti-AAV antibodies, or antigen-binding fragments thereof, comprising an HCVR comprising an amino acid sequence selected from any of the HCVR amino acid sequences listed in Table 1 , or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.
[00292] Also provided herein are anti-AAV antibodies, or antigen-binding fragments thereof, comprising an LCVR comprising an amino acid sequence selected from any of the LCVR amino acid sequences listed in Table 1 , or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.
[00293] Provided herein are anti-AAV antibodies, or antigen-binding fragments thereof, comprising an HCVR and an LCVR amino acid sequence pair (HCVR/LCVR) comprising any of the HCVR amino acid sequences listed in Table 1 paired with any of the LCVR amino acid sequences listed in Table 1. According to certain embodiments, the present disclosure provides antibodies, or antigen-binding fragments thereof, comprising an HCVR/LCVR amino acid sequence pair contained within any of the exemplary anti-AAV antibodies listed in Table 1. In certain embodiments, the HCVR/LCVR amino acid sequence pair is selected from SEQ ID NOs: 2/10 (e.g., REGN13876); 22/10 (e.g., REGN13877); 32/10 (e.g., REGN13878); 42/10 (e.g., REGN13879); 52 or 1 159/10 or 1 157 (e.g., REGN13880); 62/10 (e.g., REGN13881); 71/10 (e.g., REGN13882); 81/10 (e.g., REGN13883); 91/10 (e.g., REGN13884); 101/10 (e.g., REGN13885); 1 11/119 (e.g., REGN13070); 131/119 (e.g., REGN13071); 141/119 (e.g., REGN13072); 151/1 19 (e.g., REGN13073); 161/1 19 (e.g., REGN13074); 171/119 (e.g., REGN13075); 180/1 19 (e.g., REGN13076); 190/1 19 (e.g., REGN13220); 200/119 (e.g., REGN13221); and, 210/119 (e.g., REGN13284).
[00294] Provided herein are anti-AAV antibodies, or antigen-binding fragments thereof, comprising a heavy chain CDR1 (HCDR1) comprising an amino acid sequence selected from any of the HCDR1 amino acid sequences listed in Table 1 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00295] Provided herein are anti-AAV antibodies, or antigen-binding fragments thereof, comprising a heavy chain CDR2 (HCDR2) comprising an amino acid sequence selected from any of the HCDR2 amino acid sequences listed in Table 1 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00296] Provided herein are anti-AAV antibodies, or antigen-binding fragments thereof, comprising a heavy chain CDR3 (HCDR3) comprising an amino acid sequence selected from any of the HCDR3 amino acid sequences listed in Table 1 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00297] Provided herein are anti-AAV antibodies, or antigen-binding fragments thereof, comprising a light chain CDR1 (LCDR1) comprising an amino acid sequence selected from any of the LCDR1 amino acid sequences listed in Table 1 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00298] Provided herein are anti- AAV antibodies, or antigen-binding fragments thereof, comprising a light chain CDR2 (LCDR2) comprising an amino acid sequence selected from any of the LCDR2 amino acid sequences listed in Table 1 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00299] Provided herein are anti-AAV antibodies, or antigen-binding fragments thereof, comprising a light chain CDR3 (LCDR3) comprising an amino acid sequence selected from any of the LCDR3 amino acid sequences listed in Table 1 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00300] Provided herein are antibodies, or antigen-binding fragments thereof, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within any of the exemplary anti-AAV antibodies listed in Table 1. In certain embodiments, the HCDR1- HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequences set is selected from SEQ ID NOs: 4-6-8-12-14-16 (e.g., REGN13876); 24-26-28-12-14-16 (e.g.-REGN13877); 34-36-38- 12-14-16 (e.g., REGN13878); 44-46-48-12-14-16 (e.g., REGN13879; 54-56-58-12-14-16 (e.g., REGN13880); 64-56-67-12-14-16 (e.g., REGN13881); 73-75-77-12-14-16 (e.g., REGN13882); 83-85-87-12-14-16 (e.g., REGN13883); 93-95-97-12-14-16 (e.g.- REGN13884); 103-105-107-12-14-16 (e.g., REGN13885); 113-115-117-121-123-125 (e.g.- REGN13070); 133-135-137-121-123-125 (e.g., REGN13071); 143-145-147-121-123-125 (e.g.-REGN13072); 153-155-157-121-123-125 (e.g., REGN13073); 163-165-167-121-123- 125 (e.g.-REGN13074); 173-145-176-121-123-125 (e.g., REGN13075); 182-184-186-121- 123-125 (e.g.-REGN13076); 192-194-196-121-123-125 (e.g., REGN13220); 202-204-206- 121-123-125 (e.g.-REGN13221); and-212-214-216-121-123-125 (e.g.-REGN13284). [00301] In a related embodiment, provided herein are antibodies, or antigen-binding fragments thereof, comprising a set of six CDRs (i.e. , HCDR1-HCDR2-HCDR3-LCDR1- LCDR2-LCDR3) contained within an HCVR/LCVR amino acid sequence pair as defined by any of the exemplary anti-AAV antibodies listed in Table 1. For example, provided herein are antibodies, or antigen-binding fragments thereof, comprising the HCDR1-HCDR2-HCDR3- LCDR1-LCDR2-LCDR3 amino acid sequences set contained within an HCVR/LCVR amino acid sequence pair selected from SEQ ID NOs: 2/10 (e.g., REGN13876); 22/10 (e.g., REGN13877); 32/10 (e.g., REGN13878); 42/10 (e.g., REGN13879); 52 or 1159/10 or 1157 (e.g., REGN13880); 62/10 (e.g., REGN13881); 71/10 (e.g., REGN13882); 81/10 (e.g., REGN13883); 91/10 (e.g., REGN13884); 101/10 (e.g., REGN13885); 111/119 (e.g., REGN13070); 131/119 (e.g., REGN13071); 141/119 (e.g., REGN13072); 151/119 (e.g., REGN13073); 161/119 (e.g., REGN13074); 171/119 (e.g., REGN13075); 180/119 (e.g., REGN13076); 190/119 (e.g., REGN13220); 200/119 (e.g., REGN13221); and, 210/119 (e.g., REGN 13284).
[00302] In an embodiment provided herein, the anti-AAV antibody or antigen-binding fragment thereof can include: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; k) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 111 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 119; l) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 131 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 119; m) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 141 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 119; n) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 151 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 119; o) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 161 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 119; p) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 171 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 119; q) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 180, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 119; r) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 190, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 119; s) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 200, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 119; and/or t) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 210, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 119. [00303] In an embodiment provided herein, the anti-AAV antibody or antigen-binding fragment thereof can include: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; k) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 113, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 115, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 117; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 121 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 125; l) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 133, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 135, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 137; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 121 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 125; m) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 143, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 145, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 147; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 121 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 125; n) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 153, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 155, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 157; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 121 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 125; o) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 163, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 165, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 167; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 121 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 125; p) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 173, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 145, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 176; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 121 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 125; q) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 182, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 184, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 186; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 121 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 125; r) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 192, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 194, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 196; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 121 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 125; s) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 202, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 204, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 206; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 121 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 125; and/or t) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 212, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 214, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 216; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 121 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 123, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 125.
[00304] In an embodiment provided herein, the anti-AAV antibody or antigen-binding fragment thereof can include: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; k) a HCVR comprising the amino acid sequence of SEQ ID NO: 111 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 119; l) a HCVR comprising the amino acid sequence of SEQ ID NO: 131 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 119; m) a HCVR comprising the amino acid sequence of SEQ ID NO: 141, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 119; n) a HCVR comprising the amino acid sequence of SEQ ID NO: 151 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 119; o) a HCVR comprising the amino acid sequence of SEQ ID NO: 161 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 119; p) a HCVR comprising the amino acid sequence of SEQ ID NO: 171 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 119; q) a HCVR comprising the amino acid sequence of SEQ ID NO: 180, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 119; r) a HCVR comprising the amino acid sequence of SEQ ID NO: 190, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 119; s) a HCVR comprising the amino acid sequence of SEQ ID NO: 200, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 119; and/or t) a HCVR comprising the amino acid sequence of SEQ ID NO: 210, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 119.
[00305] In an embodiment provided herein, the anti-AAV antigen-binding fragment is an Fab. In some embodiments, an anti-AAV Fab of the present disclosure includes: a) an HC that comprises the amino acid sequence of SEQ ID NO: 18, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; b) an HC that comprises the amino acid sequence of SEQ ID NO: 30, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; c) an HC that comprises the amino acid sequence of SEQ ID NO: 40, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; d) an HC that comprises the amino acid sequence of SEQ ID NO: 50, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; e) an HC that comprises the amino acid sequence of SEQ ID NO: 60 or 1108, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; f) an HC that comprises the amino acid sequence of SEQ ID NO: 69, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; g) an HC that comprises the amino acid sequence of SEQ ID NO: 79, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; h) an HC that comprises the amino acid sequence of SEQ ID NO: 89, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; i) an HC that comprises the amino acid sequence of SEQ ID NO: 99, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; or j) an HC that comprises the amino acid sequence of SEQ ID NO: 109, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00306] In an embodiment provided herein, the anti-AAV antibody comprises a constant region derived from lgG4 subclass. In some embodiments, an anti-AAV Fab of the present disclosure includes: k) an HC that comprises the amino acid sequence of SEQ ID NO: 127, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; l) an HC that comprises the amino acid sequence of SEQ ID NO: 139, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; m) an HC that comprises the amino acid sequence of SEQ ID NO: 149, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; n) an HC that comprises the amino acid sequence of SEQ ID NO: 159, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; o) an HC that comprises the amino acid sequence of SEQ ID NO: 169, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; p) an HC that comprises the amino acid sequence of SEQ ID NO: 178, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; q) an HC that comprises the amino acid sequence of SEQ ID NO: 188, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; r) an HC that comprises the amino acid sequence of SEQ ID NO: 198, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; s) an HC that comprises the amino acid sequence of SEQ ID NO: 208, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; and/or t) an HC that comprises the amino acid sequence of SEQ ID NO: 218, or a variant thereof; and/or an LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof.
[00307] The anti-AAV antibodies or antigen-binding fragments thereof described herein may bind to a capsid of an AAV particle with a KD value of about 5x10-6 M or less, such as about 10'7 M or less, about 10'8 M or less, such as about 10-9 M or less when determined by, for instance, surface plasmon resonance (SPR) technology in a BIAcore instrument using the antigen as the ligand and the antibody, Ig, antibody-binding fragment, or Fc-containing protein as the analyte (or antiligand). Cell-based binding strategies, such as fluorescent- activated cell sorting (FACS) binding assays, are also routinely used, and FACS data correlates well with other methods such as radioligand competition binding and SPR (Benedict, CA, J Immunol Methods. 1997, 201 (2):223-31 ; Geuijen, CA, et al. J Immunol Methods. 2005, 302(1 -2):68-77). In some embodiments, an anti-AAV antibody or antigenbinding fragment thereof described herein may bind to a capsid of an AAV particle with a KD value of about 5x106 M to 1x10'® M (e.g., 1x1 O'6 M, 1.5x106 M, 2x1 O’6 M, 3x10 ® M, 4x1 O'6 M, 5x1 O'6 M), about 1x10 s M to 1x107 M (e.g., 1x107 M, 2x107 M, 3x10 7 M, 4x1 O'7 M, 5x10 7 M, 6x10-7 M, 7x1 CL7 M, 8x107 M, 9x1 O’7 M), about 1x107 M to 1x108 M (e.g., 1x108 M, 2x10’ 8 M, 3x108 M, 4x108 M, 5x1 O’8 M, 6x108 M, 7x108 M, 8x108 M, 9x108 M), about 1x108 M to 1x109 M (e.g., 1x109 M, 2x109 M, 3x109 M, 4x109 M, 5x109 M, 6x109 M, 7x109 M, 8x10 9 M, 9x10‘9 M), or about 1x10‘9 M to 1x10 10 M (e.g., 1x1 O'10 M, 2xW1° M, 3x10‘1° M, 4x10'1° M, 5x10 1° M, 6x10'1° M, 7x10‘1° M, 8x10 10 M, 9x10'1° M).
[00308] The antibody or antigen-binding protein of the disclosure may bind to the predetermined antigen or cell surface molecule (receptor) having an affinity corresponding to a KD value that is at least ten-fold lower than its affinity for binding to a non-specific antigen (e.g., BSA). According to the present disclosure, the affinity of an antibody corresponding to a KD value that is equal to or less than ten-fold lower than a non-specific antigen may be considered non-detectable binding, however such an antibody may be paired with a second antigen-binding domain for the production of a multispecific antibody of the disclosure. [00309] The term "KD" (M) can refer to the dissociation equilibrium constant of a particular antibody-antigen interaction, or the dissociation equilibrium constant of an antibody or antibody-binding fragment binding to an antigen. There is an inverse relationship between KD and binding affinity, therefore the smaller the KD value, the higher, i.e. stronger, the affinity. Thus, the terms "higher affinity” or “stronger affinity” relate to a higher ability to form an interaction and therefore a smaller KD value, and conversely the terms "lower affinity” or “weaker affinity” relate to a lower ability to form an interaction and therefore a larger KD value. In some circumstances, a higher binding affinity (or KD) of a particular molecule (e.g. antibody) to its interactive partner molecule (e.g. antigen X) compared to the binding affinity of the molecule (e.g. antibody) to another interactive partner molecule (e.g. antigen Y) may be expressed as a binding ratio determined by dividing the larger KD value (lower, or weaker, affinity) by the smaller KD (higher, or stronger, affinity), for example expressed as 5-fold or 10-fold greater binding affinity, as the case may be.
[00310] The term "kd" (sec -1 or 1/s) refers to the dissociation rate constant of a particular antibody-antigen interaction, or the dissociation rate constant of an antibody or antibodybinding fragment. Said value is also referred to as the kOfr value.
[00311] The term "ka" (M-1 x sec-1 or 1/M/s) can refer to the association rate constant of a particular antibody-antigen interaction, or the association rate constant of an antibody or antibody-binding fragment.
[00312] The term "KA" (M-1 or 1/M) can refer to the association equilibrium constant of a particular antibody-antigen interaction, or the association equilibrium constant of an antibody or antibody-binding fragment. The association equilibrium constant is obtained by dividing the ka by the kd.
[00313] The term “EC50” or “EC50” can refer to the half maximal effective concentration, which includes the concentration of an antibody which induces a response halfway between the baseline and maximum after a specified exposure time. The EC50 essentially represents the concentration of an antibody where 50% of its maximal effect is observed. In certain embodiments, the EC50 value equals the concentration of an antibody of the disclosure that gives half-maximal binding to a capsid protein of an AAV particle (e.g., a wild-type or a non- wild-type AAV capsid protein(s) or to cells expressing a molecule on a cell surface described herein, as determined by e.g., a FACS binding assay. Thus, reduced or weaker binding is observed with an increased EC50, or half maximal effective concentration value.
[00314] Also provided herein are nucleic acid molecules encoding anti-AAV antibodies or antigen-binding fragments thereof. [00315] Provided herein are nucleic acid molecules encoding any of the HCVR amino acid sequences listed in Table 1 ; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the HCVR nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.
[00316] Provided herein are nucleic acid molecules encoding any of the HCDR1 amino acid sequences listed in Table 1 ; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the HCDR1 nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.
[00317] Provided herein are nucleic acid molecules encoding any of the HCDR2 amino acid sequences listed in Table 1 ; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the HCDR2 nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.
[00318] Provided herein are nucleic acid molecules encoding any of the HCDR3 amino acid sequences listed in Table 1 ; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the HCDR3 nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.
[00319] Provided herein are nucleic acid molecules encoding any of the LCVR amino acid sequences listed in Table 1 ; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the LCVR nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.
[00320] Provided herein are nucleic acid molecules encoding any of the LCDR1 amino acid sequences listed in Table 1 ; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the LCDR1 nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.
[00321] Provided herein are nucleic acid molecules encoding any of the LCDR2 amino acid sequences listed in Table 1 ; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the LCDR2 nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.
[00322] Provided herein are nucleic acid molecules encoding any of the LCDR3 amino acid sequences listed in Table 1 ; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the LCDR3 nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.
[00323] Provided herein are nucleic acid molecules encoding an HCVR, wherein the HCVR comprises a set of three CDRs (i.e., HCDR1-HCDR2-HCDR3), wherein the HCDR1-HCDR2- HCDR3 amino acid sequence set is as defined by any of the exemplary anti-AAV antibodies listed in Table 1.
[00324] Provided herein are nucleic acid molecules encoding an LCVR, wherein the LCVR comprises a set of three CDRs (i.e., LCDR1-LCDR2-LCDR3), wherein the LCDR1-LCDR2- LCDR3 amino acid sequence set is as defined by any of the exemplary anti-AAV antibodies listed in Table 1.
[00325] Provided herein are nucleic acid molecules encoding both an HCVR and an LCVR, wherein the HCVR comprises an amino acid sequence of any of the HCVR amino acid sequences listed in Table 1 , and wherein the LCVR comprises an amino acid sequence of any of the LCVR amino acid sequences listed in Table 1. In certain embodiments, the nucleic acid molecule comprises a polynucleotide sequence selected from any of the HCVR nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto, and a polynucleotide sequence selected from any of the LCVR nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto. In certain embodiments according to this aspect of the disclosure, the nucleic acid molecule encodes an HCVR and LCVR, wherein the HCVR and LCVR are both derived from the same anti-AAV antibody listed in Table 1.
[00326] Also provided herein are nucleic acid molecules encoding any of the HC amino acid sequences listed in Table 1 ; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the HC nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto. As another example, the present disclosure provides nucleic acid molecules encoding any of the LC amino acid sequences listed in Table 1 ; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the LC nucleic acid sequences listed in Table 2, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.
[00327] Provided herein are recombinant expression vectors capable of expressing one or more polypeptides of an anti-AAV antibody or antigen-binding fragment thereof. For example, provided herein are recombinant expression vectors comprising any of the nucleic acid molecules mentioned above, i.e. , nucleic acid molecules encoding any of the HCVR, LCVR, and/or CDR sequences as set forth in Table 1. Also included within the scope of the present disclosure are host cells into which such vectors have been introduced, as well as methods of producing the antibodies or portions thereof by culturing the host cells under conditions permitting production of the antibodies or antibody fragments and recovering the antibodies and antibody fragments so produced. The term "host cell” as used herein can refer to cells into which a nucleic acid of the disclosure has been introduced. The terms “host cell” and “recombinant host cell” are used interchangeably herein. It is understood that such terms can refer to the particular subject cell and to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. Typical host cells are eukaryotic host cells, such as mammalian host cells. Exemplary eukaryotic host cells include yeast and mammalian cells, for example vertebrate cells such as a mouse, rat, monkey or human cell line, for example HKB11 cells, PER.C6 cells, HEK cells or CHO cells.
Multispecific Antigen-binding Molecules
[00328] The antigen-binding molecules (e.g., antibodies) of the present disclosure may be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding molecules (also referred to as “multispecific binding molecules” or “MBMs” herein) may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for more than one target polypeptide. See, e.g., Tutt et al., 1991 , J. Immunol. 147:60-69; Kufer et al., 2004, Trends Biotechnol. 22:238-244. The multispecific antigen-binding molecules of the disclosure may comprise at least one antigen-binding domain that binds to a capsid of an AAV particle, and at least one antigen-binding domain that binds to a different target molecule.
[00329] The MBMs of the disclosure specifically bind to at least two different epitopes (and in some instances three or more different epitopes). The at least two different epitopes can be on the same target molecule or different target molecules. Generally, the MBMs of the disclosure specifically bind to two or more different target molecules. In some embodiments, the MBMs described herein may bind to one or more epitopes of a capsid of an AAV particle. In some, the MBMs described herein may bind to one or more epitopes of a molecule on a cell surface.
[00330] The anti-AAV monospecific antibodies or anti-AAV x anti-cell surface molecule multispecific antibodies of the present disclosure can be linked to or co-expressed with another functional molecule, e.g., another peptide or protein. For example, an antibody or fragment thereof can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment to produce a multispecific antibody with a second or additional binding specificity.
[00331] Use of the expression "anti-AAV antibody" or ‘‘anti-cell surface molecule antibody” herein is intended to include both monospecific anti-AAV antibodies or anti-cell surface antibodies as well as multispecific antibodies (e.g., bispecific antibodies) which may comprise a first-binding domain that binds to a capsid of an AAV and a second binding domain that binds to a molecule on a cell surface. Thus, the present disclosure includes bispecific antibodies wherein one domain of an immunoglobulin binds to a capsid of an AAV particle (e.g., a capsid comprising a wild-type and/or non-wild-type AAV capsid protein(s)), and the other domain of the immunoglobulin binds to a molecule of a cell surface. The AAV- binding domain can comprise any of the CDR, HCVR/LCVR or HC/LC amino acid sequences as set forth in Table 1 herein. The cell surface molecule-binding domain can comprise any of various CDR, HCVR/LCVR or HC/LC amino acid sequences that bind any of various cell-surface molecules disclosed herein, or otherwise within the knowledge of one skilled in the art. As a non-limiting example, the cell surface molecule-binding domain can comprise any of CDR, HCVR/LCVR or HC/LC amino acid sequences which bind to Asialoglycoprotein Receptor 1 (ASGR1) as set forth in Table 5 herein. Nucleic acid molecules encoding any of the CDR, HCVR/LCVR or HC/LC amino acid sequences of the anti-AAV/anti-cell surface molecule multispecific antigen-binding molecules disclosed herein may include, for example, nucleic acid molecules comprising the polynucleotide sequences as set forth in Table 2 herein, as well as, e.g., nucleic acid molecules comprising the polynucleotide sequences as set forth in Table 6 herein.
[00332] In some embodiments, MBMs of the present disclosure may two or more (e.g., three, four) antigen-binding domains. In some embodiments, the two or more (e.g., three, four) antigen-binding domains may independently be in a Fab or an scFv format.
[00333] Single chain Fv or “scFv” antibody fragments comprise the VH and . domains of an antibody in a single polypeptide chain, are capable of being expressed as a single chain polypeptide and retain the specificity of the intact antibodies from which they are derived. Generally, an scFv polypeptide may further comprise a polypeptide linker between the VH and VL domain that enables the scFv to form the desired structure for target binding. Examples of linkers suitable for connecting the VH and V chains of an scFV are the linkers are described herein.
[00334] Unless specified, as used herein an scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VH or may comprise VH-linker-VL.
[00335] The scFv can comprise VL and VH sequences from any suitable species, such as murine, human or humanized V and VL sequences.
[00336] To create an scFv-encoding nucleic acid, the VL and Vn-encoding DNA fragments are operably linked to another fragment encoding a linker, e.g., encoding any of the linkers described herein, such that the VL and VH sequences can be expressed as a contiguous single-chain protein, with the VL and VH regions joined by the flexible linker (see, e.g., Bird et al., 1988, Science 242:423- 426; Huston et ai, 1988, Proc. Natl. Acad. Sci. USA 85:5879- 5883; McCafferty et ai, 1990, Nature 348:552-554).
[00337] The MBMs of the disclosure may comprise at least one Fab domain. Fab domains were traditionally produced from by proteolytic cleavage of immunoglobulin molecules using enzymes such as papain. In the MBMs of the disclosure, the Fab domains are recombinantly expressed as part of a larger molecule.
[00338] The Fab domains can comprise constant domain and variable region sequences from any suitable species, and thus can be murine, chimeric, human or humanized.
[00339] Fab domains typically comprise a CH1 domain attached to a VH domain which pairs with a CL domain attached to a VL domain. In a wild-type immunoglobulin, the VH domain is paired with the VL domain to constitute the Fv region, and the CH1 domain is paired with the CL domain to further stabilize the binding module. A disulfide bond between the two constant domains can further stabilize the Fab domain.
[00340] For the MBMs of the disclosure, particularly when the light chain is not a common or universal light chain, it is advantageous to use Fab heterodimerization strategies to permit the correct association of Fab domains belonging to the same ABD and minimize aberrant pairing of Fab domains belonging to different ABDs. For example, the Fab heterodimerization strategies shown in Table 3 below can be used:
Table 3. Fab Heterodimerization Strategies
[00341] Accordingly, in certain embodiments, correct association between the two polypeptides of a Fab is promoted by exchanging the VL and VH domains of the Fab for each other or exchanging the CH1 and CL domains for each other, e.g., as described in WO 2009/080251.
[00342] Correct Fab pairing can also be promoted by introducing one or more amino acid modifications in the CH1 domain and one or more amino acid modifications in the CL domain of the Fab and/or one or more amino acid modifications in the VH domain and one or more amino acid modifications in the VL domain. The amino acids that are modified are typically part of the VH:VL and CH1 :CL interface such that the Fab components preferentially pair with each other rather than with components of other Fabs.
[00343] In one embodiment, the one or more amino acid modifications are limited to the conserved framework residues of the variable (VH, VL) and constant (CH1 , CL) domains as indicated by the Kabat numbering of residues. Almagro, 2008, Frontiers In Bioscience 13:1619-1633 provides a definition of the framework residues on the basis of Kabat, Chothia, and IMGT numbering schemes.
[00344] In one embodiment, the modifications introduced in the VH and CH1 and/or VL and CL domains are complementary to each other. Complementarity at the heavy and light chain interface can be achieved on the basis of steric and hydrophobic contacts, electrostatic/charge interactions or a combination of the variety of interactions. The complementarity between protein surfaces is broadly described in the literature in terms of lock and key fit, knob into hole, protrusion and cavity, donor and acceptor etc., all implying the nature of structural and chemical match between the two interacting surfaces.
[00345] In one embodiment, the one or more introduced modifications introduce a new hydrogen bond across the interface of the Fab components. In one embodiment, the one or more introduced modifications introduce a new salt bridge across the interface of the Fab components. Exemplary substitutions are described in WO 2014/150973 and WO 2014/082179, the contents of which are hereby incorporated by reference.
[00346] In some embodiments, the Fab domain comprises a 192E substitution in the CH1 domain and 114A and 137K substitutions in the CL domain, which introduces a salt-bridge between the CFM and CL domains (see, e.g., Golay et al., 2016, J Immunol 196:3199-211). [00347] In some embodiments, the Fab domain comprises a 143Q and 188V substitutions in the CH1 domain and 113T and 176V substitutions in the CL domain, which serves to swap hydrophobic and polar regions of contact between the CH1 and CL domain (see, e.g., Golay et al., 2016, J Immunol 196:3199-211).
[00348] In some embodiments, the Fab domain can comprise modifications in some or all of the VH, CH1 , VL, CL domains to introduce orthogonal Fab interfaces which promote correct assembly of Fab domains (Lewis et al., 2014 Nature Biotechnology 32:191-198). In an embodiment, 39K, 62E modifications are introduced in the VH domain, H172A, F174G modifications are introduced in the CH1 domain, 1 R, 38D, (36F) modifications are introduced in the VL domain, and L135Y, S176W modifications are introduced in the CL domain. In another embodiment, a 39Y modification is introduced in the V domain and a 38R modification is introduced in the VL domain.
[00349] Fab domains can also be modified to replace the native CH1 :CL disulfide bond with an engineered disulfide bond, thereby increasing the efficiency of Fab component pairing. For example, an engineered disulfide bond can be introduced by introducing a 126C in the CH1 domain and a 121 C in the CL domain (see, e.g., Mazor et al., 2015, MAbs 7:377-89). [00350] Fab domains can also be modified by replacing the CH1 domain and CL domain with alternative domains that promote correct assembly. For example, Wu et al., 2015, Mabs 7:364-76, describes substituting the CH1 domain with the constant domain of a T cell receptor and substituting the CL domain with the b domain of the T cell receptor, and pairing these domain replacements with an additional charge-charge interaction between the VL and VH domains by introducing a 38D modification in the . domain and a 39K modification in the VH domain.
[00351] In lieu of, or in addition to, the use of Fab heterodimerization strategies to promote correct VH-VL pairings, the VL of common light chain (also referred to as a universal light chain) can be used for each Fab VL region of a MBM of the disclosure. In various embodiments, employing a common light chain as described herein reduces the number of inappropriate species of MBMs as compared to employing original cognate VLS. In various embodiments, the L domains of the MBMs are identified from monospecific antibodies comprising a common light chain. In various embodiments, the VH regions of the MBMs comprise human heavy chain variable gene segments that are rearranged in vivo within mouse B cells that have been previously engineered to express a limited human light chain repertoire, or a single human light chain, cognate with human heavy chains and, in response to exposure with an antigen of interest, generate an antibody repertoire containing a plurality of human VHs that are cognate with one or one of two possible human VLs, wherein the antibody repertoire specific for the antigen of interest. Common light chains are those derived from a rearranged human VK1-39JK5 sequence or a rearranged human VK3-20JK1 sequence, and include somatically mutated (e.g., affinity matured) versions. See, for example, U.S. Patent No. 10,412,940.
[00352] The anti-AAV monospecific antibodies or anti-AAV x anti-cell surface molecule multispecific (e.g., bispecific) antibodies disclosed herein can comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy chain variable domains as compared to the corresponding germline sequences from which the antibodies were derived.
[00353] Provided herein are antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as “germline mutations”), and having weak or no detectable binding to a AAV capsid antigen or a cell surface molecule antigen.
[00354] The antibodies and antigen-binding molecules of the present disclosure may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the individual antigen-binding domains were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The antigen-binding molecules of the present disclosure may comprise antigen-binding domains which are derived from any of the exemplary amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as “germline mutations”). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and/or CDR residues within the VH and/or VL domains are mutated back to the residues found in the original germline sequence from which the antigen-binding domain was originally derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1 , CDR2 or CDR3. In other embodiments, one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (/.e., a germline sequence that is different from the germline sequence from which the antigen-binding domain was originally derived).
[00355] Furthermore, the antigen-binding domains may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antigen-binding domains that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Bispecific antigen-binding molecules comprising one or more antigen-binding domains obtained in this general manner are encompassed within the present disclosure.
Linkers
[00356] In certain aspects, the present disclosure provides MBM in which two or more components of an ABD (e.g., a VH and a VL of an scFv), two or more ABDs (e.g., an scFv and a Fab, or a Fab and a Fab), or an ABD and a non-ABD component (e.g., an Fc region) are connected to one another by a peptide linker.
[00357] A peptide linker can range from 2 amino acids to 60 or more amino acids, and in certain aspects a peptide linker ranges from 3 amino acids to 50 amino acids, from 4 to 30 amino acids, from 5 to 25 amino acids, from 10 to 25 amino acids, 10 amino acids to 60 amino acids, from 12 amino acids to 20 amino acids, from 20 amino acids to 50 amino acids, or from 25 amino acids to 35 amino acids in length.
[00358] In particular aspects, a peptide linker, e.g., a peptide linker separating an scFv domain and a heavy chain constant region, is at least 5 amino acids, at least 6 amino acids or at least 7 amino acids in length and optionally is up to 30 amino acids, up to 40 amino acids, up to 50 amino acids or up to 60 amino acids in length.
[00359] In some embodiments of the foregoing, the linker ranges from 5 amino acids to 50 amino acids in length, e.g., ranges from 5 to 50, from 5 to 45, from 5 to 40, from 5 to 35, from 5 to 30, from 5 to 25, or from 5 to 20 amino acids in length. In other embodiments of the foregoing, the linker ranges from 6 amino acids to 50 amino acids in length, e.g., ranges from 6 to 50, from 6 to 45, from 6 to 40, from 6 to 35, from 6 to 30, from 6 to 25, or from 6 to 20 amino acids in length. In yet other embodiments of the foregoing, the linker ranges from 7 amino acids to 50 amino acids in length, e.g., ranges from 7 to 50, from 7 to 45, from 7 to 40, from 7 to 35, from 7 to 30, from 7 to 25, or from 7 to 20 amino acids in length.
[00360] Charged (e.g., charged hydrophilic linkers) and/or flexible linkers are particularly preferred.
[00361] Examples of flexible linkers that can be used in the MBMs of the disclosure include those disclosed by Chen et ai, 2013, Adv Drug Deliv Rev. 65(10): 1357-1369 and Klein et a/., 2014, Protein Engineering, Design & Selection 27(10): 325-330. Particularly useful flexible linkers are or comprise repeats of glycines and serines, e.g., a monomer or multimer of GnS (SEQ ID NO: 239) or SGn (SEQ ID NO: 240), where n is an integer from 1 to 10, e.g., 1 2, 3, 4, 5, 6, or 7, 8, 9 or 10. In one embodiment, the linker is or comprises a monomer or multimer of repeat of G4S (SEQ ID NO: 242), e.g., (GGGGS)n (SEQ ID NO: 241), where n is an integer from 1 to 10, e.g., 1 , 2, 3, 4, 5, 6, or 7, 8, 9 or 10. In some embodiments, the linker is or comprises, e.g., (GGGGS)3 (SEQ ID NO: 1115). In some embodiments, the linker is or comprises, e.g., (GGGGS)4 (SEQ ID NO: 1161).
[00362] Polyglycine linkers can suitably be used in the MBMs of the disclosure. In some embodiments, the peptide linker, e.g., a peptide linker separating an scFv domain and a heavy chain such as the scFv domain of ABD1 and the heavy chain variable region of ABD2, comprises two consecutive glycines (2Gly), three consecutive glycines (3Gly), four consecutive glycines (4Gly) (SEQ ID NO: 243), five consecutive glycines (5Gly) (SEQ ID NO: 244), six consecutive glycines (6Gly) (SEQ ID NO: 245), seven consecutive glycines (7Gly) (SEQ ID NO: 246), eight consecutive glycines (8Gly) (SEQ ID NO: 247), or nine consecutive glycines (9Gly) (SEQ ID NO: 248).
[00363] In particular embodiments, the linker, e.g., a peptide linker separating an scFv domain and a heavy chain constant region, is composed of both G4S (SEQ ID NO: 242) or a multimer thereof and one or more additional glycines, e.g., 2Gly, 3Gly or 4Gly (SEQ ID NO: 243). Examples of such linkers include G4S (SEQ ID NO: 242), GG, 4xG4S GG (SEQ ID NO: 249), and 7xG4S GG (SEQ ID NO: 250).
Constant Regions [00364] In some embodiments, MBMs of the disclosure comprise constant regions (e.g., CH1 , hinge, CH2, CH3, CL) derived from any suitable class of antibody. In some embodiments, the constant regions are derived from a human antibody.
[00365] In some embodiments, the constant regions can be derived from any suitable class of antibody, including IgA (including subclasses lgA1 and lgA2), IgD, IgE, IgG (including subclasses IgG 1 , lgG2, lgG3 and lgG4), and IgM. In one embodiment, the Fc domain is derived from lgG1 , lgG2, lgG3 or lgG4. In one embodiment the constant region is derived from IgG 1 . In one embodiment the Fc domain is derived from lgG4.
[00366] In some embodiments, a heavy chain constant region of a human IgG 1 which may be used in accordance with the disclosure may comprise the amino acid sequence of ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 259) which may be encoded by the nucleic acid sequence of
GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC AGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGG CACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG AAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGA ACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGC CGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGC ACCAG G ACTG G CTG AATG G CAAG G AGTACAAGTG CAAGGTCTCC AACAAAG CCCTCCC AGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT GTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC CTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCAT GCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTC TCCGGGTAAA (SEQ ID NO: 260).
[00367] In some embodiments, a heavy chain constant region of a human IgG 1 which may be used in accordance with the disclosure may comprise the amino acid sequence of ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTY RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1164) which may be encoded by the nucleic acid sequence of GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC AGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGG CACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG AAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGA ACTCCTG G G GG G ACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG G ACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGC CGCGGGAGGAGCAGTACGGCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGC ACCAG G ACTG G CTG AATG G CAAG G AGTACAAGTG CAAGGTCTCC AACAAAG CCCTCCC AGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT GTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC CTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCAT GCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTC TCCGGGTAAA (SEQ ID NO: 1 163).
[00368] In some embodiments, a heavy chain constant region of a human IgG 1 which may be used in accordance with the disclosure may comprise the amino acid sequence of ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTY RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKN QVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGN VFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 1144) which may be encoded by the nucleic acid sequence of
GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC AGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGG
CACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG
AAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGA
ACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG
ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT
GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGC
CGCGGGAGGAGCAGTACGGTAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGC
ACCAG G ACTG G CTG AATG G CAAG G AGTACAAGTG CAAGGTCTCCAACAAAG CCCTCCC
AGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT
GTGCACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGTCCTG
CGCCGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA
GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC
CTCGTGAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTCAT
GCTCCGTGATGCATGAGGCTCTGCACAACAGATTCACGCAGAAGTCCCTCTCCCTGTC
TCCGGGTAAA (SEQ ID NO: 1 142) or
GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG
TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC
AGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGG
CACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG
AAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGA
ACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG
ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT
GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGC
CGCGGGAGGAGCAGTACGGTAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGC
ACCAG G ACTG G CTG AATG G CAAG G AGTACAAGTG CAAGGTCTCCAACAAAG CCCTCCC
AGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT
GTGCACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGTCCTG
CGCCGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA
GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC
CTCGTGAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTCAT
GCTCCGTGATGCATGAGGCTCTGCACAACAGATTCACGCAGAAGTCCCTCTCCCTGTC
TCCGGGTAAA (SEQ ID NO: 1 143).
[00369] In some embodiments, a heavy chain constant region of a human IgG 1 which may be used in accordance with the disclosure may comprise the amino acid sequence of
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTSKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRD ELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR
WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1178) which may be encoded by the nucleic acid sequence of
GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG
TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC
AGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGG
CACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG
AAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATCAAAAACTCACACATGCCCACC GTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC AAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGA
GCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATA
ATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGGCAGCACGTACCGTGTGGTCAGCG
TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTC CAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAACCACAGGTGTACACCCTGCCCCCATGCCGGGATGAGCTGACCAAGAACCAG
GTCAGCCTGTGGTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGG
GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCC GACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGG GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAA
GTCCCTCTCCCTGTCTCCGGGTAAA (SEQ ID NO: 1176) or GCCTCAACCAAGGGACCGTCCGTGTTTCCCCTCGCTCCTTCATCAAAATCAACTTCCGG CGGAACCGCAGCGCTGGGCTGCCTCGTGAAGGATTACTTCCCCGAGCCTGTGACCGT
GTCCTGGAACTCGGGCGCCCTGACCTCCGGTGTCCACACGTTCCCCGCGGTCCTTCA
GTCCTCCGGCTTGTATTCCCTGTCGTCCGTCGTGACCGTCCCGAGCAGCAGCCTGGGA
ACTCAGACCTACATCTGCAACGTGAACCACAAGCCGTCGAACACCAAGGTCGATAAGA
AAGTGGAGCCGAAGTCGTGCGACAAAACTCATACATCAAAAACTCACACATGCCCACC GTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC AAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGA
GCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATA
ATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGGCAGCACGTACCGTGTGGTCAGCG
TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTC
CAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAACCACAGGTGTACACCCTGCCCCCATGCCGGGATGAGCTGACCAAGAACCAG GTCAGCCTGTGGTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCC GACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGG GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAA GTCCCTCTCCCTGTCTCCGGGTAAA (SEQ ID NO: 1177)
[00370] In some embodiments, a heavy chain constant region of a human lgG4, hlgG4us, which may be used in accordance with the disclosure may comprise the amino acid sequence of
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPSVFLF PPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRW SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 261) which may be encoded by the nucleic acid sequence of
GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCC GAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGG
GCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAA GAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCAGGCGGTGG CGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGA CCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGT
TCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTG GCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTG
CCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAAC AACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGA
TG CATGAG G CTCTGC ACAACCACTACACACAG AAGTCCCTCTCCCTGTCTCTG G GTAAA (SEQ ID NO: 262).
[00371] Hinge Regions
[00372] The MBMs of the disclosure can also comprise hinge regions, e.g., connecting an ABD module to an Fc region. The hinge region can be a native or a modified hinge region. Hinge regions are typically found at the N-termini of Fc regions.
[00373] A native hinge region is the hinge region that would normally be found between Fab and Fc domains in a naturally occurring antibody. A modified hinge region is any hinge that differs in length and/or composition from the native hinge region. Such hinges can include hinge regions from other species, such as human, mouse, rat, rabbit, shark, pig, hamster, camel, llama or goat hinge regions. Other modified hinge regions may comprise a complete hinge region derived from an antibody of a different class or subclass from that of the heavy chain Fc region. Alternatively, the modified hinge region may comprise part of a natural hinge or a repeating unit in which each unit in the repeat is derived from a natural hinge region. In a further alternative, the natural hinge region may be altered by converting one or more cysteine or other residues into neutral residues, such as serine or alanine, or by converting suitably placed residues into cysteine residues. By such means the number of cysteine residues in the hinge region may be increased or decreased. Other modified hinge regions may be entirely synthetic and may be designed to possess desired properties such as length, cysteine composition and flexibility.
[00374] A number of modified hinge regions have already been described for example, in U.S. Patent No. 5,677,425, WO9915549, W02005003170, W02005003169, W02005003170, WO9825971 and W02005003171 and these are incorporated herein by reference.
[00375] In one embodiment, the Fc region of one or both chains of the MBMs of the disclosure possess an intact hinge region, e.g., a hinge domain, at its N-terminus. In some embodiments, “hinge domain” refers to the sequence from about Glu216 or about Cys226 to about Pro230 of human lgG1 (Burton, 1985 Molec. Immunol. 22:161-206), or the corresponding sequence in another antibody class or isotype.
[00376] In various embodiments, positions 233-236 within a hinge domain may be G, G, G and unoccupied; G, G, unoccupied, and unoccupied; G, unoccupied, unoccupied, and unoccupied; or all unoccupied, with positions numbered by EU numbering.
[00377] In some embodiments, the MBMs of the disclosure comprise a modified hinge domain that reduces binding affinity for an Fey receptor relative to a wild-type hinge domain of the same isotype (e.g., human IgG 1 or human lgG4).
[00378] In one embodiment, the Fc region of one or both heavy chains of the MBMs of disclosure possesses an intact hinge domain at its N-terminus.
[00379] In one embodiment both the Fc region and the hinge region of an MBM of the disclosure are derived from lgG4 and the hinge region comprises the modified sequence CPPC (SEQ ID NO: 251). The core hinge region of human lgG4 contains the sequence CPSC (SEQ ID NO: 252) compared to IgG 1 that contains the sequence CPPC (SEQ ID NO: 251).
[00380] The serine residue which may be present in the lgG4 sequence can lead to increased flexibility in this region, and therefore a proportion of molecules form disulfide bonds within the same protein chain (an intrachain disulfide) rather than bridging to the other heavy chain in the IgG molecule to form the interchain disulfide (Angel et ai, 1993, Mol Immunol 30(1 ): 105-108). Changing the serine residue to a proline to give the same core sequence as IgG 1 allows complete formation of inter-chain disulfides in the lgG4 hinge region, thus reducing heterogeneity in the purified product.
[00381] The hinge region can be a chimeric hinge region.
[00382] For example, a chimeric hinge may comprise an “upper hinge” sequence, derived from a human lgG1 , a human lgG2 or a human lgG4 hinge region, combined with a “lower hinge” sequence, derived from a human lgG1 , a human lgG2 or a human lgG4 hinge region. [00383] In various embodiments, a chimeric hinge region comprises the amino acid sequence EPKSCDKTHTCPPCPAPPVA (SEQ ID NO: 253) (see, e.g., SEQ ID NO: 8 of W02014/121087, which is incorporated by reference in its entirety herein) or ESKYGPPCPPCPAPPVA (SEQ ID NO: 254) (see, e.g., SEQ ID NO: 9 of W02014/121087). Such chimeric hinge sequences can be suitably linked to an lgG4 CH2 region (for example by incorporation into an lgG4 Fc domain, for example a human or murine Fc domain, which can be further modified in the CH2 and/or CH3 domain to reduce effector function.
[00384] In further embodiments, the hinge region can be modified to reduce effector function, for example as described in WQ2016161010, which is incorporated by reference in its entirety herein. In various embodiments, the positions 233-236 of the modified hinge region are G, G, G and unoccupied; G, G, unoccupied, and unoccupied; G, unoccupied, unoccupied, and unoccupied; or all unoccupied, with positions numbered by EU numbering (as shown in FIG. 1 of WQ2016161010A2). These segments can be represented as GGG-, GG-, G — or - with representing an unoccupied position.
[00385] Position 236 is unoccupied in canonical human lgG2 but is occupied by in other canonical human IgG isotypes. Positions 233-235 are occupied by residues other than G in all four human isotypes (as shown in FIG. 1 of WQ2016161010A2).
[00386] The hinge modification within positions 233-236 can be combined with position 228 being occupied by P. Position 228 is naturally occupied by P in human IgG 1 and lgG2 but is occupied by S in human lgG4 and R in human lgG3. An S228P mutation in an lgG4 antibody is advantageous in stabilizing an lgG4 antibody and reducing exchange of heavy chain light chain pairs between exogenous and endogenous antibodies. Preferably positions 226-229 are occupied by C, P, P and C respectively.
[00387] Exemplary hinge regions have residues 226-236, sometimes referred to as middle (or core) and lower hinge, occupied by the modified hinge sequences designated GGG-(233- 236), GG-(233-236), G — (233-236) and no G(233-236). Optionally, the hinge domain amino acid sequence comprises CPPCPAPGGG-GPSVF (SEQ ID NO: 255) (see, e.g., SEQ ID NO:1 of WQ2016161010A2), CPPCPAPGG-GPSVF (SEQ ID NO: 256) (see, e.g., SEQ ID NO:2 of W02016161010A2), CPPCPAPG— GPSVF (SEQ ID NO: 257) (see, e.g., SEQ ID NO:3 of W02016161010A2), or CPPCPAP — GPSVF (SEQ ID NO: 258) (see, e.g., SEQ ID NO:4 of WQ2016161010A2).
[00388] The modified hinge regions described above can be incorporated into a heavy chain constant region, which typically include CH2 and CH3 domains, and which may have an additional hinge segment (e.g., an upper hinge) flanking the designated region. Such additional constant region segments present are typically of the same isotype, preferably a human isotype, although can be hybrids of different isotypes. The isotype of such additional human constant regions segments is preferably human lgG4 but can also be human IgG 1 , lgG2, or lgG3 or hybrids thereof in which domains are of different isotypes. Exemplary sequences of human IgG 1 , lgG2 and lgG4 are shown in FIGS. 2-4 of WQ2016161010A2. [00389] In specific embodiments, the modified hinge sequences can be linked to an lgG4 CH2 region (for example by incorporation into an lgG4 Fc domain, for example a human or murine Fc domain, which can be further modified in the CH2 and/or CH3 domain to reduce effector function).
[00390] Fc Domains
[00391] The MBMs of the disclosure can include an Fc region derived from any suitable species. In one embodiment the Fc region is derived from a human Fc domain.
[00392] In some embodiments, MBMs disclosed herein can have, e.g., fully human variable regions but can have mouse constant regions (e.g., a mouse IgG 1 Fc or a mouse lgG2 Fc (a or b isotype)) or human constant regions (e.g., a human IgG 1 Fc or a human lgG4 Fc). As will be appreciated by a person of ordinary skill in the art, a MBM having a particular Fc isotype can be converted to an antibody with a different Fc isotype (e.g., an antibody with a mouse I gG 1 Fc can be converted to an antibody with a human lgG4, etc.), but in any event, the variable domains (including the CDRs) will remain the same, and the binding properties to antigen are expected to be identical or substantially similar regardless of the nature of the constant domain.
[00393] The Fc domain can be derived from any suitable class of antibody, including IgA (including subclasses lgA1 and lgA2), IgD, IgE, IgG (including subclasses lgG1 , lgG2, lgG3 and lgG4), and IgM. In one embodiment, the Fc domain is derived from IgG 1 , lgG2, lgG3 or lgG4. In one embodiment the Fc domain is derived from IgG 1 . In one embodiment the Fc domain is derived from lgG4.
[00394] The two Fc domains within the Fc region can be the same or different from one another. In a native antibody the Fc domains are typically identical, but for the purpose of producing multispecific binding molecules of the disclosure, the Fc domains might advantageously be different to allow for heterodimerization.
[00395] In native antibodies, the heavy chain Fc domain of IgA, IgD and IgG is composed of two heavy chain constant domains (CH2 and CH3) and that of IgE and IgM is composed of three heavy chain constant domains (CH2, CH3 and CH4). These dimerize to create an Fc region.
[00396] In MBMs of the present disclosure, the Fc region, and/or the Fc domains within it, can comprise heavy chain constant domains from one or more different classes of antibody, for example one, two or three different classes.
[00397] In some embodiments, the Fc region comprises CH2 and CH3 domains derived from lgG1.
[00398] In some embodiments, the Fc region comprises CH2 and CH3 domains derived from lgG2.
[00399] In some embodiments, the Fc region comprises CH2 and CH3 domains derived from lgG3.
[00400] In some embodiments, the Fc region comprises CH2 and CH3 domains derived from lgG4.
[00401] In some embodiments, the Fc region comprises a CH4 domain from IgM. The IgM CH4 domain is typically located at the C-terminus of the CH3 domain.
[00402] In some embodiments, the Fc region comprises CH2 and CH3 domains derived from IgG and a CH4 domain derived from IgM.
[00403] It will be appreciated that the heavy chain constant domains for use in producing an Fc region for the MBMs of the present disclosure may include variants of the naturally occurring constant domains described above. Such variants may comprise one or more amino acid variations compared to wild type constant domains. In one example the Fc region of the present disclosure comprises at least one constant domain that varies in sequence from the wild-type constant domain. It will be appreciated that the variant constant domains may be longer or shorter than the wild-type constant domain. Preferably the variant constant domains are at least 60% identical or similar to a wild-type constant domain. In another example the variant constant domains are at least 70% identical or similar. In another example the variant constant domains are at least 80% identical or similar. In another example the variant constant domains are at least 90% identical or similar. In another example the variant constant domains are at least 95% identical or similar.
[00404] IgM and IgA occur naturally in humans as covalent multimers of the common H2L2 antibody unit. IgM occurs as a pentamer when it has incorporated a J-chain, or as a hexamer when it lacks a J-chain. IgA occurs as monomer and dimer forms. The heavy chains of IgM and IgA possess an 18 amino acid extension to the C-terminal constant domain, known as a tailpiece. The tailpiece includes a cysteine residue that forms a disulfide bond between heavy chains in the polymer and is believed to have an important role in polymerization. The tailpiece also contains a glycosylation site. In certain embodiments, the MBMs of the present disclosure do not comprise a tailpiece.
[00405] The Fc domains that are incorporated into the MBMs of the present disclosure may comprise one or more modifications that alter the functional properties of the proteins, for example, binding to Fc-receptors such as FcRn or leukocyte receptors, binding to complement, modified disulfide bond architecture, or altered glycosylation patterns.
[00406] The Fc domains can also be altered to include modifications that improve manufacturability of asymmetric MBMs, for example by allowing heterodimerization, which is the preferential pairing of non-identical Fc domains over identical Fc domains. Heterodimerization permits the production of MBMs in which different A BSs are connected to one another by an Fc region containing Fc domains that differ in sequence.
[00407] It will be appreciated that any of the modifications mentioned above can be combined in any suitable manner to achieve the desired functional properties and/or combined with other modifications to alter the properties of the MBMs.
[00408] In some embodiments, the Fc domain comprises one or more amino acid substitutions that reduces binding to an Fc receptor and/or effector function.
[00409] In a particular embodiment the Fc receptor is an Fey receptor. In one embodiment the Fc receptor is a human Fc receptor. In one embodiment the Fc receptor is an activating Fc receptor. In a specific embodiment the Fc receptor is an activating human Fey receptor, more specifically human FcyRllla, FcyRI or FcyRlla, most specifically human FcyRllla. In one embodiment the effector function is one or more selected from the group of complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and cytokine secretion. In a particular embodiment, the effector function is ADCC.
[00410] In some embodiments, the Fc region comprises an amino acid substitution at a position selected from the group of E233, L234, L235, N297, P331 and P329 (numberings according to Kabat EU index). In a more specific embodiment, the Fc region comprises an amino acid substitution at a position selected from the group of L234, L235 and P329 (numberings according to Kabat EU index). In some embodiments, the Fc region comprises the amino acid substitutions L234A and L235A (numberings according to Kabat EU index). In one such embodiment, the Fc region is an Igd Fc region, particularly a human Igd Fc region. In one embodiment, the Fc region comprises an amino acid substitution at position P329. In a more specific embodiment, the amino acid substitution is P329A or P329G, particularly P329G (numberings according to Kabat EU index). In one embodiment, the Fc region comprises an amino acid substitution at position P329 and a further amino acid substitution at a position selected from E233, L234, L235, N297 and P331 (numberings according to Kabat EU index). In a more specific embodiment, the further amino acid substitution is E233P, L234A, L235A, L235E, N297A, N297D or P331S. In particular embodiments, the Fc region comprises amino acid substitutions at positions P329, L234 and L235 (numberings according to Kabat EU index). In more particular embodiments, the Fc region comprises the amino acid mutations L234A, L235A and P329G (“P329G LALA”, “PGLALA” or “LALAPG”).
[00411] Typically, the same one or more amino acid substitution is present in each of the two Fc domains of an Fc region. Thus, in a particular embodiment, each Fc domain of the Fc region comprises the amino acid substitutions L234A, L235A and P329G (Kabat EU index numbering), i.e. in each of the first and the second Fc domains in the Fc region the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A) and the proline residue at position 329 is replaced by a glycine residue (P329G) (numbering according to Kabat EU index).
[00412] In one embodiment, the Fc domain is an IgG 1 Fc domain, particularly a human lgG1 Fc domain.
[00413] Typically, the same one or more amino acid substitution is present in each of the two Fc domains of an Fc region. Thus, in a particular embodiment, each Fc domain of the Fc region comprises the amino acid substitutions L234A, L235A and P329G (Kabat EU index numbering), i.e. in each of the first and the second Fc domains in the Fc region the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A) and the proline residue at position 329 is replaced by a glycine residue (P329G) (numbering according to Kabat EU index).
[00414] In one embodiment, the Fc domain is an IgG 1 Fc domain, particularly a human lgG1 Fc domain. In some embodiments, the IgG 1 Fc domain is a variant IgG 1 comprising D265A, N297A mutations (EU numbering) to reduce effector function.
[00415] In another embodiment, the Fc domain is an lgG4 Fc domain with reduced binding to Fc receptors. Exemplary lgG4 Fc domains with reduced binding to Fc receptors may comprise an amino acid sequence selected from Table 4 below. In some embodiments, the Fc domain includes only the bolded portion of the sequences shown below.
Table 4. lgG4 Fc domains
[00416] In a particular embodiment, the lgG4 with reduced effector function comprises the bolded portion of the amino acid sequence of SEQ ID NO:31 of W02014/121087, sometimes referred to herein as lgG4s or hlgG4s.
[00417] For heterodimeric MBMs, it is possible to incorporate a combination of the variant lgG4 Fc sequences set forth above, for example an Fc region comprising a combination of SEQ ID NO:30 of WQ2014/121087 (or the bolded portion thereof) and SEQ ID NO:37 of WQ2014/121087 (or the bolded portion thereof) or an Fc region comprising a combination of SEQ ID NO:31 of WQ2014/121087 (or the bolded portion thereof) and SEQ ID NO:38 of WQ2014/121087 (or the bolded portion thereof).
[00418] Many multispecific molecule formats entail dimerization between two Fc domains that, unlike a native immunoglobulin, are operably linked to non-identical antigen-binding domains (or portions thereof, e.g., a VH or VH-CH1 of a Fab). Inadequate heterodimerization of two Fc regions to form an Fc domain has can be an obstacle for increasing the yield of desired multispecific molecules and represents challenges for purification. A variety of approaches available in the art can be used in for enhancing dimerization of Fc domains that might be present in the MBMs of the disclosure, for example as disclosed in EP 1870459A1 ; U.S. Patent No. 5,582,996; U.S. Patent No. 5,731 ,168; U.S. Patent No. 5,910,573; U.S. Patent No. 5,932,448; U.S. Patent No. 6,833,441 ; U.S. Patent No. 7,183,076; U.S. Patent Application Publication No. 2006204493A1 ; and PCT Publication No. W02009/089004A1. [00419] The present disclosure provides MBMs comprising Fc heterodimers, i.e., Fc regions comprising heterologous, non-identical Fc domains. Heterodimerization strategies are used to enhance dimerization of Fc regions operably linked to different ABDs (or portions thereof, e.g., a VH or VH-CH1 of a Fab) and reduce dimerization of Fc domains operably linked to identical ABDs. Typically, each Fc domain in the Fc heterodimer comprises a CH3 domain of an antibody. The CH3 domains are derived from the constant region of an antibody of any isotype, class or subclass, and preferably of IgG (IgG 1 , lgG2, lgG3 and lgG4) class, as described in the preceding section.
[00420] Heterodimerization of the two different heavy chains at CH3 domains give rise to the desired MBM, while homodimerization of identical heavy chains will reduce yield of the desired MBM. Thus, in a preferred embodiment, the two heavy chains that associate to form an MBM of the disclosure will contain CH3 domains with modifications that favor heterodimeric association relative to unmodified chains.
[00421] In a specific embodiment said modification promoting the formation of Fc heterodimers is a so-called “knob-into-hole” or “knob-in-hole” (KiH) modification, comprising a “knob” modification in one of the Fc domains and a “hole” modification in the other Fc domain. The knob-into-hole technology is described e.g. in U.S. Patent No. 5,731 ,168; US 7,695,936; Ridgway et al., 1996, Prot Eng 9:617-621 , and Carter, 2001 , Immunol Meth 248:7-15. Generally, the method involves introducing a protuberance (“knob”) at the interface of a first polypeptide and a corresponding cavity (“hole”) in the interface of a second polypeptide, such that the protuberance can be positioned in the cavity so as to promote heterodimer formation and hinder homodimer formation. Protuberances are constructed by replacing small amino acid side chains from the interface of the first polypeptide with larger side chains (e.g., tyrosine or tryptophan). Compensatory cavities of identical or similar size to the protuberances are created in the interface of the second polypeptide by replacing large amino acid side chains with smaller ones (e.g., alanine or threonine).
[00422] Accordingly, in some embodiments, an amino acid residue in the CH3 domain of the first subunit of the Fc domain is replaced with an amino acid residue having a larger side chain volume, thereby generating a protuberance within the CH3 domain of the first subunit which is positionable in a cavity within the CH3 domain of the second subunit, and an amino acid residue in the CH3 domain of the second subunit of the Fc domain is replaced with an amino acid residue having a smaller side chain volume, thereby generating a cavity within the CH3 domain of the second subunit within which the protuberance within the CH3 domain of the first subunit is positionable. Preferably said amino acid residue having a larger side chain volume is selected from arginine (R), phenylalanine (F), tyrosine (Y), and tryptophan (W). Preferably said amino acid residue having a smaller side chain volume is selected from alanine (A), serine (S), threonine (T), and valine (V). The protuberance and cavity can be made by altering the nucleic acid encoding the polypeptides, e.g. by site-specific mutagenesis, or by peptide synthesis. An exemplary substitution is Y470T.
[00423] In a specific such embodiment, in the first Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W), and in the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V) and optionally the threonine residue at position 366 is replaced with a serine residue (T366S) and the leucine residue at position 368 is replaced with an alanine residue (L368A) (numbering according to Kabat EU index). In a further embodiment, in the first Fc domain additionally the serine residue at position 354 is replaced with a cysteine residue (S354C) or the glutamic acid residue at position 356 is replaced with a cysteine residue (E356C) (particularly the serine residue at position 354 is replaced with a cysteine residue), and in the second Fc domain additionally the tyrosine residue at position 349 is replaced by a cysteine residue (Y349C)
(numbering according to Kabat EU index). In a particular embodiment, the first Fc domain comprises the amino acid substitutions S354C and T366W, and the second Fc domain comprises the amino acid substitutions Y349C, T366S, L368A and Y407V (numbering according to Kabat EU index).
[00424] In some embodiments, electrostatic steering (e.g., as described in Gunasekaran et al., 2010, J Biol Chem 285(25): 19637-46) can be used to promote the association of the first and the second subunit of the Fc domain.
[00425] As an alternative, or in addition, to the use of Fc domains that are modified to promote heterodimerization, an Fc domain can be modified to allow a purification strategy that enables selections of Fc heterodimers. In one such embodiment, one heavy chain comprises a modified Fc domain that abrogates its binding to Protein A, thus enabling a purification method that yields a heterodimeric protein. See, for example, U.S. Patent No. 8,586,713. As such, the MBMs comprise a first CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the MBM to Protein A as compared to a corresponding MBM lacking the amino acid difference. In one embodiment, the first CH3 domain binds Protein A and the second CH3 domain contains a mutation/modification that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second CH3 may further comprise a Y96F modification (by IMGT ; Y436F by EU). This class of modifications is referred to herein as “star” mutations.
[00426] According to certain embodiments of the present disclosure, anti-AAV antigenbinding molecules and anti-AAV x anti-cell surface molecule antigen-binding molecules, are provided comprising an Fc domain comprising one or more mutations. Non-limiting examples of Fc modifications include, e.g., a modification at position 250 (e.g., E or Q); 250 and 428 (e.g., L or F); 252 (e.g., L/Y/F/W or T), 254 (e.g., S or T), and 256 (e.g., S/R/Q/E/D or T); or a modification at position 428 and/or 433 (e.g., H/L/R/S/P/Q or K) and/or 434 (e.g., H/F or Y); or a modification at position 250 and/or 428; or a modification at position 307 or 308 (e.g., 308F, V308F), and 434. In one embodiment, the modification comprises a 428L (e.g., M428L) and 434S (e.g., N434S) modification; a 428L, 2591 (e.g., V259I), and 308F (e.g., V308F) modification; a 433K (e.g., H433K) and a 434 (e.g., 434Y) modification; a 252, 254, and 256 (e.g., 252Y, 254T, and 256E) modification; a 250Q and 428L modification (e.g., T250Q and M428L); and a 307 and/or 308 modification (e.g., 308F or 308P).
[00427] In certain embodiments of the disclosure, the anti-AAV monospecific antibodies or anti-AAV x anti-cell surface molecule multispecific antibodies provided herein are human antibodies. The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and, in particular, CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
[00428] The antibodies of the disclosure may, in some embodiments, be recombinant human antibodies. The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created, or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
[00429] Human antibodies can exist in two forms that are associated with hinge heterogeneity. In one form, an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In a second form, the dimers are not linked via interchain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody). These forms have been extremely difficult to separate, even after affinity purification.
[00430] The frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human lgG4 hinge can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular Immunology 30:105) to levels typically observed using a human IgG 1 hinge. The instant disclosure encompasses antibodies having one or more mutations in the hinge, CH2 or CH3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.
[00431] The antibodies of the disclosure may be isolated antibodies. An "isolated antibody," as used herein, means an antibody that has been identified and separated and/or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an "isolated antibody" for purposes of the present disclosure. An isolated antibody also includes an antibody in situ within a recombinant cell. Isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and/or chemicals.
[00432] The anti-AAV monospecific antibodies or anti-AAV x anti-cell surface molecule multispecific antibodies disclosed herein may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present disclosure includes antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as "germline mutations"). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and/or CDR residues within the VH and/or VL domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1 , CDR2 or CDR3. In other embodiments, one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (/.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). [00433] Furthermore, the antibodies of the present disclosure may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g. , wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present disclosure.
[00434] Provided herein are anti-AAV monospecific antibodies or anti-AAV x anti-cell surface molecule multispecific antibodies comprising variants of any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present disclosure includes anti-AAV monospecific antibodies or anti-AAV x anti-cell surface molecule multispecific antibodies having HCVR, LCVR, and/or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, 3 or fewer, 2, or 1 conservative amino acid substitutions relative to any of the HCVR, LCVR, and/or CDR amino acid sequences set forth in Table 1 herein. Multispecific Antigen-Binding Molecules Comprising Anti-AAV and Anti-Cell Surface Molecule Antigen-Binding Domains
[00435] The present disclosure provides antigen-binding molecules such as antibodies or fragments thereof, including multispecific antigen-binding molecules such as multispecific antibodies (e.g., bispecific antibodies) or fragments thereof, that can bind to a capsid of an adeno-associated virus (AAV) particle and/or a molecule on a cell surface (i.e., a cell surface molecule). In some embodiments, the antigen-binding molecule is a multispecific antigenbinding molecule, e.g., a bispecific antigen-binding molecule. In some embodiments the bispecific antigen-binding molecule is a bispecific antibody.
[00436] The multispecific antibodies (e.g., bispecific antibodies) provided herein comprise a first antigen-binding domain that binds to a capsid of an AAV particle, and a second antigenbinding domain that binds to a molecule on a cell surface (i.e., a cell surface molecule). In some embodiments, the capsid comprises a wild-type AAV capsid protein(s). In some embodiments, the capsid comprises a non-wild-type AAV capsid protein(s).
[00437] Provided herein are anti-AAV/anti-cell surface molecule multispecific antibodies, wherein the first antigen-binding domain that binds to a capsid of an AAV particle comprises any of the HCVR amino acid sequences as set forth in Table 1. The first antigen-binding domain that binds to a capsid of an AAV particle may also comprise any of the LCVR amino acid sequences as set forth in Table 1. According to certain embodiments, the first antigenbinding domain that binds to a capsid of a AAV particle comprises any of the HCVR/LCVR amino acid sequence pairs as set forth in Table 1. The present disclosure also anti- AAV/anti-cell surface multispecific antibodies (e.g., bispecific antibodies), wherein the first antigen-binding domain that binds to a capsid of an AAV particle comprises any of the heavy chain CDR1-CDR2-CDR3 amino acid sequences as set forth in Table 1, and/or any of the light chain CDR1-CDR2-CDR3 amino acid sequences as set forth in Table 1.
[00438] According to certain embodiments, provided herein are anti-AAV/anti-cell surface molecules, wherein the first antigen-binding domain that binds to a capsid of an AAV particle comprises a heavy chain variable region (HCVR) having an amino acid sequence selected from SEQ ID NOs: 2, 22, 32, 42, 52, 1159, 62, 71 , 81 , 91 , 101 , 111 , 131, 141 , 151, 161 , 171 , 180, 190, 200, and 210, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00439] Provided herein are anti-AAV/anti-cell surface molecule multispecific antibodies, wherein the first antigen-binding domain that binds to a capsid of an AAV particle comprises a light chain variable region (LCVR) having an amino acid sequence selected from SEQ ID NOs: 10 and 119, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00440] Provided herein are anti-AAV/anti-cell surface molecule multispecific antibodies, wherein the first antigen-binding domain that binds to a capsid of an AAV particle comprises a HCVR and LCVR (HCVR/LCVR) amino acid sequence pair selected from SEQ ID Nos: 2/10 (e.g., REGN13876); 22/10 (e.g., REGN13877); 32/10 (e.g., REGN13878); 42/10 (e.g., REGN13879); 52 or 1159/10 or 1157 (e.g., REGN13880); 62/10 (e.g., REGN13881); 71/10 (e.g., REGN13882); 81/10 (e.g., REGN13883); 91/10 (e.g., REGN13884); 101/10 (e.g., REGN13885); 111/119 (e.g., REGN13070); 131/119 (e.g., REGN13071); 141/119 (e.g., REGN13072); 151/119 (e.g., REGN13073); 161/119 (e.g., REGN13074); 171/119 (e.g., REGN13075); 180/119 (e.g., REGN13076); 190/119 (e.g., REGN13220); 200/119 (e.g., REGN13221); and, 210/119 (e.g., REGN13284).
[00441] In some embodiments, provided herein are anti-AAV/anti-cell surface molecule multispecific antibodies, wherein the first antigen-binding domain that binds to a capsid of an AAV particle comprises a heavy chain CDR1 (HCDR1) domain having an amino acid sequence selected from SEQ ID NOs: 4, 24, 34, 44, 54, 64, 73, 83, 93, 103, 113, 133, 143, 153, 163, 173, 182, 192, 202, and 212, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a heavy chain CDR2 (HCDR2) domain having an amino acid sequence selected from SEQ ID NOs: 6, 26, 36, 46, 56, 56, 75, 85, 95, 105, 115, 135, 145, 155, 165, 145, 184, 194, 204, and 214, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a heavy chain CDR3 (HCDR3) domain having an amino acid sequence selected from SEQ ID NOs: 8, 28, 38, 48, 58, 67, 77, 87, 97, 107, 117, 137, 147, 157, 167, 176, 186, 196, 206, and 216, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a light chain CDR1 (LCDR1) domain having an amino acid sequence selected from SEQ ID NOs: 12 and 121 , or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a light chain CDR2 (LCDR2) domain having an amino acid sequence selected from SEQ ID NOs: 14 and 123, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; and a light chain CDR3 (LCDR3) domain having an amino acid sequence selected from SEQ ID NOs: 16 and 125, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00442] Certain non-limiting, exemplary anti-AAV/anti-cell surface molecule multispecific antibodies of the disclosure include a first antigen-binding domain that binds to a capsid of an AAV particle comprising HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, having the amino acid sequences selected from: SEQ ID NOs: 4-6-8-12-14-16 (e.g., REGN13876); 24-26-28-12-14-16 (e.g.-REGN13877); 34-36-38-12-14-16 (e.g., REGN13878); 44-46-48-12-14-16 (e.g., REGN13879; 54-56-58-12-14-16 (e.g., REGN13880); 64-56-67-12-14-16 (e.g., REGN13881); 73-75-77-12-14-16 (e.g., REGN13882); 83-85-87-12-14-16 (e.g., REGN13883); 93-95-97-12-14-16 (e.g. REGN13884); 103-105-107-12-14-16 (e.g., REGN13885); 113-115-117-121-123-125 (e.g. REGN13070); 133-135-137-121-123-125 (e.g., REGN13071); 143-145-147-121-123-125 (e.g. REGN13072); 153-155-157-121-123-125 (e.g., REGN13073); 163-165-167-121-123- 125 (e.g. REGN13074); 173-145-176-121-123-125 (e.g., REGN13075); 182-184-186-121- 123-125 (e.g. REGN13076); 192-194-196-121-123-125 (e.g., REGN13220); 202-204-206- 121-123-125 (e.g. REGN13221); and-212-214-216-121-123-125 (e.g. REGN13284).
[00443] In some embodiments, provided herein are anti-AAV/anti-cell surface multispecific antibodies, wherein the second antigen-binding domain binds to a cell surface molecule (i.e., a molecule on the cell surface). Such second antigen-binding domains may, therefore, bind to a protein(s) that is expressed on the surface of a cell in vitro or in vivo such that at least a portion of the protein is exposed to the extracellular side of the cell membrane and is accessible to the antigen-binding portion of the antigen-binding domain. In various embodiments, a cell surface molecule described herein may be a membrane protein, or a membrane-bound protein. A membrane protein may be an integral membrane protein which can be a part of a cell membrane that can, e.g., penetrate the membrane (e.g., a transmembrane protein) and can span the whole way across the membrane, or can associate with one or the other side of a membrane (e.g., an integral monotopic protein). In some embodiments, the membrane protein may be permanently associated with the cell membrane. In some embodiments, the membrane protein may be transiently associated with the cell membrane. In some embodiments, a membrane protein described herein may be a muti-subunit protein. Non-limiting examples cell surface molecules useful in the practice of the present disclosure include, e.g., Asialoglycoprotein Receptor 1 (ASGR1), Transferrin Receptor (TfR), and Calcium Voltage-Gated Channel Auxiliary Subunit Gamma 1 (CACNG1).
[00444] An exemplary molecule on the cell surface which may be bound by an anti- AAV/anti-cell surface multispecific antibody herein is Asialoglycoprotein Receptor 1 (ASGR1). However, disclosure of ASGR1 as a molecule on a cell surface is not intended to be limiting. Thus, a skilled artisan will understand that where anti-cell surface molecule antibodies are to be used, such anti-cell surface antibodies may target any of various cell surface molecules known to a person of ordinary skill in the art. According to certain exemplary embodiments, an anti-AAV/anti-cell surface molecule multispecific antibody described herein may comprise a second antigen-binding domain that binds to cell surface molecule (e.g., ASGR1), wherein the second antigen-binding domain comprises any of the heavy chain variable region (HCVR) amino acid sequences as set forth in Table 5. The second antigen-binding domain that binds to a cell surface molecule may also comprise any of the LCVR amino acid sequences as set forth in Table 5. In some embodiments, the second antigen-binding domain that binds to a cell surface molecule may comprise any of the HCVR/LCVR amino acid sequence pairs as set forth in Table 5. The present disclosure also provides exemplary anti-AAV/anti-cell surface molecule multispecific antibodies, wherein the second antigen-binding domain that binds to a cell surface molecule comprises any of the heavy chain CDR1-CDR2-CDR3 amino acid sequences as set forth in Table 5, and/or any of the light chain CDR1-CDR2-CDR3 amino acid sequences as set forth in Table 5
[00445] In another aspect, provided herein are nucleic acid molecules encoding any of the CDR, HCVR, LCVR, HC, or LC sequences of the anti-AAV/anti-cell surface molecule multispecific antigen-binding molecules disclosed herein, including nucleic acid molecules comprising the polynucleotide sequences as set forth in Table 2 herein, as well as nucleic acid molecules comprising the polynucleotide sequences as set forth in Table 6 herein, in any combination or arrangement thereof. Recombinant expression vectors carrying the nucleic acids of the disclosure, and host cells into which such vectors have been introduced, are also encompassed by the disclosure, as are methods of producing the antibodies by culturing the host cells under conditions permitting production of the antibodies, and recovering the antibodies produced.
Table 5. Amino Acid Sequence Identifiers for Anti-ASGR1 Antibodies
Table 6. Nucleic Acid Sequence Identifiers for Anti-ASGR1 Antibodies
REGN3954 (13383P2)
HCVR DNA Sequence
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC
CTCACCTGCACTGTCTCTGGTGACTCCATCAGTGATTATTACTGGAACTGGATCCGGCA GTCCCCAGGAAAGGGACTGGAGTGGATTGGGTATATCCATTATAGAGGGAGCACCAAT
CACAACCCCTCCCTCAAAAGTCGAGTCACCATATCACTAGACACGTCCAAGAACCAGTT
CTCCCTGAGGCTGACCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAAA
GAAAGGTGGGACCTTCCCGGTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA
(SEQ ID NO: 219) or
CAAGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC
CTCACGTGCACTGTCTCTGGTGACTCCATCAGTGATTATTACTGGAACTGGATCCGGCA
GTCCCCAGGAAAGTGTCTGGAGTGGATTGGGTATATCCATTATAGAGGGAGCACCAAT
CACAACCCCTCCCTCAAAAGTCGAGTCACCATATCACTAGACACGTCCAAGAACCAGTT
CTCCCTGAGGCTGACCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAAA
GAAAGGTGGGACCTTCCCGGTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA
(SEQ ID NO: 1246) or
CAAGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC
CTCACGTGCACTGTCTCTGGTGACTCCATCAGTGATTATTACTGGAACTGGATCCGGCA
GTCCCCAGGAAAGGGACTGGAGTGGATTGGGTATATCCATTATAGAGGGAGCACCAAT
CACAACCCCTCCCTCAAAAGTCGAGTCACCATATCACTAGACACGTCCAAGAACCAGTT
CTCCCTGAGGCTGACCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAAA
GAAAGGTGGGACCTTCCCGGTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA
(SEQ ID NO: 1281)
HCVR Amino Acid Sequence
QVQLQESGPGLVKPSETLSLTCTVSGDSISDYYWNWIRQSPGKGLEWIGYIHYRGSTNHNP
SLKSRVTISLDTSKNQFSLRLTSVTAADTAVYYCAKERWDLPGFDYWGQGTLVTVSS
(SEQ ID NO: 220) or
QVQLQESGPGLVKPSETLSLTCTVSGDSISDYYWNWIRQSPGKCLEWIGYIHYRGSTNHNP
SLKSRVTISLDTSKNQFSLRLTSVTAADTAVYYCAKERWDLPGFDYWGQGTLVTVSS
(SEQ ID NO: 1239)
HCDR1 DNA Sequence
GGTGACTCCATCAGTGATTATTAC
(SEQ ID NO: 221)
HCDR1 Amino Acid Sequence
GDSISDYY
(SEQ ID NO: 222) HCDR2 DNA Sequence
ATCCATTATAGAGGGAGCACC
(SEQ ID NO: 223)
HCDR2 Amino Acid Sequence
IHYRGST
(SEQ ID NO: 224)
HCDR3 DNA Sequence
GCGAAAGAAAGGTGGGACCTTCCCGGTTTTGACTAC
(SEQ ID NO: 225)
HCDR3 Amino Acid Sequence
AKERWDLPGFDY
(SEQ ID NO: 226)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 9) or
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCTGTGGGACACGACTGGAGATTAAA
(SEQ ID NO: 1156)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 10) or
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIK
(SEQ ID NO: 1157)
LCDR1 DNA Sequence C AG AG CATTAG C AG CTAT
(SEQ ID NO: 11)
LCDR1 Amino Acid Sequence
QSISSY
(SEQ ID NO: 12)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 13)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 14)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 15)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 16)
HC DNA Sequence
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC CTCACCTGCACTGTCTCTGGTGACTCCATCAGTGATTATTACTGGAACTGGATCCGGCA GTCCCCAGGAAAGGGACTGGAGTGGATTGGGTATATCCATTATAGAGGGAGCACCAAT CACAACCCCTCCCTCAAAAGTCGAGTCACCATATCACTAGACACGTCCAAGAACCAGTT CTCCCTGAGGCTGACCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAAA GAAAGGTGGGACCTTCCCGGTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCAGCCTCTACAAAGGGACCTTCTGTGTTTCCTCTGGCTCCTTGTTCTAGATCTACAT CTGAATCTACAGCTGCTCTGGGATGTCTGGTGAAGGATTATTTTCCTGAACCTGTGACA GTGTCTTGGAATTCTGGAGCTCTGACATCTGGAGTGCATACATTTCCTGCTGTGCTGCA GTCTTCTGGACTGTATTCTCTGTCTTCTGTGGTGACAGTGCCTTCTTCTTCTCTGGGAAC AAAGACATATACATGTAATGTGGATCATAAGCCTTCTAATACAAAGGTGGATAAGAGAGT GGAATCTAAGTATGGACCTCCTTGTCCTCCTTGTCCTGCTCCTGAATTTCTGGGAGGAC CTTCTGTGTTTCTGTTTCCTCCTAAGCCTAAGGATACACTGATGATCTCTAGAACACCTG AAGTGACATGTGTGGTGGTGGATGTGTCTCAGGAAGATCCTGAAGTGCAGTTTAATTGG TATG TGG ATG G AGTG G AAGTG C ATAATG CTAAG ACAAAG CCTAG AG AAG AACAGTTTAA TTCTACATATAGAGTGGTGTCTGTGCTGACAGTGCTGCATCAGGATTGGCTGAATGGAA AGGAATATAAGTGTAAGGTGTCTAATAAGGGACTGCCTTCTTCTATCGAAAAGACAATCT CTAAGGCTAAGGGACAGCCTAGAGAACCTCAGGTGTATACACTGCCTCCTTCTCAGGA AGAAATGACAAAGAATCAGGTGTCTCTGACATGTCTGGTGAAGGGATTTTATCCTTCTG ATATCGCTG TG GAATG G G AATCTAATGG AC AG CCTG AAAATAATTATAAG ACAAC ACCT CCTGTGCTGGATTCTGATGGATCTTTTTTTCTGTATTCTAGACTGACAGTGGATAAGTCT AGATGGCAGGAAGGAAATGTGTTTTCTTGTTCTGTGATGCATGAAGCTCTGCATAATAG ATTTACACAGAAGTCTCTGTCTCTGTCTCCTGGAAAG
(SEQ ID NO: 227) HC Amino Acid Sequence
QVQLQESGPGLVKPSETLSLTCTVSGDSISDYYWNWIRQSPGKGLEWIGYIHYRGSTNHNP SLKSRVTISLDTSKNQFSLRLTSVTAADTAVYYCAKERWDLPGFDYWGQGTLVTVSSASTK GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPK PKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV MHEALHNRFTQKSLSLSPGK
(SEQ ID NO: 228)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG COG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAACACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG
(SEQ ID NO: 19)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 20)
REGN3955 (13396P2)
HCVR DNA Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAG ACTTTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGGTCTGCCATGAGCTGGGTCCGC CAGGCTCCAGGAAAGGGACTGGAGTGGGTCTCAGATATTAGTGGTAGTGGTCGTAACA CATTCTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAA CACGCTGTTTCTGCAAATGAATAGCCTGAGAGCCGAGGACACGGCCGTATATTATTGTG CGAAAGTTCAGCTAAATGGGGATATTTTCTTTGACTACTGGGGCCAGGGAACCCTGGTC ACCGTCTCCTCA
(SEQ ID NO: 229)
HCVR Amino Acid Sequence
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRSAMSWVRQAPGKGLEWVSDISGSGRNTF YADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCAKVQLNGDIFFDYWGQGTLVTVSS
(SEQ ID NO: 230) HCDR1 DNA Sequence
G G ATTCACCTTTAG CAGGTCTG CC
(SEQ ID NO: 231)
HCDR1 Amino Acid Sequence
GFTFSRSA
(SEQ ID NO: 232)
HCDR2 DNA Sequence
ATTAGTGGTAGTGGTCGTAACACA
(SEQ ID NO: 233)
HCDR2 Amino Acid Sequence
ISGSGRNT
(SEQ ID NO: 234)
HCDR3 DNA Sequence
G CG AAAGTTC AG CTAAATG GG G ATATTTTCTTTG ACTAC
(SEQ ID NO: 235)
HCDR3 Amino Acid Sequence
AKVQLNGDIFFDY
(SEQ ID NO: 236)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA
(SEQ ID NO: 9)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
(SEQ ID NO: 10)
LCDR1 DNA Sequence
C AG AG CATTAG C AG CTAT
(SEQ ID NO: 11)
LCDR1 Amino Acid Sequence
QSISSY (SEQ ID NO: 12)
LCDR2 DNA Sequence
GCTGCATCC
(SEQ ID NO: 13)
LCDR2 Amino Acid Sequence
AAS
(SEQ ID NO: 14)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC
(SEQ ID NO: 15)
LCDR3 Amino Acid Sequence
QQSYSTPPIT
(SEQ ID NO: 16)
HC DNA Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAG
ACTTTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGGTCTGCCATGAGCTGGGTCCGC
CAGGCTCCAGGAAAGGGACTGGAGTGGGTCTCAGATATTAGTGGTAGTGGTCGTAACA
CATTCTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAA
CACGCTGTTTCTGCAAATGAATAGCCTGAGAGCCGAGGACACGGCCGTATATTATTGTG
CGAAAGTTCAGCTAAATGGGGATATTTTCTTTGACTACTGGGGCCAGGGAACCCTGGTC
ACCGTCTCCTCAGCCAGCACAAAAGGTCCTAGCGTTTTTCCACTTGCCCCATGTTCAAG
GTCAACCTCCGAAAGTACCGCCGCTCTTGGCTGTCTCGTAAAAGATTATTTTCCCGAAC
CTGTAACTGTCTCCTGGAACTCCGGCGCACTCACTTCCGGCGTACATACCTTCCCCGC
TGTCCTCCAATCTTCCGGTCTCTACTCCCTGTCTTCTGTTGTCACTGTTCCATCATCCTC
ACTCGGCACAAAAACATATACCTGCAACGTTGATCACAAGCCAAGTAATACCAAAGTTG
ATAAGCGCGTCGAATCCAAATACGGTCCCCCCTGCCCCCCATGTCCCGCTCCAGAGTT
TCTCGGTGGCCCCTCTGTTTTCCTTTTTCCCCCTAAACCCAAAGATACCCTCATGATTTC
CAGAACCCCCGAGGTCACCTGCGTCGTCGTTGATGTAAGCCAAGAAGATCCCGAAGTC
CAGTTCAATTGGTATGTAGACGGTGTTGAAGTCCATAATGCAAAAACAAAACCCAGAGA
GGAACAGTTTAATTCAACCTATCGTGTCGTTAGCGTACTCACCGTTCTTCATCAAGACTG
GCTCAATGGAAAAGAATATAAATGTAAAGTTAGCAACAAAGGTCTGCCCAGTTCAATCG
AAAAAACAATTAGCAAAGCCAAAGGCCAACCTCGCGAACCCCAAGTCTATACCTTGCCC
CCTTCTCAGGAAGAAATGACCAAAAACCAAGTTTCACTCACATGCCTCGTAAAAGGATT
CTATCCATCAGACATTGCAGTAGAATGGGAATCTAACGGCCAACCTGAAAATAATTACA
AAACCACTCCTCCTGTCCTCGATTCTGACGGCTCTTTTTTCCTTTACTCCAGATTGACTG
TTGATAAATCCCGCTGGCAGGAAGGTAACGTTTTTTCTTGTTCTGTGATGCACGAAGCC
CTCCATAACAGATTCACTCAAAAATCTCTTTCTCTCTCCCCTGGCAAATAA
(SEQ ID NO: 237)
HC Amino Acid Sequence
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRSAMSWVRQAPGKGLEWVSDISGSGRNTF
YADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCAKVQLNGDIFFDYWGQGTLVTVSS
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL
FPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SCSVMHEALHNRFTQKSLSLSPGK*
(SEQ ID NO:238)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA
CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA
ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA
GAGTGTTAG
(SEQ ID NO: 19)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
(SEQ ID NO: 20)
[00446] According to certain exemplary embodiments, provided herein are anti-AAV/anti- cell surface molecule multispecific antibodies, wherein the second antigen-binding domain that binds to a molecule on the cell surface comprises a heavy chain variable region (HCVR) having an amino acid sequence selected from SEQ ID NOs: 220 or 1239 and 230 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00447] In some embodiments, provided herein are anti-AAV/anti-cell surface molecule multispecific molecules, wherein the second antigen-binding domain that binds molecule on the cell surface comprises a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NOs: 10 or 1157, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00448] In some embodiments, provided herein are anti-AAV/anti-cell surface molecule multispecific antibodies, wherein the second antigen-binding domain that binds to a cell surface molecule comprises a HCVR and LCVR (HCVR/LCVR) amino acid sequence pair selected from SEQ ID NOs: 220 or 1239/10 or 1 157 (e.g., REGN3954) and 230/10 (e.g., REGN3955). [00449] In some embodiments, provided herein are anti-AAV/anti-cell surface molecule multispecific antibodies, wherein the second antigen-binding domain that binds to a molecule on the cell surface comprises a heavy chain CDR1 (HCDR1) domain having an amino acid sequence selected from SEQ ID NOs: 222 and 232, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a heavy chain CDR2 (HCDR2) domain having an amino acid sequence selected from SEQ ID NOs: 224 and 234, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a heavy chain CDR3 (HCDR3) domain having an amino acid sequence selected from SEQ ID NOs: 226 and 236, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a light chain CDR1 (LCDR1) domain having an amino acid sequence of SEQ ID NOs: 12, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a light chain CDR2 (LCDR2) domain having an amino acid sequence of SEQ ID NOs: 14, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; and a light chain CDR3 (LCDR3) domain having an amino acid sequence of SEQ ID NOs: 16, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00450] Certain non-limiting, exemplary anti-AAV/anti-cell surface molecule multispecific antibodies provided herein include a second antigen-binding domain that binds to a molecule on the cell surface comprising HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, having the amino acid sequences selected from SEQ ID NOs: 222-224-226-12- 14-16 (e.g., REGN3954) and 232-234-236-12-14-16 (e.g., REGN3955).
[00451] In some embodiments, the cell surface molecule which may be bound by an anti- AAV/anti-cell surface multispecific antibody herein is Transferrin Receptor (TfR). According to certain embodiments, an anti-AAV/anti-TfR multispecific antibody may comprise a second antigen-binding domain that binds to TfR, wherein the second antigen-binding domain comprises any of the heavy chain variable region (HCVR) amino acid sequences as set forth in Table 7. The second antigen-binding domain that binds to TfR may also comprise any of the light chain variable region (LCVR) amino acid sequences as set forth in Table 7. In some embodiments, the second antigen-binding domain that binds to TfR may comprise any of the HCVR/LCVR amino acid sequence pairs as set forth in Table 7. The present disclosure also provides anti-AAV/anti-TfR multispecific antibodies, wherein the second antigen-binding domain that binds to TfR comprises any of the heavy chain CDR1-CDR2-CDR3 amino acid sequences as set forth in Table 7, and/or any of the light chain CDR1-CDR2-CDR3 amino acid sequences as set forth in Table 7.
[00452] In another aspect, provided herein are nucleic acid molecules encoding any of the CDR, HCVR, LCVR, HC, or LC sequences of the anti-AAV/anti-TfR mutispecific antigenbinding molecules disclosed herein, or variants thereof, including nucleic acid molecules comprising any of the polynucleotide sequences as set forth in Table 2 herein, as well as nucleic acid molecules comprising any of the polynucleotide sequences as set forth in Table 8 herein, in any combination thereof. In some embodiments, the nucleic acid molecules described herein may comprise one or more polynucleotide sequence(s) in Table 2 that encode a pair of HCVR/LCVR amino acid sequences, and one or more polynucleotide sequence(s) selected from Table 8 that encode a pair of HCVR/LCVR amino acid sequences. In some embodiments, the nucleic acid molecules described herein may comprise one or more polynucleotide sequence(s) selected from Table 2 that encode a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3), and one or more polynucleotide sequence(s) selected from Table 8 that encode a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3).
Table 7. Amino Acid Sequence Identifiers for Anti-TfR Antibodies
Table 8. Nucleic Acid Sequence Identifiers for Anti-TfR Antibodies
31874B
HCVR (VH) Nucleotide Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCGCCTTTAGCAGCTATGCCATGACCTGGGTCCGA CAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATCAGTGGTACTGGTGGTAGT ACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGA
ACACGCTGTATCTACAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTG TGCGAAAGGGGGAGCAGCTCGTAGAATGGAATACTTCCAGTACTGGGGCCAGGGCAC CCTGGTCACCGTCTCCTCA (SEQ ID NO: 269)
HCVR (VH) Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCAASG F AFSSYAMTWVRQ APG KG LEWVSVI SGTGG STY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGGAARRMEYFQYWGQGTLVTV SS (SEQ ID NO: 270) or
EVQ LVESG G G LVQ PG G SLRLSCAASG F AFSSYAMTWVRQ APG KG LEWVSVI SGTGG STY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGGAARRMEYFQYWGQGTTVTV SS (SEQ ID NO: 271)
HCDR1 : GFAFSSYA (SEQ ID NO: 272) HCDR2: ISGTGGST (SEQ ID NO: 273)
HCDR3: AKGGAARRMEYFQY (SEQ ID NO: 274)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCGAGTCAG GG CATTAG CAATTATTTAG CCTG GTATCAG CAG AAA CCAGGGAAAGTTCCTAACCTCCTTATCTATGCTGCATCCACTTTGCAATCAGGGGTCCC ATCTCG ATTCAGTG G CAGTG G ATCTGG G ACAG ATTTCACTCTCACCATCAGCAG CCTG C AGCCTGAAGATGTTGCAACTTATTACTGTCAAAAGTATAACAGTGCCCCTCTCACTTTCG
GCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 275)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPNLLIYAASTLQSGVPSRF SGSGSGTDFTLTISSLQPEDVATYYCQKYNSAPLTFGGGTKVEIK (SEQ ID NO: 276) LCDR1 : QGISNY (SEQ ID NO: 277)
LCDR2: AAS (SEQ ID NO: 278)
LCDR3: QKYNSAPLT (SEQ ID NO: 279)
HC Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCAASG F AFSSYAMTWVRQ APG KG LEWVSVI SGTGG STY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGGAARRMEYFQYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 974)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPNLLIYAASTLQSGVPSRF SGSGSGTDFTLTISSLQPEDVATYYCQKYNSAPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 975)
31863B
HCVR (VH) Nucleotide Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCTTTAACAGCTATGCCATGACCTGGGTCCGCC AGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATTTATTGGTGGTAGTACTGGTAACAC ATACTACGCAGGCTCCGTGAAGGGCCGGTTCACCATCTCCAGCGACAATTCCAAGAAG
ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTG CGAAAGGGGGAGCAGCTCGTAGAATGGAATACTTCCAGCACTGGGGCCAGGGCACCC TGGTCACCGTCTCCTCA (SEQ ID NO: 280)
HCVR (VH) Amino Acid Sequence
EVQLVESGGGLVQPGGSLRLSCAASGFTFNSYAMTWVRQAPGKGLEWVSFIGGSTGNTY YAGSVKGRFTISSDNSKKTLYLQMNSLRAEDTAVYYCAKGGAARRMEYFQHWGQGTLVTV SS (SEQ ID NO: 281) or
EVQ LVESG G G LVQ PG G SLR LSCAASG FTF NSYAMTWVRQ APG KG LEWVSF I GG STG NTY
YAGSVKGRFTISSDNSKKTLYLQMNSLRAEDTAVYYCAKGGAARRMEYFQHWGQGTTVTV
SS (SEQ ID NO: 282)
HCDR1 : GFTFNSYA (SEQ ID NO: 283)
HCDR2: IGGSTGNT (SEQ ID NO: 284)
HCDR3: AKGGAARRMEYFQH (SEQ ID NO: 285)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTATAGGAGACAGAGTCAC CATCACTTGCCGGGCGAGTCAGGGCATTAGCAATTATTTAGCCTGGTATCAACAGAAAC CAGGGAAAGTTCCTAAGCTCCTGATCTATGCTGCATCCACTTTGCAATCAGGGGTCCCA TCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGC AGCCTGAAGATGTTGCAACTTATTACTGTCAAAACCATAACAGTGTCCCTCTCACTTTCG
GCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 286)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASIGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRF
SGSGSGTDFTLTISSLQPEDVATYYCQNHNSVPLTFGGGTKVEIK (SEQ ID NO: 287)
LCDR1 : QGISNY (SEQ ID NO: 288)
LCDR2: AAS (SEQ ID NO: 289)
LCDR3: QNHNSVPLT (SEQ ID NO: 290)
HC Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLR LSCAASG FTF NSYAMTWVRQ APG KG LEWVSF I GG STG NTY
YAGSVKGRFTISSDNSKKTLYLQMNSLRAEDTAVYYCAKGGAARRMEYFQHWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 976)
LC Amino Acid Sequence
DIQMTQSPSSLSASIGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRF SGSGSGTDFTLTISSLQPEDVATYYCQNHNSVPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 977)
69348
HCVR (VH) Nucleotide Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG
ACTCTCCTGTGCAGCGTCTGGATTCACCTTCACTACCTATGGCATGCACTGGGTCCGC
CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCTGTTATATGGTATGATGGAAGTAATA
AATATTATGGAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAAC
ACACTGTATCTGCAAATGAACAGCCTGAGAGTCGACGACACGGCTGTTTATTACTGTAC GAGAACCCATGGCTATACCAGGTCGTCGGACGGTTTTGACTACTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCA (SEQ ID NO: 291)
HCVR (VH) Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFTTYGMHWVRQAPGKGLEWVAVIWYDGSNK
YYGDSVKGRFTISRDNSKNTLYLQMNSLRVDDTAVYYCTRTHGYTRSSDGFDYWGQGTLV TVSS (SEQ ID NO: 292) or
EVQLVESGGGWQPGRSLRLSCAASGFTFTTYGMHWVRQAPGKGLEWVAVIWYDGSNKY
YGDSVKGRFTISRDNSKNTLYLQMNSLRVDDTAVYYCTRTHGYTRSSDGFDYWGQGTMV
TVSS (SEQ ID NO: 293)
HCDR1 : GFTFTTYG (SEQ ID NO: 294)
HCDR2: IWYDGSNK (SEQ ID NO: 295)
HCDR3: TRTHGYTRSSDGFDY (SEQ ID NO: 296)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG C ATTAG AAATGTTTTAG G CTGGTTTC AG CAG AAA
CCAGGGAAAGCCCCTCAGCGCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCT
ACAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATTTTTACCCGCTCACTTT
CGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 297)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSIRNVLGWFQQKPGKAPQRLIYAASSLQSGVPSR
FSGSGSGTEFTLTISSLQPEDFATYYCLQHNFYPLTFGGGTKVEIK (SEQ ID NO: 298)
LCDR1 : QSIRNV (SEQ ID NO: 299)
LCDR2: AAS (SEQ ID NO: 300)
LCDR3: LQHNFYPLT (SEQ ID NO: 301)
HC Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFTTYGMHWVRQAPGKGLEWVAVIWYDGSNK
YYGDSVKGRFTISRDNSKNTLYLQMNSLRVDDTAVYYCTRTHGYTRSSDGFDYWGQGTLV
TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL
QSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL
GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
YNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW
QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 978)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSIRNVLGWFQQKPGKAPQRLIYAASSLQSGVPSR
FSGSGSGTEFTLTISSLQPEDFATYYCLQHNFYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 979)
69340
HCVR (VH) Nucleotide Sequence
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGA
CTCTCCTGTG CAGCCTCTG G ATTCACCTTTG ATG ATAAAG CCATG CACTGG GTCCGG CA
AGTTCCAGGGAAGGGCCTGGAATGGATCTCAGGTATTAGTTGGAATAGTGGTACTATA
GGCTATGCGGACTCTGTGAAGGGCCGATTCATCATCTCCAGAGACAACGCCAAGAACT
CCCTGTATCTACAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGCGCA
AAAGATGGAGATACCAGTGGCTGGTACTGGTACGGTTTGGACGTCTGGGGCCAAGGG ACCACGGTCACCGTCTCCTCA (SEQ ID NO: 302)
HCVR (VH) Amino Acid Sequence
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDKAMHWVRQVPGKGLEWISGISWNSGTIGY
ADSVKGRFIISRDNAKNSLYLQMNSLRAEDTALYYCAKDGDTSGWYWYGLDVWGQGTTVT
VSS (SEQ ID NO: 303)
HCDR1 : GFTFDDKA (SEQ ID NO: 304)
HCDR2: ISWNSGTI (SEQ ID NO: 305)
HCDR3: AKDGDTSGWYWYGLDV (SEQ ID NO: 306)
LCVR (VL) Nucleotide Sequence
GAAATTGTGTTGACACAGTCTCCTGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCAC
CCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAA
CCTGGCCAGGCTCCCAGGCTCCTCATCCATGATGTATCCAACAGGGCCACTGGCATCC
CAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGTCT
AGAGCCTGAAGATTTTGTAGTTTATTACTGTCAGCAGCGTAGCGACTGGCCCATCACCT
TCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 307)
LCVR (VL) Amino Acid Sequence
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIHDVSNRATGIPARF
SGSGSGTDFTLTISSLEPEDFWYYCQQRSDWPITFGQGTRLEIK (SEQ ID NO: 308) or
DIVMTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIHDVSNRATGIPAR
FSGSGSGTDFTLTISSLEPEDFWYYCQQRSDWPITFGQGTRLEIK (SEQ ID NO: 309)
LCDR1: QSVSSY (SEQ ID NO: 310)
LCDR2: DVS (SEQ ID NO: 311)
LCDR3: QQRSDWPIT (SEQ ID NO: 312)
HC Amino Acid Sequence
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDKAMHWVRQVPGKGLEWISGISWNSGTIGY
ADSVKGRFIISRDNAKNSLYLQMNSLRAEDTALYYCAKDGDTSGWYWYGLDVWGQGTTVT
VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG
GPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
NSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE
LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 980) LC Amino Acid Sequence
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIHDVSNRATGIPARF
SGSGSGTDFTLTISSLEPEDFWYYCQQRSDWPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 981)
69331
HCVR (VH) Nucleotide Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG
ACTCTCCTGTATAGCCTCTGGATTCACCTTCAGTGTCTATGGCATTCACTGGGTCCGCC
AGGCTCCAGGCAAGGGGCTGGAGTGGATGGCAGTAATATCACATGATGGAAATATTAA ACACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA
CGCTGTATCTTCAAATTAACAGCCTGAGAACTGAGGACACGGCTGTGTATTACTGTGCG AAAG ATACCTG GAACTCCCTTG ATACTTTTG ATATCTG GG G CCAAGG G ACAATG GTCAC CGTCTCTTCA (SEQ ID NO: 313)
HCVR (VH) Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCIASGFTFSVYGIHWVRQAPGKGLEWMAVISHDGNIKHY
ADSVKGRFTISRDNSKNTLYLQINSLRTEDTAVYYCAKDTWNSLDTFDIWGQGTMVTVSS (SEQ ID NO: 314)
HCDR1 : GFTFSVYG (SEQ ID NO: 315)
HCDR2: ISHDGNIK (SEQ ID NO: 316)
HCDR3: AKDTWNSLDTFDI (SEQ ID NO: 317)
LCVR (VL) Nucleotide Sequence
GACATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCAC
CATCACTTGCTGGGCCAGTCAGGGCATTAGCAGTTATTTAGCCTGGTATCAGCAAAAAC
CAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCACTTTGCAAAGTGGGGTCCC
ATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTG CAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGCTTAATAGTTACCCTCTCACTTTC GGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 318)
LCVR (VL) Amino Acid Sequence
DIQLTQSPSSLSASVGDRVTITCWASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRF
SGSGSGTEFTLTISSLQPEDFATYYCQQLNSYPLTFGGGTKVEIK (SEQ ID NO: 319) or DIQMTQSPSSLSASVGDRVTITCWASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSR
FSGSGSGTEFTLTISSLQPEDFATYYCQQLNSYPLTFGGGTKVEIK (SEQ ID NO: 320)
LCDR1: QGISSY (SEQ ID NO: 321)
LCDR2: AAS (SEQ ID NO: 322)
LCDR3: QQLNSYPLT (SEQ ID NO: 323)
HC Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCIASGFTFSVYGIHWVRQAPGKGLEWMAVISHDGNIKHY
ADSVKGRFTISRDNSKNTLYLQINSLRTEDTAVYYCAKDTWNSLDTFDIWGQGTMVTVSSA
STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
WSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ
VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 982)
LC Amino Acid Sequence
DIQLTQSPSSLSASVGDRVTITCWASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRF
SGSGSGTEFTLTISSLQPEDFATYYCQQLNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQL
KSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD
YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 983)
69332
HCVR (VH) Nucleotide Sequence
CAGGTCACCTTGAGGGAGTCTGGTCCCGCGCTGGTGAAACCCTCACAGACCCTCACAC
TGACCTGCACCTTCTCTGGATTCTCACTCAACACTTATGGGATGTTTGTGAGCTGGATC
CGTCAGCCTCCAGGGAAGGCCCTAGAGTGGCTTGCACACATTCATTGGGATGATGATA
AATACTACAGCACATCTCTGAAGACCAGGCTCACCATCTCCAAGGACACCTCCAAAAAC
CAGGTGGTCCTTACAATGACCAACATGGACCCTGTGGACACAGCCACGTATTATTGTGC
ACGGGGGCACAATAATTTGAACTACATCATCCACTGGGGCCAGGGAACCCTGGTCACC
GTCTCCTCA (SEQ ID NO: 324)
HCVR (VH) Amino Acid Sequence
QVTLRESGPALVKPSQTLTLTCTFSGFSLNTYGMFVSWIRQPPGKALEWLAHIHWDDDKYY
STSLKTRLTISKDTSKNQWLTMTNMDPVDTATYYCARGHNNLNYIIHWGQGTLVTVSS (SEQ ID NO: 325) or QVQLVESGPALVKPSQTLTLTCTFSGFSLNTYGMFVSWIRQPPGKALEWLAHIHWDDDKYY STSLKTRLTISKDTSKNQWLTMTNMDPVDTATYYCARGHNNLNYIIHWGQGTLVTVSS (SEQ ID NO: 326)
HCDR1 : GFSLNTYGMF (SEQ ID NO: 327)
HCDR2: IHWDDDK (SEQ ID NO: 328)
HCDR3: ARGHNNLNYIIH (SEQ ID NO: 329)
LCVR (VL) Nucleotide Sequence
GCCATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATC ACTTG COG G G C AAG TC AG G G C ATT AG AAATG ATTT AG G CTG G TATC AG C AG AA ACCAG G G AAAG CCCCTAAG CTCCTG ATCTATG CTG CATCCACTTTACAAAGTG G GGTC CCATCAAGGTTCAG CG G CAGTG G ATCTG G CACAG ATTTCACTCTCACCATC AG CAG CC TGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAAGATTACAATTACCCATTCACTTT CGGCCCTGGGACCAAAGTGGATATCAAA (SEQ ID NO: 330)
LCVR (VL) Amino Acid Sequence
AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASTLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCLQDYNYPFTFGPGTKVDIK (SEQ ID NO: 331) or DILMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASTLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCLQDYNYPFTFGPGTKVEIK (SEQ ID NO: 332) LCDR1 : QGIRND (SEQ ID NO: 333)
LCDR2: AAS (SEQ ID NO: 334)
LCDR3: LQDYNYPFT (SEQ ID NO: 335)
HC Amino Acid Sequence
QVTLRESGPALVKPSQTLTLTCTFSGFSLNTYGMFVSWIRQPPGKALEWLAHIHWDDDKYY STSLKTRLTISKDTSKNQWLTMTNMDPVDTATYYCARGHNNLNYIIHWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 984)
LC Amino Acid Sequence
AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASTLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCLQDYNYPFTFGPGTKVDIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 985)
69326
HCVR (VH) Nucleotide Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGAGGGTCCCTGAGA CTCTCCTGTGCAGTCTCTGGATTCATCTTCAGTAGTTATGAAATGAACTGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTAGTGGTAGTACCATA TTCTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACT CACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGTG TCTGGAGTGGTCCTTTTTGATGTCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA (SEQ ID NO: 336)
HCVR (VH) Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLR LSCAVSG F I FSSYEM N WVRQ APG KG LEWVSYI SSSGST I F YA DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCVSGWLFDVWGQGTMVTVSS (SEQ ID NO: 337) or
QVQLVESGGGLVQPGGSLRLSCAVSGFIFSSYEMNWVRQAPGKGLEWVSYISSSGSTIFY ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCVSGWLFDVWGQGTMVTVSS (SEQ ID NO: 338)
HCDR1 : GFIFSSYE (SEQ ID NO: 339)
HCDR2: ISSSGSTI (SEQ ID NO: 340)
HCDR3: VSGWLFDV (SEQ ID NO: 341)
LCVR (VL) Nucleotide Sequence
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCGGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTTGCCTGGTACCAACAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCTATAGTGCATCCTCCAGGGCCACTGGTATC CCAGTCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCC TGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATATCTGGCCTCGGACGT
TCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 342)
LCVR (VL) Amino Acid Sequence
EIVMTQSPATLSVSPGERATLSCRASQSVSSNFAWYQQKPGQAPRLLIYSASSRATGIPVR
FSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIWPRTFGQGTKVEIK (SEQ ID NO: 343) or
DIVMTQSPATLSVSPGERATLSCRASQSVSSNFAWYQQKPGQAPRLLIYSASSRATGIPVR
FSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIWPRTFGQGTKVEIK (SEQ ID NO: 344)
LCDR1 : QSVSSN (SEQ ID NO: 345)
LCDR2: SAS (SEQ ID NO: 346)
LCDR3: QQYNIWPRT (SEQ ID NO: 347)
HC Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCAVSG F I FSSYEM N WVRQ APG KG LEWVSYI SSSGST I F YA
DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCVSGWLFDVWGQGTMVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWS
VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 986)
LC Amino Acid Sequence
EIVMTQSPATLSVSPGERATLSCRASQSVSSNFAWYQQKPGQAPRLLIYSASSRATGIPVR
FSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIWPRTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 987)
69329
HCVR (VH) Nucleotide Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAG
ACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTAACTATTGGATGACCTGGGTCCGCC
AGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAAGGAAGATGGAAGTGAGA
AAGACTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAA CTCACTGTATCTGCAAATGAACAGCCTGAGAGGCGAGGACACGGCTGTGTATTACTGT G CG AG AG ATGG G G AG CAG CTCGTCG ATTACTACTACTACTACGTTATG G ACGTCTG GG
GCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 348)
HCVR (VH) Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLR LSCAASG FTFSNYWMTWVRQ APG KG LEWVAN I KEDG SEKD YVDSVKGRFTISRDNAKNSLYLQMNSLRGEDTAVYYCARDGEQLVDYYYYYVMDVWGQG TTVTVSS (SEQ ID NO: 349) or
QVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMTWVRQAPGKGLEWVANIKEDGSEKD
YVDSVKGRFTISRDNAKNSLYLQMNSLRGEDTAVYYCARDGEQLVDYYYYYVMDVWGQG
TTVTVSS (SEQ ID NO: 350)
HCDR1 : GFTFSNYW (SEQ ID NO: 351)
HCDR2: IKEDGSEK (SEQ ID NO: 352)
HCDR3: ARDGEQLVDYYYYYVMDV (SEQ ID NO: 353)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCAC
CATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCT
GCAGCCTGAAGATTTTGCAACTTACTATTGTCAAAAGGCTAACAGTTTCCCGTACACTTT
TGGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 354)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR
FSGSGSGTDFTLTISSLQPEDFATYYCQKANSFPYTFGQGTKLEIK (SEQ ID NO: 355) or
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR
FSGSGSGTDFTLTISSLQPEDFATYYCQKANSFPYTFGQGTKVEIK (SEQ ID NO: 356)
LCDR1 : QGISSW (SEQ ID NO: 357)
LCDR2: AAS (SEQ ID NO: 358)
LCDR3: QKANSFPYT (SEQ ID NO: 359)
HC Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCAASG FTFSN YWMTWVRQ APG KG LE WVAN I KEDG SEKD
YVDSVKGRFTISRDNAKNSLYLQMNSLRGEDTAVYYCARDGEQLVDYYYYYVMDVWGQG
TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP
AVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP
ELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE
EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS
RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS
RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 988)
LC Amino Acid Sequence DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQKANSFPYTFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 989)
69323
HCVR (VH) Nucleotide Sequence
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGACTATGCCATGCACTGGGTCCGGCA AGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTTACATA GGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCGAGAACT CCCTACATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCA AGAGGGGGATCTACTCTGGTTCGGGGAGTTAAGGGAGGCTACTACGGTATGGACGTCT
GGGGCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 360)
HCVR (VH) Amino Acid Sequence
EVQ LVESGGG LVQ PG RSLRLSCAASG FTFDDYAM H WVRQAPG KG LEWVSG ISWNSG YIG YADSVKGRFTISRDNAENSLHLQMNSLRAEDTALYYCARGGSTLVRGVKGGYYGMDVWG QGTTVTVSS (SEQ ID NO: 361)
HCDR1 : GFTFDDYA (SEQ ID NO: 362)
HCDR2: ISWNSGYI (SEQ ID NO: 363)
HCDR3: ARGGSTLVRGVKGGYYGMDV (SEQ ID NO: 364)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CC ATCACTTG CCG G GCAAGTCAG AG C ATAAGTAGCTATTTAAATTG GTATCAG CAG AAA CCAGGTAAAGCCCCTAAGGTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTG CAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTATTCCGCTCACTTTC GGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 365)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKVLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSIPLTFGGGTKVEIK (SEQ ID NO: 366) LCDR1 : QSISSY (SEQ ID NO: 367)
LCDR2: AAS (SEQ ID NO: 368)
LCDR3: QQSYSIPLT (SEQ ID NO: 369) HC Annino Acid Sequence
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGYIG YADSVKGRFTISRDNAENSLHLQMNSLRAEDTALYYCARGGSTLVRGVKGGYYGMDVWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD
KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 990)
LG Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKVLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSIPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQL KSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 991)
69305
HCVR (VH) Nucleotide Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG
ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATA AATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACATTTCCAAGAAC
ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTG CGGGTCAACTGGATCTCTTCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTC CTCA (SEQ ID NO: 370)
HCVR (VH) Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNK YYADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAGQLDLFFDYWGQGTLVTVSS (SEQ ID NO: 371) or
EVQ LVESG G G WQ PG RSLRLSCAASG FTFSS YG M H WVRQAPG KG LEWVAVI WYDG SN K YYADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAGQLDLFFDYWGQGTLVTVSS (SEQ ID NO: 372)
HCDR1 : GFTFSSYG (SEQ ID NO: 373)
HCDR2: IWYDGSNK (SEQ ID NO: 374) HCDR3: AGQLDLFFDY (SEQ ID NO: 375)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCATCACTTG CCG G GCAAGTCAG AG C ATTG ACAG GTATTTAAATTG GTATCG G CAG AAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATACTACATCCAGTTTGCAAAGTGGGGTCC
CATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCCTCAGCAGTCT
GCAGCCTGAAGATTTTGCAACTTACTACTGTCAGCAGAGTTACAGTCCCCCGCTCACTT
TCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 376)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSIDRYLNWYRQKPGKAPKLLIYTTSSLQSGVPSRF
SGSGSGTDFTLTLSSLQPEDFATYYCQQSYSPPLTFGGGTKVEIK (SEQ ID NO: 377)
LCDR1 : QSIDRY (SEQ ID NO: 378)
LCDR2: TTS (SEQ ID NO: 379)
LCDR3: QQSYSPPLT (SEQ ID NO: 380)
HC Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNK
YYADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAGQLDLFFDYWGQGTLVTVSSAS
TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF
LFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
WSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ
VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 992)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSIDRYLNWYRQKPGKAPKLLIYTTSSLQSGVPSRF
SGSGSGTDFTLTLSSLQPEDFATYYCQQSYSPPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 993)
69307
HCVR (VH) Nucleotide Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAG
ACTCTCCTGTACAGCCTCTGGATTCACCTTTAGTAACTATTGGATGACCTGGGTCCGCC AGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAAGGAAGATGGAAGTGAGA
AAGAGTATGTGGACTCTGTGAAGGGCCGGTTCACCATCTCCAGAGACAACGCCAAGAA
TTCACTGTATCTGCAAATGAACAGCCTGAGAGGCGAGGACACGGCTGTATATTACTGTG
CGAGAGATGGGGAGCAGCTCGTCGATTACTATTACTACTACGTTATGGACGTCTGGGG
CCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 381)
HCVR (VH) Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCTASG FTFSN Y WMTWVRQAPG KG LEWVAN I KEDG SEKE
YVDSVKGRFTISRDNAKNSLYLQMNSLRGEDTAVYYCARDGEQLVDYYYYYVMDVWGQG
TTVTVSS (SEQ ID NO: 382)
HCDR1 : GFTFSNYW (SEQ ID NO: 383)
HCDR2: IKEDGSEK (SEQ ID NO: 384)
HCDR3: ARDGEQLVDYYYYYVMDV (SEQ ID NO: 385)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTTGGAGACAGAGTCAC
CATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCT
GCAGCCTGAAGATTTTGCAACTTACTATTGTCAAAAGGCTGACAGTCTCCCGTACGCTT
TTGGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 386)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR
FSGSGSGTDFTLTISSLQPEDFATYYCQKADSLPYAFGQGTKLEIK (SEQ ID NO: 387)
LCDR1 : QGISSW (SEQ ID NO: 388)
LCDR2: AAS (SEQ ID NO: 389)
LCDR3: QKADSLPYA (SEQ ID NO: 390)
HC Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCTASG FTFSN Y WMTWVRQAPG KG LEWVAN I KEDG SEKE
YVDSVKGRFTISRDNAKNSLYLQMNSLRGEDTAVYYCARDGEQLVDYYYYYVMDVWGQG
TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP
AVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP
ELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE
EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS
RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 994)
LC Amino Acid Sequence
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQKADSLPYAFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 995)
12795B
HCVR (VH) Nucleotide Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTTCAGCCTGGGGGGTCCCTGAGA CTCTCCTGTGCAACCTCTGGATTCACCTTTACCAGCTATGACATGAAGTGGGTCCGCCA GGCTCCAGGGCTGGGCCTGGAGTGGGTCTCAGCTATTAGTGGTAGTGGTGGTAACAC ATACTACG CAG ACTCCGTG AAG GG CCG GTTCACCATCTCCAG AG ACAATTCCAG G AAC ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTA CGAGGTCCCATGACTTCGGTGCCTTCGACTACTTTGACTACTGGGGCCAGGGAACCCT
GGTCACCGTCTCCTCA (SEQ ID NO: 391)
HCVR (VH) Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCATSG FTFTSYDM KWVRQ APG LG LE WVSAI SG SG G NTY YADSVKGRFTISRDNSRNTLYLQMNSLRAEDTAVYYCTRSHDFGAFDYFDYWGQGTLVTV SS (SEQ ID NO: 392) or EVQLVQSGGGLVQPGGSLRLSCATSGFTFTSYDMKWVRQAPGLGLEWVSAISGSGGNTY YADSVKGRFTISRDNSRNTLYLQMNSLRAEDTAVYYCTRSHDFGAFDYFDYWGQGTMVTV
SS (SEQ ID NO: 393)
HCDR1 : GFTFTSYD (SEQ ID NO: 394)
HCDR2: ISGSGGNT (SEQ ID NO: 395)
HCDR3: TRSHDFGAFDYFDY (SEQ ID NO: 396)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG G G CATTAG AG ATCATTTTG G CTGGTATCAG CAG AA ACCAGGGAAAGCCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTGCACAGTGGGGTC CCATCAAGGTTCAG CG G CAGTG G ATCTG GG ACAG AATTCACTCTCACAATCAGCAG CT TGCAGCCTGAAGATTTTGCAACCTATTACTGTCTACAGTATGATACTTACCCGCTCACTT TCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 397) LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQGIRDHFGWYQQKPGKAPKRLIYAASSLHSGVPSR
FSGSGSGTEFTLTISSLQPEDFATYYCLQYDTYPLTFGGGTKVEIK (SEQ ID NO: 398) or
DIQLTQSPSSLSASVGDRVTITCRASQGIRDHFGWYQQKPGKAPKRLIYAASSLHSGVPSR
FSGSGSGTEFTLTISSLQPEDFATYYCLQYDTYPLTFGGGTKVEIK (SEQ ID NO: 399)
LCDR1 : QGIRDH (SEQ ID NO: 400)
LCDR2: AAS (SEQ ID NO: 401)
LCDR3: LQYDTYPLT (SEQ ID NO: 402)
HC Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLR LSCATSG FTFTSYDM KWVRQ APG LG LE WVSAI SG SG G NTY
YADSVKGRFTISRDNSRNTLYLQMNSLRAEDTAVYYCTRSHDFGAFDYFDYWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG
PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 996)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQGIRDHFGWYQQKPGKAPKRLIYAASSLHSGVPSR
FSGSGSGTEFTLTISSLQPEDFATYYCLQYDTYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 997)
12798B
HCVR (VH) Nucleotide Sequence
GAAGTGCAGCTGGTGGAGTCTGGGGGAGACTTGGTACAGCCTGGCAGGTCCCTGAGA
CTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCA
AGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGCTACCAGA
GTCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAATT
TCCTGTATCTGCAAATGAACAGTCTGAGATCTGAGGACACGGCCTTGTATCACTGTGCA
AAAGATATGGATATCTCGCTAGGGTACTACGGTTTGGACGTCTGGGGCCAAGGGACCA
CGGTCACCGTCTCCTCA (SEQ ID NO: 403) HCVR (VH) Amino Acid Sequence
EVQLVESGG DLVQPG RSLRLSCAASG FTFDDYAM H WVRQAPG KG LEWVSG I SWNSATRV YADSVKGRFTISRDNAKNFLYLQMNSLRSEDTALYHCAKDMDISLGYYGLDVWGQGTTVTV SS (SEQ ID NO: 404)
HCDR1 : GFTFDDYA (SEQ ID NO: 405)
HCDR2: ISWNSATR (SEQ ID NO: 406)
HCDR3: AKDMDISLGYYGLDV (SEQ ID NO: 407)
LCVR (VL) Nucleotide Sequence
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTG CAGG G CCAGTCAG ACTG TTAGCAG CAACTTAGCCTG GTATCAG GAG AA ACCTG G CCAGG CTCCCAG G CTCCTC ATCTATG GTTCATCCTCCAG G G CCACTG GTATC CCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCC TG CAGTCTG AAG ATTTTG CAGTTTATTACTGTCAG CAGTATAATAACTG G CCTCCCTAC A CTTTTGGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 408)
LCVR (VL) Amino Acid Sequence
EIVMTQSPATLSVSPGERATLSCRASQTVSSNLAWYQQKPGQAPRLLIYGSSSRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPYTFGQGTKLEIK (SEQ ID NO: 409) LCDR1 : QTVSSN (SEQ ID NO: 410)
LCDR2: GSS (SEQ ID NO: 411)
LCDR3: QQYNNWPPYT (SEQ ID NO: 412)
HC Amino Acid Sequence
EVQLVESGG DLVQPG RSLRLSCAASG FTFDDYAM H WVRQAPG KG LEWVSG I SWNSATRV YADSVKGRFTISRDNAKNFLYLQMNSLRSEDTALYHCAKDMDISLGYYGLDVWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 998)
LC Amino Acid Sequence
EIVMTQSPATLSVSPGERATLSCRASQTVSSNLAWYQQKPGQAPRLLIYGSSSRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPYTFGQGTKLEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 999)
12799B
HCVR (VH) Nucleotide Sequence
CAGATCACCTTGAAGGAGTCTGGTCCTACGCTGGTGAAACCCACACAGACCCTCACGC TGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTAGTGGAGTGGGTGTGGTCTGGAT CCGTCAG CCCCCCG G AAAG G CCCTG G AGTGG CTTGCACTCATTTATTG GAATG ATCAT AAG CG GTACAG CCC ATCTCTG GG G AG CAGG CTCACCATCACCAAG G AC ACCTCCAAAA ACCAGGTGGTCCTTACAATGACCAACATGGACCCTGTGGACACAGCCACATATTACTGT GCACACTACAGTGGGAGCTATTCCTACTACTACTATGGTTTGGACGTCTGGGGCCAAG
GGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 413)
HCVR (VH) Amino Acid Sequence
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGWWIRQPPGKALEWLALIYWNDHKRYS PSLGSRLTITKDTSKNQWLTMTNMDPVDTATYYCAHYSGSYSYYYYGLDVWGQGTTVTV SS (SEQ ID NO: 414)
HCDR1 : GFSLSTSGVG (SEQ ID NO: 415)
HCDR2: IYWNDHK (SEQ ID NO: 416)
HCDR3: AHYSGSYSYYYYGLDV (SEQ ID NO: 417)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCAC CATCACTTGTCGGGCGAGTCAGGGTATTGCCAGCTGGTTAGCCTGGTATCAGCAGAAA CCAGGGAAAGCCCCTGAGCTCCTGATCTATGCTGCATCCAGTTTGCAAGGTGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCT GCAGCCTGAAGATTTTGCAATTTACTATTGTCAACAGGCTAACTATTTCCCGTGGACGTT CGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 418)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSVSASVGDRVTITCRASQGIASWLAWYQQKPGKAPELLIYAASSLQGGVPSR FSGSGSGTDFTLTISSLQPEDFAIYYCQQANYFPWTFGQGTKVEIK (SEQ ID NO: 419)
LCDR1 : QGIASW (SEQ ID NO: 420)
LCDR2: AAS (SEQ ID NO: 421)
LCDR3: QQANYFPWT (SEQ ID NO: 422)
HC Amino Acid Sequence
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGWWIRQPPGKALEWLALIYWNDHKRYS PSLGSRLTITKDTSKNQWLTMTNMDPVDTATYYCAHYSGSYSYYYYGLDVWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG
PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1000)
LG Amino Acid Sequence
DIQMTQSPSSVSASVGDRVTITCRASQGIASWLAWYQQKPGKAPELLIYAASSLQGGVPSR FSGSGSGTDFTLTISSLQPEDFAIYYCQQANYFPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK
ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1001)
12801B
HCVR (VH) Nucleotide Sequence
GAGGTGCAGCTGTTGGAGTCTGGGGGAGCCTTGGTACAGCCTGGGGGGTCCCTGAGA
CTCTCCTGTGCAGCCTCTGGATTCACCTTTACCTCCTATGCCATGCACTGGGTCCGCCA
GGCTCCAGGGAAGGGTCTGGAGTGGGTCTCATCTATTAGAGGTAGTGGTGGTGGCAC
ATACTCCGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAGGGAC ACTCTATATCTGCAAATGAACAGTGTGAGAGCCGAGGACACGGCCGTTTATTACTGTGC GAGGTCCCATGACTACGGTGCCTTCGACTTCTTTGACTACTGGGGCCAGGGAACCCTG
GTCACCGTCTCCTCA (SEQ ID NO: 423)
HCVR (VH) Amino Acid Sequence
EVQLLESGGALVQPGGSLRLSCAASGFTFTSYAMHWVRQAPGKGLEWVSSIRGSGGGTY
SADSVKGRFTISRDNSRDTLYLQMNSVRAEDTAVYYCARSHDYGAFDFFDYWGQGTLVTV
SS (SEQ ID NO: 424) or
EVQLLESGGALVQPGGSLRLSCAASGFTFTSYAMHWVRQAPGKGLEWVSSIRGSGGGTY
SADSVKGRFTISRDNSRDTLYLQMNSVRAEDTAVYYCARSHDYGAFDFFDYWGQGTTVTV
SS (SEQ ID NO: 425)
HCDR1 : GFTFTSYA (SEQ ID NO: 426)
HCDR2: IRGSGGGT (SEQ ID NO: 427)
HCDR3: ARSHDYGAFDFFDY (SEQ ID NO: 428)
LCVR (VL) Nucleotide Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGGGCATTAGAACTGATTTAGGCTGGTATCAGCAGAA
ACCAGGGAAAGCCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTC CC ATCAAGGTTC AG CG G CAGTG G ATCTG GG ACAG AATTCACTCTCACAATCAGCAG CO TGCGGCCTGAAGATTTTGCAACTTTTTACTGTCTACAGTATAATAGTTACCCGCTCACTT TCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 429)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQGIRTDLGWYQQKPGKAPKRLIYAASSLQSGVPSR
FSGSGSGTEFTLTISSLRPEDFATFYCLQYNSYPLTFGGGTKVEIK (SEQ ID NO: 430) or
DIQMTQSPSSLSASVGDRVTITCRASQGIRTDLGWYQQKPGKAPKRLIYAASSLQSGVPSR
FSGSGSGTEFTLTISSLRPEDFATFYCLQYNSYPLTFGGGTKVDIK (SEQ ID NO: 431)
LCDR1 : QGIRTD (SEQ ID NO: 432)
LCDR2: AAS (SEQ ID NO: 433)
LCDR3: LQYNSYPLT (SEQ ID NO: 434)
HC Amino Acid Sequence
EVQLLESGGALVQPGGSLRLSCAASGFTFTSYAMHWVRQAPGKGLEWVSSIRGSGGGTY SADSVKGRFTISRDNSRDTLYLQMNSVRAEDTAVYYCARSHDYGAFDFFDYWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1002)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQGIRTDLGWYQQKPGKAPKRLIYAASSLQSGVPSR FSGSGSGTEFTLTISSLRPEDFATFYCLQYNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1003)
12802B
HCVR (VH) Nucleotide Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTTCATGAGCTGGATCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTACTGGTAGTACCATA
AATTATGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAATGTCAAGAATTC
ACTGTATCTGCAAATGACCAGCCTGAGAGTCGAGGACACGGCCGTGTATTACTGTACG
AGAGATAACTGGAACTATGAATACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 435)
HCVR (VH) Amino Acid Sequence
QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYFMSWIRQAPGKGLEWVSYISSTGSTINYA
DSVKGRFTISRDNVKNSLYLQMTSLRVEDTAVYYCTRDNWNYEYWGQGTLVTVSS (SEQ
ID NO: 436)
HCDR1 : GFTFSDYF (SEQ ID NO: 437)
HCDR2: ISSTGSTI (SEQ ID NO: 438)
HCDR3: TRDNWNYEY (SEQ ID NO: 439)
LCVR (VL) Nucleotide Sequence
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCA
CCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCATCAACTTAGCCTGGTACCAGCAGAA
ACCTGGCCAGGCTCCCAGGCTCCTCATCTTTGTTGCATCCACCAGGGCCACTGGTATC CCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCC TGCAGTCTGAAGATTTTGCAACTTATTACTGTCAGCAGTATGATATCTGGCCGTACACTT TTGGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 440)
LCVR (VL) Amino Acid Sequence
EIVMTQSPATLSVSPGERATLSCRASQSVSINLAWYQQKPGQAPRLLIFVASTRATGIPARF
SGSGSGTEFTLTISSLQSEDFATYYCQQYDIWPYTFGQGTKLEIK (SEQ ID NO: 441)
LCDR1: QSVSIN (SEQ ID NO: 442)
LCDR2: VAS (SEQ ID NO: 443)
LCDR3: QQYDIWPYT (SEQ ID NO: 444)
HC Amino Acid Sequence
QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYFMSWIRQAPGKGLEWVSYISSTGSTINYA
DSVKGRFTISRDNVKNSLYLQMTSLRVEDTAVYYCTRDNWNYEYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS
SWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP
PKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWS
VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT
CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1004)
LC Amino Acid Sequence
EIVMTQSPATLSVSPGERATLSCRASQSVSINLAWYQQKPGQAPRLLIFVASTRATGIPARF SGSGSGTEFTLTISSLQSEDFATYYCQQYDIWPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQL KSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD
YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1005)
12808B
HCVR (VH) Nucleotide Sequence
CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC CTC ACCTG CACTGTGTCTG GTG AATCCATCAG CAGTAATACTTACTACTG G GG CTGG AT CCGCCAGCCCCCAGGGAAGGGGCTGGAATGGATTGGGAGTATCGATTATAGTGGGAC CACCAATTATAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTAGACACGTCCAGGA ATCACTTCTCCCTGAGGCTGAGGTCTGTGACCGCCGCAGACACGGCTGTGTATTACTG TGCGAGAGAGTGGGGAAACTACGGCTACTATTACGGTATGGACGTTTGGGGCCAAGG GACCACGGTCACCGTCTCCTCA (SEQ ID NO: 445)
HCVR (VH) Amino Acid Sequence
QLQLQESGPGLVKPSETLSLTCTVSGESISSNTYYWGWIRQPPGKGLEWIGSIDYSGTTNY NPSLKSRVTISVDTSRNHFSLRLRSVTAADTAVYYCAREWGNYGYYYGMDVWGQGTTVTV SS (SEQ ID NO: 446) or
QVQLVESGPGLVKPSETLSLTCTVSGESISSNTYYWGWIRQPPGKGLEWIGSIDYSGTTNY NPSLKSRVTISVDTSRNHFSLRLRSVTAADTAVYYCAREWGNYGYYYGMDVWGQGTTVTV SS (SEQ ID NO: 447)
HCDR1 : GESISSNTYY (SEQ ID NO: 448)
HCDR2: IDYSGTT (SEQ ID NO: 449)
HCDR3: AREWGNYGYYYGMDV (SEQ ID NO: 450)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCAATTG COG G G CAAGTCAG GG CATTAG AAATGATTT AG G CTGGTATCAG CAG AAA CCAGGGAAAGCCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CATTAAGGTTCAGTGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAACAACCTG CAGCCTGAAGATTTTGCAACTTATTACTGTCTATCGCATAATAGTTACCCGTGGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 451) LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTINCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPLR FSGSGSGTEFTLTINNLQPEDFATYYCLSHNSYPWTFGQGTKVEIK (SEQ ID NO: 452) LCDR1: QGIRND (SEQ ID NO: 453)
LCDR2: AAS (SEQ ID NO: 454)
LCDR3: LSHNSYPWT (SEQ ID NO: 455)
HC Amino Acid Sequence
QLQLQESGPGLVKPSETLSLTCTVSGESISSNTYYWGWIRQPPGKGLEWIGSIDYSGTTNY NPSLKSRVTISVDTSRNHFSLRLRSVTAADTAVYYCAREWGNYGYYYGMDVWGQGTTVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG
PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1006)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTINCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPLR FSGSGSGTEFTLTINNLQPEDFATYYCLSHNSYPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK
ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1007)
12812B
HCVR (VH) Nucleotide Sequence
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAGG
GTCTCCTGCAAGGCTTCTAGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGAC
AGGCCCCTGGACAAGGCCTTGAGTGGATGGGAGGGATCATCCCCATCTTTGGTACAGC
AAACTACGCACAGAAGTTCCTGGCCAGAGTCACGATTACCGCGGACGAATCCACGAGC
ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTG CGAGAGAGAAGGGGTGGAACTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCG TCTCCTCA (SEQ ID NO: 456)
HCVR (VH) Amino Acid Sequence
QVQLVQSGAEVKKPGSSVRVSCKASRGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANY
AQKFLARVTITADESTSTAYMELSSLRSEDTAVYYCAREKGWNYFDYWGQGTLVTVSS (SEQ ID NO: 457)
HCDR1 : RGTFSSYA (SEQ ID NO: 458)
HCDR2: IIPIFGTA (SEQ ID NO: 459)
HCDR3: AREKGWNYFDY (SEQ ID NO: 460)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCACCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTC CCATCAAGGTTCAG CG G CAGTG G ATCTG GG ACAG ATTTCACTCTC ACCATCAGCAG CO
TG CAG CCTG AAG ATTTTG CAACTTACTATTGTCAACAG GCTAACAGTTTCCCTCG G ACG TTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 461)
LCVR (VL) Amino Acid Sequence
DIQMTQSPPSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR
FSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPRTFGQGTKVEIK (SEQ ID NO: 462)
LCDR1 : QGISSW (SEQ ID NO: 463)
LCDR2: AAS (SEQ ID NO: 464)
LCDR3: QQANSFPRT (SEQ ID NO: 465)
HC Amino Acid Sequence
QVQLVQSGAEVKKPGSSVRVSCKASRGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANY AQKFLARVTITADESTSTAYMELSSLRSEDTAVYYCAREKGWNYFDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF
PPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1008)
LC Amino Acid Sequence
DIQMTQSPPSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPRTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1009)
12816B HCVR (VH) Nucleotide Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAACTGGATCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTAGTGGGACTACCATA TACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAAAT CACTGTATCTGGAGATGAACAGCCTCAGAGCCGAGGACACGGCCGTGTACTACTGTGC GAGAGAGGGGTACGGTAATGACTACTATTACTACGGTATAGACGTCTGGGGCCAAGGG
ACCACGGTCACCGTCTCCTCA (SEQ ID NO: 466)
HCVR (VH) Amino Acid Sequence
QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMNWIRQAPGKGLEWVSYISSSGTTIYYA DSVKGRFTISRDNAKKSLYLEMNSLRAEDTAVYYCAREGYGNDYYYYGIDVWGQGTTVTV SS (SEQ ID NO: 467) or
EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMNWIRQAPGKGLEWVSYISSSGTTIYYA
DSVKGRFTISRDNAKKSLYLEMNSLRAEDTAVYYCAREGYGNDYYYYGIDVWGQGTTVTV SS (SEQ ID NO: 468)
HCDR1 : GFTFSDYY (SEQ ID NO: 469)
HCDR2: ISSSGTTI (SEQ ID NO: 470)
HCDR3: AREGYGNDYYYYGIDV (SEQ ID NO: 471)
LCVR (VL) Nucleotide Sequence
GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCT CO ATCTC CTG CAG GTCTAGTCAG AG CCTCCTG CATGGTAATGG ATAC AACTATTTG ACT TGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTTGGGTTCTAATCG GGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTG AAAATAAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTCTACA AACTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 472)
LCVR (VL) Amino Acid Sequence
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHGNGYNYLTWYLQKPGQSPQLLIYLGSNRAS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYTFGQGTKLEIK (SEQ ID NO:
473) or DIQLTQSPLSLPVTPGEPASISCRSSQSLLHGNGYNYLTWYLQKPGQSPQLLIYLGSNRASG VPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYTFGQGTKVEIK (SEQ ID NO:
474) LCDR1: QSLLHGNGYNY (SEQ ID NO: 475)
LCDR2: LGS (SEQ ID NO: 476)
LCDR3: MQALQTPYT (SEQ ID NO: 477)
HC Amino Acid Sequence
QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMNWIRQAPGKGLEWVSYISSSGTTIYYA
DSVKGRFTISRDNAKKSLYLEMNSLRAEDTAVYYCAREGYGNDYYYYGIDVWGQGTTVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG
PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1010)
LC Amino Acid Sequence
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHGNGYNYLTWYLQKPGQSPQLLIYLGSNRAS
GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYTFGQGTKLEIKRTVAAPSVFIF
PPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST
LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1011)
12833B
HCVR (VH) Nucleotide Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG
ACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTTTGGCATGCACTGGGTCCGC
CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGATATTTATATCATATGATGGAAGTGATA
AATACTATGCAGACTCCGTGAAGGGCCGATTCGCCATCTCCAGAGACAGTTCCAAGAA
CACGCTATATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGT
GCGAAAGAAAACGGTATTTTGACTGATTCCTACGGTATGGACGTCTGGGGCCAAGGGA
CCACGGTCACCGTCTCCTCA (SEQ ID NO: 478)
HCVR (VH) Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVIFISYDGSDKY
YADSVKGRFAISRDSSKNTLYLQMNSLRAEDTAVYYCAKENGILTDSYGMDVWGQGTTVT
VSS (SEQ ID NO: 479) or
EVQLVESGGGWQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVIFISYDGSDKYY
ADSVKGRFAISRDSSKNTLYLQMNSLRAEDTAVYYCAKENGILTDSYGMDVWGQGTTVTV SS (SEQ ID NO: 480)
HCDR1 : GFTFSSFG (SEQ ID NO: 481)
HCDR2: ISYDGSDK (SEQ ID NO: 482)
HCDR3: AKENGILTDSYGMDV (SEQ ID NO: 483)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG COG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGO AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 484)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 485)
LCDR1 : QSISSY (SEQ ID NO: 486)
LCDR2: AAS (SEQ ID NO: 487)
LCDR3: QQSYSTPPIT (SEQ ID NO: 488)
HC Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVIFISYDGSDKY YADSVKGRFAISRDSSKNTLYLQMNSLRAEDTAVYYCAKENGILTDSYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE
LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1012)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
12834B HCVR (VH) Nucleotide Sequence
CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCTGTGAAG GTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTATGGTATCAGCTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGTGTTTACCATGGTAACACA
AACTATGCACAGAAGTTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCA CAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGC GAGAGAGGGGTATTACGATTTTTGGAGTGGTTATTACCCTTTTGACTACTGGGGCCAGG GAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 489)
HCVR (VH) Amino Acid Sequence
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISVYHGNTN YAQKFQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAREGYYDFWSGYYPFDYWGQGT LVTVSS (SEQ ID NO: 490) or
EVQLVESGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISVYHGNTN
YAQKFQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAREGYYDFWSGYYPFDYWGQGT TVTVSS (SEQ ID NO: 491)
HCDR1 : GYTFTSYG (SEQ ID NO: 492)
HCDR2: ISVYHGNT (SEQ ID NO: 493)
HCDR3: AREGYYDFWSGYYPFDY (SEQ ID NO: 494)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 495)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 496)
LCDR1: QSISSY (SEQ ID NO: 497)
LCDR2: AAS (SEQ ID NO: 498)
LCDR3: QQSYSTPPIT (SEQ ID NO: 499)
HC Amino Acid Sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISVYHGNTN YAQKFQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAREGYYDFWSGYYPFDYWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1014)
LG Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
12835B
HCVR (VH) Nucleotide Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGATACAACCTGGAGGGTCCCTGAGA CTCTCCTGTG AAG CCTCTG GATTO ACCTTCAG AAATTATG AAATG AATTG G GTCCG CCA GGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATATATTAGTAGTAGTGGTAATATGAAA GACTACGCAGAGTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGTCAAGAATT CACTGCAGCTGCAAATGAACAGCCTGAGAGTCGAGGACACGGCTGTTTATTACTGTGC GAGAGACGAGTTTCCTTACGGAATGGACGTCTGGGGCCAAGGGACCACGGTCACCGT CTCCTCA (SEQ ID NO: 500)
HCVR (VH) Amino Acid Sequence
EVQLVESGGGLIQPGGSLRLSCEASGFTFRNYEMNWVRQAPGKGLEWVSYISSSGNMKD YAESVKGRFTISRDNVKNSLQLQMNSLRVEDTAVYYCARDEFPYGMDVWGQGTTVTVSS (SEQ ID NO: 501)
HCDR1 : GFTFRNYE (SEQ ID NO: 502)
HCDR2: ISSSGNMK (SEQ ID NO: 503)
HCDR3: ARDEFPYGMDV (SEQ ID NO: 504)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG GAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT
GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA
CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 505)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 506)
LCDR1: QSISSY (SEQ ID NO: 507)
LCDR2: AAS (SEQ ID NO: 508)
LCDR3: QQSYSTPPIT (SEQ ID NO: 509)
HC Amino Acid Sequence
EVQLVESGGGLIQPGGSLRLSCEASGFTFRNYEMNWVRQAPGKGLEWVSYISSSGNMKD
YAESVKGRFTISRDNVKNSLQLQMNSLRVEDTAVYYCARDEFPYGMDVWGQGTTVTVSSA
STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
WSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ
VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1015)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
12847B
HCVR (VH) Nucleotide Sequence
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTTCAGCCTGGCAGGTCCCTGAGA
CTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGAACTGGGTCCGGCA
AGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAGTAGTGGTAGCATG
GACTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAAAACT
CCCTGTATCTGCAAATGAACAGTCTGAGAACTGAGGACACGGCCTTATATTACTGTGCA
AAAGCTAGGGAAGTTGGAGACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACG
GTCACCGTCTCCTCA (SEQ ID NO: 510) HCVR (VH) Amino Acid Sequence
EVQ LVESG G G LVQ PG RSLRLSC AASG FTF DDYAM N WVRQ APG KG LEWVSG I SWSSG SM DYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCAKAREVGDYYGMDVWGQGTTVT VSS (SEQ ID NO: 51 1)
HCDR1 : GFTFDDYA (SEQ ID NO: 512)
HCDR2: ISWSSGSM (SEQ ID NO: 513)
HCDR3: AKAREVGDYYGMDV (SEQ ID NO: 514)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG COG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGO AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 515)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 516)
LCDR1 : QSISSY (SEQ ID NO: 517)
LCDR2: AAS (SEQ ID NO: 518)
LCDR3: QQSYSTPPIT (SEQ ID NO: 519)
HC Amino Acid Sequence
EVQ LVESG G G LVQ PG RSLRLSC AASG FTF DDYAM N WVRQ APG KG LEWVSG I SWSSG SM DYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCAKAREVGDYYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE
LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1016)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
12848B
HCVR (VH) Nucleotide Sequence
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGACA CTCTCCTGTG CAGCCTCTG G ATTCACCTTTG ATAATTTTG G CATG CACTG G GTCCG GC A AGGTCCAGGGAAGGGCCTGGAATGGGTCTCAGGTCTTACTTGGAATAGTGGTGTCATA GGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACT CCCTGTATCTGCAAATGAACAGTCTGAGACCTGAGGACACGGCCTTATATTACTGTGCA AAAGATATACGGAATTACGGCCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCG TCTCCTCA (SEQ ID NO: 520)
HCVR (VH) Amino Acid Sequence
EVQLVESGGGLVQPGRSLTLSCAASGFTFDNFGMHWVRQGPGKGLEWVSGLTWNSGVIG YADSVKGRFTISRDNAKNSLYLQMNSLRPEDTALYYCAKDIRNYGPFDYWGQGTLVTVSS (SEQ ID NO: 521)
HCDR1 : GFTFDNFG (SEQ ID NO: 522)
HCDR2: LTWNSGVI (SEQ ID NO: 523)
HCDR3: AKDIRNYGPFDY (SEQ ID NO: 524)
LCVR (VL) Nucleotide Sequence
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCA GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGG CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC AGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCACCTTG GACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 525)
LCVR (VL) Amino Acid Sequence
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR FSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 526)
LCDR1 : QSVSSSY (SEQ ID NO: 527)
LCDR2: GAS (SEQ ID NO: 528)
LCDR3: QQYGSSPWT (SEQ ID NO: 529)
HC Amino Acid Sequence
EVQLVESGGGLVQPGRSLTLSCAASGFTFDNFGMHWVRQGPGKGLEWVSGLTWNSGVIG YADSVKGRFTISRDNAKNSLYLQMNSLRPEDTALYYCAKDIRNYGPFDYWGQGTLVTVSSA
STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
WSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ
VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1017)
LC Amino Acid Sequence
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR
FSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK
ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1018)
12843B
HCVR (VH) Nucleotide Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTAGTACAGCCTGGAGGGTCCCTAAGA
CTCTCCTGTGCAGCCTCTGGATTCACCTTCAATATTTTTGAAATGAACTGGGTCCGCCA
GGCTCCAGGGAAGGGGCTGGAGTGGATTTCCTACATTAGTAGTCGTGGAACTACCACA
TACTACGCAGACTCTGTGAGGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACT
CACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGC GAGAGATTATGAAGCAACAATCCCTTTTGACTTCTGGGGCCAGGGAACCCTGGTCACC
GTCTCCTCA (SEQ ID NO: 530)
HCVR (VH) Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCAASG FTF N I FEM N WVRQAPG KG LEWI SYI SSRGTTTYYA
DSVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDYEATIPFDFWGQGTLVTVSS
(SEQ ID NO: 531)
HCDR1 : GFTFNIFE (SEQ ID NO: 532)
HCDR2: ISSRGTTT (SEQ ID NO: 533)
HCDR3: ARDYEATIPFDF (SEQ ID NO: 534)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG COG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA
CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 535)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 536)
LCDR1 : QSISSY (SEQ ID NO: 537)
LCDR2: AAS (SEQ ID NO: 538)
LCDR3: QQSYSTPPIT (SEQ ID NO: 539)
HC Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLR LSCAASG FTF N I FEM N WVRQAPG KG LEWI SYI SSRGTTT YYA
DSVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDYEATIPFDFWGQGTLVTVSSAST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF
PPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW
SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSL
TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC
SVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1019)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
12844B
HCVR (VH) Nucleotide Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAAGTGTGGTACGGCCTGGGGGGTCCCTGAG
ACTCTCCTGTGAAGCCTCTGGATTCACCTTTGATGATTATGGCATGAGCTGGGTCCGCC
AAGATCCAGGGAAGGGGCTGGAGTGGGTCTCTGGTATTAATTGGAATGGTGATAGAAC
AAATTATGCAGACTCTGTGAAGGGCCGATTCATCATTTCCAGAGACAACGCCAAGAACT
CTGTGTATCTACAAATGAACAGTCTGAGAGCGGAGGACTCGGCCTTGTATCACTGTGC
GAGAGATCAGGGACTCGGAGTGGCAGCTACCCTTGACTACTGGGGCCAGGGAACCCT
GGTCACCGTCTCCTCA (SEQ ID NO: 540)
HCVR (VH) Amino Acid Sequence EVQLVESGGSWRPGGSLRLSCEASGFTFDDYGMSWVRQDPGKGLEWVSGINWNGDRT NYADSVKGRFIISRDNAKNSVYLQMNSLRAEDSALYHCARDQGLGVAATLDYWGQGTLVT
VSS (SEQ ID NO: 541) or
EVQLVESGGSWRPGGSLRLSCEASGFTFDDYGMSWVRQDPGKGLEWVSGINWNGDRT
NYADSVKGRFIISRDNAKNSVYLQMNSLRAEDSALYHCARDQGLGVAATLDYWGQGTMVT
VSS (SEQ ID NO: 542)
HCDR1 : GFTFDDYG (SEQ ID NO: 543)
HCDR2: INWNGDRT (SEQ ID NO: 544)
HCDR3: ARDQGLGVAATLDY (SEQ ID NO: 545)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCATCACTTG CCG G GCAAGTCAG AG CATTAG GAG CTATTTAAATTG GTATC AGO AG AAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT
GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA
CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 546)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 547)
LCDR1 : QSISSY (SEQ ID NO: 548)
LCDR2: AAS (SEQ ID NO: 549)
LCDR3: QQSYSTPPIT (SEQ ID NO: 550)
HC Amino Acid Sequence
EVQLVESGGSWRPGGSLRLSCEASGFTFDDYGMSWVRQDPGKGLEWVSGINWNGDRT
NYADSVKGRFIISRDNAKNSVYLQMNSLRAEDSALYHCARDQGLGVAATLDYWGQGTLVT
VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG
GPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE
LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1020)
LC Amino Acid Sequence
Til DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
12845B
HCVR (VH) Nucleotide Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGAGGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTAATTATGAAATGAACTGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTAGTACCAGTAACATA TACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCGAGAACT CACTGTATCTGCAGATGAACAGCCTGAGAGTCGAGGACACGGCTGTTTATTACTGTGTG AGAGATGGGATTGTAGTAGTTCCAGTTGGTCGTGGATACTACTATTACGGTTTGGACGT
CTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 551)
HCVR (VH) Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLR LSCAASG FTVSN YEM N WVRQ APG KG LEWVSYI SSSTSN I YY ADSVKGRFTISRDNAENSLYLQMNSLRVEDTAVYYCVRDGIVWPVGRGYYYYGLDVWGQ GTTVTVSS (SEQ ID NO: 552)
HCDR1 : GFTVSNYE (SEQ ID NO: 553)
HCDR2: ISSSTSNI (SEQ ID NO: 554)
HCDR3: VRDGIVWPVGRGYYYYGLDV (SEQ ID NO: 555)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CO ATCACTTG COG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 556)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 557)
LCDR1 : QSISSY (SEQ ID NO: 558)
LCDR2: AAS (SEQ ID NO: 559)
LCDR3: QQSYSTPPIT (SEQ ID NO: 560)
T1Z HC Annino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCAASG FTVSN YEM N WVRQ APG KG LEVWSYI SSSTSN I YY
ADSVKGRFTISRDNAENSLYLQMNSLRVEDTAVYYCVRDGIWVPVGRGYYYYGLDVWGQ
GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF
PAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA
PELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK
SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1021)
LG Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
12839B
HCVR (VH) Nucleotide Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGAAGGTCCCTGAGA
CTCTCCTGCGCAGCCTCTGGATTCCCCTTTAGTAATTATGTCATGTATTGGGTCCGCCA
GGCTCCAGGCAAGGGGCTGGAGTGGGTGGCTCTTATTTTTTTTGACGGAAAGAAAAAC
TATCATGCAGACTCCGTGAAGGGCCGATTCACCATAACCAGAGACAATTCCAAAAATAT
GTTATATCTGCAAATGAACAGCCTGAGACCTGAGGACGCGGCTGTGTATTACTGTGCG
AAAATCCATTGTCCTAATGGTGTATGTTACAAGGGGTATTACGGAATGGACGTCTGGGG
CCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 561)
HCVR (VH) Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFPFSNYVMYWVRQAPGKGLEWVALIFFDGKKNY
HADSVKGRFTITRDNSKNMLYLQMNSLRPEDAAVYYCAKIHCPNGVCYKGYYGMDVWGQ
GTTVTVSS (SEQ ID NO: 562)
HCDR1 : GFPFSNYV (SEQ ID NO: 563)
HCDR2: IFFDGKKN (SEQ ID NO: 564)
HCDR3: AKIHCPNGVCYKGYYGMDV (SEQ ID NO: 565)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA
CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 566)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 567)
LCDR1 : QSISSY (SEQ ID NO: 568)
LCDR2: AAS (SEQ ID NO: 569)
LCDR3: QQSYSTPPIT (SEQ ID NO: 570)
HC Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFPFSNYVMYWVRQAPGKGLEWVALIFFDGKKNY HADSVKGRFTITRDNSKNMLYLQMNSLRPEDAAVYYCAKIHCPNGVCYKGYYGMDVWGQ GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA
PELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK
SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1022)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
12841 B
HCVR (VH) Nucleotide Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTAAGA CTCTCCTGTG CAGCCTCTG G ATTCACCTTTAGTAACTATTG G ATG AACTG G GTCCG CCA GGCTCCAGGGAAGGGACTGGAGTGGGTGGCCAATATAAAAGAAGATGGAGGTAAGAA ATTGTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACT CACTGTTTCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTATTGTGC GAGAGAAGATACAACTTTGGTTGTGGACTACTACTACTACGGTATGGACGTCTGGGGC CAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 571)
HCVR (VH) Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCAASG FTFSN YWM N WVRQAPG KG LE WVAN I KEDG G KKL YVDSVKGRFTISRDNAKNSLFLQMNSLRAEDTAVYYCAREDTTLWDYYYYGMDVWGQGT TVTVSS (SEQ ID NO: 572)
HCDR1 : GFTFSNYW (SEQ ID NO: 573)
HCDR2: IKEDGGKK (SEQ ID NO: 574)
HCDR3: AREDTTLWDYYYYGMDV (SEQ ID NO: 575)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG COG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGO AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 576)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 577) LCDR1 : QSISSY (SEQ ID NO: 578)
LCDR2: AAS (SEQ ID NO: 579)
LCDR3: QQSYSTPPIT (SEQ ID NO: 580)
HC Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLRLSCAASG FTFSN YWM N WVRQAPG KG LEWVAN I KEDG G KKL YVDSVKGRFTISRDNAKNSLFLQMNSLRAEDTAVYYCAREDTTLWDYYYYGMDVWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR
DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1023)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
12850B
HCVR (VH) Nucleotide Sequence
CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAG
GTCTCCTGCAAGGCTTCTGGAGGCACCTTCAACACCTATGCTATCACCTGGGTGCGAC
AGGCCCCTGGACAAGGGCTTGAATGGATGGGGGGAATCATCCCTATCTCTGGCATAGC
AGAGTACGCACAGAAGTTCCAGGGCAGAGTCACGATCACCACGGATGACTCCTCGACC
ACAGCCTACATGGAACTGAACAGTCTGAGATCTGAGGACACGGCCGTGTATTACTGTG
CGAGCTGGAACTACGCACTCTACTACTTCTACGGTATGGACGTCTGGGGCCGAGGGAC
CACGGTCACCGTCTCCTCA (SEQ ID NO: 581)
HCVR (VH) Amino Acid Sequence
QVQLVQSGAEVKKPGSSVKVSCKASGGTFNTYAITWVRQAPGQGLEWMGGIIPISGIAEYA
QKFQGRVTITTDDSSTTAYMELNSLRSEDTAVYYCASWNYALYYFYGMDVWGRGTTVTVS
S (SEQ ID NO: 582)
HCDR1 : GGTFNTYA (SEQ ID NO: 583)
HCDR2: IIPISGIA(SEQ ID NO: 584)
HCDR3: ASWNYALYYFYGMDV (SEQ ID NO: 585)
LCVR (VL) Nucleotide Sequence
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCA
CCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCA
GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGG
CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC
AGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCACCTTG
GACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 586)
LCVR (VL) Amino Acid Sequence
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR
FSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 587)
LCDR1: QSVSSSY (SEQ ID NO: 588)
LCDR2: GAS (SEQ ID NO: 589)
LCDR3: QQYGSSPWT (SEQ ID NO: 590) HC Amino Acid Sequence
QVQLVQSGAEVKKPGSSVKVSCKASGGTFNTYAITWVRQAPGQGLEWMGGIIPISGIAEYA
QKFQGRVTITTDDSSTTAYMELNSLRSEDTAVYYCASWNYALYYFYGMDVWGRGTTVTVS
SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
GLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1024)
LG Amino Acid Sequence
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR
FSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDE
QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK
ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1018)
69261
HCVR (VH) Nucleotide Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGA
CTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGTCTATTACATGAACTGGATCCGCCA
GGCTCCAGGGAAGGGCCTGGAGTGGGTTTCATACATTAGTAGTAGTGGTAGTACCATA
TACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACT
CACTGTATCTCCAAATGAACAGTCTGAGAGCCGAGGACACGGCCGTATATTACTGTGG
GAGAGAAGGGTATAGTGGGACTTATTCTTATTACGGTATGGACGTCTGGGGCCAAGGG
ACCACGGTCACCGTCTCCTCA (SEQ ID NO: 591)
HCVR (VH) Amino Acid Sequence
QVQLVESGGGLVKPGGSLRLSCAASGFTFSVYYMNWIRQAPGKGLEWVSYISSSGSTIYYA
DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCGREGYSGTYSYYGMDVWGQGTTVT
VSS (SEQ ID NO: 592) or
EVQLVESGGGLVKPGGSLRLSCAASGFTFSVYYMNWIRQAPGKGLEWVSYISSSGSTIYYA
DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCGREGYSGTYSYYGMDVWGQGTTVT
VSS (SEQ ID NO: 593)
HCDR1 : GFTFSVYY (SEQ ID NO: 594)
HCDR2: ISSSGSTI (SEQ ID NO: 595)
HCDR3: GREGYSGTYSYYGMDV (SEQ ID NO: 596) LCVR (VL) Nucleotide Sequence
GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCT CC ATCTCCTG CAG GTCTAGTCAG AG CCTCCTG CATAGTAATGG ATACAACTATTTG G AT TGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGTTCCTGATCTATTTGGGTTCTAATCG GGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTG
AAAATCAACAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTCTACA AACTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 597)
LCVR (VL) Amino Acid Sequence
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQFLIYLGSNRAS GVPDRFSGSGSGTDFTLKINRVEAEDVGVYYCMQALQTPYTFGQGTKLEIK (SEQ ID NO:
598) or
DIQLTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQFLIYLGSNRASG
VPDRFSGSGSGTDFTLKINRVEAEDVGVYYCMQALQTPYTFGQGTKVEIK (SEQ ID NO:
599)
LCDR1 : QSLLHSNGYNY (SEQ ID NO: 600)
LCDR2: LGS (SEQ ID NO: 601)
LCDR3: MQALQTPYT (SEQ ID NO: 602)
HC Amino Acid Sequence
QVQLVESGGGLVKPGGSLRLSCAASGFTFSVYYMNWIRQAPGKGLEWVSYISSSGSTIYYA DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCGREGYSGTYSYYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG
GPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1025)
LC Amino Acid Sequence
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQFLIYLGSNRAS GVPDRFSGSGSGTDFTLKINRVEAEDVGVYYCMQALQTPYTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1026) 69263
HCVR (VH) Nucleotide Sequence
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGGTTGGTACAGCCTGGCAGGTCCCTGAGA
CTCTCCTGTGCAGTCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCA
AGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTACCAGA
GGATATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACT
CCCTGTATCTGCAAATGAACAGTCTGAGAGGTGAGGACACGGCCTTGTATTACTGTGTA
AAAGATATTACGATATCCCCCAACTACTACGGTATGGACGTCTGGGGCCAAGGGACCA
CGGTCACCGTCTCCTCA (SEQ ID NO: 603)
HCVR (VH) Amino Acid Sequence
EVQ LVESG G G LVQ PG RSLRLSC AVSG FTF DD YAM H WVRQ APG KG LEWVSG I SWNSGTR
GYADSVKGRFTISRDNAKNSLYLQMNSLRGEDTALYYCVKDITISPNYYGMDVWGQGTTVT
VSS (SEQ ID NO: 604)
HCDR1 : GFTFDDYA (SEQ ID NO: 605)
HCDR2: ISWNSGTR (SEQ ID NO: 606)
HCDR3: VKDITISPNYYGMDV (SEQ ID NO: 607)
LCVR (VL) Nucleotide Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCATCACTTGCCGGGCGAGTCAGGACATTAGCCATTATTCAGCCTGGTATCAGCAGAA
ACCAGGGAAACTTCCTAACCTCCTGATCTATGCTGCATCCACTTTGCAATCAGGGGTCC
CATCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCTCTCTCACCACCAGCAGCCT
GCAGCCTGAAGATGTTGCAACTTATTACTGTCAAAAGTATAACAGTGTCCCTCTCACTTT
CGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 608)
LCVR (VL) Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQDISHYSAWYQQKPGKLPNLLIYAASTLQSGVPSRF
SGSGSGTDFSLTTSSLQPEDVATYYCQKYNSVPLTFGGGTKVEIK (SEQ ID NO: 609) or
DIQLTQSPSSLSASVGDRVTITCRASQDISHYSAWYQQKPGKLPNLLIYAASTLQSGVPSRF
SGSGSGTDFSLTTSSLQPEDVATYYCQKYNSVPLTFGGRTKVEIK (SEQ ID NO: 610)
LCDR1 : QDISHY (SEQ ID NO: 611)
LCDR2: AAS (SEQ ID NO: 612)
LCDR3: QKYNSVPLT (SEQ ID NO: 613)
HC Amino Acid Sequence EVQ LVESG G G LVQ PG RSLRLSC AVSG FTF DDYAM H WVRQ APG KG LEWVSG I SWNSGTR
GYADSVKGRFTISRDNAKNSLYLQMNSLRGEDTALYYCVKDITISPNYYGMDVWGQGTTVT
VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG
GPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
NSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE
LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1027)
LG Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQDISHYSAWYQQKPGKLPNLLIYAASTLQSGVPSRF
SGSGSGTDFSLTTSSLQPEDVATYYCQKYNSVPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1028)
8D3
HCVR (VH) Nucleotide Sequence
GAAGTACAGCTCGTCGAAAGTGGCGGTGGTCTTGTTCAGCCTGGAAACTCCCTCACCC
TCTCATGTGTCGCAAGTGGATTTACTTTCTCAAATTATGGAATGCATTGGATTAGGCAAG
CACCAAAAAAAGGACTTGAATGGATAGCTATGATATATTACGACTCCTCTAAAATGAATT
ACGCAGATACTGTAAAAGGCAGGTTTACAATTTCTCGGGATAACTCTAAAAACACTCTTT
ACCTTGAAATGAACTCTCTTAGATCCGAAGATACAGCTATGTACTATTGCGCAGTGCCA
ACTAGTCATTACGTCGTCGATGTTTGGGGACAAGGCGTAAGTGTAACAGTCAGCTCA
(SEQ ID NO: 11 18)
HCDR1 : GGATTTACTTTCTCAAATTATGGAATGCAT (SEQ ID NO: 1 120)
HCDR2: ATGATATATTACGACTCCTCTAAAATGAATTACGCAGATACTGTAAAAGGC
(SEQ ID NO: 1122)
HCDR3: CCAACTAGTCATTACGTCGTCGATGTT (SEQ ID NO: 1 124)
HCVR (VH) Amino Acid Sequence
EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSKMNY
ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYWDVWGQGVSVTVSS
(SEQ ID NO: 11 19)
HCDR1 : GFTFSNYGMH (SEQ ID NO: 1 121)
HCDR2: MIYYDSSKMNYADTVKG (SEQ ID NO: 1 123)
HCDR3: PTSHYWDV (SEQ ID NO: 1125) LCVR (VL) Nucleotide Sequence
GACATTCAGATGACACAATCCCCAGCATCCCTCTCAGCATCACTCGAAGAAATCGTAAC AATCACCTGTCAAGCATCTCAAGATATCGGCAACTGGCTCGCATGGTACCAACAGAAAC CCGGCAAATCCCCTCAACTTCTTATTTATGGCGCAACATCCCTCGCAGACGGCGTTCCC TCAAG GTTCTCAG G CTCACG ATCAG G CACTCAGTTCTCACTTAAAATCTCCAG AGTTCA AGTCG AAG ATATAG G AATTTATTATTG TCTCCAAG CATATAACAC ACCATG G AC ATTCG G CGGCGGCACCAAACTCGAACTTAAA (SEQ ID NO: 1126)
LCDR1 : CAAGCATCTCAAGATATCGGCAACTGGCTCGCA (SEQ ID NO: 1 128) LCDR2: GGCGCAACATCCCTCGCAGAC (SEQ ID NO: 1 130)
LCDR3: CAAGCATATAACACACCATGGACAT (SEQ ID NO: 1 132)
LCVR (VL) Amino Acid Sequence
DIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLLIYGATSLADGVPSRF SGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELK (SEQ ID NO: 1 127) LCDR1 : QASQDIGNWLA (SEQ ID NO: 1129)
LCDR2: GATSLAD (SEQ ID NO: 1 131)
LCDR3: QAYNTPWT (SEQ ID NO: 1 133)
[00453] According to certain exemplary embodiments, provided herein are anti-AAV/anti- TfR multispecific antibodies, wherein the second antigen-binding domain that binds to TfR comprises a heavy chain variable region (HCVR) having an amino acid sequence selected from SEQ ID NOs: 270, 271 , 281 , 282, 292, 293, 303, 314, 325, 326, 337, 338, 349, 350, 361 , 371 , 372, 382, 392, 393, 404, 414, 424, 425, 436, 446, 447, 457, 467, 468, 479, 480, 490, 491 , 501 , 51 1 , 521 , 531 , 541 , 542, 552, 562, 572, 582, 592, 593, 604, or 1 1 19 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00454] In some embodiments, provided herein are anti-AAV/anti-TfR multispecific antibodies, wherein the second antigen-binding domain that binds to TfR comprises a light chain variable region (LCVR) having an amino acid sequence selected from SEQ ID NOs: 276, 287, 298, 308, 309, 319, 320, 331 , 332, 343, 344, 355, 356, 366, 377, 387, 398, 399, 409, 419, 430, 431 , 441 , 452, 462, 473, 474, 485, 496, 506, 516, 526, 536, 547, 557, 567, 577, 587, 598, 599, 609, 610, or 1127 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00455] In some embodiments, provided herein are anti-AAV/anti-TfR multispecifc antibodies, wherein the second antigen-binding domain that binds to TfR comprises a HCVR and LCVR (HCVR/LCVR) amino acid sequence pair selected from SEQ ID NOs: 270 or 271/276 (e.g., REGN31874B), SEQ ID NOs: 281 or 282/287 (e.g., REGN31863B), SEQ ID NOs: 292 or 293/298 (e.g., REGN69348), SEQ ID NOs: 303/308 or 309 (e.g., REGN69340), SEQ ID NOs: 314/319 or 320 (e.g., REGN69331), SEQ ID NOs: 325 or 326/331 or 332 (e.g., REGN69332), SEQ ID NOs: 337 or 338/343 or 344 (e.g., REGN69326), SEQ ID NOs: 349 or 350/355 or 356 (e.g., REGN69329), SEQ ID NOs: 361/366 (e.g., REGN69323), SEQ ID NOs: 371 or 372/377 (e.g., REGN69305), SEQ ID NOs: 382/387 (e.g., REGN69307), SEQ ID NOs: 392 or 393/398 or 399 (e.g., REGN12795B), SEQ ID NOs: 404/409 (e.g., REGN12798B), SEQ ID NOs: 414/419 (e.g., REGN12799B), SEQ ID NOs: 424 or 425/430 or 431 (e.g., REGN12801 B), SEQ ID NOs: 436/441 (e.g., REGN12802B), SEQ ID NOs: 446 or 447/452 (e.g., REGN12808B), SEQ ID NOs: 457/462 (e.g., REGN12812B), SEQ ID NOs: 467 or 468/473 or 474 (e.g., REGN12816B), SEQ ID NOs: 479 or 480/485 (e.g., REGN12833B), SEQ ID NOs: 490 or 491/496 (e.g., REGN12834B), SEQ ID NOs: 501/506 (e.g., REGN12835B), SEQ ID NOs: 511/516 (e.g., REGN12847B), SEQ ID NOs: 521/526 (e.g., REGN12848B), SEQ ID NOs: 531/536 (e.g., REGN12843B), SEQ ID NOs: 541 or 542/547 (e.g., REGN12844B), SEQ ID NOs: 552/557 (e.g., REGN12845B), SEQ ID NOs: 562/567 (e.g., REGN12839B), SEQ ID NOs: 572/577 (e.g., REGN12841B), SEQ ID NOs: 582/587 (e.g., REGN12850B), SEQ ID NOs: 592 or 593/598 or 599 (e.g., REGN69261), SEQ ID NOs: 604/609 or 610 (e.g., REGN69263), and SEQ ID NOs: 1119/1127 (e.g., REGN8D3).
[00456] In some embodiments, provided herein are anti-AAV/anti-TfR multispecific antibodies, wherein the second antigen-binding domain that binds to TfR comprises a heavy chain CDR1 (HCDR1) domain having an amino acid sequence selected from SEQ ID NOs: 272, 283, 294, 304, 315, 327, 339, 351 , 362, 373, 383, 394, 405, 415, 426, 437, 448, 458, 469, 481 , 492, 502, 512, 522, 532, 543, 553, 563, 573, 583, 594, 605, or 1121 , or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a heavy chain CDR2 (HCDR2) domain having an amino acid sequence selected from SEQ ID NOs: 273, 284, 295, 305, 316, 328, 340, 352, 363, 374, 384, 395, 406, 416, 427, 438, 449, 459, 470, 482, 493, 503, 513, 523, 533, 544, 554, 564, 574, 584, 595, 606, or 1123, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a heavy chain CDR3 (HCDR3) domain having an amino acid sequence selected from SEQ ID NOs: 274, 285, 296, 306, 317, 329, 341 , 353, 364, 375, 385, 396, 407, 417, 428, 439, 450, 460, 471, 483, 494, 504, 514, 524, 534, 545, 555, 565, 575, 585, 596, 607, or 1125, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a light chain CDR1 (LCDR1) domain having an amino acid sequence of SEQ ID NOs: 277, 288, 299, 310, 321 , 333, 345, 357, 367, 378, 388, 400, 410, 420, 432, 442, 453, 463, 475, 486, 497, 507, 517, 527, 537, 548, 558, 568, 578, 588, 600, 611, or 1129, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a light chain CDR2 (LCDR2) domain having an amino acid sequence of SEQ ID NOs: 278, 289, 300, 311 , 322, 334, 346, 358, 368, 379, 389, 401 , 411 , 421 , 433, 443, 454, 464, 476, 487, 498, 508, 518, 528, 538, 549, 559, 569, 579, 589, 601, 612, or 1131 , or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; and a light chain CDR3 (LCDR3) domain having an amino acid sequence of SEQ ID NOs: 279, 290, 301 , 312, 323, 335, 347, 359, 369, 380, 390, 402, 412, 422, 434, 444, 455, 465, 477, 488, 499, 509, 519, 529, 539, 550, 560, 570, 580, 590, 602, 613, or 1133, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00457] Certain non-limiting, exemplary anti-AAV/anti-TfR multispecific antibodies provided herein include a second antigen-binding domain that binds to TfR comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3), respectively, having the amino acid sequences selected from SEQ ID NOs: 272- 273- 274- 277- 278- 279 (e.g., REGN31874B), SEQ ID NOs: 283- 284- 285- 288- 289- 290 (e.g., REGN31863B), SEQ ID NOs: 294- 295- 296- 299- 300- 301 (e.g., REGN69348), SEQ ID NOs: 304- 305- 306- 310- 311- 312 (e.g., REGN69340), SEQ ID NOs: 315- 316- 317- 321- 322- 323 (e.g., REGN69331), SEQ ID NOs: 327- 328- 329- 333- 334- 335 (e.g., REGN69332), SEQ ID NOs: 339- 340- 341- 345- 346- 347 (e.g., REGN69326), SEQ ID NOs: 351- 352- 353- 357- 358- 359 (e.g., REGN69329), SEQ ID NOs: 362- 363- 364- 367- 368- 369 (e.g., REGN69323), SEQ ID NOs: 373- 374- 375- 378- 379- 380 (e.g., REGN69305), SEQ ID NOs: 383- 384- 385- 388- 389- 390 (e.g., REGN69307), SEQ ID NOs: 394- 395- 396- 400- 401- 402 (e.g., REGN12795B), SEQ ID NOs: 405- 406- 407- 410- 411- 412 (e.g., REGN12798B), SEQ ID NOs: 415- 416- 417- 420- 421- 422 (e.g., REGN12799B), SEQ ID NOs: 426- 427- 428- 432- 433- 434 (e.g., REGN12801 B), SEQ ID NOs: 437- 438- 439- 442- 443- 444 (e.g., REGN12802B), SEQ ID NOs: 448- 449- 450- 453- 454- 455 (e.g., REGN12808B), SEQ ID NOs: 458- 459- 460- 463- 464- 465 (e.g., REGN12812B), SEQ ID NOs: 469- 470- 471- 475- 476- 477 (e.g., REGN12816B), SEQ ID NOs: 481- 482- 483- 486- 487- 488 (e.g., REGN12833B), SEQ ID NOs: 492- 493- 494- 497- 498- 499 (e.g., REGN12834B), SEQ ID NOs: 502- 503- 504- 507- 508- 509 (e.g., REGN12835B), SEQ ID NOs: 512- 513- 514- 517- 518- 519 (e.g., REGN12847B), SEQ ID NOs: 522- 523- 524- 527- 528- 529 (e.g., REGN12848B), SEQ ID NOs: 532- 533- 534- 537- 538- 539 (e.g., REGN12843B), SEQ ID NOs: 543- 544- 545- 548- 549- 550 (e.g., REGN12844B), SEQ ID NOs: 553- 554- 555- 558- 559- 560 (e.g., REGN12845B), SEQ ID NOs: 563- 564- 565- 568- 569- 570 (e.g., REGN12839B), SEQ ID NOs: 573- 574- 575- 578- 579- 580 (e.g., REGN12841B), SEQ ID NOs: 583- 584- 585- 588- 589- 590 (e.g., REGN12850B), SEQ ID NOs: 594- 595- 596- 600- 601- 602 (e.g., REGN69261), SEQ ID NOs: 605- 606- 607- 611- 612- 613 (e.g., REGN69263), and SEQ ID NOs: 1121- 1123- 1125- 1129- 1131- 1133 (e.g., REGN8D3).
[00458] In an embodiment provided herein, an anti-AAV/anti-TfR multispecific antibody herein can comprise an anti-TfR antibody, or antigen-binding fragment thereof, wherein the anti-TfR antibody or antigen-binding fragment thereof can include: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366; j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377; k) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387; l) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399; m) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409; n) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419; o) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ; p) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ; q) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452; r) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462; s) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474; t) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485; u) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496; v) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506; w) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516; x) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526; y) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536; z) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547; aa) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557; bb) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567; cc) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577; dd) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587; ee) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ; ff) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; and/or gg) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127. [00459] In an embodiment provided herein, an anti-AAV/anti-TfR multispecific antibody herein can comprise an anti-TfR antibody or antigen-binding fragment thereof, wherein the anti-TfR antibody or antigen-binding fragment thereof, can include: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369; j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380; k) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390; l) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402; m) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412; n) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422; o) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434; p) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444; q) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455; r) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465; s) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477; t) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488; u) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499; v) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509; w) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519; x) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529; y) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539; z) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550; aa) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560; bb) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570; cc) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580; dd) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590; ee) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602; ff) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 611 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; and/or gg) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133. [00460] In an embodiment provided herein, an anti-AAV/anti-TfR multispecific antibody herein can comprise an anti-TfR antibody, or antigen-binding fragment thereof, wherein the anti-TfR antibody or antigen-binding fragment thereof can include: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 276; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366; j) a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377; k) a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387; l) a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399; m) a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409; n) a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419; o) a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ; p) a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ; q) a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452; r) a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462; s) a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474; t) a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485; u) a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496; v) a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 506; w) a HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 516; x) a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 526; y) a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536; z) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547; aa) a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557; bb) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567; cc) a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577; dd) a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587; ee) a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ; ff) a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; and/or gg) a HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
[00461] In an embodiment provided herein, an anti-AAV/anti-TfR multispecific antibody herein can comprise an anti-TfR antigen-binding fragment comprising an anti-TfR Fab, wherein the anti-TfR Fab can include: a) a HC region that comprises the amino acid sequence of SEQ ID NO: 974, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 975, or a variant thereof; b) a HC region that comprises the amino acid sequence of SEQ ID NO: 976, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 977, or a variant thereof; c) a HC region that comprises the amino acid sequence of SEQ ID NO: 978, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 979, or a variant thereof; d) a HC region that comprises the amino acid sequence of SEQ ID NO: 980, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 981 , or a variant thereof; e) a HC region that comprises the amino acid sequence of SEQ ID NO: 982, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 983, or a variant thereof; f) a HC region that comprises the amino acid sequence of SEQ ID NO: 984, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 985, or a variant thereof; g) a HC region that comprises the amino acid sequence of SEQ ID NO: 986, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 987, or a variant thereof; h) a HC region that comprises the amino acid sequence of SEQ ID NO: 988, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 989, or a variant thereof; i) a HC region that comprises the amino acid sequence of SEQ ID NO: 990, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 991 , or a variant thereof; j) a HC region that comprises the amino acid sequence of SEQ ID NO: 992, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 993, or a variant thereof; k) a HC region that comprises the amino acid sequence of SEQ ID NO: 994, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 995, or a variant thereof; l) a HC region that comprises the amino acid sequence of SEQ ID NO: 996, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 997, or a variant thereof; m) a HC region that comprises the amino acid sequence of SEQ ID NO: 998, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 999, or a variant thereof; n) a HC region that comprises the amino acid sequence of SEQ ID NO: 1000, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1001 , or a variant thereof; o) a HC region that comprises the amino acid sequence of SEQ ID NO: 1002, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1003, or a variant thereof; p) a HC region that comprises the amino acid sequence of SEQ ID NO: 1004, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1005, or a variant thereof; q) a HC region that comprises the amino acid sequence of SEQ ID NO: 1006, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1007, or a variant thereof; r) a HC region that comprises the amino acid sequence of SEQ ID NO: 1008, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1009, or a variant thereof; s) a HC region that comprises the amino acid sequence of SEQ ID NO: 1010, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1011 , or a variant thereof; t) a HC region that comprises the amino acid sequence of SEQ ID NO: 1012, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1013, or a variant thereof; u) a HC region that comprises the amino acid sequence of SEQ ID NO: 1014, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1013, or a variant thereof; v) a HC region that comprises the amino acid sequence of SEQ ID NO: 1015, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1013, or a variant thereof; w) a HC region that comprises the amino acid sequence of SEQ ID NO: 1016, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1013, or a variant thereof; x) a HC region that comprises the amino acid sequence of SEQ ID NO: 1017, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1018, or a variant thereof; y) a HC region that comprises the amino acid sequence of SEQ ID NO: 1019, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1013, or a variant thereof; z) a HC region that comprises the amino acid sequence of SEQ ID NO: 1020, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1013, or a variant thereof; aa) a HC region that comprises the amino acid sequence of SEQ ID NO: 1021, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1013, or a variant thereof; bb) a HC region that comprises the amino acid sequence of SEQ ID NO: 1022, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1013, or a variant thereof; cc) a HC region that comprises the amino acid sequence of SEQ ID NO: 1023, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1013, or a variant thereof; dd) a HC region that comprises the amino acid sequence of SEQ ID NO: 1024, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1018, or a variant thereof; ee) a HC region that comprises the amino acid sequence of SEQ ID NO: 1025, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1026, or a variant thereof; and/or ff) a HC region that comprises the amino acid sequence of SEQ ID NO: 1027, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 1028, or a variant thereof.
[00462] Any of the HCVR and/or LCVR of the anti-TfR antibodies, or variants thereof, disclosed herein can be contained within an antigen-binding fragment such as but not limited to (i) Fab fragment; (ii) F(ab')2 fragment; (iii) Fd fragment; (iv) Fv fragment; (v) single-chain Fv (scFv) molecules; and (vi) dAb fragments.
[00463] In various embodiments, for example, when a HCVR and a LCVR of an anti-TfR antibody, or variant thereof, are contained within an antigen binding fragment (e.g., an scFv or a Fab), the HCVR and the LCVR can be in either orientation (HCVR-LCVR or LCVR- HCVR). In some embodiments, the HCVR and LCVR are optionally linked by a linker, e.g., that comprises an amino acid sequence, e.g., about 10 amino acids in length, for example: (Gly4Ser)n (SEQ ID NO: 241) wherein n is 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[00464] In some embodiments, the scFv comprises (i) a heavy chain variable region that comprises the HCDR1 , HCDR2 and HCDR3 of a HCVR comprising the amino acid sequence of SEQ ID NO: 270, 271 , 281, 282, 292, 293, 303, 314, 325, 326, 337, 338, 349, 350, 361 , 371 , 372, 382, 392, 393, 404, 414, 424, 425, 436, 446, 447, 457, 467, 468, 479, 480, 490, 491 , 501 , 511 , 521 , 531 , 541 , 542, 552, 562, 572, 582, 592, 593, 604, or 1119; and/or
(ii) a light chain variable region that comprises the LCDR1 , LCDR2 and LCDR3 of a LCVR comprising the amino acid sequence of SEQ ID NO: 276, 287, 298, 308, 309, 319, 320, 331 , 332, 343, 344, 355, 356, 366, 377, 387, 398, 399, 409, 419, 430, 431 , 441, 452, 462, 473, 474, 485, 496, 506, 516, 526, 536, 547, 557, 567, 577, 587, 598, 599, 609, 610, or 1127; or the scFv comprises:
(1) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 270 or 271 , or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 276, or a variant thereof;
(2) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 281 or 282, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 287, or a variant thereof;
(3) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 292 or 293, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 298, or a variant thereof;
(4) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 303, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 308 or 309, or a variant thereof;
(5) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 314, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 319 or 320, or a variant thereof;
(6) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 325 or 326, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 331 or 332, or a variant thereof;
(7) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 337 or 338, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 343 or 344, or a variant thereof;
(8) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 349 or 350, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 355 or 356, or a variant thereof;
(9) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 361 , or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 366, or a variant thereof;
(10) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 371 or 372, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 377, or a variant thereof;
(11) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 382, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 387, or a variant thereof;
(12) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 392 or 393, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 398 or 399, or a variant thereof;
(13) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 404, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 409, or a variant thereof;
(14) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 414, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 419, or a variant thereof;
(15) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 424 or 425, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 430 or 431 , or a variant thereof;
(16) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 436, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 441 , or a variant thereof;
(17) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 446 or 447, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 452, or a variant thereof;
(18) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 457, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 462, or a variant thereof;
(19) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 467 or 468, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 473 or 474, or a variant thereof;
(20) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 479 or 480, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 485, or a variant thereof;
(21) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 490 or 491 , or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 496, or a variant thereof;
(22) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 501 , or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 506, or a variant thereof;
(23) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 511 , or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 516, or a variant thereof;
(24) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 521 , or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 526, or a variant thereof;
(25) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 531 , or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 536, or a variant thereof;
(26) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 541 or 542, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 547, or a variant thereof;
(27) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 552, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 557, or a variant thereof;
(28) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 562, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 567, or a variant thereof;
(29) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 572, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 577, or a variant thereof;
(30) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 582, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 587, or a variant thereof;
(31) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 592 or 593, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 598 or 599 , or a variant thereof; (32) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 604, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 609 or 610, or a variant thereof;
(33) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 1119, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 1127, or a variant thereof; or the scFv comprises: a) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 274, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 279, or a variant thereof; b) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 285, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 290, or a variant thereof; c) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 296, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 , or a variant thereof; d) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 306, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 312, or a variant thereof; e) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 317, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 321 , or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 323, or a variant thereof; f) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 329, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 335, or a variant thereof; g) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 347, or a variant thereof; h) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 353, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 359, or a variant thereof; i) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 364, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 369, or a variant thereof; j) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 375, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 380, or a variant thereof; k) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 385, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 390, or a variant thereof; l) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 396, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 402, or a variant thereof; m) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 407, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 412, or a variant thereof; n) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 417, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 422, or a variant thereof; o) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 428, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 434, or a variant thereof; p) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 439, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 444, or a variant thereof; q) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 450, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 455, or a variant thereof; r) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 460, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 465, or a variant thereof; s) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 477, or a variant thereof; t) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 483, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 488, or a variant thereof; u) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 494, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 499, or a variant thereof; v) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 504, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 509, or a variant thereof; w) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 514, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 519, or a variant thereof; x) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 524, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 529, or a variant thereof; y) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 534, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 539, or a variant thereof; z) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 545, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 550, or a variant thereof; aa) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 555, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 560, or a variant thereof; bb) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 565, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 570, or a variant thereof; cc) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 575, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 580, or a variant thereof; dd) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 585, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 590, or a variant thereof; ee) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 596, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 602, or a variant thereof; ff) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 607, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 611 , or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 613, or a variant thereof; gg) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1121 , or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 1123, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 1125, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 1129, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 1131 , or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133, or a variant thereof; or the scFv comprises:
(i) a HCVR that comprises the amino acid sequence of SEQ ID NO: 270 or 271 , or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 276, or a variant thereof;
(ii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 281 or 282, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 287, or a variant thereof;
(iii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 292 or 293, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 298, or a variant thereof;
(iv) a HCVR that comprises the amino acid sequence of SEQ ID NO: 303, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 308 or 309, or a variant thereof;
(v) a HCVR that comprises the amino acid sequence of SEQ ID NO: 314, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 319 or 320, or a variant thereof;
(vi) a HCVR that comprises the amino acid sequence of SEQ ID NO: 325 or 326, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 331 or 332, or a variant thereof;
(vii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 337 or 338, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 343 or 344, or a variant thereof;
(viii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 349 or 350, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 355 or 356, or a variant thereof;
(ix) a HCVR that comprises the amino acid sequence of SEQ ID NO: 361 , or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 366, or a variant thereof;
(x) a HCVR that comprises the amino acid sequence of SEQ ID NO: 371 or 372, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 377, or a variant thereof;
(xi) a HCVR that comprises the amino acid sequence of SEQ ID NO: 382, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 387, or a variant thereof;
(xii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 392 or 393, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 398 or 399, or a variant thereof;
(xiii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 404, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 409, or a variant thereof;
(xiv) a HCVR that comprises the amino acid sequence of SEQ ID NO: 414, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 419, or a variant thereof;
(xv) a HCVR that comprises the amino acid sequence of SEQ ID NO: 424 or 425, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 430 or 431 , or a variant thereof;
(xvi) a HCVR that comprises the amino acid sequence of SEQ ID NO: 436, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 441 , or a variant thereof;
(xvii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 446 or 447, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 452, or a variant thereof;
(xviii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 457, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 462, or a variant thereof;
(xix) a HCVR that comprises the amino acid sequence of SEQ ID NO: 467 or 468, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 473 or 474, or a variant thereof;
(xx) a HCVR that comprises the amino acid sequence of SEQ ID NO: 479 or 480, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 485, or a variant thereof;
(xxi) a HCVR that comprises the amino acid sequence of SEQ ID NO: 490 or 491 , or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 496, or a variant thereof;
(xxii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 501 , or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 506, or a variant thereof;
(xxiii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 511 , or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 516, or a variant thereof;
(xxiv) a HCVR that comprises the amino acid sequence of SEQ ID NO: 521 , or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 526, or a variant thereof;
(xxv) a HCVR that comprises the amino acid sequence of SEQ ID NO: 531 , or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 536, or a variant thereof;
(xxvi) a HCVR that comprises the amino acid sequence of SEQ ID NO: 541 or 542, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 547, or a variant thereof;
(xxvii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 552, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 557, or a variant thereof;
(xxviii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 562, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 567, or a variant thereof;
(xxix) a HCVR that comprises the amino acid sequence of SEQ ID NO: 572, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 577, or a variant thereof;
(xxx) a HCVR that comprises the amino acid sequence of SEQ ID NO: 582, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 587, or a variant thereof;
(xxxi) a HCVR that comprises the amino acid sequence of SEQ ID NO: 592 or 593, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 598 or 599 , or a variant thereof;
(xxxii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 604, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 609 or 610, or a variant thereof;
(xxxiii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 1119, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 1127, or a variant thereof; e.g., wherein the HCVR and LCVR are in either orientation (HCVR-LCVR or LCVR-HCVR), optionally, wherein the HCVR and LCVR are linked by a linker, e.g., that comprises an amino acid sequence, e.g., about 10 amino acids in length, for example: (Gly4Ser)n (SEQ ID NO: 241) wherein n is 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[00465] In some embodiments, an anti-TfR scFv of the present disclosure, in VL-(Gly4Ser)3 (SEQ ID NO: 1115)-VH format, comprises an amino acid sequence as of Table 9. In other embodiments, the present disclosure includes scFvs that are in the format VH- (Gly4Ser)3(SEQ ID NO: 1115)-VL. Table 9. Anti-hTfR scFv Molecules
[00466] Fab fragments that bind specifically to TfR form part of the present disclosure. Fab fragments typically contain one complete light chain, VL and a constant light (CL) domain, e.g., kappa (e.g., RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1147)); and the VH and IgG 1 CH1 portion (e.g.,
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1 179)) or ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1112); or lgG4 CH1 (e.g., ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG (SEQ ID NO: 1171), or ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1135)) of one heavy chain. Fab fragment antibodies can be generated by papain digestion of whole IgG antibodies to remove the entire Fc fragment, including the hinge region. For example, the present disclosure includes Fab proteins comprising:
(1) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 270 or 271 , or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 276, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(2) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 281 or 282, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 287, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(3) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 292 or 293, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 298, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(4) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 303, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 308 or 309, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(5) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 314, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 319 or 320, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(6) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 325 or 326, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 331 or 332, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(7) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 337 or 338, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 343 or 344, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(8) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 349 or 350, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 355 or 356, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(9) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 361, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 366, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(10) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 371 or 372, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 377, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(11) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 382, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 387, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(12) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 392 or 393, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 398 or 399, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(13) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 404, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 409, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(14) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 414, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 419, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(15) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 424 or 425, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 430 or 431 , or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(16) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 436, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 441 , or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(17) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 446 or 447, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 452, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(18) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 457, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 462, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(19) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 467 or 468, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 473 or 474, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(20) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 479 or 480, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 485, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(21) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 490 or 491 , or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 496, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(22) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 501, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 506, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(23) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 511 , or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 516, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(24) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 521, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 526, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(25) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 531, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 536, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(26) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 541 or 542, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 547, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(27) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 552, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 557, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(28) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 562, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 567, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(29) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 572, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 577, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(30) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 582, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 587, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(31) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 592 or 593, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 598 or 599 , or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(32) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 604, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 609 or 610, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain; and/or
(33) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 1119, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 1127, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain; e.g., wherein CH1 is from IgG 1 or lgG4; e.g., wherein CH1 is SEQ ID NO: 1147, 1179, 1112, 1171, or 1135.
[00467] The heavy and light chains of anti-TfR Fabs in anti-AAV/anti-TfR multispecific antibodies of the present disclosure are set forth below.
(1) 31874B
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPNLLIYAASTLQSGVPSRF
SGSGSGTDFTLTISSLQPEDVATYYCQKYNSAPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 975)
Fab Heavy Chain
EVQ LVESG G G LVQ PG G SLRLSCAASG F AFSSYAMTWVRQ APG KG LEWVSVI SGTGG STY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGGAARRMEYFQYWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1061)
(2) 31863B
Fab Light Chain
DIQMTQSPSSLSASIGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRF SGSGSGTDFTLTISSLQPEDVATYYCQNHNSVPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 977)
Fab Heavy Chain
EVQLVESGGGLVQPGGSLRLSCAASGFTFNSYAMTWVRQAPGKGLEWVSFIGGSTGNTY
YAGSVKGRFTISSDNSKKTLYLQMNSLRAEDTAVYYCAKGGAARRMEYFQHWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1062)
(3) 69348
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQSIRNVLGWFQQKPGKAPQRLIYAASSLQSGVPSR FSGSGSGTEFTLTISSLQPEDFATYYCLQHNFYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 979)
Fab Heavy Chain
QVQLVESGGGWQPGRSLRLSCAASGFTFTTYGMHWVRQAPGKGLEWVAVIWYDGSNK
YYGDSVKGRFTISRDNSKNTLYLQMNSLRVDDTAVYYCTRTHGYTRSSDGFDYWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO:
1063) (4) 69340
Fab Light Chain
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIHDVSNRATGIPARF SGSGSGTDFTLTISSLEPEDFWYYCQQRSDWPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 981)
Fab Heavy Chain
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDKAMHWVRQVPGKGLEWISGISWNSGTIGY ADSVKGRFIISRDNAKNSLYLQMNSLRAEDTALYYCAKDGDTSGWYWYGLDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1064)
(5) 69331
Fab Light Chain
DIQLTQSPSSLSASVGDRVTITCWASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRF SGSGSGTEFTLTISSLQPEDFATYYCQQLNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQL KSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD
YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 983)
Fab Heavy Chain
QVQLVESGGGWQPGRSLRLSCIASGFTFSVYGIHWVRQAPGKGLEWMAVISHDGNIKHY ADSVKGRFTISRDNSKNTLYLQINSLRTEDTAVYYCAKDTWNSLDTFDIWGQGTMVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1065)
(6) 69332
Fab Light Chain
AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASTLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCLQDYNYPFTFGPGTKVDIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK
ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 985)
Fab Heavy Chain QVTLRESGPALVKPSQTLTLTCTFSGFSLNTYGMFVSWIRQPPGKALEWLAHIHWDDDKYY
STSLKTRLTISKDTSKNQWLTMTNMDPVDTATYYCARGHNNLNYIIHWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1066)
(7) 69326
Fab Light Chain
EIVMTQSPATLSVSPGERATLSCRASQSVSSNFAWYQQKPGQAPRLLIYSASSRATGIPVR
FSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIWPRTFGQGTKVEIKRTVAAPSVFIFPPSDE
QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 987)
Fab Heavy Chain
EVQ LVESG G G LVQ PG G SLRLSCAVSG F I FSSYEM N WVRQ APG KG LEWVSYI SSSGST I FYA
DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCVSGWLFDVWGQGTMVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1067)
(8) 69329
Fab Light Chain
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQKANSFPYTFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK
ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 989)
Fab Heavy Chain
EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMTWVRQAPGKGLEWVANIKEDGSEKD
YVDSVKGRFTISRDNAKNSLYLQMNSLRGEDTAVYYCARDGEQLVDYYYYYVMDVWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1068)
(9) 69323
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKVLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSIPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQL KSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 991)
Fab Heavy Chain
EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGYIG YADSVKGRFTISRDNAENSLHLQMNSLRAEDTALYYCARGGSTLVRGVKGGYYGMDVWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID
NO: 1069)
(10) 69305
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQSIDRYLNWYRQKPGKAPKLLIYTTSSLQSGVPSRF SGSGSGTDFTLTLSSLQPEDFATYYCQQSYSPPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 993)
Fab Heavy Chain
QVQLVESGGGWQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNK YYADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAGQLDLFFDYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1070)
(1 1) 69307
Fab Light Chain
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQKADSLPYAFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK
ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 995)
Fab Heavy Chain
EVQ LVESG G G LVQ PG G SLRLSCTASG FTFSN YWMTWVRQAPG KG LEWVAN I KEDG SEKE YVDSVKGRFTISRDNAKNSLYLQMNSLRGEDTAVYYCARDGEQLVDYYYYYVMDVWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1071)
(12) 12795B
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQGIRDHFGWYQQKPGKAPKRLIYAASSLHSGVPSR FSGSGSGTEFTLTISSLQPEDFATYYCLQYDTYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 997)
Fab Heavy Chain
EVQ LVESG G G LVQ PG G SLR LSCATSG FTFTSYDM KWVRQ APG LG LE WVSAI SG SG G NTY YADSVKGRFTISRDNSRNTLYLQMNSLRAEDTAVYYCTRSHDFGAFDYFDYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1072)
(13) 12798B
Fab Light Chain
EIVMTQSPATLSVSPGERATLSCRASQTVSSNLAWYQQKPGQAPRLLIYGSSSRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPYTFGQGTKLEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 999)
Fab Heavy Chain
EVQ LVESGG DLVQ PG RSLRLSCAASG FTFDDYAM H WVRQAPG KG LEWVSG I SWNSATRV YADSVKGRFTISRDNAKNFLYLQMNSLRSEDTALYHCAKDMDISLGYYGLDVWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1073);
EVQLVESGG DLVQPG RSLRLSCAASG FTFDDYAM H WVRQAPG KG LEWVSG I SWNSATRV YADSVKGRFTISRDNAKNFLYLQMNSLRSEDTALYHCAKDMDISLGYYGLDVWGQGTTVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG (SEQ ID NO: 1074); or
EVQLVESGG DLVQPG RSLRLSCAASG FTFDDYAM H WVRQAPG KG LEWVSG I SWNSATRV YADSVKGRFTISRDNAKNFLYLQMNSLRSEDTALYHCAKDMDISLGYYGLDVWGQGTTVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1075)
(14) 12799B
Fab Light Chain
DIQMTQSPSSVSASVGDRVTITCRASQGIASWLAWYQQKPGKAPELLIYAASSLQGGVPSR FSGSGSGTDFTLTISSLQPEDFAIYYCQQANYFPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK
ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1001)
Fab Heavy Chain
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGWWIRQPPGKALEWLALIYWNDHKRYS PSLGSRLTITKDTSKNQWLTMTNMDPVDTATYYCAHYSGSYSYYYYGLDVWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1076);
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGWWIRQPPGKALEWLALIYWNDHKRYS PSLGSRLTITKDTSKNQWLTMTNMDPVDTATYYCAHYSGSYSYYYYGLDVWGQGTTVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG (SEQ ID NO: 1077); or
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGWWIRQPPGKALEWLALIYWNDHKRYS PSLGSRLTITKDTSKNQWLTMTNMDPVDTATYYCAHYSGSYSYYYYGLDVWGQGTTVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1078)
(15) 12801B
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQGIRTDLGWYQQKPGKAPKRLIYAASSLQSGVPSR FSGSGSGTEFTLTISSLRPEDFATFYCLQYNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1003)
Fab Heavy Chain EVQLLESGGALVQPGGSLRLSCAASGFTFTSYAMHWVRQAPGKGLEWVSSIRGSGGGTY
SADSVKGRFTISRDNSRDTLYLQMNSVRAEDTAVYYCARSHDYGAFDFFDYWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1079)
(16) 12802B
Fab Light Chain
EIVMTQSPATLSVSPGERATLSCRASQSVSINLAWYQQKPGQAPRLLIFVASTRATGIPARF
SGSGSGTEFTLTISSLQSEDFATYYCQQYDIWPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQL
KSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD
YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1005)
Fab Heavy Chain
QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYFMSWIRQAPGKGLEWVSYISSTGSTINYA
DSVKGRFTISRDNVKNSLYLQMTSLRVEDTAVYYCTRDNWNYEYWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS
SWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1080)
(17) 12808B
Fab Light Chain
DIQMTQSPSSLSASVGDRVTINCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPLR
FSGSGSGTEFTLTINNLQPEDFATYYCLSHNSYPWTFGQGTKVEIKRTVAAPSVFIFPPSDE
QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK
ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1007)
Fab Heavy Chain
QLQLQESGPGLVKPSETLSLTCTVSGESISSNTYYWGWIRQPPGKGLEWIGSIDYSGTTNY
NPSLKSRVTISVDTSRNHFSLRLRSVTAADTAVYYCAREWGNYGYYYGMDVWGQGTTVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1081)
(18) 12812B
Fab Light Chain
DIQMTQSPPSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR
FSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPRTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK
ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1009)
Fab Heavy Chain
QVQLVQSGAEVKKPGSSVRVSCKASRGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANY AQKFLARVTITADESTSTAYMELSSLRSEDTAVYYCAREKGWNYFDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1082)
(19) 12816B
Fab Light Chain
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHGNGYNYLTWYLQKPGQSPQLLIYLGSNRAS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST
LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1011)
Fab Heavy Chain
QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMNWIRQAPGKGLEWVSYISSSGTTIYYA DSVKGRFTISRDNAKKSLYLEMNSLRAEDTAVYYCAREGYGNDYYYYGIDVWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1083)
(20) 12833B
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
Fab Heavy Chain
QVQLVESGGGWQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVIFISYDGSDKY YADSVKGRFAISRDSSKNTLYLQMNSLRAEDTAVYYCAKENGILTDSYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1084) (21) 12834B
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
Fab Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISVYHGNTN YAQKFQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAREGYYDFWSGYYPFDYWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1085)
(22) 12835B
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
Fab Heavy Chain
EVQLVESGGGLIQPGGSLRLSCEASGFTFRNYEMNWVRQAPGKGLEWVSYISSSGNMKD YAESVKGRFTISRDNVKNSLQLQMNSLRVEDTAVYYCARDEFPYGMDVWGQGTTVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1086)
(23) 12847B
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
Fab Heavy Chain EVQ LVESG G G LVQ PG RSLRLSC AASG FTF DDYAM N WVRQ APG KG LEWVSG I SWSSG SM DYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCAKAREVGDYYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1087);
EVQ LVESG G G LVQ PG RSLRLSC AASG FTF DDYAM N WVRQ APG KG LEWVSG I SWSSG SM DYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCAKAREVGDYYGMDVWGQGTTVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG (SEQ ID NO: 1088); or
EVQ LVESG G G LVQ PG RSLRLSC AASG FTF DDYAM N WVRQ APG KG LEWVSG I SWSSG SM DYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCAKAREVGDYYGMDVWGQGTTVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1089)
(24) 12848B
Fab Light Chain
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR FSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1018)
Fab Heavy Chain
EVQLVESGGGLVQPGRSLTLSCAASGFTFDNFGMHWVRQGPGKGLEWVSGLTWNSGVIG YADSVKGRFTISRDNAKNSLYLQMNSLRPEDTALYYCAKDIRNYGPFDYWGQGTLVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1090)
(25) 12843B
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013) Fab Heavy Chain
EVQ LVESG G G LVQ PG G SLRLSCAASG FTF N I FEM N WVRQAPG KG LEWI SYI SSRGTTTYYA DSVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDYEATIPFDFWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1091);
EVQ LVESG G G LVQ PG G SLRLSCAASG FTF N I FEM N WVRQAPG KG LEWI SYI SSRGTTTYYA DSVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDYEATIPFDFWGQGTLVTVSSAST KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG
(SEQ ID NO: 1092); or
EVQ LVESG G G LVQ PG G SLR LSCAASG FTF N I FEM N WVRQAPG KG LEWI SYI SSRGTTTYYA DSVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDYEATIPFDFWGQGTLVTVSSAST KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP
(SEQ ID NO: 1093)
(26) 12844B
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
Fab Heavy Chain
EVQLVESGGSWRPGGSLRLSCEASGFTFDDYGMSWVRQDPGKGLEWVSGINWNGDRT NYADSVKGRFIISRDNAKNSVYLQMNSLRAEDSALYHCARDQGLGVAATLDYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1094)
(27) 12845B
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
Fab Heavy Chain
EVQ LVESG G G LVQ PG G SLRLSCAASG FTVSN YEM N WVRQ APG KG LEWVSYI SSSTSN I YY ADSVKGRFTISRDNAENSLYLQMNSLRVEDTAVYYCVRDGIWVPVGRGYYYYGLDVWGQ GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1095);
EVQ LVESG G G LVQ PG G SLR LSCAASG FTVSN YEM N WVRQ APG KG LEWVSYI SSSTSN I YY ADSVKGRFTISRDNAENSLYLQMNSLRVEDTAVYYCVRDGIVWPVGRGYYYYGLDVWGQ GTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG
(SEQ ID NO: 1096); or
EVQ LVESG G G LVQ PG G SLRLSCAASG FTVSN YEM N WVRQ APG KG LEWVSYI SSSTSN I YY ADSVKGRFTISRDNAENSLYLQMNSLRVEDTAVYYCVRDGIWVPVGRGYYYYGLDVWGQ GTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP
(SEQ ID NO: 1097)
(28) 12839B
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
Fab Heavy Chain
QVQLVESGGGWQPGRSLRLSCAASGFPFSNYVMYWVRQAPGKGLEWVALIFFDGKKNY HADSVKGRFTITRDNSKNMLYLQMNSLRPEDAAVYYCAKIHCPNGVCYKGYYGMDVWGQ GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1098); QVQLVESGGGWQPGRSLRLSCAASGFPFSNYVMYWVRQAPGKGLEWVALIFFDGKKNY HADSVKGRFTITRDNSKNMLYLQMNSLRPEDAAVYYCAKIHCPNGVCYKGYYGMDVWGQ GTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG
(SEQ ID NO: 1099)
QVQLVESGGGWQPGRSLRLSCAASGFPFSNYVMYWVRQAPGKGLEWVALIFFDGKKNY HADSVKGRFTITRDNSKNMLYLQMNSLRPEDAAVYYCAKIHCPNGVCYKGYYGMDVWGQ GTTVTVSSASTKGPSVFPL7\PCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP
(SEQ ID NO: 1100)
(29) 12841B
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
Fab Heavy Chain
EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMNWVRQAPGKGLEWVANIKEDGGKKL YVDSVKGRFTISRDNAKNSLFLQMNSLRAEDTAVYYCAREDTTLWDYYYYGMDVWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1101)
(30) 12850B
Fab Light Chain
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR FSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK
ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1018)
Fab Heavy Chain
QVQLVQSGAEVKKPGSSVKVSCKASGGTFNTYAITWVRQAPGQGLEWMGGIIPISGIAEYA QKFQGRVTITTDDSSTTAYMELNSLRSEDTAVYYCASWNYALYYFYGMDVWGRGTTVTVS
SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
GLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1102)
(31) 69261
Fab Light Chain
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQFLIYLGSNRAS GVPDRFSGSGSGTDFTLKINRVEAEDVGVYYCMQALQTPYTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1026)
Fab Heavy Chain
QVQLVESGGGLVKPGGSLRLSCAASGFTFSVYYMNWIRQAPGKGLEWVSYISSSGSTIYYA DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCGREGYSGTYSYYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO:
1103)
(32) 69263
Fab Light Chain
DIQMTQSPSSLSASVGDRVTITCRASQDISHYSAWYQQKPGKLPNLLIYAASTLQSGVPSRF SGSGSGTDFSLTTSSLQPEDVATYYCQKYNSVPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1028)
Fab Heavy Chain
EVQLVESGGGLVQPGRSLRLSCAVSGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGTR GYADSVKGRFTISRDNAKNSLYLQMNSLRGEDTALYYCVKDITISPNYYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO:
1104)
[00468] In some embodiments, the cell surface molecule which may be bound by an anti- AAV/anti-cell surface multispecific antibody herein is calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1). According to certain embodiments, an anti-AAV/anti- CACNG1 multispecific antibody may comprise a second antigen-binding domain that binds to CACNG1 , wherein the second antigen-binding domain comprises any of the heavy chain variable region (HCVR) amino acid sequences as set forth in Table 10. The second antigenbinding domain that binds to CACNG1 may also comprise any of the light chain variable region (LCVR) amino acid sequences as set forth in Table 10. In some embodiments, the second antigen-binding domain that binds to CACNG1 may comprise any of the HCVR/LCVR amino acid sequence pairs as set forth in Table 10. The present disclosure also provides anti-AAV/anti-CACNG1 multispecific antibodies, wherein the second antigenbinding domain that binds to CACNG1 comprises any of the heavy chain CDR1-CDR2- CDR3 amino acid sequences as set forth in Table 10, and/or any of the light chain CDR1- CDR2-CDR3 amino acid sequences as set forth in Table 10.
[00469] In another aspect, provided herein are nucleic acid molecules encoding any of the CDR, HCVR, LCVR, HC, or LC sequences of the anti-AAV/anti-CACNG1 mutispecific antigen-binding molecules disclosed herein, or variants thereof, including nucleic acid molecules comprising any of the polynucleotide sequences as set forth in Table 2 herein, as well as nucleic acid molecules comprising any of the polynucleotide sequences as set forth in Table 11 herein, in any combination thereof. In some embodiments, the nucleic acid molecules described herein may comprise one or more polynucleotide sequence(s) in Table 2 that encode a pair of HCVR/LCVR amino acid sequences, and one or more polynucleotide sequence(s) selected from Table 11 that encode a pair of HCVR/LCVR amino acid sequences. In some embodiments, the nucleic acid molecules described herein may comprise one or more polynucleotide sequence(s) selected from Table 2 that encode a set of six CDRs (i.e. , HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3), and one or more polynucleotide sequence(s) selected from Table 11 that encode a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3).
Table 10. Amino Acid Sequence Identifiers for Anti-CACNG1 Antibodies
Table 11. Nucleic Acid Sequence Identifiers for Anti-CACNG1 Antibodies
H2aM31929N/REGN10728
HCVR DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG
ACTCTCCTGTACAG CGTCTG G AATCACCTTCAG AAATTATG G CATG CACTG G GTCCGCC
AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAA
GTACTATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGGTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAA GGGGCACTATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCCTCA (SEQ ID NO: 614)
HCVR Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNK
YYADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTVSS (SEQ ID NO: 615)
HCDR1 DNA Sequence
GGAATCACCTTCAGAAATTATGGC (SEQ ID NO: 616)
HCDR1 Amino Acid Sequence GITFRNYG (SEQ ID NO: 617)
HCDR2 DNA Sequence
ATGTGGTATGATGGAAGTAATAAG (SEQ ID NO: 618)
HCDR2 Amino Acid Sequence
MWYDGSNK (SEQ ID NO: 619)
HCDR3 DNA Sequence
GCGAGAAGGGGCACTATAAGAACAGCTGCCCCTTTTGACTAC (SEQ ID NO: 620)
HCDR3 Amino Acid Sequence
ARRGTIRTAAPFDY (SEQ ID NO: 621)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA
CO ATCACTTG COG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGO AG AAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT
GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA
CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 622)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 623)
LCDR1 DNA Sequence
CAGAG CATTAG CAG CTAT (SEQ ID NO: 624)
LCDR1 Amino Acid Sequence
QSISSY (SEQ ID NO: 625)
LCDR2 DNA Sequence
GCTGCATCC (SEQ ID NO: 626)
LCDR2 Amino Acid Sequence
AAS (SEQ ID NO: 627) LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 628)
LCDR3 Amino Acid Sequence
QQSYSTPPIT (SEQ ID NO: 629)
HC DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTACAG CGTCTG G AATCACCTTCAG AAATTATG G CATG CACTG G GTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAA GTACTATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGGTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAA GGGGCACTATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGA ACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC AGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCA AGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACC AGGCGGTGGCGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATG ATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCC GAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGC CGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGC ACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCC GTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTG TACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCC TGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGC CGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCT CTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATG CTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTC
TGGGTAAATGA (SEQ ID NO: 630)
HC Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNK YYADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPSVFLF PPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRW SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 631)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 632)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 633)
H2aM31944N
HCVR DNA Sequence
CAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA CTCTCCTGTGAAGCGTCTGGAATCACCTTCAGAAACTATGGCATGCACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAA ATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA CGGTGTATCTGCAAATGAACAGCCTGAGAGCCGAAGACACGGCTGTGTATTACTGTGC GAGACGGGGTCATATAGCAACAGCTGCTCCCTTTGACTACTGGGGCCAGGGAACCCTG GTCACCGTCTCCTCA (SEQ ID NO: 634)
HCVR Amino Acid Sequence QVQLVESGGGWQPGRSLRLSCEASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNK
YYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARRGHIATAAPFDYWGQGTLVTV
SS (SEQ ID NO: 635)
HCDR1 DNA Sequence
GGAATCACCTTCAGAAACTATGGC (SEQ ID NO: 636)
HCDR1 Amino Acid Sequence
GITFRNYG (SEQ ID NO: 637)
HCDR2 DNA Sequence
ATGTGGTATGATGGAAGTAATAAA (SEQ ID NO: 638)
HCDR2 Amino Acid Sequence
MWYDGSNK (SEQ ID NO: 639)
HCDR3 DNA Sequence
GCGAGACGGGGTCATATAGCAACAGCTGCTCCCTTTGACTAC (SEQ ID NO: 640)
HCDR3 Amino Acid Sequence
ARRGHIATAAPFDY (SEQ ID NO: 641)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCCGTAGGAGACAGAGTCA
CCATCAGTTGCCGGGCAAGTCAGAGCATTAGTAGTTATTTAAATTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAAGGTCCTGATGTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTG
CAACCTGAGGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCAC
CTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 642)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTISCRASQSISSYLNWYQQKPGKAPKVLMYAASSLQSGVPSR
FSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 643)
LCDR1 DNA Sequence
CAGAGCATTAGTAGTTAT (SEQ ID NO: 644) LCDR1 Amino Acid Sequence
QSISSY (SEQ ID NO: 645)
LCDR2 DNA Sequence
GCTGCATCC (SEQ ID NO: 646)
LCDR2 Amino Acid Sequence
AAS (SEQ ID NO: 647)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 648)
LCDR3 Amino Acid Sequence
QQSYSTPPIT (SEQ ID NO: 649)
HC DNA Sequence
CAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA
CTCTCCTGTGAAGCGTCTGGAATCACCTTCAGAAACTATGGCATGCACTGGGTCCGCC
AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAA
ATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA
CGGTGTATCTGCAAATGAACAGCCTGAGAGCCGAAGACACGGCTGTGTATTACTGTGC
GAGACGGGGTCATATAGCAACAGCTGCTCCCTTTGACTACTGGGGCCAGGGAACCCTG
GTCACCGTCTCCTCAGCCAAAACAACAGCCCCATCGGTCTATCCACTGGCCCCTGTGT
GTGGAGATACAACTGGCTCCTCGGTGACTCTAGGATGCCTGGTCAAGGGTTATTTCCC
TGAGCCAGTGACCTTGACCTGGAACTCTGGATCCCTGTCCAGTGGTGTGCACACCTTC
CCAGCTGTCCTGCAGTCTGACCTCTACACCCTCAGCAGCTCAGTGACTGTAACCTCGA
GCACCTGGCCCAGCCAGTCCATCACCTGCAATGTGGCCCACCCGGCAAGCAGCACCA
AGGTGGACAAGAAAATTGAGCCCAGAGGGCCCACAATCAAGCCCTGTCCTCCATGCAA
ATGCCCAGCACCTAACCTCTTGGGTGGACCATCCGTCTTCATCTTCCCTCCAAAGATCA
AGGATGTACTCATGATCTCCCTGAGCCCCATAGTCACATGTGTGGTGGTGGATGTGAG
CGAGGATGACCCAGATGTCCAGATCAGCTGGTTTGTGAACAACGTGGAAGTACACACA
GCTCAGACACAAACCCATAGAGAGGATTACAACAGTACTCTCCGGGTGGTCAGTGCCC
TCCCCATCCAGCACCAGGACTGGATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAA
CAAAGACCTCCCAGCGCCCATCGAGAGAACCATCTCAAAACCCAAAGGGTCAGTAAGA GCTCCACAGGTATATGTCTTGCCTCCACCAGAAGAAGAGATGACTAAGAAACAGGTCAC
TCTG ACCTG CATG GTCACAG ACTTCATG CCTG AAG ACATTTACGTG G AGTGG ACCAAC A ACGGGAAAACAGAGCTAAACTACAAGAACACTGAACCAGTCCTGGACTCTGATGGTTCT TACTTCATGTACAGCAAGCTGAGAGTGGAAAAGAAGAACTGGGTGGAAAGAAATAGCTA
CTCCTGTTCAGTGGTCCACGAGGGTCTGCACAATCACCACACGACTAAGAGCTTCTCC
CGGACTCCGGGTAAATGA (SEQ ID NO: 650)
HC Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCEASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNK
YYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARRGHIATAAPFDYWGQGTLVTV
SSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQS
DLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGP
SVFIFPPKIKDVLMISLSPIVTCWVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLR
WSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQ
VTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNS
YSCSWHEGLHNHHTTKSFSRTPGK (SEQ ID NO: 651)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCCGTAGGAGACAGAGTCA
CCATCAGTTGCCGGGCAAGTCAGAGCATTAGTAGTTATTTAAATTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAAGGTCCTGATGTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTG
CAACCTGAGGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCAC
CTTCGGCCAAGGGACACGACTGGAGATTAAACGAGCTGATGCTGCACCAACTGTATCC
ATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCTT
GAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGAC
AAAATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCAT
GAGCAGCACCCTCACGTTGACCAAGGACGAGTATGAACGACATAACAGCTATACCTGT
GAGGCCACTCACAAGACATCAACTTCACCCATTGTCAAGAGCTTCAACAGGGGAGAGT GTTGA (SEQ ID NO: 652)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTISCRASQSISSYLNWYQQKPGKAPKVLMYAASSLQSGVPSR
FSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRADAAPTVSIFPPSSE
QLTSGGASWCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTK
DEYERHNSYTCEATHKTSTSPIVKSFNRGEC (SEQ ID NO: 653)
H4H31265P2/REGN5972
HCVR DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTACAGCGTCTGGATTCACCTTCCGTTCCTATGGCATGCACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGTCAGTTATTTGGATTGATGGAAATAATAT ATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA CGCTGTATCTGCAAATGGACAGCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGC G AG AAG ACTG G CTATAACATCAG CTG CCCCCTTTG ACTACTG G GG CCAGG G AACCCTG GTCACCGTCTCCTCA (SEQ ID NO: 654)
HCVR Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCTASGFTFRSYGMHWVRQAPGKGLEWVSVIWIDGNNIY YADSVKGRFTISRDNSKNTLYLQMDSLRAEDTAVYYCARRLAITSAAPFDYWGQGTLVTVS S (SEQ ID NO: 655)
HCDR1 DNA Sequence
GGATTCACCTTCCGTTCCTATGGC (SEQ ID NO: 656)
HCDR1 Amino Acid Sequence
GFTFRSYG (SEQ ID NO: 657)
HCDR2 DNA Sequence
ATTTGGATTGATGGAAATAATATA (SEQ ID NO: 658)
HCDR2 Amino Acid Sequence
IWIDGNNI (SEQ ID NO: 659)
HCDR3 DNA Sequence
GCGAGAAGACTGGCTATAACATCAGCTGCCCCCTTTGACTAC (SEQ ID NO: 660)
HCDR3 Amino Acid Sequence
ARRLAITSAAPFDY (SEQ ID NO: 661)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG COG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGO AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 662) LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 663)
LCDR1 DNA Sequence
CAGAG CATTAG C AG CTAT (SEQ ID NO: 664)
LCDR1 Amino Acid Sequence
QSISSY (SEQ ID NO: 665)
LCDR2 DNA Sequence
GCTGCATCC (SEQ ID NO: 666)
LCDR2 Amino Acid Sequence
AAS (SEQ ID NO: 667)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 668)
LCDR3 Amino Acid Sequence
QQSYSTPPIT (SEQ ID NO: 669)
HC DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTACAGCGTCTGGATTCACCTTCCGTTCCTATGGCATGCACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGTCAGTTATTTGGATTGATGGAAATAATAT ATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA CGCTGTATCTGCAAATGGACAGCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGC G AG AAG ACTG G CTATAACATCAG CTG CCCCCTTTG ACTACTG G GG CCAGG G AACCCTG GTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCT CCAG GAG CACCTCCG AG AG CAGAG COG CCCTG GG CTG CCTG GTCAAG GACTACTTCC CCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCT
TCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCC CTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAAC ACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAG CACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACAC TCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGA
AGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAG
ACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACC
GTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAG
GCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCC
ACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCT
GACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAA
TGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTC
CTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTC
TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTC
CCTGTCTCTGGGTAAATGA (SEQ ID NO: 670)
HC Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCTASGFTFRSYGMHWVRQAPGKGLEWVSVIWIDGNNIY
YADSVKGRFTISRDNSKNTLYLQMDSLRAEDTAVYYCARRLAITSAAPFDYWGQGTLVTVS
SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
GLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF
LFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR
WSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ
VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV
FSCSVMHEALHNHYTQKSLSLSLGK* (SEQ ID NO: 671)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA
CC ATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT
GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA
CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT
CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC
TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA
ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAACACAAAGTCTACG CC
TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA
GAGTGTTAG (SEQ ID NO: 672)
LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 673)
H2aM31941N
HCVR DNA Sequence
CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAG
GTCTCCTGCAAGGCTTCTGGTTACGCCTTCACCACCTATGGTATCACCTGGGTGCGAC
AGGCCCCTGGACAAGGACTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAATAC
AAACTATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAAT
ACAGCCTACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGTG
CGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTGG
GGCCAAGGGACAATGGTCACCGTCTCTTCA (SEQ ID NO: 674)
HCVR Amino Acid Sequence
QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNTN
YAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWGQ
GTMVTVSS (SEQ ID NO: 675)
HCDR1 DNA Sequence
GGTTACGCCTTCACCACCTATGGT (SEQ ID NO: 676)
HCDR1 Amino Acid Sequence
GYAFTTYG (SEQ ID NO: 677)
HCDR2 DNA Sequence
ATCAGCGCTTACAATGGAAATACA (SEQ ID NO: 678)
HCDR2 Amino Acid Sequence
ISAYNGNT (SEQ ID NO: 679)
HCDR3 DNA Sequence
GCGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTT (SEQ ID NO: 680)
HCDR3 Amino Acid Sequence ARKGHYGSGTYYNPFGFDF (SEQ ID NO: 681)
LCVR DNA Sequence
GAAATTATGTTGATGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCAC
CCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACAG AAACCTG G CCAG G CTCCCAGGCTCCTCATCTATG GTG CATCCAG CAG GG CCACTG ACA TCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAG ACTGGAGCCTGAAGATTTTGCAGTTTATTTCTGTCAGCAGTATTATGGCTCACCTTGGA CGTTCGGCCAAGGGACCAAGGTGGAAATCAAGCG (SEQ ID NO: 682)
LCVR Amino Acid Sequence
EIMLMQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATDIPD RFSGSGSGTDFTLTISRLEPEDFAVYFCQQYYGSPWTFGQGTKVEIK (SEQ ID NO: 683)
LCDR1 DNA Sequence
CAGAGTGTTAGCAGCAGCTAC (SEQ ID NO: 684)
LCDR1 Amino Acid Sequence
QSVSSSY (SEQ ID NO: 685)
LCDR2 DNA Sequence
GGTGCATCC (SEQ ID NO: 686)
LCDR2 Amino Acid Sequence
GAS (SEQ ID NO: 687)
LCDR3 DNA Sequence
CAGCAGTATTATGGCTCACCTTGGACG (SEQ ID NO: 688)
LCDR3 Amino Acid Sequence
QQYYGSPWT (SEQ ID NO: 689)
HC DNA Sequence
CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAG GTCTCCTGCAAGGCTTCTGGTTACGCCTTCACCACCTATGGTATCACCTGGGTGCGAC AGGCCCCTGGACAAGGACTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAATAC
AAACTATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAAT ACAGCCTACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGTG CGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTGG GGCCAAGGGACAATGGTCACCGTCTCTTCAGCCAAAACGACACCCCCATCTGTCTATC CACTGGCCCCTGGATCTGCTGCCCAAACTAACTCCATGGTGACCCTGGGATGCCTGGT CAAGGGCTATTTCCCTGAGCCAGTGACAGTGACCTGGAACTCTGGATCCCTGTCCAGC GGTGTGCACACCTTCCCAGCTGTCCTGCAGTCTGACCTCTACACTCTGAGCAGCTCAG TGACTGTCCCCTCCAGCACCTGGCCCAGCGAGACCGTCACCTGCAACGTTGCCCACCC GGCCAGCAGCACCAAGGTGGACAAGAAAATTGTGCCCAGGGATTGTGGTTGTAAGCCT TGCATATGTACAGTCCCAGAAGTATCATCTGTCTTCATCTTCCCCCCAAAGCCCAAGGA TGTGCTCACCATTACTCTGACTCCTAAGGTCACGTGTGTTGTGGTAGACATCAGCAAGG ATGATCCCGAGGTCCAGTTCAGCTGGTTTGTAGATGATGTGGAGGTGCACACAGCTCA G ACG CAACCCCG G G AGG AG CAGTTCAACAG CACTTTCCGCTCAGTCAGTG AACTTCCC ATCATGCACCAGGACTGGCTCAATGGCAAGGAGTTCAAATGCAGGGTCAACAGTGCAG CTTTCCCTGCCCCCATCGAGAAAACCATCTCCAAAACCAAAGGCAGACCGAAGGCTCC ACAGGTGTACACCATTCCACCTCCCAAGGAGCAGATGGCCAAGGATAAAGTCAGTCTG ACCTG CATG ATAACAG ACTTCTTCCCTG AAG ACATTACTGTGG AGTG G CAGTG G AATG G GCAGCCAGCGGAGAACTACAAGAACACTCAGCCCATCATGGACACAGATGGCTCTTAC TTCGTCTACAGCAAGCTCAATGTGCAGAAGTCCAACTGGGAGGCAGGAAATACTTTCAC CTGCTCTGTGTTACATGAGGGCCTGCACAACCACCATACTGAGAAGTCCCTCTCCCACT CTCCTGGTAAATGA (SEQ ID NO: 690)
HC Amino Acid Sequence
QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNTN YAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWGQ GTMVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHT FPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEV SSVFIFPPKPKDVLTITLTPKVTCVWDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNST FRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKD KVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGN TFTCSVLHEGLHNHHTEKSLSHSPGK (SEQ ID NO: 691)
LG DNA Sequence
GAAATTATGTTGATGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCAC CCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACAG AAACCTG G CCAG G CTCCCAGGCTCCTCATCTATG GTG CATCCAG CAG GG CCACTG ACA TCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAG ACTGGAGCCTGAAGATTTTGCAGTTTATTTCTGTCAGCAGTATTATGGCTCACCTTGGA CGTTCGGCCAAGGGACCAAGGTGGAAATCAAGCGAGCTGATGCTGCACCAACTGTATC CATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCT TGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGA CAAAATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCA TGAGCAGCACCCTCACGTTGACCAAGGACGAGTATGAACGACATAACAGCTATACCTG TGAGGCCACTCACAAGACATCAACTTCACCCATTGTCAAGAGCTTCAACAGGGGAGAG
TGTTGA (SEQ ID NO: 692)
LC Amino Acid Sequence
EIMLMQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATDIPD RFSGSGSGTDFTLTISRLEPEDFAVYFCQQYYGSPWTFGQGTKVEIKRADAAPTVSIFPPSS EQLTSGGASWCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLT
KDEYERHNSYTCEATHKTSTSPIVKSFNRGEC (SEQ ID NO: 693)
REGN7660
HCVR DNA Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCGGGGGGGTCCCTGAA
ACTCTCCTGTACAGCCTCTGGGTTGACCCTCAGTGACTCTGCTATGCACTGGGTCCGC CAGGCTTCCGGGAAAGGGCTGGAGTGGGTTGGCCGTATAAGAAATAAGGCTAATAGGT ACGCGACAGAATATGCTGCGTCGGTGAAAGGCAGGTTCACCATTTCAAGAGATGATTC
AAAGAACACGGCGTATCTACAAATGAACAGCCTGAAAACCGAGGACACGGCCGTGTAT TATTGTACTAGAAACTGGAAGATTTTCCTCTTTGACTACTGGGGCCAGGGAACCCTGGT CACCGTCTCCTCA (SEQ ID NO: 694)
HCVR Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLKLSCTASG LTLSDSAM H WVRQ ASG KG LE WVG Rl RN KAN RYA TEYAASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRNWKIFLFDYWGQGTLVTVSS (SEQ ID NO: 695)
HCDR1 DNA Sequence
GGGTTGACCCTCAGTGACTCTGCT (SEQ ID NO: 696)
HCDR1 Amino Acid Sequence
GLTLSDSA (SEQ ID NO: 697)
HCDR2 DNA Sequence
ATAAGAAATAAGGCTAATAGGTACGCGACA (SEQ ID NO: 698) HCDR2 Amino Acid Sequence
IRNKANRYAT (SEQ ID NO: 699)
HCDR3 DNA Sequence
ACTAGAAACTGGAAGATTTTCCTCTTTGACTAC (SEQ ID NO: 700)
HCDR3 Amino Acid Sequence
TRNWKIFLFDY (SEQ ID NO: 701)
LCVR DNA Sequence
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGACTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTG CAGG G CCAGTCAG AGTGTTGG CAG CAAATACTTAG CCTG GTTCCAG CA GAAACGTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGACCAGTGG CATCCCCGACAGGATCAGTGGCAGTGGGTCAGGGACAGACTTCACTCTCACCATCAGC AGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGAAGTTCACCCTG GACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 702)
LCVR Amino Acid Sequence
EIVLTQSPGTLTLSPGERATLSCRASQSVGSKYLAWFQQKRGQAPRLLIYGASSRTSGIPDR ISGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 703)
LCDR1 DNA Sequence
CAGAGTGTTGGCAGCAAATAC (SEQ ID NO: 704)
LCDR1 Amino Acid Sequence
QSVGSKY (SEQ ID NO: 705)
LCDR2 DNA Sequence
GGTGCATCC (SEQ ID NO: 706)
LCDR2 Amino Acid Sequence
GAS (SEQ ID NO: 707)
LCDR3 DNA Sequence
CAGCAGTATGGAAGTTCACCCTGGACG (SEQ ID NO: 708) LCDR3 Amino Acid Sequence
QQYGSSPWT (SEQ ID NO: 709)
HC DNA Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCGGGGGGGTCCCTGAA
ACTCTCCTGTACAGCCTCTGGGTTGACCCTCAGTGACTCTGCTATGCACTGGGTCCGC
CAGGCTTCCGGGAAAGGGCTGGAGTGGGTTGGCCGTATAAGAAATAAGGCTAATAGGT
ACGCGACAGAATATGCTGCGTCGGTGAAAGGCAGGTTCACCATTTCAAGAGATGATTC
AAAGAACACGGCGTATCTACAAATGAACAGCCTGAAAACCGAGGACACGGCCGTGTAT
TATTGTACTAGAAACTGGAAGATTTTCCTCTTTGACTACTGGGGCCAGGGAACCCTGGT
CACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCC
AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC
GAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTC
CCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCT
CCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCA
CCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTC
TCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAG
ACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGAC
AAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGT
CCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGG
CCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCA
CAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTG
ACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT
GGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCC
TTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCT
TCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCC
CTGTCTCTGGGTAAATGA (SEQ ID NO: 710)
HC Amino Acid Sequence
EVQ LVESG G G LVQ PG G SLKLSCTASG LTLSDSAM H WVRQ ASG KG LE WVG Rl RN KAN RYA
TEYAASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRNWKIFLFDYWGQGTLVTVSS
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL
FPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV
VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV
SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 711)
LC DNA Sequence
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGACTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTG CAGG G CCAGTCAG AGTGTTGG CAG CAAATACTTAG CCTG GTTCC AG CA GAAACGTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGACCAGTGG CATCCCCGACAGGATCAGTGGCAGTGGGTCAGGGACAGACTTCACTCTCACCATCAGC AGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGAAGTTCACCCTG GACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTC TTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCT GCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACA G CCTC AG CAG CACCCTG ACG CTG AG C AAAG CAGACTACG AG AAACACAAAGTCTACGC CTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTAG (SEQ ID NO: 712)
LC Amino Acid Sequence
EIVLTQSPGTLTLSPGERATLSCRASQSVGSKYLAWFQQKRGQAPRLLIYGASSRTSGIPDR ISGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 713)
REGN9909
HCVR DNA Sequence
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCGGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCTTTAACAACTATGGCATGAGCTGGGTCCGCC AGGGTCCAGGGAAGGGGCTGGAGTGGGTCTCATCTATTAGTGGTAGTGGTGGTACCA CATTCTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAA CACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGT GGCAAAGGAGGATATTGTAGTAGTAGCGGCTGCCGTCACTACGGTATGGACGTCTGGG GCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 714)
HCVR Amino Acid Sequence
EVQLLESGGGLVQPGGSLRLSCAASGFTFNNYGMSWVRQGPGKGLEWVSSISGSGGTTF YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWGQG TTVTVSS (SEQ ID NO: 715) HCDR1 DNA Sequence
GGATTCACCTTTAACAACTATGGC (SEQ ID NO: 716)
HCDR1 Amino Acid Sequence
GFTFNNYG (SEQ ID NO: 717)
HCDR2 DNA Sequence
ATTAGTGGTAGTGGTGGTACCACA (SEQ ID NO: 718)
HCDR2 Amino Acid Sequence
ISGSGGTT (SEQ ID NO: 719)
HCDR3 DNA Sequence
GGCAAAGGAGGATATTGTAGTAGTAGCGGCTGCCGTCACTACGGTATGGACGTC (SEQ ID NO: 720)
HCDR3 Amino Acid Sequence
GKGGYCSSSGCRHYGMDV (SEQ ID NO: 721)
LCVR DNA Sequence
CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACC ATCTCTTGTTCTG G AAG C AG CTC C AACATCG G AAATAATTATATATACTG GTACCAG CG GCTCCCAGGAACGACCCCCAAACTCCTCATCTATAGGAATAATCAGCGGCCCTCAGGG GTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTG GGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACACCCTGAG TGGGTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA (SEQ ID NO: 722)
LCVR Amino Acid Sequence
QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNYIYWYQRLPGTTPKLLIYRNNQRPSGVPD RFSGSKSGTSASLAISGLRSEDEADYYCAAWDDTLSGYVFGTGTKVTVL (SEQ ID NO: 723)
LCDR1 DNA Sequence
AGCTCCAACATCGGAAATAATTAT (SEQ ID NO: 724)
LCDR1 Amino Acid Sequence
SSNIGNNY (SEQ ID NO: 725) LCDR2 DNA Sequence
AGGAATAAT (SEQ ID NO: 726)
LCDR2 Amino Acid Sequence
RNN (SEQ ID NO: 727)
LCDR3 DNA Sequence
GCAGCATGGGATGACACCCTGAGTGGGTATGTC (SEQ ID NO: 728)
LCDR3 Amino Acid Sequence
AAWDDTLSGYV (SEQ ID NO: 729)
HC DNA Sequence
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCGGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCTTTAACAACTATGGCATGAGCTGGGTCCGCC AGGGTCCAGGGAAGGGGCTGGAGTGGGTCTCATCTATTAGTGGTAGTGGTGGTACCA CATTCTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAA CACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGT GGCAAAGGAGGATATTGTAGTAGTAGCGGCTGCCGTCACTACGGTATGGACGTCTGGG GCCAAGGGACCACGGTCACCGTCTCCTCAGCCAAAACAACAGCCCCATCGGTCTATCC ACTGGCCCCTGTGTGTGGAGATACAACTGGCTCCTCGGTGACTCTAGGATGCCTGGTC AAGGGTTATTTCCCTGAGCCAGTGACCTTGACCTGGAACTCTGGATCCCTGTCCAGTG GTGTGCACACCTTCCCAGCTGTCCTGCAGTCTGACCTCTACACCCTCAGCAGCTCAGT GACTGTAACCTCGAGCACCTGGCCCAGCCAGTCCATCACCTGCAATGTGGCCCACCCG G C AAG CAGC ACCAAG GTG G ACAAG AAAATTG AGCCCAG AGG G CCCACAATC AAG CCCT GTCCTCCATGCAAATGCCCAGCACCTAACCTCTTGGGTGGACCATCCGTCTTCATCTTC
CCTCCAAAGATCAAGGATGTACTCATGATCTCCCTGAGCCCCATAGTCACATGTGTGGT GGTGGATGTGAGCGAGGATGACCCAGATGTCCAGATCAGCTGGTTTGTGAACAACGTG GAAGTACACACAGCTCAGACACAAACCCATAGAGAGGATTACAACAGTACTCTCCGGG TGGTCAGTGCCCTCCCCATCCAGCACCAGGACTGGATGAGTGGCAAGGAGTTCAAATG CAAGGTCAACAACAAAGACCTCCCAGCGCCCATCGAGAGAACCATCTCAAAACCCAAA GGGTCAGTAAGAGCTCCACAGGTATATGTCTTGCCTCCACCAGAAGAAGAGATGACTA AGAAACAGGTCACTCTGACCTGCATGGTCACAGACTTCATGCCTGAAGACATTTACGTG GAGTGGACCAACAACGGGAAAACAGAGCTAAACTACAAGAACACTGAACCAGTCCTGG ACTCTGATGGTTCTTACTTCATGTACAGCAAGCTGAGAGTGGAAAAGAAGAACTGGGTG GAAAGAAATAGCTACTCCTGTTCAGTGGTCCACGAGGGTCTGCACAATCACCACACGA CTAAGAGCTTCTCCCGGACTCCGGGTAAATGA (SEQ ID NO: 730)
HC Annino Acid Sequence
EVQLLESGGGLVQPGGSLRLSCAASGFTFNNYGMSWVRQGPGKGLEWVSSISGSGGTTF
YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWGQG
TTVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFP
AVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPN
LLGGPSVFIFPPKIKDVLMISLSPIVTCWVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDY
NSTLRWSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEE
MTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNW
VERNSYSCSWHEGLHNHHTTKSFSRTPGK (SEQ ID NO: 731)
LC DNA Sequence
CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACC
ATCTCTTGTTCTG G AAG GAG CTCCAACATCG G AAATAATTATATATACTG GTACCAG CG
GCTCCCAGGAACGACCCCCAAACTCCTCATCTATAGGAATAATCAGCGGCCCTCAGGG
GTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTG
GGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACACCCTGAG
TGGGTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTACGAGCTGATGCTGCACCA
ACTGTATCCATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGT
GTGCTTCTTGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCA
GTGAACGACAAAATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCAC
CTACAGCATGAGCAGCACCCTCACGTTGACCAAGGACGAGTATGAACGACATAACAGC
TATACCTGTGAGGCCACTCACAAGACATCAACTTCACCCATTGTCAAGAGCTTCAACAG
GGGAGAGTGTTGA (SEQ ID NO: 732)
LC Amino Acid Sequence
QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNYIYWYQRLPGTTPKLLIYRNNQRPSGVPD
RFSGSKSGTSASLAISGLRSEDEADYYCAAWDDTLSGYVFGTGTKVTVLRADAAPTVSIFP
PSSEQLTSGGASWCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTL
TLTKDEYERHNSYTCEATHKTSTSPIVKSFNRGEC (SEQ ID NO: 733)
REGN10713
HCVR DNA Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAGA
CTCTCCTGTG CAGCCTCTG G ATTCACCTTTACCAG CCATG CCATG AACTG GGTCCG CO
AGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTACTGGTAGAGGTTTTGACAC ACACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACATTTCCAAAAACA CGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTACTGTGC GAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTACTGGGGCCAGGGAACCCTGG TCACCGTCTCCTCA (SEQ ID NO: 734)
HCVR Amino Acid Sequence
EVQLVESGGNLVQPGGSLRLSCAASGFTFTSHAMNWVRQAPGKGLEWVSVITGRGFDTH YADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAKGLYDSGNYYIDYWGQGTLVTVS S (SEQ ID NO: 735)
HCDR1 DNA Sequence
GGATTCACCTTTACCAGCCATGCC (SEQ ID NO: 736)
HCDR1 Amino Acid Sequence
GFTFTSHA (SEQ ID NO: 737)
HCDR2 DNA Sequence
ATTACTGGTAGAGGTTTTGACACA (SEQ ID NO: 738)
HCDR2 Amino Acid Sequence
ITGRGFDT (SEQ ID NO: 739)
HCDR3 DNA Sequence
GCGAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTAC (SEQ ID NO: 740)
HCDR3 Amino Acid Sequence
AKGLYDSGNYYIDY (SEQ ID NO: 741)
LCVR DNA Sequence
CAGTCTGTGTTG ACG CAG COG CCCTCAGTGTCTG CG G CCCCAG G ACAG AAG GTCACC ATCTCCTG CTCTG G AAG CAGCTCCAAC ATTG G G AATAATTATGTTTCCTG GTACCAG CA GCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGA TTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGG ACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATCTCAGCCTGAGT TTCAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 742)
LCVR Amino Acid Sequence QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPD
RFSGSKSGTSATLGITGLQTGDEADYYCGTWDLSLSFNWVFGGGTKLTVL (SEQ ID NO: 743)
LCDR1 DNA Sequence
AGCTCCAACATTGGGAATAATTAT (SEQ ID NO: 744)
LCDR1 Amino Acid Sequence
SSNIGNNY (SEQ ID NO: 745)
LCDR2 DNA Sequence
GACAATAAT (SEQ ID NO: 746)
LCDR2 Amino Acid Sequence
DNN (SEQ ID NO: 747)
LCDR3 DNA Sequence
GGAACATGGGATCTCAGCCTGAGTTTCAATTGGGTG (SEQ ID NO: 748)
LCDR3 Amino Acid Sequence
GTWDLSLSFNWV (SEQ ID NO: 749)
HC DNA Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAGA CTCTCCTGTG CAGCCTCTG G ATTC ACCTTTACCAG CCATG CCATG AACTG GGTCCG CC AGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTACTGGTAGAGGTTTTGACAC ACACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACATTTCCAAAAACA CGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTACTGTGC GAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTACTGGGGCCAGGGAACCCTGG TCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTC CAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC CGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC TCCAG CAG CTTG GGCACG AAG ACCTAC ACCTG CAACGTAG ATCACAAGCCCAG CAACA CCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGC ACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACT CTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAA GACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGA CAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCG TCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGG CCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCA CAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTG ACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT GGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCC TTCTTCCTCTAC AG CAG G CTC ACCGTG G AC AAG AG CAG GTGG CAGG AG G GG AATGTCT TCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCC CTGTCTCTGGGTAAATGA (SEQ ID NO: 750)
HC Amino Acid Sequence
EVQLVESGGNLVQPGGSLRLSCAASGFTFTSHAMNWVRQAPGKGLEWVSVITGRGFDTH YADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAKGLYDSGNYYIDYWGQGTLVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR WSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK* (SEQ ID NO: 751)
LC DNA Sequence
CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACC ATCTCCTG CTCTG G AAG CAGCTCCAAC ATTG G G AATAATTATGTTTCCTG GTACC AGC A GCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGA TTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGG ACTCCAG ACTG GG G ACG AG G CCG ATTATTACTG CG G AACATG G G ATCTCAG CCTG AGT TTCAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGCCAGCCCAAGGCC GCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCTGCAGGCCAACAAGGCC ACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGTGACCGTGGCCTGGAAG GCCGACTCCTCCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCTCCAAGCAGTCC AACAACAAGTACGCCGCCTCCTCCTACCTGTCCCTGACCCCCGAGCAGTGGAAGTCCC ACCGGTCCTACTCCTGCCAGGTGACCCACGAGGGCTCCACCGTGGAGAAGACCGTGG CCCCCACCGAGTGCTCCTGA (SEQ ID NO: 752)
LC Amino Acid Sequence
QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPD RFSGSKSGTSATLGITGLQTGDEADYYCGTWDLSLSFNWVFGGGTKLTVLGQPKAAPSVT
LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSY
LSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS* (SEQ ID NO: 753)
REGN10715
HCVR DNA Sequence
CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGCGACCCTGTCC
CGCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAACTGGATCCGCC
AGTCCCCAGGGAAGGGGCTGGAATGGATTGGGGAAATCCTTCATAGTGGAAGAACCAA
CTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGT TCTCCCTGAAGCTGACCTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGGG AAGGATAGCAGCTCGTCACGGCTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCAC
CGTCTCCTCA (SEQ ID NO: 754)
HCVR Amino Acid Sequence
QVQLQQWGAGLLKPSATLSRTCAVYGGSFSGYYWNWIRQSPGKGLEWIGEILHSGRTNY NPSLKSRVTISVDTSKNQFSLKLTSVTAADTAVYYCAGRIAARHGWFDPWGQGTLVTVSS (SEQ ID NO: 755)
HCDR1 DNA Sequence
GGTGGGTCCTTCAGTGGTTACTAC (SEQ ID NO: 756)
HCDR1 Amino Acid Sequence
GGSFSGYY (SEQ ID NO: 757)
HCDR2 DNA Sequence
ATCCTTCATAGTGGAAGAACC (SEQ ID NO: 758)
HCDR2 Amino Acid Sequence
ILHSGRT (SEQ ID NO: 759)
HCDR3 DNA Sequence
GCGGGAAGGATAGCAGCTCGTCACGGCTGGTTCGACCCC (SEQ ID NO: 760)
HCDR3 Amino Acid Sequence
AGRIAARHGWFDP (SEQ ID NO: 761) LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCAC CATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAAAC CAGGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTCCCT TCAAG GTTCAG CGG CAGTGG ATCTGGG ACAG ATTTCACTCTCACCATCAG CAG CCTG C
AGCCTGAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACTTTTG GCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 762)
LCVR Amino Acid Sequence
DIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSR
FSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIK (SEQ ID NO: 763)
LCDR1 DNA Sequence
CAGGATATTCGCAAGTGG (SEQ ID NO: 764)
LCDR1 Amino Acid Sequence
QDIRKW (SEQ ID NO: 765)
LCDR2 DNA Sequence
GCTACATCC (SEQ ID NO: 766)
LCDR2 Amino Acid Sequence
ATS (SEQ ID NO: 767)
LCDR3 DNA Sequence
CAACAGGCTAACAGTTTCCCGTTCACT (SEQ ID NO: 768)
LCDR3 Amino Acid Sequence
QQANSFPFT (SEQ ID NO: 769)
HC DNA Sequence
CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGCGACCCTGTCC
CGCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAACTGGATCCGCC AGTCCCCAGGGAAGGGGCTGGAATGGATTGGGGAAATCCTTCATAGTGGAAGAACCAA
CTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGT TCTCCCTGAAGCTGACCTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGGG AAGGATAGCAGCTCGTCACGGCTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCAC
CGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAG
GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGA
ACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCC
GGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC
AGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCA
AGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACC
TGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTC
ATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGAC
CCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAA
AGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC
TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCT
CCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAG
GTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT
GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC
AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTT
CCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTC
ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGT
CTCTGGGTAAATGA (SEQ ID NO: 770)
HC Amino Acid Sequence
QVQLQQWGAGLLKPSATLSRTCAVYGGSFSGYYWNWIRQSPGKGLEWIGEILHSGRTNY
NPSLKSRVTISVDTSKNQFSLKLTSVTAADTAVYYCAGRIAARHGWFDPWGQGTLVTVSSA
STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLF
PPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRW
SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS
CSVMHEALHNHYTQKSLSLSLGK* (SEQ ID NO: 771)
LG DNA Sequence
GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCAC
CATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAAAC
CAGGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTCCCT
TCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGC
AGCCTGAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACTTTTG GCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTT CCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATA ACTTCTATCCC AG AG AGGCCAAAGTAC AGTG G AAG GTG G ATAACG CCCTCCAATCG G G TAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGC AGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAG TCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTA G (SEQ ID NO: 772)
LC Amino Acid Sequence
DIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 773)
REGN10716
HCVR DNA Sequence
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC CTC ACCTG CACTGTCTCTG GTG ACTCCATCAATAATTACTACTG G ACCTG G CTCCGG CA GCCCCCAGGGAAGGGACTGGAGTGGATTGGTTATATCTATTACAGTGGGAGCGCCAAC TACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTT CTCCCTGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGA GGGGCGGTCAAGTACTTCCGGCATTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 774)
HCVR Amino Acid Sequence
QVQLQESGPGLVKPSETLSLTCTVSGDSINNYYWTWLRQPPGKGLEWIGYIYYSGSANYN PSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARGAVKYFRHWGQGTLVTVSS (SEQ ID NO: 775)
HCDR1 DNA Sequence
GGTGACTCCATCAATAATTACTAC (SEQ ID NO: 776)
HCDR1 Amino Acid Sequence
GDSINNYY (SEQ ID NO: 777)
HCDR2 DNA Sequence
ATCTATTACAGTGGGAGCGCC (SEQ ID NO: 778) HCDR2 Amino Acid Sequence
IYYSGSA (SEQ ID NO: 779)
HCDR3 DNA Sequence
GCGAGAGGGGCGGTCAAGTACTTCCGGCAT (SEQ ID NO: 780)
HCDR3 Amino Acid Sequence
ARGAVKYFRH (SEQ ID NO: 781)
LCVR DNA Sequence
GAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCA
CCCTCTCCTG CAGG G CCAGTCAG ACTATTAACCACAACAACTTAGCCTG GTACCAG CA
GAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGCC
ATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCA
GACTGGAGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGCTC
ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 782)
LCVR Amino Acid Sequence
EIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPDR
FSGSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIK (SEQ ID NO: 783)
LCDR1 DNA Sequence
CAGACTATTAACCACAACAAC (SEQ ID NO: 784)
LCDR1 Amino Acid Sequence
QTINHNN (SEQ ID NO: 785)
LCDR2 DNA Sequence
GGTGCATCC (SEQ ID NO: 786)
LCDR2 Amino Acid Sequence
GAS (SEQ ID NO: 787)
LCDR3 DNA Sequence
CAGCAGTATGGTAGCTTGCCGCTCACT (SEQ ID NO: 788) LCDR3 Amino Acid Sequence
QQYGSLPLT (SEQ ID NO: 789)
HC DNA Sequence
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC CTC ACCTG CACTGTCTCTG GTG ACTCCATCAATAATTACTACTG G ACCTG G CTCCGG CA GCCCCCAGGGAAGGGACTGGAGTGGATTGGTTATATCTATTACAGTGGGAGCGCCAAC TACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTT CTCCCTGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGA GGGGCGGTCAAGTACTTCCGGCATTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCC GAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGG GCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAA GAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTG GGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCC GGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCC AGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGG AGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCC ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCC TGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAA AGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAA CAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGC AGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTG ATG CATG AGG CTCTG CAC AACCACTAC ACACAG AAGTCCCTCTCCCTGTCTCTG G GTAA ATGA (SEQ ID NO: 790)
HC Amino Acid Sequence
QVQLQESGPGLVKPSETLSLTCTVSGDSINNYYWTWLRQPPGKGLEWIGYIYYSGSANYN PSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARGAVKYFRHWGQGTLVTVSSASTKG PSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKP KDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLT VLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVM HEALHNHYTQKSLSLSLGK* (SEQ ID NO: 791)
LC DNA Sequence
GAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTG CAGG G CCAGTCAG ACTATTAACCACAACAACTTAGCCTG GTACCAG CA GAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGCC
ATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCA
GACTGGAGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGCTC ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCT TCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTG
CTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCC
AATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACA
G CCTC AG CAG CACCCTG ACG CTG AG C AAAG CAGACTACG AG AAACACAAAGTCTACGC CTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTAG (SEQ ID NO: 792)
LC Amino Acid Sequence
EIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPDR
FSGSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIKRTVAAPSVFIFPPSDE
QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK
ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 793)
REGN10717
HCVR DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG
ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC
CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGAT AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAA CACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTG
CGAGAAGGGGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCAC CGTCTCCTCA (SEQ ID NO: 794)
HCVR Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS (SEQ ID NO: 795) HCDR1 DNA Sequence
GGATTCACCTTCAGTACATATGGC (SEQ ID NO: 796)
HCDR1 Amino Acid Sequence
GFTFSTYG (SEQ ID NO: 797)
HCDR2 DNA Sequence
ATTTGGCATGATGGAAGTGATAAA (SEQ ID NO: 798)
HCDR2 Amino Acid Sequence
IWHDGSDK (SEQ ID NO: 799)
HCDR3 DNA Sequence
GCGAGAAGGGGTATACGTGGAACCGTTTTTGACCAC (SEQ ID NO: 800)
HCDR3 Amino Acid Sequence
ARRGIRGTVFDH (SEQ ID NO: 801)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCCTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTCC
CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCT
GCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACGTT
CGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 802)
LCVR Amino Acid Sequence
DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR
FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIK (SEQ ID NO: 803)
LCDR1 DNA Sequence
CAGAGTATTAGTAACAAG (SEQ ID NO: 804)
LCDR1 Amino Acid Sequence
QSISNK (SEQ ID NO: 805)
LCDR2 DNA Sequence AAGGCGTCT (SEQ ID NO: 806)
LCDR2 Amino Acid Sequence
KAS (SEQ ID NO: 807)
LCDR3 DNA Sequence
CAACAGTATAATAGTTATTCGTGGACG (SEQ ID NO: 808)
LCDR3 Amino Acid Sequence
QQYNSYSWT (SEQ ID NO: 809)
LC Constant Light (CL) Domain DNA Sequence
CGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTAC AGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCA G G ACAG CAAG G ACAGCACCTACAG CCTCAG CAGC ACCCTG ACG CTG AG C AAAG CAG A
CTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCC GTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 1 170)
LC Constant Light (CL) Domain Amino Acid Sequence
RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1147)
HC DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGAT AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAA
CACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTG CGAGAAGGGGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCAC CGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGA
ACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC AGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCA
AGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACC TGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTC ATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGAC CCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAA AGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCT CCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAG GTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTT CCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTC ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGT CTCTGGGTAAATGA (SEQ ID NO: 810), or
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGAT AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAA CACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTG CGAGAAGGGGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCAC CGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG GCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA G C AG CTTG G GCACCC AG ACCTACATCTG CAACGTG AATCACAAG CCCAGC AACACC AA G GTG G ACAAG AAAGTTG AG CCCAAATCTTGTG ACAAAACTC ACACATG CCC ACCGTG C CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGG ACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCA CGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTACGGCAGCACGTACCGTGTGGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACA AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA ACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAG CCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATG GG GAG COG G AG AACAACTACAAG ACC ACG CCTCCCGTG CTG G ACTCCG ACGG CTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAAC GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCT CTCCCTGTCTCCGGGTAAA (SEQ ID NO: 1172) HC Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK
YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL
FPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV
VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV
SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF
SCSVMHEALHNHYTQKSLSLSLGK* (SEQ ID NO: 811), or
QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK
YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS
VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTY
RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1173)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCCTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTCC
CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCT
GCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACGTT
CGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATC
TTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAA
TAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCG
GGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC
AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCG
AAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT GTTAG (SEQ ID NO: 812)
LC Amino Acid Sequence
DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR
FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE
QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 813)
REGN10783
HCVR DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGACGTCCCTGAG ACTCTCCTGTGCAGCGTCAGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGATTGATGGAAGTAATA AATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTG CGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCC
TGGTCACCGTCTCCTCA (SEQ ID NO: 814)
HCVR Amino Acid Sequence
QVQLVESGGGWQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIWAAPFDYWGQGTLVTVS S (SEQ ID NO: 815)
HCDR1 DNA Sequence
GGATTCACCTTCAGTAGCTATGGC (SEQ ID NO: 816)
HCDR1 Amino Acid Sequence
GFTFSSYG (SEQ ID NO: 817)
HCDR2 DNA Sequence
ATATGGATTGATGGAAGTAATAAA (SEQ ID NO: 818)
HCDR2 Amino Acid Sequence
IWIDGSNK (SEQ ID NO: 819)
HCDR3 DNA Sequence
GCGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTAC (SEQ ID NO: 820)
HCDR3 Amino Acid Sequence
ARRGGIWAAPFDY (SEQ ID NO: 821)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT
GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA
CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 822)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 823)
LCDR1 DNA Sequence
CAGAG CATTAG C AG CTAT (SEQ ID NO: 824)
LCDR1 Amino Acid Sequence
QSISSY (SEQ ID NO: 825)
LCDR2 DNA Sequence
GCTGCATCC (SEQ ID NO: 826)
LCDR2 Amino Acid Sequence
AAS (SEQ ID NO: 827)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 828)
LCDR3 Amino Acid Sequence
QQSYSTPPIT (SEQ ID NO: 829)
HC DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGACGTCCCTGAG
ACTCTCCTGTGCAGCGTCAGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC
CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGATTGATGGAAGTAATA
AATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAAC
ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTG
CGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCC
TGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTG
CTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTT CCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACAC CTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTG
CCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCA ACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCC AGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGAC ACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAG GAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAA AGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAG CCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGC
CTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGC AATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGC
TCCTTCTTCCTCTAC AG CAG G CTCACCGTG G ACAAG AG CAGGTGG CAG GAG G GG AATG TCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTC TCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 830)
HC Amino Acid Sequence
QVQLVESGGGWQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIWAAPFDYWGQGTLVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR WSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK* (SEQ ID NO: 831)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC
TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA
GAGTGTTAG (SEQ ID NO: 832)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 833)
REGN7854
HCVR DNA Sequence
CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAG
GTCTCCTGCAAGGCTTCTGGTTACGCCTTCACCACCTATGGTATCACCTGGGTGCGAC
AGGCCCCTGGACAAGGACTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAATAC
AAACTATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAAT
ACAGCCTACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGTG
CGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTGG
GGCCAAGGGACAATGGTCACCGTCTCTTCA (SEQ ID NO: 834)
HCVR Amino Acid Sequence
QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNTN
YAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWGQ
GTMVTVSS (SEQ ID NO: 835)
HCDR1 DNA Sequence
GGTTACGCCTTCACCACCTATGGT (SEQ ID NO: 836)
HCDR1 Amino Acid Sequence
GYAFTTYG (SEQ ID NO: 837)
HCDR2 DNA Sequence
ATCAGCGCTTACAATGGAAATACA (SEQ ID NO: 838)
HCDR2 Amino Acid Sequence
ISAYNGNT (SEQ ID NO: 839) HCDR3 DNA Sequence
GCGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTT
(SEQ ID NO: 840)
HCDR3 Amino Acid Sequence
ARKGHYGSGTYYNPFGFDF (SEQ ID NO: 841)
LCVR DNA Sequence
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCA
CCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACA
GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGG
CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC
AGACTGGAGCCTGAAGATTTTGCTTTGTATTTCTGTCAGCAGTATTATGGCTCACCTTG
GACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 842)
LCVR Amino Acid Sequence
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR
FSGSGSGTDFTLTISRLEPEDFALYFCQQYYGSPWTFGQGTKVEIK (SEQ ID NO: 843)
LCDR1 DNA Sequence
CAGAGTGTTAGCAGCAGCTAC (SEQ ID NO: 844)
LCDR1 Amino Acid Sequence
QSVSSSY (SEQ ID NO: 845)
LCDR2 DNA Sequence
GGTGCATCC (SEQ ID NO: 846)
LCDR2 Amino Acid Sequence
GAS (SEQ ID NO: 847)
LCDR3 DNA Sequence
CAGCAGTATTATGGCTCACCTTGGACG (SEQ ID NO: 848)
LCDR3 Amino Acid Sequence
QQYYGSPWT (SEQ ID NO: 849) HC DNA Sequence
CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAG GTCTCCTGCAAGGCTTCTGGTTACGCCTTCACCACCTATGGTATCACCTGGGTGCGAC AGGCCCCTGGACAAGGACTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAATAC AAACTATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAAT ACAGCCTACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGTG
CGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTGG GGCCAAGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCC CCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGG TCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCA
GCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAG CGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGAT CACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCAT GCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCC
AAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTG GACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAG GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTG GTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGC
AAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAG GGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCA AGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGT GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCT
G G ACTCCG ACG G CTCCTTCTTCCTCTAC AGO AG G CTC ACCGTG G ACAAG AG CAG GTG G CAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACA CACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 850)
HC Amino Acid Sequence
QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNTN YAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWGQ GTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEF
LGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE QFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR
WQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 851)
LC DNA Sequence GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACA GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGG CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC AGACTGGAGCCTGAAGATTTTGCTTTGTATTTCTGTCAGCAGTATTATGGCTCACCTTG GACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTC TTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCT GCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACA G CCTC AG GAG CACCCTG ACG CTG AG C AAAG CAGACTACG AG AAACACAAAGTCTACGC
CTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTAG (SEQ ID NO: 852)
LC Amino Acid Sequence
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR FSGSGSGTDFTLTISRLEPEDFALYFCQQYYGSPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 853)
REGN14570
HCVR DNA Sequence
CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGCGACCCTGTCC
CGCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAACTGGATCCGCC AGTCCCCAGGGAAGGGGCTGGAATGGATTGGGGAAATCCTTCATAGTGGAAGAACCAA CTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGT TCTCCCTGAAGCTGACCTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGGG
AAGGATAGCAGCTCGTCACGGCTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCAC CGTCTCCTCA (SEQ ID NO: 854)
HCVR Amino Acid Sequence
QVQLQQWGAGLLKPSATLSRTCAVYGGSFSGYYWNWIRQSPGKGLEWIGEILHSGRTNY NPSLKSRVTISVDTSKNQFSLKLTSVTAADTAVYYCAGRIAARHGWFDPWGQGTLVTVSS (SEQ ID NO: 855)
HCDR1 DNA Sequence
GGTGGGTCCTTCAGTGGTTACTAC (SEQ ID NO: 856) HCDR1 Amino Acid Sequence
GGSFSGYY (SEQ ID NO: 857)
HCDR2 DNA Sequence
ATCCTTCATAGTGGAAGAACC (SEQ ID NO: 858)
HCDR2 Amino Acid Sequence
ILHSGRT (SEQ ID NO: 859)
HCDR3 DNA Sequence
GCGGGAAGGATAGCAGCTCGTCACGGCTGGTTCGACCCC (SEQ ID NO: 860)
HCDR3 Amino Acid Sequence
AGRIAARHGWFDP (SEQ ID NO: 861)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCAC
CATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAAAC
CAGGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTCCCT
TCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGC
AGCCTGAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACTTTTG
GCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 862)
LCVR Amino Acid Sequence
DIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSR
FSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIK (SEQ ID NO: 863)
LCDR1 DNA Sequence
CAGGATATTCGCAAGTGG (SEQ ID NO: 864)
LCDR1 Amino Acid Sequence
QDIRKW (SEQ ID NO: 865)
LCDR2 DNA Sequence
GCTACATCC (SEQ ID NO: 866)
LCDR2 Amino Acid Sequence ATS (SEQ ID NO: 867)
LCDR3 DNA Sequence
CAACAGGCTAACAGTTTCCCGTTCACT (SEQ ID NO: 868)
LCDR3 Amino Acid Sequence
QQANSFPFT (SEQ ID NO: 869)
HC DNA Sequence
CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGCGACCCTGTCC CGCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAACTGGATCCGCC AGTCCCCAGGGAAGGGGCTGGAATGGATTGGGGAAATCCTTCATAGTGGAAGAACCAA CTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGT TCTCCCTGAAGCTGACCTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGGG AAGGATAGCAGCTCGTCACGGCTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCAC CGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG GCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA G C AG CTTG G GCACCC AG ACCTACATCTG CAACGTG AATCACAAG CCCAGC AACACC AA G GTG G ACAAG AAAGTTG AG CCC AAATCTTGTG ACAAAACTC ACACATG CCC ACCGTG C CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGG ACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCA CGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACA AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA ACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAG CCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGG CTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAAC GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCT CTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 870)
HC Amino Acid Sequence (N297Q is indicated in bold)
QVQLQQWGAGLLKPSATLSRTCAVYGGSFSGYYWNWIRQSPGKGLEWIGEILHSGRTNY NPSLKSRVTISVDTSKNQFSLKLTSVTAADTAVYYCAGRIAARHGWFDPWGQGTLVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTY RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 871)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCAC CATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAAAC CAGGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTCCCT TCAAG GTTCAG CGG CAGTGG ATCTGGG ACAG ATTTCACTCTCACCATCAG CAG CCTG C AGCCTGAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACTTTTG GCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTT CCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATA ACTTCTATCCC AG AG AGGCCAAAGTAC AGTG G AAG GTG G ATAACG CCCTCCAATCG G G TAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGC AGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAG TCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTA G (SEQ ID NO: 872)
LC Amino Acid Sequence
DIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 873)
REGN14571
HCVR DNA Sequence
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC CTC ACCTG CACTGTCTCTG GTG ACTCCATCAATAATTACTACTG G ACCTG G CTCCGG CA GCCCCCAGGGAAGGGACTGGAGTGGATTGGTTATATCTATTACAGTGGGAGCGCCAAC TACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTT CTCCCTGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGA GGGGCGGTCAAGTACTTCCGGCATTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 874) HCVR Amino Acid Sequence
QVQLQESGPGLVKPSETLSLTCTVSGDSINNYYWTWLRQPPGKGLEWIGYIYYSGSANYN
PSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARGAVKYFRHWGQGTLVTVSS (SEQ ID NO: 875)
HCDR1 DNA Sequence
GGTGACTCCATCAATAATTACTAC (SEQ ID NO: 876)
HCDR1 Amino Acid Sequence
GDSINNYY (SEQ ID NO: 877)
HCDR2 DNA Sequence
ATCTATTACAGTGGGAGCGCC (SEQ ID NO: 878)
HCDR2 Amino Acid Sequence
IYYSGSA (SEQ ID NO: 879)
HCDR3 DNA Sequence
GCGAGAGGGGCGGTCAAGTACTTCCGGCAT (SEQ ID NO: 880)
HCDR3 Amino Acid Sequence
ARGAVKYFRH (SEQ ID NO: 881)
LCVR DNA Sequence
GAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCA
CCCTCTCCTGCAGGGCCAGTCAGACTATTAACCACAACAACTTAGCCTGGTACCAGCA
GAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGCC
ATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCA
GACTGGAGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGCTC
ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 882)
LCVR Amino Acid Sequence
EIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPDR
FSGSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIK (SEQ ID NO: 883)
LCDR1 DNA Sequence
CAGACTATTAACCACAACAAC (SEQ ID NO: 884) LCDR1 Amino Acid Sequence
QTINHNN (SEQ ID NO: 885)
LCDR2 DNA Sequence
GGTGCATCC (SEQ ID NO: 886)
LCDR2 Amino Acid Sequence
GAS (SEQ ID NO: 887)
LCDR3 DNA Sequence
CAGCAGTATGGTAGCTTGCCGCTCACT (SEQ ID NO: 888)
LCDR3 Amino Acid Sequence
QQYGSLPLT (SEQ ID NO: 889)
HC DNA Sequence
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC CTC ACCTG CACTGTCTCTG GTG ACTCCATC AATAATTACTACTG G ACCTG G CTCCGG CA GCCCCCAGGGAAGGGACTGGAGTGGATTGGTTATATCTATTACAGTGGGAGCGCCAAC TACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTT CTCCCTGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGA GGGGCGGTCAAGTACTTCCGGCATTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC AGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGG CACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG AAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGA ACTCCTG G G GG G ACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG G ACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGC CGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGC ACCAG G ACTG G CTG AATG G CAAG G AGTACAAGTG CAAGGTCTCCAACAAAG CCCTCCC AGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT GTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC CTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCAT GCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTC
TCCGGGTAAATGA (SEQ ID NO: 890)
HC Amino Acid Sequence (N297Q is indicated in bold)
QVQLQESGPGLVKPSETLSLTCTVSGDSINNYYWTWLRQPPGKGLEWIGYIYYSGSANYN
PSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARGAVKYFRHWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRWS
VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 891)
LC DNA Sequence
GAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCA
CCCTCTCCTGCAGGGCCAGTCAGACTATTAACCACAACAACTTAGCCTGGTACCAGCA
GAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGCC
ATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCA
GACTGGAGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGCTC
ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCT
TCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTG
CTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCC
AATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACA G CCTC AG C AG CACCCTG ACG CTG AG C AAAG CAGACTACG AG AAAC ACAAAGTCTACGC CTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG
AGAGTGTTAG (SEQ ID NO: 892)
LC Amino Acid Sequence
EIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPDR
FSGSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 893)
REGN14572
HCVR DNA Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG
ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC
CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGAT AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAA CACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTG
CGAGAAGGGGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCAC CGTCTCCTCA (SEQ ID NO: 894)
HCVR Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK
YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS (SEQ ID NO: 895)
HCDR1 DNA Sequence
GGATTCACCTTCAGTACATATGGC (SEQ ID NO: 896)
HCDR1 Amino Acid Sequence
GFTFSTYG (SEQ ID NO: 897)
HCDR2 DNA Sequence
ATTTGGCATGATGGAAGTGATAAA (SEQ ID NO: 898)
HCDR2 Amino Acid Sequence
IWHDGSDK (SEQ ID NO: 899)
HCDR3 DNA Sequence
GCGAGAAGGGGTATACGTGGAACCGTTTTTGACCAC (SEQ ID NO: 900)
HCDR3 Amino Acid Sequence
ARRGIRGTVFDH (SEQ ID NO: 901)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCA CCCTCACTTGTCG G GCCAGTCAG AGTATTAGTAACAAGTTG G CCTG GTATCAG CAG AAA CCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTCC
CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCT GCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACGTT CGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 902)
LCVR Amino Acid Sequence
DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR
FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIK (SEQ ID NO: 903)
LCDR1 DNA Sequence
CAGAGTATTAGTAACAAG (SEQ ID NO: 904)
LCDR1 Amino Acid Sequence
QSISNK (SEQ ID NO: 905)
LCDR2 DNA Sequence
AAGGCGTCT (SEQ ID NO: 906)
LCDR2 Amino Acid Sequence
KAS (SEQ ID NO: 907)
LCDR3 DNA Sequence
CAACAGTATAATAGTTATTCGTGGACG (SEQ ID NO: 908)
LCDR3 Amino Acid Sequence
QQYNSYSWT (SEQ ID NO: 909)
HC DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG
ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC
CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGAT AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAA
CACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTG CGAGAAGGGGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCAC
CGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG
AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA
CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG
GCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA G C AG CTTG G GCACCCAG ACCTACATCTG CAACGTG AATCACAAG CCCAGCAACACCAA G GTG G ACAAG AAAGTTG AG CCCAAATCTTGTG ACAAAACTCACACATG CCC ACCGTG C CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGG ACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCA CGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACA AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAG CCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATG GG GAG COG G AG AACAACTACAAG ACC ACG CCTCCCGTG CTG G ACTCCG ACGG CTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAAC GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCT
CTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 910)
HC Amino Acid Sequence (N297Q is indicated in bold)
QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTY
RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 91 1)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCA CCCTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCT GCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACGTT CGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATC TTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAA TAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCG GGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCG
AAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT GTTAG (SEQ ID NO: 912) LC Amino Acid Sequence
DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 913)
REGN14573
HCVR DNA Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAGA CTCTCCTGTG CAGCCTCTG G ATTCACCTTTACCAG CCATG CCATG AACTG GGTCCG CO AGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTACTGGTAGAGGTTTTGACAC ACACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACATTTCCAAAAACA CGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTACTGTGC GAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTACTGGGGCCAGGGAACCCTGG TCACCGTCTCCTCA (SEQ ID NO: 914)
HCVR Amino Acid Sequence
EVQLVESGGNLVQPGGSLRLSCAASGFTFTSHAMNWVRQAPGKGLEWVSVITGRGFDTH YADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAKGLYDSGNYYIDYWGQGTLVTVS S (SEQ ID NO: 915)
HCDR1 DNA Sequence
GGATTCACCTTTACCAGCCATGCC (SEQ ID NO: 916)
HCDR1 Amino Acid Sequence
GFTFTSHA (SEQ ID NO: 917)
HCDR2 DNA Sequence
ATTACTGGTAGAGGTTTTGACACA (SEQ ID NO: 918)
HCDR2 Amino Acid Sequence
ITGRGFDT (SEQ ID NO: 919)
HCDR3 DNA Sequence
GCGAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTAC (SEQ ID NO: 920)
HCDR3 Amino Acid Sequence AKGLYDSGNYYIDY (SEQ ID NO: 921)
LCVR DNA Sequence
CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACC ATCTCCTG CTCTG G AAG CAGCTCCAAC ATTG G G AATAATTATGTTTCCTG GTACCAGC A GCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGA TTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGG ACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATCTCAGCCTGAGT TTCAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 922)
LCVR Amino Acid Sequence
QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPD RFSGSKSGTSATLGITGLQTGDEADYYCGTWDLSLSFNWVFGGGTKLTVL (SEQ ID NO: 923)
LCDR1 DNA Sequence
AGCTCCAACATTGGGAATAATTAT (SEQ ID NO: 924)
LCDR1 Amino Acid Sequence
SSNIGNNY (SEQ ID NO: 925)
LCDR2 DNA Sequence
GACAATAAT (SEQ ID NO: 926)
LCDR2 Amino Acid Sequence
DNN (SEQ ID NO: 927)
LCDR3 DNA Sequence
GGAACATGGGATCTCAGCCTGAGTTTCAATTGGGTG (SEQ ID NO: 928)
LCDR3 Amino Acid Sequence
GTWDLSLSFNWV (SEQ ID NO: 929)
HC DNA Sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAGA CTCTCCTGTG CAGCCTCTG G ATTCACCTTTACCAG CCATG CCATG AACTG GGTCCG CC AGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTACTGGTAGAGGTTTTGACAC ACACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACATTTCCAAAAACA CGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTACTGTGC GAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTACTGGGGCCAGGGAACCCTGG TCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTC
CAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC CGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC TCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACA
CCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACC GTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC AAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGA GCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATA
ATGCCAAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTC CAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAG
GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG ACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAG
TCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 930)
HC Amino Acid Sequence (N297Q is indicated in bold)
EVQLVESGGNLVQPGGSLRLSCAASGFTFTSHAMNWVRQAPGKGLEWVSVITGRGFDTH YADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAKGLYDSGNYYIDYWGQGTLVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQST YRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 931)
LG DNA Sequence
CAGTCTGTGTTG ACG CAG CCG CCCTCAGTGTCTG CG G CCCCAG G ACAG AAG GTCACC ATCTCCTG CTCTG G AAG CAGCTCCAAC ATTG G G AATAATTATGTTTCCTG GTACCAGC A GCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGA TTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGG ACTCCAG ACTG GG G ACG AG G CCG ATTATTACTG CG G AAC ATG G G ATCTCAG CCTG AGT
TTCAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGCCAGCCCAAGGCC
GCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCTGCAGGCCAACAAGGCC
ACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGTGACCGTGGCCTGGAAG
GCCGACTCCTCCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCTCCAAGCAGTCC
AACAACAAGTACGCCGCCTCCTCCTACCTGTCCCTGACCCCCGAGCAGTGGAAGTCCC
ACCGGTCCTACTCCTGCCAGGTGACCCACGAGGGCTCCACCGTGGAGAAGACCGTGG CCCCCACCGAGTGCTCCTGA (SEQ ID NO: 932)
LG Amino Acid Sequence
QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPD
RFSGSKSGTSATLGITGLQTGDEADYYCGTWDLSLSFNWVFGGGTKLTVLGQPKAAPSVT
LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSY LSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 933)
REGN14574
HCVR DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGACGTCCCTGAG
ACTCTCCTGTGCAGCGTCAGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC
CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGATTGATGGAAGTAATA
AATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAAC
ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTG CGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCC TGGTCACCGTCTCCTCA (SEQ ID NO: 934)
HCVR Amino Acid Sequence
QVQLVESGGGWQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIWAAPFDYWGQGTLVTVS S (SEQ ID NO: 935)
HCDR1 DNA Sequence
GGATTCACCTTCAGTAGCTATGGC (SEQ ID NO: 936)
HCDR1 Amino Acid Sequence
GFTFSSYG (SEQ ID NO: 937)
HCDR2 DNA Sequence ATATGGATTGATGGAAGTAATAAA (SEQ ID NO: 938)
HCDR2 Amino Acid Sequence
IWIDGSNK (SEQ ID NO: 939)
HCDR3 DNA Sequence
GCGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTAC (SEQ ID NO: 940)
HCDR3 Amino Acid Sequence
ARRGGIWAAPFDY (SEQ ID NO: 941)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT
GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA
CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 942)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 943)
LCDR1 DNA Sequence
CAGAG CATTAG CAG CTAT (SEQ ID NO: 944)
LCDR1 Amino Acid Sequence
QSISSY (SEQ ID NO: 945)
LCDR2 DNA Sequence
GCTGCATCC (SEQ ID NO: 946)
LCDR2 Amino Acid Sequence
AAS (SEQ ID NO: 947)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 948) LCDR3 Amino Acid Sequence
QQSYSTPPIT (SEQ ID NO: 949)
HC DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGACGTCCCTGAG
ACTCTCCTGTGCAGCGTCAGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC
CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGATTGATGGAAGTAATA
AATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAAC
ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTG
CGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCC TGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTC
CTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTT
CCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACAC
CTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTG
CCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCA
ACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCA
CCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAAC CCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGT GAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA
TAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAG CGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC
CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACC
AGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTG
GGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTC CGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG G GG AACGTCTTCTC ATG CTCCGTG ATG CATGAG G CTCTG C ACAACCACTACACG CAG A
AGTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 950)
HC Amino Acid Sequence (N297Q is indicated in bold)
QVQLVESGGGWQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKY
YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIWAAPFDYWGQGTLVTVS
SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQST
YRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 951)
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT
GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA
CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT
CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC
TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA
ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG
CCTCAG CAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC ACAAAGTCTACG CC
TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA
GAGTGTTAG (SEQ ID NO: 952)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 953)
REG N 14647
HCVR DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG
ACTCTCCTGTACAG CGTCTG G AATCACCTTCAG AAATTATG G CATG CACTG G GTCCGCC
AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAA
GTACTATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGGTG
TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAA
GGGGCACTATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC
CGTCTCCTCA (SEQ ID NO: 954)
HCVR Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNK
YYADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTVSS
(SEQ ID NO: 955) HCDR1 DNA Sequence
GGAATCACCTTCAGAAATTATGGC (SEQ ID NO: 956)
HCDR1 Amino Acid Sequence
GITFRNYG (SEQ ID NO: 957)
HCDR2 DNA Sequence
ATGTGGTATGATGGAAGTAATAAG (SEQ ID NO: 958)
HCDR2 Amino Acid Sequence
MWYDGSNK (SEQ ID NO: 959)
HCDR3 DNA Sequence
GCGAGAAGGGGCACTATAAGAACAGCTGCCCCTTTTGACTAC (SEQ ID NO: 960)
HCDR3 Amino Acid Sequence
ARRGTIRTAAPFDY (SEQ ID NO: 961)
LCVR DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC
CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT
GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA
CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 962)
LCVR Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 963)
LCDR1 DNA Sequence
CAGAG CATTAG C AG CTAT (SEQ ID NO: 964)
LCDR1 Amino Acid Sequence
QSISSY (SEQ ID NO: 965) LCDR2 DNA Sequence
GCTGCATCC (SEQ ID NO: 966)
LCDR2 Amino Acid Sequence
AAS (SEQ ID NO: 967)
LCDR3 DNA Sequence
CAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 968)
LCDR3 Amino Acid Sequence
QQSYSTPPIT (SEQ ID NO: 969)
HC DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTACAG CGTCTG G AATCACCTTCAG AAATTATG G CATG CACTG G GTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAA GTACTATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGGTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAA GGGGCACTATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG GCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA G C AG CTTG G GCACCC AG ACCTACATCTG CAACGTG AATCACAAG CCCAGC AACACC AA G GTG G ACAAG AAAGTTG AG CCCAAATCTTGTG ACAAAACTC ACACATG CCCACCGTG C CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGG ACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCA CGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACA AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA ACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAG CCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGG CTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAAC GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCT CTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 970) HC Annino Acid Sequence
QVQLVESGGGWQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNK YYADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTY RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 971)
LG DNA Sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTG CCG G GCAAGTCAG AG CATTAG CAG CTATTTAAATTG GTATC AGC AG AAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAG CAG C ACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAAC AC AAAGTCTACG CC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 972)
LC Amino Acid Sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 973)
REGN10712
HCVR DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACATTCAGTACCTATGGCATGTACTGGGTCCGCC AG ACTCCAG G CAAGG GG CTG G AGTG G GTG AC AGTTATATCATTTG ATGG AAATAAAAAA TACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAAAACAC GCTGTTTCTGCAAATGAACAGCCTGAAAACTGAGGACACGGCTGTATATTACTGTGCGA AATCTTCTAACTG G AACTACG GTTCTTTTG ATATATG G G G CCAAG GG ACAATG GTCACC
GTCTCTTCA (SEQ ID NO: 1 180)
HCVR Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMYWVRQTPGKGLEWVTVISFDGNKKY
YADSVKGRFTISRDNSKNTLFLQMNSLKTEDTAVYYCAKSSNWNYGSFDIWGQGTMVTVS
S (SEQ ID NO: 1181)
HCDR1 DNA Sequence
GGATTCACATTCAGTACCTATGGC (SEQ ID NO: 1182)
HCDR1 Amino Acid Sequence
GFTFSTYG (SEQ ID NO: 1183)
HCDR2 DNA Sequence
ATATCATTTGATGGAAATAAAAAA (SEQ ID NO: 1 184)
HCDR2 Amino Acid Sequence
ISFDGNKK (SEQ ID NO: 1 185)
HCDR3 DNA Sequence
GCGAAATCTTCTAACTGGAACTACGGTTCTTTTGATATA (SEQ ID NO: 1 186)
HCDR3 Amino Acid Sequence
AKSSNWNYGSFDI (SEQ ID NO: 1 187)
LCVR DNA Sequence
CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACC
ATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTACC
AGCAGCTTCCAGGCACAGCCCCCAGACTCCTCATCTCTTATAACAGCAATCGGCCCTC AGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATC
ACTGGGCTCCAGGCTGAGGATGAGGCTGACTATTACTGCCAGTCCTATGACAGAAGCC TGAGTGGTTCTGTGTTCGGAGGAGGCACCCAGCTGACCGTCCTC (SEQ ID NO: 1188)
LCVR Amino Acid Sequence QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPRLLISYNSNRPSGVP
DRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRSLSGSVFGGGTQLTVL (SEQ ID NO: 1 189)
LCDR1 DNA Sequence
AGCTCCAACATCGGGGCAGGTTATGAT (SEQ ID NO: 1 190)
LCDR1 Amino Acid Sequence
SSNIGAGYD (SEQ ID NO: 1 191)
LCDR2 DNA Sequence
TATAACAGC (SEQ ID NO: 1 192)
LCDR2 Amino Acid Sequence
YNS (SEQ ID NO: 1 193)
LCDR3 DNA Sequence
CAGTCCTATGACAGAAGCCTGAGTGGTTCTGTG (SEQ ID NO: 1 194)
LCDR3 Amino Acid Sequence
QSYDRSLSGSV (SEQ ID NO: 1 195)
HC DNA Sequence
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACATTCAGTACCTATGGCATGTACTGGGTCCGCC AG ACTCC AG G CAAGG G GCTG G AGTG G GTG ACAGTTATATCATTTG ATGG AAATAAAAAA TACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAAAACAC GCTGTTTCTGCAAATGAACAGCCTGAAAACTGAGGACACGGCTGTATATTACTGTGCGA AATCTTCTAACTG G AACTACG GTTCTTTTG ATATATG G G G CCAAG GG ACAATG GTCACC GTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGA GCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAAC CGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGG CTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAG CAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAG GTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTG AGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCAT
GATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCC CGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAG CCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTG CACCAG G ACTG G CTG AACG G CAAG G AGTACAAGTG CAAGGTCTCC AACAAAG G CCTC C CGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGT GTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC CTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCAT GCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTC
TCTGGGTAAATGA (SEQ ID NO: 1196)
HC Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMYWVRQTPGKGLEWVTVISFDGNKKY YADSVKGRFTISRDNSKNTLFLQMNSLKTEDTAVYYCAKSSNWNYGSFDIWGQGTMVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR WSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 1 197)
HC constant, hlgG4 (S108P) DNA Sequence
GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCC GAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGG GCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAA GAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTG GGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCC GGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCC AGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGG AGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCC ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCC TGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAA AGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAA CAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGC AGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTG
ATG CATG AGG CTCTG CAC AACCACTAC ACACAG AAGTCCCTCTCCCTGTCTCTG G GTAA
ATGA (SEQ ID NO: 1 198)
HC constant, hlgG4 (S108P) Amino Acid Sequence
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL
FPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV
VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV
SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF
SCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 1 199)
LC DNA Sequence
CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACC
ATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTACC
AGCAGCTTCCAGGCACAGCCCCCAGACTCCTCATCTCTTATAACAGCAATCGGCCCTC
AGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATC
ACTGGGCTCCAGGCTGAGGATGAGGCTGACTATTACTGCCAGTCCTATGACAGAAGCC
TGAGTGGTTCTGTGTTCGGAGGAGGCACCCAGCTGACCGTCCTCGGCCAGCCCAAGG
CCGCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCTGCAGGCCAACAAGG
CCACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGTGACCGTGGCCTGGA
AGGCCGACTCCTCCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCTCCAAGCAGT
CCAACAACAAGTACGCCGCCTCCTCCTACCTGTCCCTGACCCCCGAGCAGTGGAAGTC
CCACCGGTCCTACTCCTGCCAGGTGACCCACGAGGGCTCCACCGTGGAGAAGACCGT
GGCCCCCACCGAGTGCTCCTGA (SEQ ID NO: 1200)
LC Amino Acid Sequence
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPRLLISYNSNRPSGVP
DRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRSLSGSVFGGGTQLTVLGQPKAAPSVTL
FPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYL
SLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 1201)
LC constant, hLamda DNA Sequence
GGCCAGCCCAAGGCCGCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCTG
CAGGCCAACAAGGCCACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGTG
ACCGTGGCCTGGAAGGCCGACTCCTCCCCCGTGAAGGCCGGCGTGGAGACCACCACC
CCCTCCAAGCAGTCCAACAACAAGTACGCCGCCTCCTCCTACCTGTCCCTGACCCCCG AGCAGTGGAAGTCCCACCGGTCCTACTCCTGCCAGGTGACCCACGAGGGCTCCACCG
TGGAGAAGACCGTGGCCCCCACCGAGTGCTCCTGA (SEQ ID NO: 1202)
LC constant, hLamda Amino Acid Sequence
GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQ
SNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 1203)
REGN9908
HCVR DNA Sequence
GAGGTGCAGTTGTTGGAGTCTGGGGGAGGCTTGGCACAGCCTGGGGGGTCCCTGAGA
CTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGTTATGCCATGAGCTGGGTCCGCCA
GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCTGTTAGTGGTAGTGGTGGTACCAC
ATATTATGCAGCCTCCGTGAAGGGCCGGTTCACCGTCTCCAGAGACAATTCCAAGAAG
ACGCTCTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTG
GGAAAGGAGGATATTGTAGTAGTAGTGGTTGCCGTCACTACGGTATGGACGTCTGGGG
CCAAGGGACCACGGTCACCGTCTCCGCA (SEQ ID NO: 1204)
HCVR Amino Acid Sequence
EVQLLESGGGLAQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSVSGSGGTTY
YAASVKGRFTVSRDNSKKTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWGQ
GTTVTVSA (SEQ ID NO: 1205)
HCDR1 DNA Sequence
GGATTCACCTTTAGCAGTTATGCC (SEQ ID NO: 1206)
HCDR1 Amino Acid Sequence
GFTFSSYA (SEQ ID NO: 1207)
HCDR2 DNA Sequence
GTTAGTGGTAGTGGTGGTACCACA (SEQ ID NO: 1208)
HCDR2 Amino Acid Sequence
VSGSGGTT (SEQ ID NO: 1209)
HCDR3 DNA Sequence
GGGAAAGGAGGATATTGTAGTAGTAGTGGTTGCCGTCACTACGGTATGGACGTC (SEQ
ID NO: 1210) HCDR3 Amino Acid Sequence
GKGGYCSSSGCRHYGMDV (SEQ ID NO: 1211)
LCVR DNA Sequence
CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCGCC
ATTTCTTGTTCTGGAAGCAACTCCAACATCGGAAATAATTACTTATACTGGTACCAGCAG
ATCCCAGGAACGACCCCCAAACTCCTCATCTATAGAAATAATCAGCGGCCCTCAGGGG TCCCTGACCGATTCTCTGCCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGG GCTCCGGTCCGGGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAGT GGGTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA (SEQ ID NO: 1212)
LCVR Amino Acid Sequence
QSVLTQPPSASGTPGQRVAISCSGSNSNIGNNYLYWYQQIPGTTPKLLIYRNNQRPSGVPD RFSASKSGTSASLAISGLRSGDEADYYCAAWDDSLSGYVFGTGTKVTVL (SEQ ID NO: 1213)
LCDR1 DNA Sequence
AACTCCAACATCGGAAATAATTA (SEQ ID NO: 1214)
LCDR1 Amino Acid Sequence
NSNIGNN (SEQ ID NO: 1215)
LCDR2 DNA Sequence
AGAAATAAT (SEQ ID NO: 1216)
LCDR2 Amino Acid Sequence
RNN (SEQ ID NO: 1217)
LCDR3 DNA Sequence
GCAGCATGGGATGACAGCCTGAGTGGGTATGTC (SEQ ID NO: 1218)
LCDR3 Amino Acid Sequence
AAWDDSLSGYV (SEQ ID NO: 1219)
HC DNA Sequence
GAGGTGCAGTTGTTGGAGTCTGGGGGAGGCTTGGCACAGCCTGGGGGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGTTATGCCATGAGCTGGGTCCGCCA
GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCTGTTAGTGGTAGTGGTGGTACCAC
ATATTATGCAGCCTCCGTGAAGGGCCGGTTCACCGTCTCCAGAGACAATTCCAAGAAG
ACGCTCTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTG
GGAAAGGAGGATATTGTAGTAGTAGTGGTTGCCGTCACTACGGTATGGACGTCTGGGG
CCAAGGGACCACGGTCACCGTCTCCGCAGCCAAGACAACACCTCCTTCTGTGTATCCT
CTGGCTCCTGGATGTGGAGATACAACAGGATCTTCTGTGACACTGGGATGTCTGGTGA
AGGGATATTTTCCTGAATCTGTGACAGTGACATGGAACTCTGGATCTCTGTCTTCTTCTG
TGCATACATTTCCTGCTCTGCTGCAGTCTGGACTGTATACAATGTCTTCTTCTGTGACAG
TGCCTTCTTCTACATGGCCTTCTCAGACAGTGACATGTTCTGTGGCTCATCCTGCTTCTT
CTACAACAGTGGATAAGAAGCTGGAACCTTCTGGACCTATCTCTACAATCAATCCTTGT
CCTCCTTGTAAGGAATGTCATAAGTGTCCTGCTCCTAATCTGGAAGGAGGACCTTCTGT
GTTTATCTTTCCTCCTAATATCAAGGATGTGCTGATGATCTCTCTGACACCTAAGGTGAC
ATGTGTGGTGGTGGATGTGTCTGAAGATGATCCTGATGTGCAGATCTCTTGGTTTGTGA
ATAATGTGGAAGTGCATACAGCTCAGACACAGACACATAGAGAAGATTATAATTCTACA
ATCAGAGTGGTGTCTACACTGCCTATCCAGCATCAGGATTGGATGTCTGGAAAGGAATT
TAAGTGTAAGGTGAATAATAAGGATCTGCCTTCTCCTATCGAAAGAACAATCTCTAAGAT
CAAGGGACTGGTGAGAGCTCCTCAGGTGTATATCCTGCCTCCTCCTGCTGAACAGCTG
TCCAGAAAGGATGTGTCTCTGACATGTCTGGTGGTGGGATTTAATCCTGGAGATATCTC
TGTGGAATGGACATCTAATGGACATACAGAAGAAAATTATAAGGATACAGCTCCTGTGC
TGGATTCTGATGGATCTTATTTTATCTATTCTAAGCTGAATATGAAGACATCTAAGTGGG
AAAAGACAGATTCTTTTTCTTGTAATGTGAGACATGAAGGACTGAAGAATTATTATCTGA
AGAAGACAATCTCCAGATCTCCTGGAAAGTGA (SEQ ID NO: 1220)
HC Amino Acid Sequence
EVQLLESGGGLAQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSVSGSGGTTY
YAASVKGRFTVSRDNSKKTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWGQ
GTTVTVSAAKTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVHTF
PALLQSGLYTMSSSVTVPSSTWPSQTVTCSVAHPASSTTVDKKLEPSGPISTINPCPPCKEC
HKCPAPNLEGGPSVFIFPPNIKDVLMISLTPKVTCVWDVSEDDPDVQISWFVNNVEVHTAQ
TQTHREDYNSTIRWSTLPIQHQDWMSGKEFKCKVNNKDLPSPIERTISKIKGLVRAPQVYIL
PPPAEQLSRKDVSLTCLWGFNPGDISVEWTSNGHTEENYKDTAPVLDSDGSYFIYSKLNM
KTSKWEKTDSFSCNVRHEGLKNYYLKKTISRSPGK (SEQ ID NO: 1221)
HC constant, mlgG2b DNA Sequence
GCCAAGACAACACCTCCTTCTGTGTATCCTCTGGCTCCTGGATGTGGAGATACAACAG
GATCTTCTGTGACACTGGGATGTCTGGTGAAGGGATATTTTCCTGAATCTGTGACAGTG ACATGGAACTCTGGATCTCTGTCTTCTTCTGTGCATACATTTCCTGCTCTGCTGCAGTCT GGACTGTATACAATGTCTTCTTCTGTGACAGTGCCTTCTTCTACATGGCCTTCTCAGACA GTG ACATGTTCTGTG G CTCATCCTG CTTCTTCTACAAC AGTG G ATAAG AAG CTG G AACC TTCTGGACCTATCTCTACAATCAATCCTTGTCCTCCTTGTAAGGAATGTCATAAGTGTCC TGCTCCTAATCTGGAAGGAGGACCTTCTGTGTTTATCTTTCCTCCTAATATCAAGGATGT GCTGATGATCTCTCTGACACCTAAGGTGACATGTGTGGTGGTGGATGTGTCTGAAGAT GATCCTGATGTGCAGATCTCTTGGTTTGTGAATAATGTGGAAGTGCATACAGCTCAGAC ACAGACACATAGAGAAGATTATAATTCTACAATCAGAGTGGTGTCTACACTGCCTATCCA GCATCAGGATTGGATGTCTGGAAAGGAATTTAAGTGTAAGGTGAATAATAAGGATCTGC CTTCTCCTATCGAAAGAACAATCTCTAAGATCAAGGGACTGGTGAGAGCTCCTCAGGTG TATATCCTGCCTCCTCCTGCTGAACAGCTGTCCAGAAAGGATGTGTCTCTGACATGTCT GGTGGTGGGATTTAATCCTGGAGATATCTCTGTGGAATGGACATCTAATGGACATACAG AAG AAAATT ATAAG GATACAGCTCCTGTG CTG GATTCTGATGGATCTTATTTTATCTATT CTAAGCTGAATATGAAGACATCTAAGTGGGAAAAGACAGATTCTTTTTCTTGTAATGTGA GACATGAAGGACTGAAGAATTATTATCTGAAGAAGACAATCTCCAGATCTCCTGGAAAG TGA (SEQ ID NO: 1222)
HC constant, mlgG2b Amino Acid Sequence
AKTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVHTFPALLQSGL YTMSSSVTVPSSTWPSQTVTCSVAHPASSTTVDKKLEPSGPISTINPCPPCKECHKCPAPN LEGGPSVFIFPPNIKDVLMISLTPKVTCVWDVSEDDPDVQISWFVNNVEVHTAQTQTHRED YNSTIRWSTLPIQHQDWMSGKEFKCKVNNKDLPSPIERTISKIKGLVRAPQVYILPPPAEQL SRKDVSLTCLWGFNPGDISVEWTSNGHTEENYKDTAPVLDSDGSYFIYSKLNMKTSKWEK TDSFSCNVRHEGLKNYYLKKTISRSPGK (SEQ ID NO: 1223)
LC DNA Sequence
CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCGCC ATTTCTTGTTCTGGAAGCAACTCCAACATCGGAAATAATTACTTATACTGGTACCAGCAG ATCCCAGGAACGACCCCCAAACTCCTCATCTATAGAAATAATCAGCGGCCCTCAGGGG TCCCTGACCGATTCTCTGCCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGG GCTCCGGTCCGGGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAGT GGGTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTAGGCCAACCTAAATCATCTC CATCCGTTACTCTCTTCCCCCCATCTTCAGAAGAACTCGAAACCAATAAAGCCACACTC GTTTGCACCATTACAGATTTCTATCCAGGAGTAGTTACAGTCGATTGGAAAGTAGACGG AACACCAGTTACACAGGGTATGGAAACCACACAACCATCTAAGCAGTCTAATAACAAAT ACATGGCCTCATCATACCTCACTCTTACCGCCCGCGCATGGGAAAGACATTCATCATAT TCTTGCCAGGTAACCCACGAAGGACACACAGTTGAAAAATCTTTGAGTAGAGCAGATTG TAGTTGA (SEQ ID NO: 1224)
LC Amino Acid Sequence
QSVLTQPPSASGTPGQRVAISCSGSNSNIGNNYLYWYQQIPGTTPKLLIYRNNQRPSGVPD RFSASKSGTSASLAISGLRSGDEADYYCAAWDDSLSGYVFGTGTKVTVLGQPKSSPSVTLF PPSSEELETNKATLVCTITDFYPGWTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLT LTARAWERHSSYSCQVTHEGHTVEKSLSRADCS (SEQ ID NO: 1225)
LC constant, mLambda DNA Sequence
GGCCAACCTAAATCATCTCCATCCGTTACTCTCTTCCCCCCATCTTCAGAAGAACTCGA AACCAATAAAGCCACACTCGTTTGCACCATTACAGATTTCTATCCAGGAGTAGTTACAGT CGATTGGAAAGTAGACGGAACACCAGTTACACAGGGTATGGAAACCACACAACCATCT AAGCAGTCTAATAACAAATACATGGCCTCATCATACCTCACTCTTACCGCCCGCGCATG GGAAAGACATTCATCATATTCTTGCCAGGTAACCCACGAAGGACACACAGTTGAAAAAT CTTTGAGTAGAGCAGATTGTAGTTGA (SEQ ID NO: 1226)
LC constant, mLambda Amino Acid Sequence
GQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGWTVDWKVDGTPVTQGMETTQPSKQ SNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS (SEQ ID NO: 1227)
[00470] According to certain exemplary embodiments, provided herein are anti-AAV/anti- CACNG1 multispecific antibodies, wherein the second antigen-binding domain that binds to CACNG1 comprises a heavy chain variable region (HCVR) having an amino acid sequence selected from SEQ ID NOs: 615, 635, 655, 675, 695, 715, 735, 755, 775, 795, 815, 835, 855, 875, 895, 915, 935, 955, 1181 , or 1205 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00471] In some embodiments, provided herein are anti-AAV/anti-CACNG1 multispecific antibodies, wherein the second antigen-binding domain that binds to CACNG1 comprises a light chain variable region (LCVR) having an amino acid sequence selected from SEQ ID NOs: 623, 643, 663, 683, 703, 723, 743, 763, 783, 803, 823, 843, 863, 883, 903, 923, 943, 963, 1189, or 1213 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00472] In some embodiments, provided herein are anti-AAV/anti-CACNG1 multispecific antibodies, wherein the second antigen-binding domain that binds to CACNG1 comprises a HCVR and LCVR (HCVR/LCVR) amino acid sequence pair selected from SEQ ID NOs: 615/623 (e.g., H2aM31929N/REGN10728), SEQ ID NOs: 635/643 (e.g., H2aM31944N), SEQ ID NOs: 655/663 (e.g., H4H31265P2/REGN5972), SEQ ID NOs: 675/683 (e.g., H2aM31941 N), SEQ ID NOs: 695/703 (e.g., REGN7660), SEQ ID NOs: 715/723 (e.g., REGN9909), SEQ ID NOs: 735/743 (e.g., REGN10713), SEQ ID NOs: 755/763 (e.g., REGN10715), SEQ ID NOs: 775/783 (e.g., REGN10716), SEQ ID NOs: 795/803 (e.g.,
REGN10717), SEQ ID NOs: 815/823 (e.g., REGN10783), SEQ ID NOs: 835/843 (e.g.,
REGN7854), SEQ ID NOs: 855/863 (e.g., REGN14570), SEQ ID NOs: 875/883 (e.g., REGN14571), SEQ ID NOs: 895/903 (e.g., REGN14572), SEQ ID NOs: 915/923 (e.g.,
REGN14573), SEQ ID NOs: 935/943 (e.g., REGN14574), SEQ ID NOs: 955/963 (e.g.,
REGN14647), SEQ ID NOs: 1181/1189 (e.g., REGN10712), and SEQ ID NOs: 1205/1213 (e.g., REGN9908).
[00473] In some embodiments, provided herein are anti-AAV/anti-CACNG1 multispecific antibodies, wherein the second antigen-binding domain that binds to CACNG1 comprises a heavy chain CDR1 (HCDR1) domain having an amino acid sequence selected from SEQ ID NOs: 617, 637, 657, 677, 697, 717, 737, 757, 777, 797, 817, 837, 857, 877, 897, 917, 937, 957, 1183, or 1207 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a heavy chain CDR2 (HCDR2) domain having an amino acid sequence selected from SEQ ID NOs: 619, 639, 659, 679, 699, 719, 739, 759, 779, 799, 819, 839, 859, 879, 899, 919, 939, 959, 1185, or 1209 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a heavy chain CDR3 (HCDR3) domain having an amino acid sequence selected from SEQ ID NOs: 621 , 641 , 661 , 681 , 701 , 721 , 741 , 761 , 781 , 801 , 821 , 841 , 861 , 881 , 901 , 921 , 941 , 961 , 1187, or 1211 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a light chain CDR1 (LCDR1) domain having an amino acid sequence of SEQ ID NOs: 625, 645, 665, 685, 705, 725, 745, 765, 785, 805, 825, 845, 865, 885, 905, 925, 945, 965, 1191, or 1215 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a light chain CDR2 (LCDR2) domain having an amino acid sequence of SEQ ID NOs: 627, 647, 667, 687, 707, 727, 747, 767, 787, 807, 827, 847, 867, 887, 907, 927, 947, 967, 1193, or 1217 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; and a light chain CDR3 (LCDR3) domain having an amino acid sequence of SEQ ID NOs: 629, 649, 669, 689, 709, 729, 749, 769, 789, 809, 829, 849, 869, 889, 909, 929, 949, 969, 1195, or 1219 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00474] Certain non-limiting, exemplary anti-AAV/anti-CACNG1 multispecific antibodies provided herein include a second antigen-binding domain that binds to CACNG1 comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3), respectively, having the amino acid sequences selected from SEQ ID NOs: 617- 619- 621- 625- 627- 629 (e.g., H2aM31929N/REGN10728), SEQ ID NOs: 637- 639- 641- 645- 647- 649 (e.g., H2aM31944N), SEQ ID NOs: 657- 659- 661- 665- 667- 669 (e.g., H4H31265P2/REGN5972), SEQ ID NOs: 677- 679- 681- 685- 687- 689 (e.g., H2aM31941 N), SEQ ID NOs: 697- 699- 701- 705- 707- 709 (e.g., REGN7660), SEQ ID NOs: 717- 719- 721- 725- 727- 729 (e.g., REGN9909), SEQ ID NOs: 737- 739- 741- 745- 747- 749 (e.g., REGN10713), SEQ ID NOs: 757- 759- 761- 765- 767- 769 (e.g., REGN10715), SEQ ID NOs: 777- 779- 781- 785- 787- 789 (e.g., REGN10716), SEQ ID NOs: 797- 799- 801- 805- 807- 809 (e.g., REGN10717), SEQ ID NOs: 817- 819- 821- 825- 827- 829 (e.g., REGN10783), SEQ ID NOs: 837- 839- 841- 845- 847- 849 (e.g., REGN7854), SEQ ID NOs: 857- 859- 861- 865- 867- 869 (e.g., REGN14570), SEQ ID NOs: 877- 879- 881- 885- 887- 889 (e.g., REGN14571), SEQ ID NOs: 897- 899- 901- 905- 907- 909 (e.g., REGN14572), SEQ ID NOs: 917- 919- 921- 925- 927- 929 (e.g., REGN14573), SEQ ID NOs: 937- 939- 941- 945- 947- 949 (e.g., REGN14574), SEQ ID NOs: 957- 959- 961- 965- 967- 969 (e.g., REGN14647), SEQ ID NOs: 1183- 1185- 1187- 1191- 1193- 1195 (e.g., REGN10712), and SEQ ID NOs: 1207- 1209- 1211- 1215- 1217- 1219 (e.g., REGN9908).
[00475] In an embodiment provided herein, an anti-AAV/anti-CACNG1 multispecific antibody herein can comprise an anti-CACNG1 antibody, or antigen-binding fragment thereof, wherein the anti-CACNG 1 antibody or antigen-binding fragment thereof can include: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783; j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803; k) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823; l) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843; m) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863; n) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883; o) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903; p) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923; q) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943; r) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963; s) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; and/or t) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213. [00476] In an embodiment provided herein, an anti-AAV/anti-CACNG1 multispecific antibody herein can comprise an anti-CACNG1 antibody or antigen-binding fragment thereof, wherein the anti-CACNG 1 antibody or antigen-binding fragment thereof, can include: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789; j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809; k) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829; l) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849; m) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869; n) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889; o) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909; p) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929; q) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949; r) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969; s) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; and/or t) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1211 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219. [00477] In an embodiment provided herein, an anti-AAV/anti-CACNG1 multispecific antibody herein can comprise an anti-CACNGI antibody, or antigen-binding fragment thereof, wherein the anti-CACNG 1 antibody or antigen-binding fragment thereof can include: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783; j) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803; k) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823; l) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843; m) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863; n) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883; o) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903; p) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923; q) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943; r) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963; s) a HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; and/or t) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[00478] In an embodiment provided herein, an anti-AAV/anti-CACNG1 multispecific antibody herein can comprise an anti-CACNG1 antigen-binding fragment comprising an anti- CACNG1 Fab, wherein the anti-CACNG1 Fab can include: a) a HC region that comprises the amino acid sequence of SEQ ID NO: 631 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 633, or a variant thereof; b) a HC region that comprises the amino acid sequence of SEQ ID NO: 651 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 653, or a variant thereof; c) a HC region that comprises the amino acid sequence of SEQ ID NO: 671 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 673, or a variant thereof; d) a HC region that comprises the amino acid sequence of SEQ ID NO: 691 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 693, or a variant thereof; e) a HC region that comprises the amino acid sequence of SEQ ID NO: 711 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 713, or a variant thereof; f) a HC region that comprises the amino acid sequence of SEQ ID NO: 731 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 733, or a variant thereof; g) a HC region that comprises the amino acid sequence of SEQ ID NO: 751 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 753, or a variant thereof; h) a HC region that comprises the amino acid sequence of SEQ ID NO: 771 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 773, or a variant thereof; i) a HC region that comprises the amino acid sequence of SEQ ID NO: 791 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 793, or a variant thereof; j) a HC region that comprises the amino acid sequence of SEQ ID NO: 811 or 1173, or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 813, or a variant thereof; k) a HC region that comprises the amino acid sequence of SEQ ID NO: 831 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 833, or a variant thereof; l) a HC region that comprises the amino acid sequence of SEQ ID NO: 851 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 853, or a variant thereof; m) a HC region that comprises the amino acid sequence of SEQ ID NO: 871 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 873, or a variant thereof; n) a HC region that comprises the amino acid sequence of SEQ ID NO: 891 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 893, or a variant thereof; o) a HC region that comprises the amino acid sequence of SEQ ID NO: 911 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 913, or a variant thereof; p) a HC region that comprises the amino acid sequence of SEQ ID NO: 931 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 933, or a variant thereof; q) a HC region that comprises the amino acid sequence of SEQ ID NO: 951 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 953, or a variant thereof; and/or r) a HC region that comprises the amino acid sequence of SEQ ID NO: 971 , or a variant thereof; and/or a LC region that comprises the amino acid sequence of SEQ ID NO: 973, or a variant thereof.
[00479] Any of the HCVR and/or LCVR of the anti-CACNG1 antibodies, or variants thereof, disclosed herein can be contained within an antigen-binding fragment such as but not limited to (i) Fab fragment; (ii) F(ab')2 fragment; (iii) Fd fragment; (iv) Fv fragment; (v) single-chain Fv (scFv) molecules; and (vi) dAb fragments.
[00480] In various embodiments, for example, when a HCVR and a LCVR of an anti- CACNG1 antibody, or variant thereof, are contained within an antigen binding fragment (e.g., an scFv or a Fab), the HCVR and the LCVR can be in either orientation (HCVR-LCVR or LCVR-HCVR). In some embodiments, the HCVR and LCVR are optionally linked by a linker, e.g, that comprises an amino acid sequence, e.g., about 10 amino acids in length, for example: (Gly4Ser)n (SEQ ID NO: 241) wherein n is 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[00481] In some embodiments, the scFv comprises (i) a heavy chain variable region that comprises the HCDR1 , HCDR2 and HCDR3 of a HCVR comprising the amino acid sequence of SEQ ID NO: 615, 635, 655, 675, 695, 715, 735, 755, 775, 795, 815, 835, 855, 875, 895, 915, 935, 955, 1181 , or 1205; and/or
(ii) a light chain variable region that comprises the LCDR1 , LCDR2 and LCDR3 of a LCVR comprising the amino acid sequence of SEQ ID NO: 623, 643, 663, 683, 703, 723, 743, 763, 783, 803, 823, 843, 863, 883, 903, 923, 943, 963, 1189, or 1213; or the scFv comprises:
(1) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 615, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 623, or a variant thereof;
(2) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 635, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 643, or a variant thereof;
(3) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 655, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 663, or a variant thereof;
(4) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 675, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 683, or a variant thereof;
(5) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 695, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 703, or a variant thereof;
(6) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 715, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 723, or a variant thereof;
(7) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 735, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 743, or a variant thereof;
(8) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 755, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 763, or a variant thereof;
(9) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 775, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 783, or a variant thereof;
(10) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 795, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 803, or a variant thereof;
(11) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 815, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 823, or a variant thereof;
(12) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 835, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 843, or a variant thereof; (13) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 855, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 863, or a variant thereof;
(14) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 875, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 883, or a variant thereof;
(15) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 895, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 903, or a variant thereof;
(16) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 915, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 923, or a variant thereof;
(17) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 935, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 943, or a variant thereof;
(18) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 955, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 963, or a variant thereof;
(19) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 1181 , or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 1189, or a variant thereof;
(20) a HCVR comprising the HCDR1 , HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence of SEQ ID NO: 1205, or a variant thereof; and a LCVR comprising the LCDR1 , LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence of SEQ ID NO: 1213, or a variant thereof; or the scFv comprises:
(a) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 629, or a variant thereof;
(b) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 649, or a variant thereof;
(c) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 669, or a variant thereof;
(d) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 689, or a variant thereof;
(e) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 709, or a variant thereof;
(f) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 729, or a variant thereof;
(g) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 749, or a variant thereof;
(h) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 769, or a variant thereof;
(i) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 789, or a variant thereof;
(j) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 809, or a variant thereof;
(k) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 829, or a variant thereof;
(l) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 849, or a variant thereof;
(m) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 869, or a variant thereof;
(n) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 889, or a variant thereof;
(o) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 909, or a variant thereof;
(p) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 929, or a variant thereof;
(q) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 949, or a variant thereof;
(r) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 969, or a variant thereof;
(s) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1183, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 1185, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 1187, or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 1191 , or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 1193, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195, or a variant thereof;
(t) a HCVR that comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, or a variant thereof, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, or a variant thereof, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 1211 , or a variant thereof; and a LCVR that comprises: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, or a variant thereof, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, or a variant thereof, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219, or a variant thereof; or the scFv comprises:
(i) a HCVR that comprises the amino acid sequence of SEQ ID NO: 615, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 623, or a variant thereof;
(ii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 635, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 643, or a variant thereof;
(iii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 655, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 663, or a variant thereof;
(iv) a HCVR that comprises the amino acid sequence of SEQ ID NO: 675, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 683, or a variant thereof;
(v) a HCVR that comprises the amino acid sequence of SEQ ID NO: 695, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 703, or a variant thereof;
(vi) a HCVR that comprises the amino acid sequence of SEQ ID NO: 715, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 723, or a variant thereof;
(vii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 735, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 743, or a variant thereof;
(viii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 755, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 763, or a variant thereof;
(ix) a HCVR that comprises the amino acid sequence of SEQ ID NO: 775, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 783, or a variant thereof;
(x) a HCVR that comprises the amino acid sequence of SEQ ID NO: 795, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 803, or a variant thereof;
(xi) a HCVR that comprises the amino acid sequence of SEQ ID NO: 815, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 823, or a variant thereof;
(xii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 835, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 843, or a variant thereof;
(xiii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 855, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 863, or a variant thereof;
(xiv) a HCVR that comprises the amino acid sequence of SEQ ID NO: 875, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 883, or a variant thereof; (xv) a HCVR that comprises the amino acid sequence of SEQ ID NO: 895, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 903, or a variant thereof;
(xvi) a HCVR that comprises the amino acid sequence of SEQ ID NO: 915, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 923, or a variant thereof;
(xvii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 935, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 943, or a variant thereof;
(xviii) a HCVR that comprises the amino acid sequence of SEQ ID NO: 955, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 963, or a variant thereof;
(xix) a HCVR that comprises the amino acid sequence of SEQ ID NO: 1181 , or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 1189, or a variant thereof;
(xx) a HCVR that comprises the amino acid sequence of SEQ ID NO: 1205, or a variant thereof; and a LCVR that comprises the amino acid sequence of SEQ ID NO: 1213, or a variant thereof; e.g., wherein the HCVR and LCVR are in either orientation (HCVR-LCVR or LCVR-HCVR), optionally, wherein the HCVR and LCVR are linked by a linker, e.g., that comprises an amino acid sequence, e.g., about 10 amino acids in length, for example: (Gly4Ser)n (SEQ ID NO: 241) wherein n is 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[00482] Fab fragments that bind specifically to CACNG1 form part of the present disclosure. Fab fragments typically contain one complete light chain, VL and a constant light (CL) domain, e.g., kappa (e.g., RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1147)); and the VH and IgG 1 CH1 portion (e.g.,
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1179) or ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1112)); or lgG4 CH1 (e.g.,
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG (SEQ ID NO: 1171), or ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1135)) of one heavy chain. Fab fragment antibodies can be generated by papain digestion of whole IgG antibodies to remove the entire Fc fragment, including the hinge region. For example, the present disclosure includes Fab proteins comprising:
(1) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 615, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 623, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(2) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 635, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 643, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(3) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 655, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 663, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(4) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 675, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 683, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(5) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 695, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 703, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(6) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 715, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 723, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(7) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 735, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 743, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(8) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 755, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 763, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(9) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 775, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 783, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(10) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 795, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 803, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(11) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 815, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 823, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(12) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 835, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 843, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(13) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 855, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 863, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(14) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 875, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 883, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain; (15) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 895, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 903, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(16) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 915, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 923, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(17) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 935, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 943, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(18) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 955, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 963, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain;
(19) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 1181 , or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 1189, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain; and/or
(20) a heavy chain variable region (HCVR) that comprises the amino acid sequence of SEQ ID NO: 1205, or a heavy chain variable region that includes HCDR1 , HCDR2 and HCDR3 of such a HCVR- linked to the CH1 domain; and a light chain variable region (LCVR) that comprises the amino acid sequence of SEQ ID NO: 1213, or LCDR1 , LCDR2 and LCDR3 of such a LCVR-linked to the CL domain; e.g., wherein CH1 is from IgG 1 or lgG4; e.g., wherein CH1 is SEQ ID NO: 1147, 1179, 1112, 1171, or 1135.
The heavy and light chains of anti-CACNG1 Fabs in anti-AAV/anti-CACNG1 multispecific antibodies of the present disclosure are set forth below.
(1) REGN10717
HC Fab (VH + lgG1 CH1) DNA Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG
ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC
CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGAT
AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAA
CACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTG
CGAGAAGGGGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCAC
CGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG
AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA
CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG
GCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA
G GAG CTTG G GCACCCAG ACCTACATCTG CAACGTG AATCACAAG CCCAGCAACACCAA
GGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACA (SEQ ID NO: 1174)
(2) REGN10717
HC Fab (VH + IgG 1 CH1) Amino Acid Sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK
YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1175)
(3) REGN10717
LC DNA Sequence
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCA
CCCTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAAA
CCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTCC
CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCT
GCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACGTT
CGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATC
TTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAA
TAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCG
GGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC
AGCAG CACCCTG ACG CTG AG CAAAG CAG ACTACG AG AAACACAAAGTCTACG CCTGCG
AAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT
GTTAG (SEQ ID NO: 812)
(4) REGN10717
LC Fab Amino Acid Sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 813)
[00483] In certain exemplary embodiments, the isolated bispecific antigen-binding molecule competes for binding to a one or more capsid proteins an AAV particle or binds to the same epitope of an AAV capsid protein as a reference antibody, wherein the reference antibody comprises an antibody or antigen-binding fragment thereof, or a bispecific antibody disclosed herein.
[00484] In certain exemplary embodiments, the isolated bispecific antigen-binding molecule competes for binding to a molecule on a cell surface, or binds to the same epitope on a molecule on a cell surface as a reference antibody, wherein the reference antibody comprises an antibody or antigen-binding fragment thereof, or a bispecific antibody disclosed herein.
[00485] In some cases, the bispecific antibody comprises a human IgG heavy chain constant region. In some cases, the human IgG heavy chain constant region is isotype IgG 1 . In some cases, the human IgG heavy chain constant region is isotype lgG4. In various embodiments, the bispecific antibody comprises a chimeric hinge that reduces Fey receptor binding relative to a wild-type hinge of the same isotype.
[00486] The first antigen-binding domain and the second antigen-binding domain may be directly or indirectly connected to one another to form a bispecific antigen-binding molecule of the present disclosure. Alternatively, the first antigen-binding domain and the second antigen-binding domain may each be connected to a separate multimerizing domain. The association of one multimerizing domain with another multimerizing domain facilitates the association between the two antigen-binding domains, thereby forming a bispecific antigenbinding molecule. As used herein, a "multimerizing domain" is any macromolecule, protein, polypeptide, peptide, or amino acid that has the ability to associate with a second multimerizing domain of the same or similar structure or constitution. For example, a multimerizing domain may be a polypeptide comprising an immunoglobulin CH3 domain. A non-limiting example of a multimerizing component is an Fc portion of an immunoglobulin (comprising a CH2-CH3 domain), e.g., an Fc domain of an IgG selected from the isotypes IgG 1 , lgG2, lgG3, and lgG4, as well as any allotype within each isotype group.
[00487] Bispecific antigen-binding molecules of the present disclosure will typically comprise two multimerizing domains, e.g., two Fc domains that are each individually part of a separate antibody heavy chain. The first and second multimerizing domains may be of the same IgG isotype such as, e.g., lgG1/lgG1 , lgG2/lgG2, lgG4/lgG4. Alternatively, the first and second multimerizing domains may be of different IgG isotypes such as, e.g., lgG1/lgG2, lgG1/lgG4, lgG2/lgG4, etc.
[00488] In certain embodiments, the multimerizing domain is an Fc fragment or an amino acid sequence of from 1 to about 200 amino acids in length containing at least one cysteine residue. In other embodiments, the multimerizing domain is a cysteine residue, or a short cysteine-containing peptide. Other multimerizing domains include peptides or polypeptides comprising or consisting of a leucine zipper, a helix-loop motif, or a coiled-coil motif. Non-limiting Examples of Bispecific Antigen-Binding Molecules
[00489] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: a) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 4, or a variant thereof; a
HCDR2 that comprises the amino acid sequence of SEQ ID NO: 6, or a variant thereof; a
HCDR3 that comprises the amino acid sequence of SEQ ID NO: 8, or a variant thereof; a
LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof; a
LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 16, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 2, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 18, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00490] In another exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: b) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 24, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 26, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 28, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 16, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 22, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 30, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00491] In another exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: c) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 34, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 36, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 38, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 16, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 32, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 40, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00492] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: d) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 44, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 46, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 48, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 16, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 42, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 50, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00493] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: e) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 54, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 56, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 58, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 16, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 52 or 1159, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 60 or 1108, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00494] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: f) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 64, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 56, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 67, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 16, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 62, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 69, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof
[00495] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: g) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 73, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 75, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 77, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 16, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 71, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 79, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00496] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: h) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 83, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 85, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 87, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 16, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 81, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 89, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00497] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: i) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 93, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 95, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 97, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 16, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 91, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 99, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or (5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00498] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: j) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 103, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 105, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 107, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 16, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 101 , or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 109, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00499] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: k) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 113, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 115, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 117, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 121 , or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 123, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 125, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 111 , or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 119, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 127, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00500] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes:
I) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 133, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 135, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 137, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 121 , or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 123, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 125, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 131 , or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 119, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 139, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00501] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: m) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 143, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 145, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 147, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 121 , or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 123, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 125, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 141 , or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 119, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 149, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00502] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: n) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 153, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 155, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 157, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 121 , or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 123, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 125, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 151 , or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 119, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 159, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00503] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes:
[00504] o) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 163, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 165, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 167, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 121 , or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 123, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 125, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 161 , or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 119, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 169, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00505] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: p) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 173, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 145, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 176, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 121 , or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 123, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 125, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 171 , or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 119, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 178, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00506] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: q) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 182, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 184, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 186, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 121 , or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 123, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 125, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 180, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 119, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 188, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00507] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: r) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 192, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 194, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 196, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 121 , or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 123, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 125, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 190, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 119, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 198, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00508] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: s) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 202, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 204, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 206, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 121 , or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 123, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 125, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 200, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 119, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 208, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
[00509] In an exemplary embodiment provided herein, the multispecific (e.g., bispecific) antigen-binding molecule (e.g., antibody or antigen-binding fragment thereof) that binds to a capsid of an AAV particle and a molecule on a cell surface includes: t) (1) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 212, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 214, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 216121 , or a variant thereof; a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 123, or a variant thereof; and a LCDR3 that comprises the amino acid sequence SEQ ID NO: 125, or a variant thereof; and a second antigen binding domain that binds to a molecule on a cell surface that comprises: a HCDR1 that comprises the amino acid sequence of SEQ ID NO: 222 or 232, or a variant thereof; a HCDR2 that comprises the amino acid sequence of SEQ ID NO: 224 or 234, or a variant thereof; a HCDR3 that comprises the amino acid sequence of SEQ ID NO: 226 or 236, or a variant thereof; a LCDR1 that comprises the amino acid sequence of SEQ ID NO: 12, or a variant thereof, a LCDR2 that comprises the amino acid sequence of SEQ ID NO: 14, or a variant thereof; and a LCDR3 that comprises the amino acid sequence of SEQ ID NO: 16, or a variant thereof;
(2) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 210, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HCVR that comprises the amino acid sequence of SEQ ID NO: 220 or 1239 or 230, or a variant thereof;
(3) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 119, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof;
(4) a first antigen binding domain that binds to a capsid of an AAV that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 218, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a HC that comprises the amino acid sequence of SEQ ID NO: 228 or 238, or a variant thereof; and/or
(5) a first antigen binding domain that binds to a capsid of an AAV that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 129, or a variant thereof; and a second antigen binding domain that binds to a molecule on the cell surface that comprises: a LC that comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof.
Alternative Antibody Formats
[00510] Any multispecific antibody (e.g., bispecific antibody) format or technology may be used to make the multispecific antigen-binding molecules of the present disclosure. For example, an antibody or fragment thereof having a first antigen-binding specificity can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment having a second antigen-binding specificity to produce a bispecific antigen-binding molecule. Specific exemplary multispecific formats that can be used in the context of the present disclosure include, without limitation, e.g., scFv-based, VHH-based, or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-lg, Quadroma, knobs-into- holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG 1/lgG2, dual acting Fab (DAF)-lgG, and Mab2 bispecific formats (see, e.g., Klein et al. 2012, mAbs 4:6, 1-11 , and references cited therein, for a review of the foregoing formats).
[00511] In the context of multispecific antigen-binding molecules of the present disclosure, the multimerizing domains, e.g., Fc domains, may comprise one or more amino acid changes (e.g., insertions, deletions or substitutions) as compared to the wild-type, naturally occurring version of the Fc domain. For example, the disclosure includes bispecific antigenbinding molecules comprising one or more modifications in the Fc domain that results in a modified Fc domain having a modified binding interaction (e.g., enhanced or diminished) between Fc and FcRn. In one embodiment, the bispecific antigen-binding molecule comprises a modification in a CH2 or a CH3 region, wherein the modification increases the affinity of the Fc domain to FcRn in an acidic environment (e.g., in an endosome where pH ranges from about 5.5 to about 6.0). Non-limiting examples of such Fc modifications include, e.g., a modification at position 250 (e.g., E or Q); 250 and 428 (e.g., L or F); 252 (e.g., L/Y/F/W or T), 254 (e.g., S or T), and 256 (e.g., S/R/Q/E/D or T); or a modification at position 428 and/or 433 (e.g., L/R/S/P/Q or K) and/or 434 (e.g., H/F or Y); or a modification at position 250 and/or 428; or a modification at position 307 or 308 (e.g., 308F, V308F), and 434. In one embodiment, the modification comprises a 428L (e.g., M428L) and 434S (e.g., N434S) modification; a 428L, 259I (e.g., V259I), and 308F (e.g., V308F) modification; a 433K (e.g., H433K) and a 434 (e.g., 434Y) modification; a 252, 254, and 256 (e.g., 252Y, 254T, and 256E) modification; a 250Q and 428L modification (e.g., T250Q and M428L); and a 307 and/or 308 modification (e.g., 308F or 308P).
[00512] The present disclosure also includes multispecific antigen-binding molecules comprising a first CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bispecific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering;
H435R by EU numbering). The second CH3 may further comprise a Y96F modification (by IMGT; Y436F by EU). See, for example, US Patent No. 8,586,713. Further modifications that may be found within the second CH3 include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of IgG 1 antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of lgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of lgG4 antibodies. [00513] In certain embodiments, the Fc domain may be chimeric, combining Fc sequences derived from more than one immunoglobulin isotype. For example, a chimeric Fc domain can comprise part or all of a CH2 sequence derived from a human IgG 1 , human lgG2 or human lgG4 CH2 region, and part or all of a CH3 sequence derived from a human IgG 1 , human lgG2 or human lgG4. A chimeric Fc domain can also contain a chimeric hinge region. For example, a chimeric hinge may comprise an "upper hinge" sequence, derived from a human IgG 1 , a human lgG2 or a human lgG4 hinge region, combined with a "lower hinge" sequence, derived from a human lgG1 , a human lgG2 or a human lgG4 hinge region. A particular example of a chimeric Fc domain that can be included in any of the antigenbinding molecules set forth herein comprises, from N- to C-terminus: [lgG4 CH1] - [lgG4 upper hinge] - [lgG2 lower hinge] - [lgG4 CH2] - [lgG4 CH3], Another example of a chimeric Fc domain that can be included in any of the antigen-binding molecules set forth herein comprises, from N- to C-terminus: [IgG 1 CH1 ] - [IgG 1 upper hinge] - [lgG2 lower hinge] - [lgG4 CH2] - [IgG 1 CH3], These and other examples of chimeric Fc domains that can be included in any of the antigen-binding molecules of the present disclosure are described in US Publication 2014/0243504, published August 28, 2014, which is herein incorporated in its entirety. Chimeric Fc domains having these general structural arrangements, and variants thereof, can have altered Fc receptor binding, which in turn affects Fc effector function.
[00514] Example alternative antibody formats are described in Figures 3, 9, 18A-18B, 29A-29I, 30A-30G, 36A-36B, 46A-46I, and 47A-47I.
Non-limiting Examples of Alternative Format Antibodies [00515] The present disclosure provides any of the multispecific antibodies, or antigen binding fragments thereof, described herein in any of various alternative formats described herein.
[00516] In one aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) an scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) a first heavy chain region of a first Fab (“Fab1”), the first heavy chain region operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00517] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00518] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00519] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
[00520] In some embodiments, the scFv is linked to the first heavy chain region via a linker. [00521] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an Fc domain, the Fc domain operably linked to (iii) an scFv comprising a first antigen-binding domain (“ABD1”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00522] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00523] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00524] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[00525] In some embodiments, the scFv is linked to the Fc domain via a linker.
[00526] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”), the second heavy chain region of Fab2 operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (“Fab3”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); and e) a fifth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00527] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00528] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00529] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface. [00530] In some embodiments, the first heavy chain region is linked to the second heavy chain region via a linker.
[00531] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an Fc domain, the Fc domain operably linked to (iii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (“Fab3”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); and e) a fifth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00532] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00533] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
[00534] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[00535] In some embodiments, the second heavy chain region is linked to the Fc domain via a linker.
[00536] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an scFv comprising a first antigenbinding domain (“ABD1”), the scFv operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00537] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00538] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00539] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[00540] In some embodiments, the scFv is linked to the first heavy chain region via a linker. [00541] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an Fc domain, the Fc domain operably linked to (iii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) an scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00542] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00543] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00544] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[00545] In some embodiments, Fab2 is linked to the Fc domain via a linker.
[00546] In some embodiments of any of the above-described multispecific antibodies, or multispecific antigen-binding fragments, the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00547] In some embodiments, the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; and/or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[00548] In some embodiments, the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00549] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments, the molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
[00550] In some embodiments, the molecule on the cell surface is ASGR1 .
[00551] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00552] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[00553] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10. [00554] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments, the molecule on the cell surface is TfR.
[00555] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
11) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
[00556] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290; 3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
21) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
22) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
23) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
24) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
25) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
26) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
27) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
28) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
29) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
30) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
31) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
32) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 611 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or 33) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1121, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
[00557] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419; 15) a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ;
32) a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
[00558] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments, the molecule on the cell surface is CACNG1 . [00559] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to CACNG1 comprises
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763; 9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[00560] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to CACNG1 comprises
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1211 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.
[00561] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to
CACNG1 comprises
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 1181, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[00562] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1”); and c) a third polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); wherein ABD1 or ABD2 binds to a capsid of an adeno-associated virus (AAV) particle, and the other of ABD1 or ABD2 binds to a molecule on a cell surface.
[00563] In some embodiments, ABD1 binds to a capsid of an adeno-associated virus (AAV) particle and ABD2 binds to a molecule on the cell surface.
[00564] In some embodiments, ABD2 binds to a capsid of an adeno-associated virus (AAV) particle and ABD1 binds to a molecule on the cell surface.
[00565] In some embodiments, the first heavy chain region is linked to the second heavy chain region via a linker.
[00566] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) an Fc domain; b) a second polypeptide chain, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an Fc domain; and c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1, wherein Fab1 comprises a second antigen-binding domain (“ABD2”); wherein ABD1 or ABD2 binds to a capsid of an adeno-associated virus (AAV) particle, and the other of ABD1 or ABD2 binds to a molecule on a cell surface.
[00567] In some embodiments, ABD1 binds to a capsid of an adeno-associated virus (AAV) particle and ABD2 binds to a molecule on the cell surface.
[00568] In some embodiments, ABD2 binds to a capsid of an adeno-associated virus (AAV) particle and ABD1 binds to a molecule on the cell surface.
[00569] In some embodiments, the first scFv and/or the first heavy chain region is linked to the Fc domain via a linker.
[00570] In some embodiments, the ABD1 or ABD2 which binds to a capsid of an AAV particle comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00571] In some embodiments, the ABD1 or ABD2 which binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; and/or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[00572] In some embodiments, the ABD1 or ABD2 which binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00573] In some embodiments, the molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
[00574] In some embodiments, the molecule on the cell surface is ASGR1 .
[00575] In some embodiments, the other of ABD1 or ABD2 which binds to ASGR1 comprises: a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00576] In some embodiments, the other of ABD1 or ABD2 which binds to ASGR1 comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[00577] In some embodiments, the other of ABD1 or ABD2 which binds to ASGR1 comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00578] In some embodiments, the molecule on the cell surface is TfR.
[00579] In some embodiments, the other of ABD1 or ABD2 which binds to TfR comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356; 9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
1 1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 51 1 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1 119, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
[00580] In some embodiments, the other of ABD1 or AE3D2 which binds to TfR comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290; 3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
21) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
22) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
23) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
24) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
25) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
26) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
27) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
28) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
29) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
30) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
31) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
32) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 61 1 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
33) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1 123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1 125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1 129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
[00581] In some embodiments, the other of ABD1 or ABD2 which binds to TfR comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
1 1) a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ;
32) a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1127. [00582] In some embodiments, the molecule on the cell surface is CACNG1 .
[00583] In some embodiments, the other of ABD1 or ABD2 which binds to CACNG1 comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[00584] In some embodiments, the other of ABD1 or ABD2 which binds to CACNG1 comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1 185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1 187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1 191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 121 1 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219. [00585] In some embodiments, the other of ABD1 or ABD2 which binds to CACNG1 comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[00586] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) an scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) a first heavy chain region of a first Fab (“Fab1”), said first heavy chain region operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00587] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00588] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00589] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
[00590] In some embodiments, the scFv is linked to the first heavy chain region via a linker. [00591] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) an scFv comprising a first antigen-binding domain (“ABD1”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00592] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00593] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00594] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[00595] In some embodiments, the scFv is linked to the Fc domain via a linker.
[00596] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”), said second heavy chain region of Fab2 operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (“Fab3”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); and e) a fifth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00597] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface. [00598] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00599] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
[00600] In some embodiments, the first heavy chain region is linked to the second heavy chain region via a linker.
[00601] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (“Fab3”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABDI”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); and e) a fifth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00602] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00603] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
[00604] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[00605] In some embodiments, the second heavy chain region is linked to the Fc domain via a linker.
[00606] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ’’) operably linked to (ii) an scFv comprising a first antigen-binding domain (“ABD1 ’’), said scFv operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigenbinding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno- associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00607] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00608] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00609] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[00610] In some embodiments, the scFv is linked to the first heavy chain region via a linker. [00611] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) an scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigenbinding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno- associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00612] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00613] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00614] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[00615] In some embodiments, the second heavy chain region is linked to the Fc domain via a linker.
[00616] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”), said second heavy chain region operably linked to (iii) a third heavy chain region of a third Fab (“Fab3”); b) a second polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1”); and c) a third polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); d) a fourth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2, and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00617] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00618] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00619] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
[00620] In some embodiments, the first heavy chain region is operably linked to the second heavy chain region and/or the second heavy chain region is operably linked to the third heavy chain region via a linker.
[00621] In some embodiments, the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00622] In some embodiments, the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; and/or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[00623] In some embodiments, the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00624] In some embodiments, said molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
[00625] In some embodiments, said molecule on the cell surface is ASGR1 .
[00626] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00627] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[00628] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00629] In some embodiments, the molecule on the cell surface is TfR.
[00630] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
1 1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567; 29) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 11 19, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
[00631] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ; 4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
21) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
22) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
23) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
24) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
25) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
26) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
27) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
28) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
29) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
30) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
31) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
32) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 611 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
33) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1 131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
[00632] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
1 1) a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ;
32) a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
[00633] In some embodiments, the molecule on the cell surface is CACNG1 .
[00634] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to CACNG1 comprises
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[00635] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to CACNG1 comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709; 6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1 193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 121 1 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.
[00636] In some embodiments, the other(s) of ABD1 , ABD2 and ABD3 which binds to CACNG1 comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803; 11) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[00637] In another aspect, provided herein is a multispecific antibody , or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) a first heavy chain region of a first Fab (“Fab1”), the first heavy chain region of Fab1 operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second scFv comprising a second antigen-binding domain (“ABD2”) operably linked to (ii) a second heavy chain region of a second Fab (Tab2”), the second heavy chain region of Fab2 operably linked to (iii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a third antigen-binding domain (“ABD3”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a fourth antigen-binding domain (“ABD4”); wherein at least one of ABD1 , ABD2, ABD3 and ABD4 binds to a capsid of an adeno- associated virus (AAV) particle, and the other(s) of ABD1 , ABD2, ABD3, and ABD4 bind to a molecule on a cell surface.
[00638] In some embodiments, two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface.
[00639] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 and ABD4 binds to a molecule on a cell surface.
[00640] In some embodiments, ABD3 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD2 binds to a molecule on a cell surface.
[00641] In some embodiments, the first scFv is linked to the first heavy chain region and/or the second scFv is linked to the second heavy chain region via a linker.
[00642] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an Fc domain, the Fc domain operably linked to (iii) a first scFv comprising a first antigen-binding domain (“ABD1”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain, the Fc domain operably linked to (iii) a second scFv comprising a second antigen-binding domain (“ABD2”); c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a third antigen-binding domain (“ABD3”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a fourth antigen-binding domain (“ABD4”); wherein at least one of ABD1 , ABD2, ABD3 and ABD4 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2, ABD3, and ABD4 bind to a molecule on a cell surface.
[00643] In some embodiments, two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface.
[00644] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 and ABD4 binds to a molecule on a cell surface.
[00645] In some embodiments, ABD3 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD2 binds to a molecule on a cell surface.
[00646] In some embodiments, the first scFv and/or second scFv is linked to the Fc domain via a linker.
[00647] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”) operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (“Fab3) operable liked to (ii) a fourth heavy chain region of a fourth Fab (“Fab4”) operably linked to (iii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABDI ”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ADB2”); e) a fifth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); and f) a sixth polypeptide chain comprising a fourth light chain that pairs with the fourth heavy chain region to form Fab4, wherein Fab 4 comprises a fourth antigen-binding domain (“ABD4”); wherein at least one of ABD1 , ABD2, ABD3 and ABD4 binds to a capsid of an adeno- associated virus (AAV) particle, and the other(s) of ABD1 , ABD2, ABD3, and ABD4 bind to a molecule on a cell surface.
[00648] In some embodiments, two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface. [00649] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 and ABD4 binds to a molecule on a cell surface.
[00650] In some embodiments, ABD2 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD3 binds to a molecule on a cell surface.
[00651] In some embodiments, the first heavy chain region is linked to the second heavy chain region and/or the third heavy chain region is linked to fourth heavy chain region via a linker.
[00652] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (“Fab3”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a fourth heavy chain region of a fourth Fab (“Fab4”); c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); e) a fifth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); and f) a sixth polypeptide chain comprising a fourth light chain that pairs with the fourth heavy chain region to form Fab4, wherein Fab4 comprises a fourth antigen-binding domain (“ABD4”); wherein at least one of ABD1 , ABD2, ABD3 and ABD4 binds to a capsid of an adeno- associated virus (AAV) particle, and the other(s) of ABD1 , ABD2, ABD3, and ABD4 bind to a molecule on a cell surface.
[00653] In some embodiments, two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface. [00654] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 and ABD4 binds to a molecule on a cell surface.
[00655] In some embodiments, ABD2 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD3 binds to a molecule on a cell surface.
[00656] In some embodiments, the first heavy chain region, the second heavy chain region, the third heavy chain region, and/or the fourth heavy chain region is linked to the Fc domain via a linker.
[00657] In some embodiments, a light chain constant region (CL) and a first heavy chain constant region (CH1) of the second Fab and the fourth Fab are in a CrossmAb arrangement. [00658] In some embodiments, a light chain constant region (CL) and a first heavy chain constant region (CH1) of the first Fab and the third Fab are in a CrossmAb arrangement.
[00659] In some embodiments, a light chain constant region (CL) and a first heavy chain constant region (CH1) of the first Fab and the second Fab are in a CrossmAb arrangement.
[00660] In some embodiments, a light chain constant region (CL) and a first heavy chain constant region (CH1) of the third Fab and the fourth Fab are in a CrossmAb arrangement.
[00661] In some embodiments, a light chain constant region (CL) and a first heavy chain constant region (CH1) of the first Fab and the fourth Fab are in a CrossmAb arrangement.
[00662] In some embodiments, a light chain constant region (CL) and a first heavy chain constant region (CH1) of the second Fab and the third Fab are in a CrossmAb arrangement.
[00663] In some embodiments, one or more light chains comprise the same light chain variable region.
[00664] In some embodiments, the first, second, third, and fourth light chain comprise the same light chain variable region.
[00665] In some embodiments, the first, second, third, and fourth light chain are universal light chains. [00666] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) an Fc domain, said Fc domain operably linked to a first heavy chain region of a first Fab (“Fab1”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second scFv comprising a second antigen-binding domain (“ABD2”) operably linked to (ii) an Fc domain, said Fc domain operably linked to a second heavy chain region of a second Fab (“Fab2”); c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a third antigen-binding domain (“ABD3”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a fourth antigen-binding domain (“ABD4”); wherein at least one of ABD1 , ABD2, ABD3 and ABD4 binds to a capsid of an adeno- associated virus (AAV) particle, and the other(s) of ABD1 , ABD2, ABD3, and ABD4 bind to a molecule on a cell surface.
[00667] In some embodiments, two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface. [00668] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 and ABD4 binds to a molecule on a cell surface.
[00669] In some embodiments, ABD3 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD2 binds to a molecule on a cell surface.
[00670] In some embodiments, the first scFv and/or the second scFv is linked to the Fc domain and/or the first heavy chain region and/or the second heavy chain region is linked to the Fc domain via a linker.
[00671] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments, the at least one of ABD1 , ABD2, ABD3, and ABD4 which binds to a capsid of an AAV particle comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00672] In some embodiments, the at least one of ABD1 , ABD2, ABD3, and ABD4 which binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; and/or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[00673] In some embodiments, the at least one of ABD1 , ABD2, ABD3, and ABD4 which binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00674] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments, the molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
[00675] In some embodiments, the molecule on the cell surface is ASGR1 .
[00676] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to ASGR1 comprises a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00677] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to ASGR1 comprises a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
[00678] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to ASGR1 comprises a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
[00679] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments, the molecule on the cell surface is TfR.
[00680] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to TfR comprises
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
11) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387; 12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
[00681] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to TfR comprises
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477; 20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
21) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
22) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
23) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
24) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
25) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
26) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
27) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
28) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
29) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
30) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
31) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
32) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 611 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
33) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1121, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
[00682] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to TfR comprises
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 276; 2) a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ;
32) a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
[00683] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments, the molecule on the cell surface is CACNG1 . [00684] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to CACNG1 comprises
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213. [00685] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to CACNG1 comprises
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749; 8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1211 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.
[00686] In some embodiments, the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to CACNG1 comprises
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 1181, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
[00687] In some embodiments of the above-described multispecific antibodies or multispecific antigen-binding fragments, the linker is:
(a) at least 5 amino acids, at least 6 amino acids or at least 7 amino acids in length; and optionally (b) up to 30 amino acids, up to 40 amino acids, up to 50 amino acids or up to 60 amino acids in length.
[00688] In some embodiments, the linker is:
(a) 5 amino acids to 50 amino acids in length;
(b) 5 amino acids to 45 amino acids in length;
(c) 5 amino acids to 40 amino acids in length;
(d) 5 amino acids to 35 amino acids in length;
(e) 5 amino acids to 30 amino acids in length;
(f) 5 amino acids to 25 amino acids in length; or
(g) 5 amino acids to 20 amino acids in length.
[00689] In some embodiments, the linker is:
(a) 6 amino acids to 50 amino acids in length;
(b) 6 amino acids to 45 amino acids in length;
(c) 6 amino acids to 40 amino acids in length;
(d) 6 amino acids to 35 amino acids in length;
(e) 6 amino acids to 30 amino acids in length;
(f) 6 amino acids to 25 amino acids in length; or
(g) 6 amino acids to 20 amino acids in length.
[00690] In some embodiments, the linker is:
(a) 7 amino acids to 40 amino acids in length;
(b) 7 amino acids to 35 amino acids in length;
(c) 7 amino acids to 30 amino acids in length;
(d) 7 amino acids to 25 amino acids in length;
(e) 7 amino acids to 20 amino acids in length.
[00691] The multispecific antibody or multispecific antigen-binding fragment of claim 123, wherein the linker is 5 amino acids to 25 amino acids in length.
[00692] In some embodiments, the linker is 10 amino acids to 60 amino acids in length.
[00693] In some embodiments, the linker is 20 amino acids to 50 amino acids in length.
[00694] In some embodiments, the linker is 25 to 35 amino acids in length.
[00695] In some embodiments, the linker is or comprises a multimer of GnS (SEQ ID NO:
239) or SGn (SEQ ID NO: 240), where n is an integer from 1 to 10.
[00696] In some embodiments, the linker is or comprises a multimer of G4S (SEQ ID NO: 242).
[00697] In some embodiments, the linker is or comprises two consecutive glycines (2Gly), three consecutive glycines (3Gly), four consecutive glycines (4Gly (SEQ ID NO: 243)), five consecutive glycines (5Gly (SEQ ID NO: 244)), six consecutive glycines (6Gly (SEQ ID NO: 245)), seven consecutive glycines (7Gly (SEQ ID NO: 246)), eight consecutive glycines (8Gly (SEQ ID NO: 247)) or nine consecutive glycines (9Gly (SEQ ID NO: 248)).
[00698] In some embodiments, one or more light chains are universal light chains.
[00699] In some embodiments, a light chain constant region (CL) and a first heavy chain constant region (CH1) of one or more Fabs are in a CrossmAb arrangement.
[00700] In some embodiments, the multispecific antibody or multispecific antigen-binding comprises an Fc heterodimer.
[00701] In some embodiments, the Fc domains in the Fc heterodimer comprise knob-in- hole mutations as compared to a wild type Fc domain.
[00702] In some embodiments, one Fc domain in the Fc heterodimer comprises amino acid substitutions S354C and T366W (according to EU numbering) as compared to a wild type Fc domain, and the other Fc domain in the Fc heterodimer comprises amino acid substitutions Y349C, T366S, L368A, and Y407V (according to EU numbering) as compared to a wild type Fc domain.
[00703] In some embodiments, at least one Fc domain in the Fc heterodimer comprises a star mutation as compared to a wild type Fc domain.
[00704] T In some embodiments, one Fc domain in the Fc heterodimer comprises amino acid mutations H435R and/or Y436F (according to EU numbering) as compared to a wild type Fc domain.
[00705] In some embodiments, the capsid comprises one or more wild-type AAV capsid polypeptides.
[00706] In some embodiments, the capsid comprises one or more non-wild-type AAV capsid polypeptides.
[00707] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment is a bispecific antibody or bispecific antigen-binding fragment thereof.
[00708] In another aspect, provided herein is a pharmaceutical composition comprising a multispecific antibody or multispecific antigen-binding fragment described herein, and a pharmaceutically acceptable carrier or excipient.
[00709] In another aspect, provided herein is a molecular complex comprising an AAV particle bound to one or more antibodies and/or antigen-binding fragments described herein. [00710] In some embodiments, said AAV particle comprises one or more mutations in one or more AAV capsid proteins inhibiting the natural tropism of said AAV particle.
[00711] In another aspect, provided herein is a pharmaceutical composition comprising a molecular complex described herein and a pharmaceutically acceptable carrier or excipient. [00712] In another aspect, provided herein is a method of preparing the molecular complex described herein, comprising incubating said AAV particle in the presence of said one or more antibodies and/or antigen-binding fragments under conditions allowing specific binding of said one or more antibodies and/or antigen-binding fragments to said AAV particle capsid. [00713] In another aspect, provided herein is a molecular complex comprising an AAV particle bound to one or more multispecific antibodies and/or multispecific antigen-binding fragments described herein.
[00714] In some embodiments, said AAV particle comprises one or more mutations in one or more AAV capsid proteins inhibiting the natural tropism of said AAV particle.
[00715] In another aspect, provided herein is a pharmaceutical composition comprising a molecular complex described herein and a pharmaceutically acceptable carrier or excipient. [00716] In another aspect, provided herein is a method of preparing a molecular complex described herein, comprising incubating said AAV particle in the presence of said one or more multispecific antibodies and/or multispecific antigen-binding fragments under conditions allowing specific binding of said one or more multispecific antibodies and/or multispecific antigen-binding fragments to said AAV particle capsid.
[00717] In another aspect, provided herein is a method for targeting an AAV particle to a cell expressing a molecule on the cell surface, comprising contacting the cell with a molecular complex described herein or a pharmaceutical composition described herein, wherein said molecular complex comprises one or more multispecific antibodies and/or multispecific antigen-binding fragments which bind to said molecule on the cell surface. [00718] In another aspect, provided herein is a method for delivering a polynucleotide to a cell expressing a molecule on the cell surface, comprising contacting the cell with a molecular complex described herein or a pharmaceutical composition described herein, wherein said molecular complex comprises the AAV particle comprising said polynucleotide and bound to one or more multispecific antibodies and/or multispecific antigen-binding fragments which bind to said molecule on the cell surface.
[00719] In some embodiments, said cell is in a subject and said molecular complex is administered to the subject.
[00720] In some embodiments, said AAV particle does not target said cell in the absence of said one or more multispecific antibodies and/or multispecific antigen-binding fragments.
[00721] In one aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an scFv comprising a first antigenbinding domain (“ABD1”), the scFv operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00722] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00723] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00724] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[00725] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the first polypeptide chain can comprise the amino acid sequence
QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTGGGGSGG GGSGGGGSEVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIY YDSSKMNYADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYWDVWGQGV SVTVSSGGGGSGGGGSGGGGSDIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQK PGKSPQLLIYGATSLADGVPSRFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGG TKLELKGGGGSKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1106), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00726] In some embodiments, the first heavy chain region of the first Fab (Fab1) can comprise the amino acid sequence QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1108), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. [00727] In some embodiments, the scFv can comprise the amino acid sequence EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSKMNY ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYWDVWGQGVSVTVSSGG GGSGGGGSGGGGSDIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLL IYGATSLADGVPSRFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELK (SEQ ID NO: 1117), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, the scFv comprises a first antigen-binding domain (ABD1) comprising or contained within the amino acid sequence
EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSKMNY ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYWDVWGQGVSVTVSS (SEQ ID NO: 1119), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and/or comprising or contained within the amino acid sequence
DIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLLIYGATSLADGVPSRF SGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELK (SEQ ID NO: 1127), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, the scFv can be operably linked to an Fc domain comprising the amino acid sequence
SKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1137), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00728] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the second polypeptide chain can comprise the amino acid sequence QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSR DELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSR WQQGNVFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 1139), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00729] In some embodiments, the second heavy chain region of the second Fab (Fab2) can comprise the amino acid sequence QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1 108), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, the second heavy chain region of the second Fab2 can be operably linked to an Fc domain comprising the amino acid sequence
CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVS KLTVDKSRWQQGNVFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 1141), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00730] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the third polypeptide chain can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00731] In some embodiments, the third polypeptide chain can comprise a first light chain, e.g., that pairs with the first heavy chain region to form Fab1 . In some embodiments, the first light chain can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, Fab1 comprises a second antigen binding domain (ABD2) comprising or contained within the amino acid sequence
QVHLQESG PG LVMPSQ I LSLSCVISG DSI RNGG YYWTWTRQQ PG KG LEWIG HI H YSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSS (SEQ ID NO: 52), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and/or comprising or contained within the amino acid sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 10), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00732] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the fourth polypeptide chain can comprise the amino acid sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00733] In some embodiments, the fourth polypeptide chain can comprise a second light chain, e.g., that pairs with the second heavy chain region to form Fab2. In some embodiments, the second light chain can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, Fab2 comprises a third antigen binding domain (ABD3) comprising or contained within the amino acid sequence
QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSS (SEQ ID NO: 52), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, or comprising or contained within the amino acid sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 10), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00734] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments thereof, can comprise one or more linker, e.g., comprising the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO: 1115) and/or the amino acid sequence GGGG (SEQ ID NO: 243).
[00735] In one aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an Fc domain, the Fc domain operably linked to (iii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) an scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
[00736] In some embodiments, two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
[00737] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
[00738] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
[00739] In some embodiments, Fab2 is linked to the Fc domain via a linker.
[00740] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the first polypeptide chain can comprise the amino acid sequence
QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSR DELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSR WQQGNVFSCSVMHEALHNRFTQKSLSLSPGKGGGGSGGGGSGGGGSQVHLQESGPGL VMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSHNPSLQSRVIMSI DTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGALVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS WTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1 151), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00741] In some embodiments, the first heavy chain region of the first Fab (Fab1) can comprise the amino acid sequence QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1 108), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00742] In some embodiments, the Fc domain can comprise the amino acid sequence CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVS KLTVDKSRWQQGNVFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 1141).
[00743] In some embodiments, the second heavy chain region of the second Fab (Fab2) can comprise the amino acid sequence
QVHLQESG PG LVMPSQ I LSLSCVISG DSI RNGG YYWTWTRQQ PG KG LEWIG HI HYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1 108), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00744] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the second polypeptide chain can comprise the amino acid sequence EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSKMNY ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYWDVWGQGVSVTVSSGG GGSGGGGSGGGGSDIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLL IYGATSLADGVPSRFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELKGG GGSKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK
GQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1 149), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00745] In some embodiments, the scFv can comprise the amino acid sequence EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSKMNY ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYWDVWGQGVSVTVSSGG GGSGGGGSGGGGSDIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLL IYGATSLADGVPSRFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELK (SEQ ID NO: 11 17), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, the scFv comprises a first antigen-binding domain (ABD1) comprising or contained within the amino acid sequence
EVQLVESGGG LVQ PG NSLTLSCVASG FTFSNYG M H WIRQAPKKG LEWI AM I YYDSSKM NY ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYWDVWGQGVSVTVSS (SEQ ID NO: 11 19), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and/or comprising or contained within the amino acid sequence DIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLLIYGATSLADGVPSRF SGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELK (SEQ ID NO: 1 127), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, the scFv can be operably linked to an Fc domain comprising the amino acid sequence SKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1 137). [00746] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the third polypeptide chain can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00747] In some embodiments, the third polypeptide chain can comprise a first light chain, e.g., that pairs with the first heavy chain region to form Fab1 . In some embodiments, the first light chain can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, Fab1 comprises a second antigen binding domain (ABD2) comprising or contained within the amino acid sequence
QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSS (SEQ ID NO: 52), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and/or comprising or contained within the amino acid sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 10), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00748] In some embodiments, the fourth polypeptide chain can comprise a second light chain, e.g., that pairs with the second heavy chain region to form Fab2. In some embodiments, the second light chain can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ
LKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, Fab2 comprises a third antigen binding domain (ABD3) comprising or contained within the amino acid sequence
QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSS (SEQ ID NO: 52), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, or comprising or contained within the amino acid sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 10), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00749] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments thereof, can comprise one or more linker, e.g., comprising the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO: 1115) and/or the amino acid sequence GGGG (SEQ ID NO: 243).
[00750] In one aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) a first heavy chain region of a first Fab (“Fab1”), the first heavy chain region of Fab1 operably linked to (ii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second scFv comprising a second antigen-binding domain (“ABD2”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”), the second heavy chain region of Fab2 operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a third antigen-binding domain (“ABD3”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a fourth antigen-binding domain (“ABD4”); wherein at least one of ABD1 , ABD2, ABD3 and ABD4 binds to a capsid of an adeno- associated virus (AAV) particle, and the other(s) of ABD1 , ABD2, ABD3, and ABD4 bind to a molecule on a cell surface.
[00751] In some embodiments, two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface.
[00752] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 and ABD4 binds to a molecule on a cell surface.
[00753] In some embodiments, ABD3 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD2 binds to a molecule on a cell surface.
[00754] In some embodiments, the first scFv is linked to Fab1 and/or the second scFv is linked to Fab2 via a linker.
[00755] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the first polypeptide chain can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGG SGGGGSQVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIH YSERTSHNPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFID SWGQGALVTVSSGGGGSGGGGSGGGGSQVQLVESGGGWQPGRSLRLSCAASGFTFST YGMHWVRQAPGKGLEWVAVIWHDGSDKYYVDSVKGRFSIARDNSKNTLYLQMNSLRVED TGIYYCARRGIRGTVFDHWGLGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1153), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00756] In some embodiments, the first scFv can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGG SGGGGSQVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIH YSERTSHNPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFID SWGQGALVTVSS (SEQ ID NO: 1155), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, the first scFv comprises a first antigen-binding domain (ABD1) comprising or contained within the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIK (SEQ ID NO: 1157), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and/or comprising or contained within the amino acid sequence QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSS (SEQ ID NO: 1159), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00757] In some embodiments, the first heavy chain region of the first Fab (Fab1) can comprise the amino acid sequence QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1175), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, the first heavy chain region of the first Fab (Fab1) can be operably linked to an Fc domain comprising the amino acid sequence
CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1167).
[00758] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the second polypeptide chain can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGG SGGGGSQVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIH YSERTSHNPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFID SWGQGALVTVSSGGGGSGGGGSGGGGSQVQLVESGGGWQPGRSLRLSCAASGFTFST YGMHWVRQAPGKGLEWVAVIWHDGSDKYYVDSVKGRFSIARDNSKNTLYLQMNSLRVED TGIYYCARRGIRGTVFDHWGLGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1153), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00759] In some embodiments, the second scFv can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGG SGGGGSQVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIH YSERTSHNPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFID SWGQGALVTVSS (SEQ ID NO: 1155), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, the second scFv comprises a second antigen-binding domain (ABD2) comprising or contained within the amino acid sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIK (SEQ ID NO: 1157), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and/or comprising or contained within the amino acid sequence QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSS (SEQ ID NO: 1159), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. [00760] In some embodiments, the second heavy chain region of the second Fab (Fab2) can comprise the amino acid sequence QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1175), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, the second heavy chain region of the second Fab (Fab2) can be operably linked to an Fc domain comprising the amino acid sequence
CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1167), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00761] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the third polypeptide chain can comprise the amino acid sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 813), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00762] In some embodiments, the third polypeptide chain can comprise a first light chain, e.g., that pairs with the first heavy chain region to form Fab1 . In some embodiments, the first light chain can comprise the amino acid sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 813), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, Fab1 comprises a third antigen binding domain (ABD3) comprising or contained within the amino acid sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS (SEQ ID NO: 795), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and/or comprising or contained within the amino acid sequence
DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIK (SEQ ID NO: 803), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00763] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the fourth polypeptide chain can comprise the amino acid sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE
QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 813), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity
[00764] In some embodiments, the fourth polypeptide chain can comprise a second light chain, e.g., that pairs with the second heavy chain region to form Fab2. In some embodiments, the second light chain can comprise the amino acid sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE
QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 813), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, Fab2 comprises a fourth antigen binding domain (ABD4) comprising or contained within the amino acid sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS (SEQ ID NO: 795), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, or comprising or contained within the amino acid sequence
DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIK (SEQ ID NO: 803), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00765] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments thereof can comprise one or more of linker, e.g., comprising the amino acid sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 1161) and/or the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO: 1115).
[00766] In one aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an Fc domain, the Fc domain operably linked to (iii) a first scFv comprising a first antigen-binding domain (“ABD1”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain, the Fc domain operably linked to (iii) a second scFv comprising a second antigen-binding domain (“ABD2”); c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a third antigen-binding domain (“ABD3”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a fourth antigen-binding domain (“ABD4”); wherein at least one of ABD1 , ABD2, ABD3 and ABD4 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2, ABD3, and ABD4 bind to a molecule on a cell surface.
[00767] In some embodiments, two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface.
[00768] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 and ABD4 binds to a molecule on a cell surface.
[00769] In some embodiments, ABD3 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD2 binds to a molecule on a cell surface.
[00770] In some embodiments, the first scFv and/or second scFv is linked to the Fc domain via a linker.
[00771] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the first polypeptide chain can comprise the amino acid sequence QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTY RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDR VTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGGSGGGGSQVHLQESGPGL VMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIHYSERTSHNPSLQSRVIMSI DTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGALVTVSS (SEQ ID NO: 1169), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00772] In some embodiments, the first heavy chain region of the first Fab (Fab1) can comprise the amino acid sequence QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1175), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, the first heavy chain region of the first Fab (Fab1) can be operably linked to an Fc domain comprising the amino acid sequence CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1167), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00773] In some embodiments, the first scFv can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGG SGGGGSQVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIH YSERTSHNPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFID SWGQGALVTVSS (SEQ ID NO: 1155), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, the first scFv comprises a first antigen-binding domain (ABD1) comprising or contained within the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIK (SEQ ID NO: 1157), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and/or comprising or contained within the amino acid sequence QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSS (SEQ ID NO: 1159), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00774] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the second polypeptide chain can comprise the amino acid sequence QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTY RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDR VTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGGSGGGGSQVHLQESGPGL VMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIHYSERTSHNPSLQSRVIMSI DTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGALVTVSS (SEQ ID NO: 1169), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00775] In some embodiments, the second heavy chain region of the second Fab (Fab2) can comprise the amino acid sequence QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1175), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, the second heavy chain region of the second Fab (Fab2) can be operably linked to an Fc domain comprising the amino acid sequence
CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1167), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00776] In some embodiments, the second scFv can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGG SGGGGSQVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIH YSERTSHNPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFID SWGQGALVTVSS (SEQ ID NO: 1155), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, the second scFv comprises a second antigen-binding domain (ABD2) comprising or contained within the amino acid sequence
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIK (SEQ ID NO: 1157), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and/or comprising or contained within the amino acid sequence QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSS (SEQ ID NO: 1159), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00777] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the third polypeptide chain can comprise the amino acid sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 813), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00778] In some embodiments, the third polypeptide chain can comprise a first light chain, e.g., that pairs with the first heavy chain region to form Fab1 . In some embodiments, the first light chain can comprise the amino acid sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 813), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, Fab1 comprises a third antigen binding domain (ABD3) comprising or contained within the amino acid sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS (SEQ ID NO: 795), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, and/or comprising or contained within the amino acid sequence
DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIK (SEQ ID NO: 803), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00779] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the fourth polypeptide chain can comprise the amino acid sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE
QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 813), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00780] In some embodiments, the fourth polypeptide chain can comprise a second light chain, e.g., that pairs with the second heavy chain region to form Fab2. In some embodiments, the second light chain can comprise the amino acid sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE
QLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 813), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In some embodiments, Fab2 comprises a fourth antigen binding domain (ABD4) comprising or contained within the amino acid sequence
QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS (SEQ ID NO: 795), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity, or comprising or contained within the amino acid sequence
DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIK (SEQ ID NO: 803), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
[00781] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments thereof can comprise one or more of linker, e.g., comprising the amino acid sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 1161) and/or the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO: 1115).
Epitope Mapping and Related Technologies
[00782] The epitope on a capsid of an AAV and/or molecule on a cell surface to which the antigen-binding molecules of the present disclosure bind may consist of a single contiguous sequence of 3 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 or more) amino acids of an AAV capsid and/or molecule on a cell surface protein. Alternatively, the epitope may consist of a plurality of non-contiguous amino acids (or amino acid sequences).
[00783] The term "epitope," as used herein, can refer to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstances, an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen.
[00784] Various techniques known to persons of ordinary skill in the art can be used to determine whether an antigen-binding domain of an antibody "interacts with one or more amino acids" within a polypeptide or protein. Exemplary techniques include, e.g., cryogenic electron microscopy (cryo-EM), routine cross-blocking assay such as that described in Antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY), alanine scanning mutational analysis, peptide blots analysis (Reineke, 2004, Methods Mol Biol 248:443-463), and peptide cleavage analysis. In addition, methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer, 2000, Protein Science 9:487-496). Another method that can be used to identify the amino acids within a polypeptide with which an antigen-binding domain of an antibody interacts is hydrogen/deuterium exchange detected by mass spectrometry. In general terms, the hydrogen/deuterium exchange method involves deuterium-labeling the protein of interest, followed by binding the antibody to the deuterium-labeled protein. Next, the protein/antibody complex is transferred to water to allow hydrogen-deuterium exchange to occur at all residues except for the residues protected by the antibody (which remain deuterium- labeled). After dissociation of the antibody, the target protein is subjected to protease cleavage and mass spectrometry analysis, thereby revealing the deuterium-labeled residues which correspond to the specific amino acids with which the antibody interacts. See, e.g., Ehring (1999) Analytical Biochemistry 267(2):252-259; Engen and Smith (2001) Anal. Chem. 73:256A-265A. X-ray crystallography of the antigen/antibody complex may also be used for epitope mapping purposes.
[00785] Provided herein are anti-AAV antibodies that bind to the same epitope as any of the specific exemplary antibodies described herein (e.g., antibodies comprising any of the amino acid sequences as set forth in Table 1 herein). Likewise, the present disclosure also includes anti-AAV antibodies that compete for binding to a capsid of an AAV particle with any of the specific exemplary antibodies described herein (e.g., antibodies comprising any of the amino acid sequences as set forth in Table 1 herein).
[00786] Provided herein are anti-cell surface molecule antibodies that bind to the same epitope as any of the specific exemplary antibodies described herein (e.g., antibodies comprising any of the amino acid sequences as set forth in Tables 5, 7, and 10 herein). Likewise, the present disclosure also includes anti-cell surface molecule antibodies that compete for binding to a cell surface molecule with any of the specific exemplary antibodies described herein (e.g., antibodies comprising any of the amino acid sequences as set forth in Tables 5, 7 and 10 herein).
[00787] Likewise, the provided herein are bispecific antigen-binding molecules comprising a first antigen-binding domain that specifically binds to a capsid of an AAV, and a second antigen-binding domain that specifically binds to a molecule on a cell surface, wherein the first antigen-binding domain competes for binding to a capsid of an AAV with any of the specific exemplary AAV-specific antigen-binding domains described herein, and/or wherein the second antigen-binding domain competes for binding to a molecule on a surface of a cell with any of the specific exemplary cell surface-specific antigen-binding domains described herein.
[00788] One can easily determine whether a particular antigen-binding molecule (e.g., antibody), or antigen-binding domain thereof, binds to the same epitope as, or competes for binding with, a reference antigen-binding molecule of the present disclosure by using routine methods known in the art. For example, to determine if a test antibody binds to the same epitope on an AAV capsid (or cell surface molecule) protein as a reference bispecific antigen-binding molecule of the present disclosure, the reference bispecific molecule is first allowed to bind to the AAV capsid (or cell surface molecule) protein . Next, the ability of a test antibody to bind to the AAV capsid (or cell surface molecule) protein is assessed. If the test antibody is able to bind to the AAV capsid (or cell surface molecule) protein following saturation binding with the reference bispecific antigen-binding molecule, it can be concluded that the test antibody binds to a different epitope of the AAV capsid protein (or cell surface molecule) than the reference bispecific antigen-binding molecule. On the other hand, if the test antibody is not able to bind to the AAV capsid protein (or cell surface molecule) following saturation binding with the reference bispecific antigen-binding molecule, then the test antibody may bind to the same epitope of the AAV capsid protein as the epitope bound by the reference bispecific antigen-binding molecule of the disclosure. Additional routine experimentation (e.g., peptide mutation and binding analyses) can then be carried out to confirm whether the observed lack of binding of the test antibody is in fact due to binding to the same epitope as the reference bispecific antigen-binding molecule or if steric blocking (or another phenomenon) is responsible for the lack of observed binding. Experiments of this sort can be performed using ELISA, RIA, Biacore, flow cytometry or any other quantitative or qualitative antibody-binding assay available in the art. In accordance with certain embodiments of the present disclosure, two antigen-binding proteins bind to the same (or overlapping) epitope if, e.g., a 1-, 5-, 10-, 20- or 100-fold excess of one antigen-binding protein inhibits binding of the other by at least 50% but preferably 75%, 90% or even 99% as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 1990:50:1495-1502). Alternatively, two antigen-binding proteins are deemed to bind to the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antigen-binding protein reduce or eliminate binding of the other. Two antigenbinding proteins are deemed to have "overlapping epitopes" if only a subset of the amino acid mutations that reduce or eliminate binding of one antigen-binding protein reduce or eliminate binding of the other.
[00789] To determine if an antibody or antigen-binding domain thereof competes for binding with a reference antigen-binding molecule, the above-described binding methodology is performed in two orientations: As an example, in a first orientation, the reference antigenbinding molecule is allowed to bind to an AAV capsid (or cell surface molecule) protein under saturating conditions followed by assessment of binding of the test antibody to AAV capsid (or cell surface molecule) protein. In a second orientation, the test antibody is allowed to bind to a AAV capsid (or cell surface molecule) protein under saturating conditions followed by assessment of binding of the reference antigen-binding molecule to the AAV capsid (or cell surface molecule) protein. If, in both orientations, only the first (saturating) antigen-binding molecule is capable of binding to the AAV capsid (or cell surface molecule) protein, then it is concluded that the test antibody and the reference antigen-binding molecule compete for binding to the AAV capsid (or cell surface molecule) protein. As will be appreciated by a person of ordinary skill in the art, an antibody that competes for binding with a reference antigen-binding molecule may not necessarily bind to the same epitope as the reference antibody but may sterically block binding of the reference antibody by binding an overlapping or adjacent epitope.
Preparation of Antigen-Binding Domains and Construction of Bispecific Molecules [00790] Antigen-binding domains specific for particular antigens can be prepared by any antibody generating technology known in the art. Once obtained, two different antigenbinding domains, specific for two different antigens, can be appropriately arranged relative to one another to produce a bispecific antigen-binding molecule of the present disclosure using routine methods. (A discussion of exemplary bispecific antibody formats that can be used to construct the bispecific antigen-binding molecules of the present disclosure is provided elsewhere herein). In certain embodiments, one or more of the individual components (e.g., heavy and light chains) of the multispecific antigen-binding molecules of the disclosure are derived from chimeric, humanized or fully human antibodies. Methods for making such antibodies are well known in the art. For example, one or more of the heavy and/or light chains of the bispecific antigen-binding molecules of the present disclosure can be prepared using VELOCIMMUNE™ technology. Using VELOCIMMUNE™ technology (or any other human antibody generating technology), high affinity chimeric antibodies to a particular antigen are initially isolated having a human variable region and a mouse constant region. The antibodies are characterized and selected for desirable characteristics, including affinity, selectivity, epitope, etc. The mouse constant regions are replaced with a desired human constant region to generate fully human heavy and/or light chains that can be incorporated into the bispecific antigen-binding molecules of the present disclosure.
[00791] Genetically engineered animals may be used to make human bispecific antigenbinding molecules. For example, a genetically modified mouse can be used which is incapable of rearranging and expressing an endogenous mouse immunoglobulin light chain variable sequence, wherein the mouse expresses only one or two human light chain variable domains encoded by human immunoglobulin sequences operably linked to the mouse kappa constant gene at the endogenous mouse kappa locus. Such genetically modified mice can be used to produce fully human bispecific antigen-binding molecules comprising two different heavy chains that associate with an identical light chain that comprises a variable domain derived from one of two different human light chain variable region gene segments. (See, e.g., US 2011/0195454). Fully human can refer to an antibody, or antigen-binding fragment or immunoglobulin domain thereof, comprising an amino acid sequence encoded by a DNA derived from a human sequence over the entire length of each polypeptide of the antibody or antigen-binding fragment or immunoglobulin domain thereof. In some instances, the fully human sequence is derived from a protein endogenous to a human. In other instances, the fully human protein or protein sequence comprises a chimeric sequence wherein each component sequence is derived from human sequence. While not being bound by any one theory, chimeric proteins or chimeric sequences are generally designed to minimize the creation of immunogenic epitopes in the junctions of component sequences, e.g., compared to any wild-type human immunoglobulin regions or domains. Bioequivalents
[00792] The present disclosure encompasses antigen-binding molecules having amino acid sequences that vary from those of the exemplary molecules disclosed herein but that retain the ability to bind to a capsid of an AAV particle and/or a molecule on a surface of a cell. Such variant molecules may comprise one or more additions, deletions, or substitutions of amino acids when compared to parent sequence but exhibit biological activity that is essentially equivalent to that of the described bispecific antigen-binding molecules.
[00793] The present disclosure includes antigen-binding molecules that are bioequivalent to any of the exemplary antigen-binding molecules set forth herein. Two antigen-binding proteins, or antibodies, are considered bioequivalent if, for example, they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose under similar experimental conditions, either single does or multiple dose. Some antigen-binding proteins will be considered equivalents or pharmaceutical alternatives if they are equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on, e.g., chronic use, and are considered medically insignificant for the particular drug product studied.
[00794] In one embodiment, two antigen-binding proteins are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.
[00795] In one embodiment, two antigen-binding proteins are bioequivalent if a patient can be switched one or more times between the reference product and the biological product without an expected increase in the risk of adverse effects, including a clinically significant change in immunogenicity, or diminished effectiveness, as compared to continued therapy without such switching.
[00796] In one embodiment, two antigen-binding proteins are bioequivalent if they both act by a common mechanism or mechanisms of action for the condition or conditions of use, to the extent that such mechanisms are known.
[00797] Bioequivalence may be demonstrated by in vivo and in vitro methods. Bioequivalence measures include, e.g., (a) an in vivo test in humans or other mammals, in which the concentration of the antibody or its metabolites is measured in blood, plasma, serum, or other biological fluid as a function of time; (b) an in vitro test that has been correlated with and is reasonably predictive of human in vivo bioavailability data; (c) an in vivo test in humans or other mammals in which the appropriate acute pharmacological effect of the antibody (or its target) is measured as a function of time; and (d) in a well-controlled clinical trial that establishes safety, efficacy, or bioavailability or bioequivalence of an antigen-binding protein.
[00798] Bioequivalent variants of the exemplary bispecific antigen-binding molecules set forth herein may be constructed by, for example, making various substitutions of residues or sequences or deleting terminal or internal residues or sequences not needed for biological activity. For example, cysteine residues not essential for biological activity can be deleted or replaced with other amino acids to prevent formation of unnecessary or incorrect intramolecular disulfide bridges upon renaturation. In other contexts, bioequivalent antigenbinding proteins may include variants of the exemplary bispecific antigen-binding molecules set forth herein comprising amino acid changes which modify the glycosylation characteristics of the molecules, e.g., mutations which eliminate or remove glycosylation.
Cells
[00799] The disclosure also provides host cells comprising a nucleic acid of the disclosure. [00800] In one embodiment, the host cells are genetically engineered to comprise one or more nucleic acids described herein.
[00801] In one embodiment, the host cells are genetically engineered by using an expression cassette. The phrase “expression cassette,” refers to nucleotide sequences, which are capable of affecting expression of a gene in hosts compatible with such sequences. Such cassettes may include a promoter, an open reading frame with or without introns, and a termination signal. Additional factors necessary or helpful in effecting expression may also be used, such as, for example, an inducible promoter.
[00802] The disclosure also provides host cells comprising the vectors described herein. [00803] The cell can be, but is not limited to, a eukaryotic cell, a bacterial cell, an insect cell, or a human cell. Suitable eukaryotic cells include, but are not limited to, Vero cells, HeLa cells, COS cells, CHO cells, HEK293 cells, BHK cells and MDCKII cells. Suitable insect cells include, but are not limited to, Sf9 cells.
Therapeutic Formulation and Administration
[00804] The present disclosure provides a pharmaceutical composition comprising an antigen-binding molecule (e.g., anti-AAV monospecific antibody or anti-AAV x anti-cell surface molecule multispecific antibody) described herein and/or at least one viral capsid protein (e.g., a capsid protein of an AAV particle) described herein. In some embodiments, pharmaceutical compositions comprising a viral capsid protein, e.g., an AAV particle, may be useful as a gene transfer vector.
[00805] The pharmaceutical compositions of the disclosure are formulated with suitable carriers, excipients, and other agents that provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN™, Life Technologies, Carlsbad, CA), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Phdomain Sci Technol 52:238-311.
[00806] The dose of antigen-binding molecule administered to a patient may vary depending upon the age and the size of the patient, target disease, conditions, route of administration, and the like. The preferred dose is typically calculated according to body weight or body surface area. When a bispecific antigen-binding molecule of the present disclosure is used for therapeutic purposes in an adult patient, it may be advantageous to intravenously administer the bispecific antigen-binding molecule of the present disclosure normally at a single dose of about 0.01 to about 20 mg/kg body weight, more preferably about 0.02 to about 7, about 0.03 to about 5, or about 0.05 to about 3 mg/kg body weight. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. Effective dosages and schedules for administering a bispecific antigenbinding molecule may be determined empirically; for example, patient progress can be monitored by periodic assessment, and the dose adjusted accordingly. Moreover, interspecies scaling of dosages can be performed using well-known methods in the art (e.g., Mordenti et al., 1991, Phdomainaceut. Res. 8:1351).
[00807] Dose ranges and frequency of administration of a viral vector described herein can vary depending on the nature of, e.g., the AAV, and the medical condition, as well as parameters of a specific patient and the route of administration used. In some embodiments, viral vector compositions can be administered to a subject at a dose ranging from about 1 x105 plaque forming units (pfu) to about 1 xio15 pfu, depending on mode of administration, the route of administration, the nature of the disease and condition of the subject. In some cases, the viral vector compositions can be administered at a dose ranging from about 1 xi o8 pfu to about 1 xio15 pfu, or from about 1xio10 pfu to about 1 xio15 pfu, or from about 1 xio8 pfu to about l xio12 pfu. A more accurate dose can also depend on the subject in which it is being administered. For example, a lower dose may be required if the subject is juvenile, and a higher dose may be required if the subject is an adult human subject. In certain embodiments, a more accurate dose can depend on the weight of the subject. In certain embodiments, for example, a juvenile human subject can receive from about 1 X 8 pfu to about 1 xio10 pfu, while an adult human subject can receive a dose from about 1xi o10 pfu to about 1 xio12 pfu. [00808] Various delivery systems are known and can be used to administer the pharmaceutical composition of the disclosure, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.
[00809] A pharmaceutical composition of the present disclosure can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present disclosure. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.
[00810] Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present disclosure. Examples include, but are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present disclosure include, but are not limited to the SOLOSTAR™ pen (sanofi-aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, CA), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRA™ Pen (Abbott Labs, Abbott Park IL), to name only a few.
[00811] In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, a controlled release system can be placed in proximity of the composition’s target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.
[00812] The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule.
[00813] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the aforesaid antibody contained is generally about 5 to about 500 mg per dosage form in a unit dose; especially in the form of injection, it is preferred that the aforesaid antibody is contained in about 5 to about 100 mg and in about 10 to about 250 mg for the other dosage forms.
Uses of the Antigen-Binding Molecules
[00814] The present disclosure includes methods of using the any of antigen-binding molecules as disclosed herein or a pharmaceutically acceptable carrier or diluent.
[00815] In one aspect, provided herein is a method for reducing off-target effects of an AAV particle in vivo, comprising administering said AAV particle in a molecular complex comprising said AAV particle bound to one or more antibodies and/or antigen-binding fragments described herein or one or more multispecific antibodies and/or multispecific antigen-binding fragments described herein.
[00816] In another aspect, provided herein is a method for enhancing target specificity of an AAV particle in vivo, comprising administering said AAV particle in a molecular complex comprising said AAV particle bound to one or more antibodies and/or antigen-binding fragments described herein or one or more multispecific antibodies and/or multispecific antigen-binding fragments described herein.
[00817] In another aspect, provided herein is a method for determining the presence and/or identity of an AAV capsid in a sample, comprising contacting the sample with the antibody or antigen-binding fragment described herein, wherein said antibody or antigen-binding fragment binds to said AAV particle.
[00818] In another aspect, provided herein is a method for visualizing an AAV particle in a subject comprising administering to the subject the antibody or antigen-binding fragment described herein, wherein said antibody or antigen-binding fragment binds to said AAV particle and is attached to a detectable agent.
[00819] In another aspect, provided herein is a method for assessing quality of an AAV particle preparation comprising contacting said AAV particle preparation with the antibody or antigen-binding fragment described herein , wherein said antibody or antigen-binding fragment binds to said AAV particle and is attached to a detectable agent.
[00820] In another aspect, provided herein is an affinity matrix comprising the antibody or antigen-binding fragment described herein or the multispecific antibody or multispecific antigen-binding fragment described herein attached to a solid support.
[00821] In another aspect, provided herein is a method of isolating or purifying an AAV capsid or an AAV particle from a sample, comprising contacting the sample with the affinity matrix described herein.
[00822] In another aspect, provided herein is a method for inhibiting an infection or transduction of a cell mediated by an AAV particle comprising contacting said AAV particle with said cell in the presence of the antibody or antigen-binding fragment described herein. In some embodiments, the cell is in a subject and the antibody or antigen-binding fragment is administered to said subject.
[00823] In another aspect, provided herein is a method for neutralizing a capsid of an AAV particle comprising contacting said AAV particle with the antibody or antigen-binding fragment described herein. In some embodiments, the method for neutralizing a capsid achieves detargeting of the AAV particle from a cell and /or tissue-type naturally targeted by the capsid in the absence of the antibody of antigen-binding fragment.
[00824] In various aspects, the methods comprise administering to a subject in need thereof a therapeutic composition comprising any of the antibodies or antigen-binding molecules as disclosed herein and a pharmaceutically acceptable carrier or diluent. As used herein, the expression "a subject in need thereof means a human or non-human animal that exhibits one or more symptoms or indicia of disease, disorder, condition and/or symptom which would benefit from administration of the antibodies or antigen-molecules described herein.
Administration Regimens
[00825] According to certain embodiments of the present disclosure, an antigen-binding molecule described herein may be administered to a subject separately from an AAV particle, or in a pre-complexed form with an AAV particle. In some embodiments, an antigenbinding molecule and an AAV particle may be administered as a molecular complex described herein.
[00826] In some embodiments, when an antigen-binding molecule and an AAV particle are administered separately, the antigen-binding molecule may be administered at the same time as the AAV particle.
[00827] In some embodiments, an antigen-binding molecule and an AAV particle may be administered separately over a defined time course. In certain embodiments, multiple doses of an antigen-binding molecule and/or an AAV particle described herein, may be administered to a subject over a defined time course. The methods according to such aspects of the disclosure may comprise sequentially administering to a subject multiple doses of an antigen-binding molecule and/or an AAV particle of the disclosure. As used herein, "sequentially administering" means that each dose of an antigen-binding molecule and/or AAV is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present disclosure includes methods which comprise sequentially administering to the patient a single initial dose of an antigen-binding molecule and/or AAV, followed by one or more secondary doses of the antigen-binding molecule and/or AAV, and optionally followed by one or more tertiary doses of the antigen-binding molecule and/or AAV.
[00828] The terms "initial dose," "secondary doses," and "tertiary doses," can refer to the temporal sequence of administration of the antigen-binding molecule and/or AAV of the disclosure. Thus, the "initial dose" is the dose which is administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the "secondary doses" are the doses which are administered after the initial dose; and the "tertiary doses" are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of the antigen-binding molecule and/or AAV, but generally may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of an antigen-binding molecule and/or AAV contained in the initial, secondary and/or tertiary doses varies from one another (e.g., adjusted up or down as appropriate) during the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses" followed by subsequent doses that are administered on a less frequent basis (e.g., "maintenance doses").
[00829] In one exemplary embodiment of the present disclosure, each secondary and/or tertiary dose is administered 1 to 26 (e.g., 1 , 1 %, 2, 21/2, 3, 372, 4, 4%, 5, 51/2, 6, 6%, 7, 7%, 8, 81/2, 9, 972, 10, 1072, 1 1 , 1 172, 12, 1272, 13, 1372, 14, 1472, 15, 1572, 16, 1672, 17, 177>, 18, 1872, 19, 1972, 20, 2072, 21 , 2172, 22, 2272, 23, 2372, 24, 2472, 25, 2572, 26, 267>, or more) weeks after the immediately preceding dose. The phrase "the immediately preceding dose," as used herein, means, in a sequence of multiple administrations, the dose of antigenbinding molecule and/or AAV which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.
[00830] The methods according to this aspect of the disclosure may comprise administering to a patient any number of secondary and/or tertiary doses of an antigen-binding molecule and/or AAV described herein. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
[00831] In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the immediately preceding dose. Alternatively, the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination. [00832] In some embodiments, when an antigen-binding molecule and an AAV particle described herein are sequentially administered, the AAV particle may be administered as a first component of the dosing regimen and the antigen-binding molecule may be administered as a second component of the dosing regimen (i.e., the AAV particle may be administered before the antigen-binding molecule). In some embodiments, the AAV particle may be administered as a second component of the dosing regimen and the antigen-binding molecule may be administered as a first component of a dosing regimen (i.e., the AAV particle may be administered after the antigen-binding molecule). In some embodiments, an AAV particle and/or antigen-binding molecule may be sequentially administered, in either of the above-described orders, with variable time intervals between administration. For example, the time interval between administration of the AAV particle and the antigen binding molecule may be at least about 30 seconds, at least about 35 seconds, at least about 40 seconds, at least about 45 seconds, at least about 50 seconds, at least about 55 seconds, at least about 1 minute, at least about 2 minutes, at least about 5 minutes, at least about 10 minutes, at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, at least about 50 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 10 to 12 hours, at least about 12 to 14 hours, at least about 14 to 16 hours, at least about 16 to 18 hours, at least about 18 to 20 hours, at least about 20 to 22 hours, at least about 22 to 24 hours, at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 10 to 12 days, at least about 12 to 14 days, at least about 14 to 16 days, at least about 16 to 18 days, at least about 18 to 20 days, at least about 20 to 22 days, at least about 22 to 24 days, at least about 24 to 26 days, at least about 28 days, at least about 29 days, at least about 30 days, at least about 31 days, at least about 1 month, or more.
Devices
[00833] The present disclosure also provides a vessel (e.g., a vial or chromatography column) or injection device (e.g., syringe, pre-filled syringe or autoinjector) comprising a bispecific antigen-binding molecule (e.g., pharmaceutical formulation thereof) set forth herein. The vessel or injection device may be packaged into a kit.
[00834] An injection device is a device that introduces a substance into the body of a subject (e.g., a human) via a parenteral route, e.g., intraocular, intravitreal, intramuscular, subcutaneous or intravenous. For example, an injection device may be a syringe (e.g., prefilled with the pharmaceutical formulation, such as an auto-injector) which, for example, includes a cylinder or barrel for holding fluid to be injected (e.g., comprising the antibody or fragment or a pharmaceutical formulation thereof), a needle for piecing skin, blood vessels or other tissue for injection of the fluid; and a plunger for pushing the fluid out of the cylinder and through the needle bore and into the body of the subject.
[00835] A pharmaceutical composition provided herein can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present disclosure. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded. [00836] Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present disclosure. Examples include, but are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, Ind.), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present disclosure include, but are not limited to the SOLOSTAR™ pen (sanofi-aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, Calif.), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRA™ Pen (Abbott Labs, Abbott Park III.), to name only a few.
[00837] Provided herein are methods for administering a bispecific antigen-binding molecule of the present disclosure comprising introducing e.g., injecting, the molecule into the body of the subject, e.g., with an injection device.
Expression Methods
[00838] Provided herein are recombinant methods for making an antigen-binding molecule of the present disclosure, or an immunoglobulin chain thereof, comprising (i) introducing, into a host cell, one or more polynucleotides encoding light and/or heavy immunoglobulin chains of such an antigen-binding molecule, for example, wherein the polynucleotide is in a vector; and/or integrates into the host cell chromosome and/or is operably linked to a promoter; (ii) culturing the host cell (e.g., mammalian, fungal, Chinese hamster ovary (CHO), Pichia or Pichia pastoris) under conditions favorable to expression of the polynucleotide and, (iii) optionally, isolating the bispecific antigen-binding molecule or immunoglobulin chain from the host cell and/or medium in which the host cell is grown. The product of such a method also forms part of the present disclosure along with a pharmaceutical composition thereof.
[00839] In an embodiment, a method for making an antigen-binding molecule includes a method of purifying the molecule, e.g., by column chromatography, precipitation and/or filtration. The product of such a method also forms part of the present disclosure along with a pharmaceutical composition thereof.
[00840] Host cells comprising an antigen-binding molecule of the present disclosure and/or a polynucleotide encoding immunoglobulin chains of such a molecule (e.g., in a vector) are also part of the present disclosure. Host cells include, for example, mammalian cells such as Chinese hamster ovary (CHO) cells and fungal cells such as Pichia cells (e.g., P. pastoris).
EXAMPLES
[00841] The present disclosure is also described and demonstrated by way of the following examples. However, the use of these and other examples anywhere in the specification is illustrative only and in no way limits the scope and meaning of the disclosure or of any exemplified term. Likewise, the disclosure is not limited to any particular preferred embodiments described here. Indeed, many modifications and variations of the disclosure may be apparent to those skilled in the art upon reading this specification, and such variations can be made without departing from the disclosure in spirit or in scope. The disclosure is therefore to be limited only by the terms of the appended claims along with the full scope of equivalents to which those claims are entitled.
Example 1. Enzyme-linked immunosorbent assay (ELISA) to examine binding of anti- AAV bivalent antibodies to various AAV serotypes
[00842] The AAV capsid structure comprises three viral proteins, VP1 , VP2, and VP3, that are encoded from a single open reading frame. An icosahedral capsid is formed from the assembly of 60 monomers of VP1 , VP2, and VP3 in relative amounts of 1 :1 :10. The AAV capsid contains residues critical for mediating cell and receptor binding. Monoclonal antibodies (mAbs) to AAV have been generated and the ability of these mAbs to bind to AAV capsids of various serotypes was explored by enzyme-linked immunosorbent assay (ELISA). [00843] Table 12 shows a description of identifiers for anti-AAV antibodies of the present Example.
Table 12. Anti-AAV Antibody Identifiers
[00844] Anti-AAV mAbs of the present Example (HDQQ06E09-0017, HDQQ06F06-0018, HDPV07D04-0065, 405931 1_ULC1-39_38741_MS, 3842258JJLC1-3, _79284_MS, 4059310_ULC1-39_48703_MS, 405931 1_ULC1-39_31283_MS, 405931 1JJLC1- 39_36126_MS, 405931 1_ULC1-39_31000_MS, 4059310_ULC1-39_51231_MS) were assessed for binding to multiple AAV serotypes (AAV2 HBM [heparin binding mutant], AAV3b, AAV5, AAV6, AAV8, AAV9, AAV Sealion, AAV rh32.33). The viral particles were first diluted in PBS and used to coat black 96-well Maxisorp plates (2x108 VGs/well) overnight at 4 °C. The plates were then emptied, pat-dried, washed 4x with KPL 1x Wash Buffer, and incubated with 3%-bovine serum albumin (BSA) blocking buffer overnight at 4 °C. The bivalent antibodies were diluted 1 :8 in assay diluent buffer (ADB) from a starting concentration of 5 g/ml. The blocked plates were then emptied, pat-dried, washed 4x and incubated with the bivalent antibodies for 1 hour at room temperature (RT). Afterwards, the plates were once again emptied, pat-dried washed 4x, and then incubated with goat antihuman horseradish peroxidase (HRP) secondary antibody at a 1 : 10,000 dilution in ADB for 1 hour at RT. Finally, the plates were emptied, pat-dried, washed 6x, followed by addition of SuperSignal ELISA Pico Chemiluminescent substrate. Luminescence was detected using a plate reader (Tecan Infinite M200 Pro) and analyzed using GraphPad Prism.
[00845] An assortment of binding affinities was observed for the bivalent antibodies to the AAVs (Figures 1A-1L). REGN13076 was able to bind to all serotypes. REGN13072 bound strongly to all serotypes except for AAV rh32.33. Two hybridoma-derived antibodies (REGN13070, REGN13071) and two NGS/MS-derived antibodies (REGN13073, REGN 13074) showed strong binding to AAV2 HBM and AAV3b, but weak binding to the remaining serotypes. REGN13075 and REGN13220 bound to multiple serotypes with varying strength. REGN13284 bound most strongly to AAV8. Finally, REGN13221 showed weak affinity to all serotypes at low concentrations. However, binding for REGN13221 was observed with increased amount of antibody. Example 2. Binding kinetics of anti-AAV antibodies to surface-coupled AAV-2
[00846] Equilibrium dissociation constants (KD values) for adeno-associated virus serotype- 2 (AAV-2) binding to purified anti-AAV antibodies and the respective Fab domain proteins were determined using a real-time surface plasmon resonance biosensor technology using a Biacore T200 instrument.
[00847] Table 13 shows a description of identifiers for anti-AAV antibodies of the present Example.
Table 13. Anti-AAV Antibody Identifiers
[00848] Table 14 shows a description of the reagents used in the present Example.
Table 14. Description of Reagents
[00849] The CM5 Biacore sensor surface was derivatized by amine coupling with adeno- associated virus (AAV-2) around 850 RU. All Biacore binding studies were performed in a buffer composed of 0.01M HEPES, 0.15 M NaCI, pH 7.4 (HBS-N running buffer). Different concentrations of anti-AAV antibodies (ranging from 100 nM to 25 nM in 4-fold serial dilutions) prepared in HBS-N running buffer were injected over the amine coupled AAV-2 at a flow rate of 30 pL/minute. Antibody association was monitored for 2.5 minutes while dissociation was monitored in HBS-N running buffer for 5 minutes. At the end of each cycle, the AAV-2 capture surface was regenerated using two 10 second injections of 10mM Glycine at pH 1 .5. All binding kinetics experiments were performed at 25 °C.
[00850] The specific SPR-Biacore sensorgrams were obtained by a double referencing procedure. The double referencing was performed by first subtracting the signal of each injection over a reference surface (blank amine coupled surface) from the signal over the experimental surface (amine coupled AAV-2) thereby removing contributions from refractive index changes. In addition, running buffer injections were performed to allow subtraction of the signal changes resulting from the dissociation phase. Kinetic association (ka) and dissociation (fa) rate constants were determined by fitting the real-time sensorgrams to a 1 :1 binding model using Scrubber v2.0c curve fitting software. Binding dissociation equilibrium constants (KD) and dissociative half-lives (t%) were calculated from the kinetic rate constants as: kd ln(2)
KD (M) = - — , and VA (min) = . , ka 60*kd
[00851] The association and dissociation rate constants (ka and kd), the dissociative halflives (ti/2) and the equilibrium dissociation constants KD of ten anti-AAV antibodies and the respective Fab domain proteins binding to surface captured AAV-2 are summarized in Table 15 and Table 16, respectively.
Table 15. Kinetic and Equilibrium Binding Parameters of Anti-AAV mAb Antibodies to
Surface-coupled AAV-2 at 25 °C Table 16. Kinetic and Equilibrium Binding Parameters of Anti-AAV Fab antibodies to Surface-coupled AAV-2 at 25 °C
Example 3. Immunoglobulin gamma Fc Receptor I (FcG-R1) Internalization Assay [00852] The immunoglobulin gamma Fc Receptor I (FcG-R1) internalization assay of the present Example was designed to assess the ability of anti-AAV antibodies to bind to and enhance internalization of multiple AAV serotypes into FcG-R1 -overexpressing 293T cells. [00853] Antibodies can be used to bridge AAV capsids to target cells to enhance transduction efficiency. The high affinity immunoglobulin gamma Fc Receptor I (FcGR1) binds to the Fc of various IgG isotypes, including IgG 1 , and can be expressed on cell lines to capture antibodies on cell surface. As described herein, monoclonal antibodies (mAbs) to AAV were generated and the ability of these mAbs to enhance or neutralize transduction was explored.
[00854] Table 17 shows a description of identifiers for anti-AAV antibodies of the present Example.
Table 17. Anti-AAV Antibody Identifiers
[00855] Anti-AAV mAbs of the present Example (HDQQ06E09-0017, HDQQ06F06-0018, HDPV07D04-0065, 4059311_ULC1-39_38741_MS, 3842258JJLC1-3, _79284_MS, 4059310_ULC1-39_48703_MS, 4059311_ULC1-39_31283_MS, 4059311JJLC1- 39_36126_MS, 4059311_ULC1-39_31000_MS, 4059310_ULC1-39_51231_MS) were assessed for their ability to enhance internalization of multiple AAV serotypes expressing NanoLuc genomes (AAV1 , AAV2.Myc, AAV5, AAV8, AAV9, AAV Sealion) into FcGR1- expressing HEK 293T cells. Antibodies were first diluted in 1 x PBS for appropriate viral genome to antibody ratios (1 :4, 1 :500, 1 :2500, 1 : 10,000, undiluted) and added to 96-well CoStar Assay black with clear bottom assay plates. Afterwards, AAVs were added to plates containing antibodies and incubated for 1 hour at 37 °C and 5% CO2. A suspension of HEK 293T FcGR1+ cells in DMEM (supplemented with 10% fetal bovine serum [FBS], minimum essential medium (MEM) non-essential amino acid (NEAA) solution, Penicillin-Streptomycin [Pen Strep]) was then added to virus and antibody complexes. The transduced cells were incubated for 72 hours, and transduction was measured using the NanoGio Luciferase assay system. Luminescence was detected using a plate reader (Tecan Infinite M200 Pro) and analyzed using GraphPad Prism.
[00856] As shown in Figures 2A-2J, five of the antibodies (4059311_ULC1-39_38741_MS, 4059311_ULC1-39_31000_MS, 4059311_ULC1-39_36126_MS, HDQQ06E09-0017, HDPV07D04-0065) exhibited enhanced transduction at lower antibody concentrations for the majority of serotypes tested. The remaining antibodies (3842258_ULC1-39_79284_MS, 4059310_ULC1-39_48703_MS, 4059310_ULC1-39_51231_MS, 4059311JJLC1- 39_31283_MS, HDQQ06F06-0018) required a greater quantity of antibody for enhancement of transduction.
Example 4. Cryo-electron Microscopy (Cryo-EM)
[00857] Cryo-EM sample preparation and data collection
[00858] Purified anti-AAV Fabs were mixed with corresponding AAV samples (~1.5x1013 to 2.5 x1014 VG/ml) at approximately 220: 1 molar ratio and incubated at 4 °C for 1 hour. 3.5 L of the mixture was applied onto an UltrAufoil R1 .2/1.3, 300 mesh grid (Quantifoil). Excess liquid was blotted away using filter paper and the grid was plunge frozen in liquid ethane cooled by liquid nitrogen using a Vitrobot Mark IV (ThermoFisher) operated at 4 °C and 100% humidity. The grid was then inserted into a Titan Krios G3i microscope (ThermoFisher) equipped with a K3 camera (Gatan). Movies were collected in counted mode at a nominal magnification of 105,000x (0.86 A pixel size) and a defocus range of -0.8~-1.6 pm. Each movie contained 46 dose fractions over a 2 second exposure, and the total acquired dose per A2 was ~40 electrons. Data collection statistics are summarized in Table 18.
[00859] Cryo-EM data processing and map generation
[00860] Cryo-EM data were processed using cryoSPARC v2. Movies were motion corrected by Patch motion correction and CTF parameters were estimated by Patch CTF estimation. Particles were picked using Blob picker. Junk particles were removed by multiple rounds of 2D classification, followed by Ab initio reconstruction, Homogeneous refinement, and Heterogenous refinement to identify the best class of particles representing the target complex. These particles were further refined using non-uniform refinement to generate the final cryo-EM density map. The details of data processing for each sample are summarized in Table 18.
[00861] Model building and refinement
[00862] Manual model building was carried out using Coot version 0.8.9 and real space refinements were done in Phenix version 1.17. Published high-resolution structures of AAV2 (PDB: 6NZ0), AAV8 (PDB: 2QA0), and AAV9 (PDB: 3UX1) were used as initial models for model building. Homology models for Fab fragments used in this Example were made from a previously determined REGN Fab structure. Unambiguous docking of Fab models into their respective densities was aided by clearly interpretable side chain densities corresponding to their distinct complementarity determining region (CDR) sequences. A combination of picked initial models was docked into corresponding cryo-EM density map using Fit-in-map of UCSF Chimera. The models were adjusted manually in Coot, followed by real space refinement with secondary structure and non-crystallographic symmetry (NCS) restraints in Phenix.
[00863] Results summary and conclusions:
[00864] Cryo-EM structure of AAV2 HBM in complex with REGN13878
[00865] A 3.08 A cryo-EM structure of AAV2 HBM in complex with the anti-AAV antibody Fab REGN13878 was obtained. The structure suggests that REGN13878 binds around the icosahedral 3-fold axes. Since the binding site is located at the junction of two adjacent trimer cores which both have three VP3 protomers at two adjacent 3-fold axes, the binding site is also around the icosahedral 2-fold axis.
[00866] REGN13878 largely binds to the edge of one VP3 trimer core (trimer core #1) but also tilts towards another adjacent VP3 trimer core (trimer core #2), making extensive contacts with 5 VP3 protomers in the two trimer cores. For the convenience of describing the interaction details at the binding interface, the VP3 protomers in trimer core #1 were named as VP3-3a, VP3-3b, and VP3-3c in clockwise direction around its 3-fold axis. Similarly, the VP3 protomers in the adjacent trimer core #2 were named as VP3-3d, VP3-3e, and VP3-3f in clockwise direction around its 3-fold axis, where VP3-3d shares a 5-fold axis with VP3-3a and VP3-3d is in the counterclockwise direction of VP3-3a around this 5-fold axis.
REGN 13878 residues contacting VP3 residues of AAV2 HBM are summarized in Table 19. The binding of REGN13878 is primarily mediated by its heavy chain contacting VP3-3a and VP3-3b in trimer core #1 and is further stabilized by engagement of the light chain with VP3- 3d and VP3-3e in trimer core #2. CDRs H1 , H2, and H3 of REGN13878 engages VP3-3a by contacting two patches of residues located in variable region I (VR-1) (S264, A266, N268) and VR-III (N382, S384, Q385), as well as two additional residues H271 and G512. CDRs H2 and H3 of REGN13878 also contacts VP3-3b VR-V (R487, D494), VR-VI (K527, D529, K532). A single residue from VR-VI of VP3-3c, L538, is also involved in the interaction with CDRs H2 of REGN13878. Furthermore, CDRs H3, L1 , and L2 contacts a patch of residues in VP3-3d VR-IX (N705, K706, V708), with addition interactions mediated by VR-VI (D533, E555) and the framework region (FR) of the light chain. Lastly, VR-IV residues (T450, Q457, R459) in VP3-3e contacts REGN13878 light chain FR as well.
[00867] Crvo-EM structure of AAV2 HBM in complex with REGN13883
[00868] A 3.07 A cryo-EM structure of AAV2 HBM in complex with the anti-AAV antibody Fab REGN13883 was obtained. Similar to REGN13878, REGN13883 binds around the icosahedral 3-fold axis. Since the binding site is located at the junction of two adjacent trimer cores which both have three VP3 protomers at two adjacent 3-fold axes, the binding site is also around the icosahedral 2-fold axis.
[00869] REGN13883 binds to the boundary of two adjacent VP3 trimer cores, trimer core #1 and trimer core #2, but the interactions are largely mediated by trimer core #1 . The Fab is roughly perpendicular to the virus capsid surface. The VP3 protomers in trimer core #1 and the adjacent trimer core #2 were named following the same convention used in the AAV2 HBM-REGN13878 structure. REGN13883 residues contacting VP3 residues of AAV2 HBM are summarized in Table 20. The binding of REGN13883 is primarily mediated by the heavy chain contacting VP3-3a and VP3-3b in trimer core #1 and is further stabilized by light chain contacts with VP3-3d in trimer core #2. CDRs H1 , H2, H3, and L2 of REGN13883 engages VP3-3a by contacting two patches of residues located in variable region I (VR-I) (S264, G265, A266, S267, N268) and VR-III (N382, G383, S384), as well as an additional H271 residue. CDRs H2 and H3 of REGN13883 also contacts VP3-3b VR-VI (K527, D528, E530), VR-V (R487), and two additional residues (E574, Q575). Furthermore, CDR L1 of REGN 13883 contacts a patch of residues in VP3-3d VR-IX (K706, S707) to stabilize the binding.
[00870] Cryo-EM structure of AAV2 HBM in complex with REGN13880
[00871] A 3.10 A cryo-EM structure of AAV2 HBM in complex with the anti-AAV antibody Fab REGN13880 was obtained. The structure suggests that REGN13880 binds to the region surrounding the 5-fold symmetry pore. REGN13880 binds to the boundary of two immediately adjacent VP3 protomers around each 5-fold pore of AAV2 HBM, making extensive contacts with three VP3 protomers. For the convenience of describing the interaction details at the binding interface, the VP3 protomers surrounding the 5-fold pore were named as VP3-5a, VP3-5b, VP3-5c, VP3-5d, and VP3-5e in counterclockwise direction. REGN13880 residues contacting VP3 residues of AAV2 HBM are summarized in Table 21. The binding of REGN13880 is primarily mediated by heavy chain contacts with VP3-5a and light chain contacts with VP3-5b; the heavy chain makes additional contacts with VP3-5e. REGN13880 has a very long CDR H3 that engages the DE loop (E322, V323, T324, Q325) and HI loop (A655, A667, S668, F669, I670, T671) of VP3-5a. CDRs H1 , H2, and H3 of REGN13880 also engage VP3-5a by contacting a patch of residues spanning VR- 1 (N254, L256, K258, I260, S261 , Q263, Y272). The binding is further stabilized by CDRs L1 , L3 and H3 of REGN13880 contacting VP3-5b VR-VII (Q545, G546, S547, E548, K556) and three additional residues (I332, N717, and V719). Two residues from VP3-5e, T660 and F661, are also involved in the interaction with CDR H1 of REGN 13880. Since the epitope of REGN 13880 is primarily located at the conserved regions of VP3, the Fab can also bind to other AAV serotypes including AAV8 and AAV9 as described below.
[00872] Cryo-EM structure of AAV8 in complex with REGN 13880
[00873] A 2.99 A cryo-EM structure of AAV8 in complex with the anti-AAV antibody Fab REGN 13880 was obtained. Similar to how REGN13880 engages AAV2 HBM, the Fab binds to the region surrounding the 5-fold symmetry pore of AAV8. REGN13880 interacts with AAV8 analogous to how the Fab engages AAV2 HBM. The five VP3 protomers around the 5-fold pore were named in the same way as in the AAV2-HBM-REGN 13880 structure. REGN 13880 residues contacting VP3 residues of AAV8 were summarized in Table 22. The binding of REGN13880 is also primarily mediated by its heavy chain contacting VP3-5a and light chain contacting VP3-5b, with the heavy chain making additional contacts with VP3-5e. The long CDR H3 of REGN13880 dominates the interactions by engaging the DE loop (E325, V326, T327, Q328) and HI loop (A658, N670, S671 , F672, I673, T674) of VP3-5a as well, with an additional contact between VP3-5a N670 and CDR L1. CDRs H1 , H2, and H3 of REGN13880 also engage VP3-5a by contacting a patch of residues spanning VR-I (N255, L257, K259, 1261 , S262, N263, A269, S266, Y275). The binding is further stabilized by CDRs L1 and L3 of REGN13880 contacting VP3-5b VR-VII (Q548, N549, A550, A551 , D559) and an additional residue E720. One residue from VP3-5e, T663, is also involved in the interaction with CDR H1 of REGN13880.
[00874] Cryo-EM structure of AAV9 in complex with REGN 13880
[00875] A 3.10 A cryo-EM structure of AAV9 in complex with the anti-AAV antibody Fab REGN 13880 was obtained. Analogous to how REGN13880 engages AAV2 HBM and AAV8, the Fab binds to the region around the 5-fold symmetry pore of AAV9. REGN13880 interacts with AAV9 in a highly similar way as how the Fab engages AAV2 HBM and AAV8.
REGN 13880 residues contacting VP3 residues of AAV9 are summarized in Table 23. Binding of REGN13880 to AA9 is primarily mediated by heavy chain contacts with VP3-5a light chain contacts with VP3-5b. The long CDR H3 of REGN13880 engages the DE loop (E324, V325, T326, D327, N328) and HI loop (D665, N668, S669, F670, 1671 , T672) of VP3- 5a, with CDR L1 making additional contacts with VP3-5a D665 and N668. CDRs H1 , H2, and H3 of REGN13880 also engage VP3-5a by contacting a patch of residues between spanning VR-I (N254, I260, N262, Y274). In addition, CDR H1 contacts a single residue in VR-VII of VP3-5a (R550). The binding is further stabilized by CDRs L1 and L3 of REGN13880 contacting VP3-5b VR-VII (Q546, G547, G549) and an additional residue, E718.
[00876] Cryo-EM structure of AAV2 HBM in complex with REGN13882
[00877] A 2.91 A cryo-EM structure of AAV2 HBM in complex with the anti-AAV antibody Fab REGN13882 was obtained. Like REGN13880, REGN13882 binds to the region surrounding the 5-fold symmetry pore and the binding site is located at the boundary of two immediately adjacent VP3 protomers at each 5-fold pore of AAV2 HBM. However, REGN 13882 only contacts two VP3 protomers instead of three. To distinguish between the five VP3 protomers surrounding the 5-fold pore were designated asVP3-5a, VP3-5b, VP3- 5c, VP3-5d, and VP3-5e in a counterclockwise direction. REGN13882 residues contacting VP3 residues of AAV2 HBM are summarized in Table 24. The binding of REGN13882 is primarily mediated by its heavy chain contacting VP3-5a and VP3-5b and light chain contacting VP3-5b. The elongated CDR H3 of REGN 13882 engages the DE (V323, T324, Q325) and HI loops (A655, A667, S668, F669, I670, T671) of VP3-5a. CDRs H1 , H2, and H3 of REGN13882 also engage VP3-5a by contacting a patch of residues on the N-terminal side of VR-1 (N254, L256, Q263, S264), with additional contacts made between VR-1 (Q263) and the framework region (FR) of the heavy chain. The binding is further stabilized by CDRs L1 , L3, H2 and H3 of REGN13880 contacting VP3-5b VR-II (G328), VR-VII (G546, E548) and two additional residues (T716, N717). As with REGN13880, the epitope of
REGN 13882 is primarily located at conserved regions of VP3, allowing this Fab to bind other AAV serotypes including AAV8 and AAV9 as described below.
[00878] Cryo-EM structure of AAV8 in complex with REGN 13882
[00879] A 3.10 A cryo-EM structure of AAV8 in complex with the anti-AAV antibody Fab REGN 13882 was obtained. Similar to how REGN13882 engages AAV2 HBM, the Fab binds to the region surrounding the 5-fold symmetry pore of AAV8. REGN13882 interacts with AAV8 analogous to how the Fab engages AAV2 HBM. The names used to distinguish between the five VP3 protomers around the 5-fold pore follows the same naming convention used in the AAV2-HBM-REGN13882 structure. REGN13882 residues contacting VP3 residues of AAV8 are summarized in Table 25. The binding of REGN13882 is primarily mediated by heavy chain contacts with VP3-5a and VP3-5b, and by additional contacts of the light chain with VP3-5b. The long CDR H3 of REGN13882 engages the DE (E325, V326, T327, Q328) and HI loops (N670, S671 , F672, I673, T674) of VP3-5a. CDRs H2 and H3 of REGN 13882 also engage VP3-5a by contacting a patch of residues on the N-terminal side of VR-I (N255, L257, S266). The binding of REGN13882 is further stabilized by CDR L3 contacting VP3-5b VR-VII (N549) and CDRs H2 and H3 engaging two additional residues, T719 and E720.
[00880] Cryo-EM structure of AAV9 in complex with REGN 13882
[00881] A 2.96 A cryo-EM structure of AAV9 in complex with the anti-AAV antibody Fab REGN 13882 was obtained. Similar to how REGN13882 engages AAV2 HBM and AAV8, the Fab binds to the region surrounding the 5-fold symmetry pore of AAV9. REGN13882 interacts with AAV9 analogous to how the Fab engages AAV2 HBM and AAV8. REGN13882 residues contacting VP3 residues of AAV9 are summarized in Table 26. The binding of REGN 13882 is solely mediated by its heavy chain contacting VP3-5a and VP3-5b. The long CDR H3 of REGN13882 engages the DE loop (E324, V325, T326, D327) and HI loop (N668, S669, F670, T672) of VP3-5a. CDRs H1 , H2, and H3 of REGN13880 also engage VP3-5a by contacting a patch of residues on the N-terminal end of VR-I (N254, L256, I260, N262). In addition, CDR H1 contacts a single residue in VR-VII of VP3-5a (D551). The binding of REGN 13882 is further stabilized by CDRs H2 and H3 contacting VP3-5b VR-II (G330) and an additional residue, E718.
[00882] Table 18 shows a summary of cryo-EM data collection and processing for the present Example.
Table 18. Summary of Cryo-EM Data Collection and Processing
[00883] Table 19 shows a summary of REGN13878 residues contacting AAV2 HBM VP3 residues. Contacting residues are defined as amino acids with non-hydrogen atoms within 4 A of non-hydrogen atoms of antibody. Residues corresponding to REGN13878 interactions with VP3 protomers from the adjacent trimer core #2, as described in the text, are italicized.
Table 19. Summary of REGN13878 Residues Contacting AAV2 HBM VP3 Residues
[00884] Table 20 shows a summary of summary of REGN13883 residues contacting AAV2
HBM VP3 residues. Contacting residues are defined as amino acids with non-hydrogen atoms within 4 A of non-hydrogen atoms of antibody. Residues corresponding to
REGN 13883 interactions with VP3 protomers from the adjacent trimer core #2, as described in the text, are italicized.
Table 20. Summary of REGN13883 Residues Contacting AAV2 HBM VP3 Residues
[00885] Table 21 shows a summary of REGN 13880 residues contacting AAV2 HBM VP3 residues. Contacting residues are defined as amino acids with non-hydrogen atoms within 4 A of non-hydrogen atoms of antibody.
Table 21. Summary of REGN13880 Residues Contacting AAV2 HBM VP3 Residues
[00886] Table 22 shows a summary of REGN13880 residues contacting AAV8 VP3 residues. Contacting residues are defined as amino acids with non-hydrogen atoms within 4 A of non-hydrogen atoms of antibody.
Table 22. Summary of REGN13880 Residues Contacting AAV8 VP3 Residues
[00887] Table 23 shows a summary of REGN13880 residues contacting AAV9 VP3 residues. Contacting residues are defined as amino acids with non-hydrogen atoms within 4 A of non-hydrogen atoms of antibody.
Table 23. Summary of REGN13880 Residues Contacting AAV9 VP3 Residues
[00888] Table 24 shows a summary of REGN 13882 residues contacting AAV2 HBM VP3 residues. Contacting residues are defined as amino acids with non-hydrogen atoms within 4 A of non-hydrogen atoms of antibody.
Table 24. Summary of REGN13882 Residues Contacting AAV2 HBM VP3 Residues
[00889] Table 25 shows summary of REGN13882 residues contacting AAV8 VP3 residues. Contacting residues are defined as amino acids with non-hydrogen atoms within 4 A of nonhydrogen atoms of antibody.
Table 25. Summary of REGN13882 Residues Contacting AAV8 VP3 Residues
[00890] Table 26 shows a summary of REGN13882 residues contacting AAV9 VP3 residues. Contacting residues are defined as amino acids with non-hydrogen atoms within 4 A of non-hydrogen atoms of antibody. Table 26. Summary of REGN13882 Residues Contacting AAV9 VP3 Residues
Example 5. AAV x ASGR1 Alternative Format Design and Binding Enzyme-linked immunosorbent assay (ELISA)
[00891] A schematic representation of alternative format antibody designs for AAV-ASGR1 bispecific antibodies is shown in Figure 3. A description of corresponding alternative format antibody molecules is displayed in Figure 4. As illustrated in Figure s, lgG1 versions of anti- AAV mAbs comprising binding arms of REGN13072 (4059311_ULC1-39_38741_MS) and REGN 13221 (4059310_ULC1-39_51231_MS) were selected for inclusion in the binding ELISA described herein based on their respective abilities to enhance internalization of AAV2 expressing NanoLuc genomes into FcGR1 -expressing HEK 293T cells. Anti-AAV mAb REGN13072 (4059311_ULC1-39_38741_MS) was functional at low antibody concentrations (1 VG:4 mAb) and did not require saturated antibody binding to the AAV. REGN13221 (4059310_ULC1-39_51231_MS) was not neutralizing when in excess concentrations (1 VG:10K mAb) and required saturated antibody binding to the AAV.
[00892] Table 27 shows a description of identifiers for the anti-AAV antibodies of the present Example. Table 27. Anti-AAV Antibody Identifiers
[00893] Anti-AAV mAbs of the present Example (4059311_ULC1-39_38741_MS, 4059310_ULC1-39_51231_MS) were assessed for binding to AAV serotype AAV2 HBM. Viral particles were first diluted in PBS and used to coat black 96-well Maxisorp plates (2x108 VGs/well) overnight at 4°C. The plates were then emptied, pat-dried, washed 4x with KPL 1x Wash Buffer, and incubated with 3%-BSA blocking buffer overnight at 4°C. Alternative format antibodies were diluted 1 :3 in ADB from a starting concentration of 1 pg/ml. The blocked plates were then emptied, pat-dried, washed 4x and incubated with alternative format antibodies for 1 hour at RT. Afterwards, the plates were once again emptied, pat- dried washed 4x, and then incubated with goat anti-human HRP secondary antibody (or goat anti-mouse HRP secondary for AAV2 A20) at a 1 :10,000 dilution in ADB for 1 hour at RT. Finally, the plates were emptied, pat-dried, washed 6x, followed by addition of SuperSignal ELISA Pico Chemiluminescent substrate. Luminescence was detected using a plate reader (Tecan Infinite M200 Pro) and analyzed using GraphPad Prism. Graphs showing binding of 36 alternative format antibodies to AAV2 HBM relative to controls across various antibody concentrations are displayed in Figures 6A-6J. Alternative format antibodies have AAV binding efficacy similar to other antibodies with the same binding arms. Alternative format antibodies with 4059311_ULC1-39_38741_MS binding arms required less antibody for saturated binding as compared to alternative format antibodies with 4059310JJLC1- 39_51231_MS binding arms.
Example 6. Bispecific antibodies can effectively retarget adeno-associated virus (AAV) to the central nervous system (CNS)
[00894] The present Example was designed to test retargeting of adeno-associated virus (AAV) to the central nervous system (CNS) using bispecific antibodies. Anti-AAV antibodies that bind, e.g., to AAV capsid epitopes, were formatted in bispecific formats for retargeting of AAV to the central nervous system (CNS). An exemplary representation of an anti-transferrin receptor (TfR) x anti-AAV bispecific antibody retargeting AAV to the CNS, including crossing of the blood-brain barrier (BBB), is schematized in Figure 7A. A comparison of wild-type (WT) AAV9, covalent-platform control and bispecific platform retargeting of AAV to cerebellum, cortex, and hippocampus assessed using histochemical staining approaches is shown in Figure 7B. Liver detargeting could also be controlled by modulating antibody concentration [Ab] and/or use of a detargeting capsid (see, e.g., Figures 8A-8B). A comparison of transduction efficiency between the covalent platform and the bispecific platform using cDNA quantitation is shown in Figure 8A. The results showed that the bispecific platform achieved comparable efficacy to the covalent platform. Higher antibody concentrations achieved partial liver detargeting with WT AAV9. Further detargeting of AAV was achieved when paired with a detargeted AAV. A comparison between detargeted AAV9 and WT AA9 using the bispecific platform in cerebellum and liver is shown in Figure 8B. These data support fine tuning of AAV retargeting and detargeting by modulating capsid and antibody concentration to achieve desired in vivo tropism.
Example 7. Transduction assay to assess the efficacy of AAV x CACNG1 bispecific antibodies
[00895] Adeno-associated viruses (AAV) are members of the Parvovirus family of nonenveloped single-stranded DNA viruses. The AAV capsid structure comprises three viral proteins, VP1 , VP2, and VP3, that are encoded from a single open reading frame. An icosahedral capsid is formed from the assembly of 60 monomers of VP1 , VP2, and VP3 in relative amounts of 1:1 :10. The AAV capsid contains residues critical for mediating cell and receptor binding. The capsids of many serotypes bind to the adeno-associated virus receptor (AAVR), which is required for efficient transport of particles to the trans-golgi network, an essential step of the viral transduction pathway. Antibodies that bind to regions of the capsid attributed to either glycan or AAVR binding have been shown to neutralize AAV transduction. It has also been shown that antibodies can be used to bridge AAV capsids to target cells to enhance transduction efficiency. Bispecific antibodies to AAV have been generated and the ability of these to enhance or neutralize transduction was explored.
[00896] AAV x CACNG1 bispecific antibodies of the present disclosure (AF70: anti-AAV#70 scFv fused to N-terminal of anti-CACNG1 REGN10717 hlgG1 N297G antibody; AF71 : anti- AAV#70 scFv fused to C-terminal of anti-CACNG1 REGN10717 hlgG1 N297G antibody; Figure 9, Figures 30A-30G, and Table 30) were assessed for their capacity to enhance internalization of AAV Hu37 particles expressing green fluorescent protein (GFP) genome into mouse CACNG1 -expressing HEK 293 cells and human CACNG1 -expressing HEK 293 cells. The day before transduction, both cell lines were seeded in a clear wall clear bottom 96-well plate at 10,000 cells per well using DMEM (supplemented with 10% FBS, MEM NEAA, Pen Strep) and incubated at 37°C and 5% CO2. The day of transduction, AF70 and AF71 antibodies were first diluted in 1xPBS and then serially diluted (3-fold) in 1xPBS to obtain the appropriate viral genome to antibody molar ratios (1 :1 , 1:3, 1 :9, 1 :27, and 1 :81). AAV Hu37 and control virus (1/8 Spytagged AAV9 W503A conjugated with anti-CACNG1 bivalent antibody) were diluted in 1xPBS + 0.001% Pluronic. Equal volumes of AAV Hu37 and antibody dilutions were combined to obtain the above viral genome to antibody molar ratios and incubated for 1 hour at 37°C and 5% CO2. After a 1-hour incubation, the appropriate volumes of the viral genome to antibody complexes were added to the cells to yield an MOI of 2E+04 and 2E+05 VG per cell. 60-hours post transduction, the transduced cells were analyzed by flow cytometry. To prepare samples for flow cytometry, the supplemented media was discarded, and the cells were washed once with 100 pL 1xPBS. Afterwards, the cells were lifted by adding 50 L of TrypLE™ Select Enzyme (1X), no phenol red, and incubated for 4-5 minutes in 37°C. 100 pL of BD Pharmingen™ Stain Buffer (BSA) was then added and cells resuspended and then transferred to a clear V-bottom 96 well plate. The cells were spun down for 2 minutes at 800xg and the supernatant was discarded. Two extra rounds of washes were performed by adding 100 pL of BSA Stain Buffer and spun down for 2 minutes at 800xg. After the last wash, 100 pL of BSA Stain Buffer was added and cells were resuspended in preparation for Flow Cytometry analysis. GFP expression was measured using a ZE5 Cell Analyzer.
[00897] C2C12 myoblasts were seeded on collagen I coated plates with black walls at 10,000 cells per well; human skeletal muscle derived myoblasts were seeded on collagen I coated plates with black walls at 12,500 cells/well. After 24 hours, human myoblasts were treated with differentiation media (Cook Myosite, MD-5555) for 3 days, and the C2C12 myoblasts were treated with DMEM + 2% horse serum for 2 days. Following confirmation of myotube formation, the cells were treated with the AAVhu37 and antibody complexes (1 E5 viral genomes per cell) as described above. WT885 (1/8 Spytagged AAV9 W503A conjugated to anti-CACNG1 antibody) diluted in PBS was used as a positive control. Three (3) days post transduction, the cells were fixed with 4% PFA for 15 minutes, washed twice with 1xPBS and blocked with 20% goat serum + 0.3% Triton X-100. The wells were incubated with MF-20 (DSHB) overnight in blocking buffer at 1 OO to stain for Myosin Heavy Chain (MyHC). The following day, the cells were washed and incubated with anti-mouse IgG Alexa 647, then washed and incubated with DAPI, and imaged on the Axio Observer. Myotube images were analyzed using HALO to determine GFP positive area as a percentage of total MyHC positive area. A separate analysis was also run to determine intensity of GFP signal in MyHC positive regions.
[00898] Co-incubation of AAV Hu37 with either AF70 or AF71 resulted in improved transduction efficiency over control AAV without antibody on HEK 293 cells overexpressing mouse CACNG1 (Figure 10 and Figure 11) and human CACNG1 (Figure 12 and Figure 13). Transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody and 1 AAV to 9 antibodies as assessed by %GFP positive cells (Figure 10 and Figure 12) and mean fluorescence intensity (Figure 11 and Figure 13). Similarly, incubation of AAV with AF70 and AF71 enhanced transduction into differentiated C2C12 myotobes (Figure 14 and Figures 16A-16D) and differentiated human myotubes (Figure 15 and Figures 17A-17D) as determined by quantification of GFP positive cells (Figures 16A-16D and Figures 17A- 17D). C2C12 was most efficiently transduced with AAV complexed with AF71 at molar ratio 1 :3 and 1 :9 (Figure 14). Peak transduction efficacy of AAV retargeted with bispecific antibodies was comparable to that of control AAV covalently conjugated to an anti-CACNG1 antibody (WT885), except for AF70 on human myotubes which showed efficacy but of lesser magnitude. These data show that AAV can be effectively targeted to CACNG1 expressing cells using bispecific antibodies.
Example 8. Testing AAV x mTfR alternative format (AF) antibodies binding to AAV9W503A virus by ELISA
[00899] The present Example was designed to test the binding of AAV x mTfR alternative format (AF) antibodies (Abs) to AAV9W503A virus by enzyme-linked immunoassay (ELISA). A schematic diagram of an example experimental setup used in this Example is shown in Figure 19. Briefly, 96-well plates were coated with AAV9W503A Ubc.Fluc (2e8 VGs/well) and incubated overnight at 4°C. Prior to introducing the primary antibodies, plates were blocked for 1 hour at room temperature (RT) using 3% bovine serum albumin (BSA). In a separate plate, alternative format (AF) antibodies (primary antibodies) were diluted 3-fold in assay diluent buffer (ADB) buffer with a starting concentration of 1 pig/ml. A description the AAV x mTfR alternative format (AF) antibodies tested in the present example (ID 1-13) is shown in Figures 18A-18B (see also, e.g., Figures 29A-29I and Table 30). REGN1932 (anti-FelD1), REGN13072 (bivalent with NGS/MS 70), and REGN13221 (bivalent with NGS/MS 64) were also included as control antibodies. Additional control conditions were AAV9W503A only and AAV9W503A + secondary antibody only. Primary antibody dilutions were then transferred to the coated plates and incubated for 1 hour at RT. For the secondary antibody, an a-Human-HRP at 1 :10,000 dilution in ADB buffer at RT was used. 1xKPL buffer was used for in-between step washes. The SuperSignal ELISA Pico Chemiluminescent Substrate Kit was used for development. The substrate was added and incubated for ~1 minute at RT and then the readout was performed using the Tecan Infinite m200 Pro instrument. The results of the experiments showed that AAV x mTfR AF antibodies with NGS/MS #70 arm bind well to AAV9W503A Ubc.Fluc at high concentrations. AAV x mTfR AF Abs with anti NGS/MS #64 arm had a lower affinity to AAV9W503A Ubc.Fluc. AAV x mTfR AF11-13 with no anti-AAV arm did not bind (Figure 20). Example 9. Retargeting AAV9W503A using mTfR alternative format (AF) antibodies on 293T cells Expressing mTfR receptor
[00900] The present Example tested retargeting of AAV9W503A using mouse TfR (mTfR) alternative format antibodies (see, e.g., Figures 18A-18B, Figures 29A-29I and Table 30) on 293T cells expressing the mTfR receptor. A schematic diagram of an example experimental setup used in this Example is shown in Figure 21. Briefly, AAV9W503A was diluted in 1xPBS+0.001% Pluronic. For the virus, the multiplicity of infection (MOI) was 1x105 per well and the total vector genomes (VGs) was 1x109 per well. Alternative format antibodies were diluted in 1XPBS and 4-fold serial dilutions were performed to attain various AAV:Antibody ratios from a starting AAV:Antibody ratio of 1 :10,0000. For AF8 (see, e.g., Figures 18A-18B), the starting AAV:Antibody ratio was 1 :7750 (low stock concentration). The virus and the antibodies were mixed and incubated for 1 hour at 37°C. The Virus:Antibody complex was then added to the 293T cells expressing the mTfR receptor and incubated for 72 hours at 37°C. After the 72-hour incubation period, a Firefly luciferase (FLuc) read-out protocol was performed to measure the luciferase signal.
[00901] For the FLuc assay read-out protocol, the plate was spun at 1500 RPM for 1 minute and then the supernatant was discarded. 50 pl lysis buffer was added per well (Gio- Lysis, Promega E2661) for 5 minutes. Then, 100 pl luciferase substrate was added per well and incubated for approximately 1 minute. The plate was analyzed using PerkinElmer2030 (or SpectraMax) with a setting selection of “Luminescence Corning Black Clear Bottom”. The wells to be read and measured were selected and following the reading/measurement, data were exported. The AAV9W503A background value was 0. The results showed that AAV x mTfR alternative format (AF) antibodies with anti-AAV NGS/MS #70 retarget AAV9W503A at low ratios and have higher peak when compared to AAV x mTfR AF Abs w/ anti-AAV NGS/MS #64 (Figure 22). A correlation between the above described ELISA data (see, e.g., Example 8) and the retargeting assay data of the present example revealed consistency between the ELISA and retargeting assay data in terms of binding and retargeting across all AAV x mTfR alternative format antibodies tested (Figures 20, 22). AAV x mTfR alternative format antibodies with NGS/MS#70 bind better and retarget AAV9W503A at lower ratios as compared to AAV x mTfR alternative format antibodies with NGS/MS#64.
Example 10. Retargeting assay using AAV9 and an eGFP reporter
[00902] The present Example tested retargeting of AAV9 using mouse TfR (mTfR) alternative format antibodies AF1 and AF7 (see, e.g., Figures 18A-18B and Table 30) on 293T cells expressing the mTfR receptor. Briefly, AAV9 was diluted in 1xPBS+0.001% Pluronic. For the virus, the multiplicity of infection (MOI) was 1x106 per well unless otherwise indicated. Alternative format antibodies were diluted in 1XPBS and 3-fold serial dilutions were performed to attain various AAV:Antibody ratios from a starting AAV:Antibody ratio of 1 :729. The virus and the antibodies were mixed and incubated for 1 hour at 37°C. The AAV:Antibody complex was then added to the 293T cells expressing the mTfR receptor and incubated for 72 hours at 37°C. After the 72-hour incubation period, a GFP read-out protocol was performed to measure fluorescence.
[00903] To prepare samples for flow cytometry, supplemented media was discarded, and cells were washed once with 100 L 1xPBS. Afterwards, cells were lifted by adding 50 pL of TrypLE™ Select Enzyme (1X), no phenol red, and incubated for 4-5 minutes in 37°C. 100 pL of BD Pharmingen™ Stain Buffer (BSA) was then added and cells resuspended and then transferred to a clear V-bottom 96 well plate. Cells were spun down for 2 minutes at 800xg and the supernatant was discarded. Two extra rounds of washes were performed by adding 100 pL of BSA Stain Buffer and spun down for 2 minutes at 800xg. After the last wash, 100 pL of BSA Stain Buffer was added and cells were resuspended in preparation for Flow Cytometry analysis. GFP expression was measured using the ZE5 Cell Analyzer.
[00904] AAV9 was effectively retargeted with AF1 and AF7 at ratios 1 AAV:0.3 antibodies to 1 AAV:27 antibodies and performed similarly to AAV9 or AAV9W503A conjugated to an anti-mTfRc ScFv as assessed by %GFP positive cells (Figure 23A and 23B) or MFI of GFP fluorescence (Figure 23C).
Example 11. In vivo retargeting of AAV9 using AAV x mTfR alternative format antibodies
[00905] The present Example tested in vivo retargeting of AAV9 using various AAV x mTfR alternative format antibodies, specifically AF1 , AF3, AF5, AF7 and AF9. The experimental groups consisted of groups 1-3 (AF1), groups 4-6 (AF3), groups 7-9 (AF5), groups 10-12 (AF7), and groups 13-15 (AF9). The AAV x mTfR alternative format antibodies in the experimental groups were complexed with a self-complementary AAV9 encoding eGFP under a hybrid chicken b-actin (CBh) promoter (AAV9 scCBH.eGFP). Each alternative format was tested at three VG to Ab ratios: 1 :9, 1 : 3, and 1 :1. The control groups consisted of groups 16-18 (AAV9 scCBH.eGFP, AAV9 1/8 a-TfRC scCBH.eGFP, and AAV9W503A 1/8 a-TfRC scFv scCBH.eGFP) and a 1xPBS control group 19. The AAV concentration used in groups 1-18 was 5x1011 vg/mL. Three mice were used in each of groups 1-15,17 and 18, two mice were used in group 16, and one in group 19.
[00906] On Day 0, 200 pL test sample was injected to the mice. 24 hours after the injection, blood samples were collected from the mice for quantitative PCR (qPCR) analyses. In week 5, animals were sacrificed and brain and liver samples were collected for eGFP staining and Taqman qPCR analysis. Figures 24A-24B show in vitro test infection results for in vivo injection samples. [00907] Fortissue staining, brain (left hemisphere) and liver (left lobe) were collected and fixed in 10% neutral buffered formalin (NBF) for approximately 24 hours before being transferred to 70% EtOH for storage until embedding and sectioning.
[00908] Each tissue sample from each individual mouse was embedded into a separate paraffin block, then sectioned and stained using the methods outlined in Table 28.
Table 28. Description of Staining Protocol
[00909] For the liver, the Abeam rabbit green fluorescent protein (GFP) antibody staining protocol comprised a rabbit monoclonal antibody [EPR14104] to GFP (Abeam, Cat# ab183734) as a primary antibody and a goat anti-rabbit biotinylated antibody as a secondary antibody (Vector Labs, Cat# BA-1000). For the brain, the Invitrogen GFP antibody staining protocol comprised an anti-green fluorescent protein (GFP) rabbit IgG Fraction (anti-GFP IgG) (2 mg/ml; Invitrogen, Cat# A11122) as a primary antibody and a goat anti-rabbit biotinylated antibody (Vector Labs, Cat# BA-1000) as a secondary antibody. GFP staining of liver and brain are shown for AAV x mTfR control groups 16-19 (AAV9 scCBH.eGFP, AAV9 1/8 a-TfRC scCBH.eGFP, and AAV9W503A 1/8 a-TfRC scFv scCBH.eGFP) in Figure 25A. Also shown are GFP staining of liver and brain for AAV x mTfR AF1 (Figure 25B), AAV x mTfR AF3 (Figure 25C), AAV x mTfR AF5 (Figure 25D), AAV x mTfR AF7 (Figure 25E), and AAV x mTfR AF9 (Figure 25F). All alternative format antibodies were effectively able to retarget AAV to Cerebellum, Cortex, and Hippocampus with superiority to AAV9 alone and similar efficacy to AAV9 or AAV9W503A covalently conjugated to an anti-TFRc ScFv.
[00910] Transduction was also assessed by TaqMan qPCR of GFP mRNA expression in Liver (Figure 26) and Brain (Figure 27). Consistent with immunohistochemistry data, AAV complexed with AFs more effectively transduced the CNS than AAV9 alone. At low antibody ratios (1 :1 and 1 :3), comparable liver transduction was seen to AAV9 alone. There was a partial reduction in liver transduction at a ratio of 1 :9 for alternative format complexed AAVs.
Example 12. In vivo retargeting of AAV9 versus AAV9W503A using AAV x mTfR alternative format antibodies
[00911] The present Example tested in vivo retargeting of AAV9 versus AAV9W503A using AAV x mTfR alternative format antibodies. A goal of the experiments described herein was to test AAV x mTfR alternative format antibody AF7 on wild-type (WT) and detargeted AAV9 across a wide range of virus vector genome (VG) to antibody (Ab) ratios (VG:Ab). The experimental groups consisted of groups 1-6 (AAV9 scCBH.eGFP), and groups 8-13 (AAV9W503A scCBH.eGFP). Each virus was tested at six VG to Ab ratios: 1 :729, 1 : 243, 1 :81 , 1 :27, 1 :9, and 1 :3. The control groups consisted of groups 7, 14, and 15 (AAV9 scCBH.eGFP, AAV9W503A scCBH.eGFP, and AAV9 1/8 a-TfRC scFv scCBH.eGFP) and a 1xPBS control group 16. The total AAV concentration used in groups 1-15 was 1x1011 vg/mouse. Three mice were used in each of groups 1-5, 7, 8-12 and 16 and five in each of groups 6 and 13-15.
[00912] On Day 0, 200 pL test sample was injected to the mice. 24 hours after the injection, blood samples were collected from the mice for quantitative PCR (qPCR) analyses. In weeks 2-4, animals were sacrificed and brain, liver, and heart samples were collected for eGFP staining and Taqman qPCR analysis.
[00913]
[00914] Fortissue staining, brain (left hemisphere), liver (left lobe), and heart were collected and fixed in 10% neutral buffered formalin (NBF) for approximately 24 hours before being transferred to 70% EtOH for storage until embedding and sectioning.
[00915] Each tissue sample from each individual mouse was embedded into a separate paraffin block, then sectioned and stained using the methods outlined in Table 29.
Table 29. Description of Staining Protocol
[00916] For the liver and heart, the Abeam rabbit green fluorescent protein (GFP) antibody staining protocol comprised a rabbit monoclonal antibody [EPR14104] to GFP (Abeam, Cat# ab183734) as a primary antibody and a goat anti-rabbit biotinylated antibody as a secondary antibody (Vector Labs, Cat# BA-1000). For the brain, the Invitrogen GFP antibody staining protocol comprised an anti-green fluorescent protein (GFP) rabbit IgG Fraction (anti-GFP IgG) (2 mg/ml; Invitrogen, Cat# A11122) as a primary antibody and a goat anti-rabbit biotinylated antibody (Vector Labs, Cat# BA-1000) as a secondary antibody. GFP staining of liver, heart, and brain are shown for AAV9-AAV x mTfR AF7 in Figures 28A-28D.
[00917] When complexed with AF7, both AAV9 (Figures 28A and 28B) and AAV9W503A (Figures 28C and 28D) can effectively transduce the CNS as determined by GFP expression in Hippocampus, Cortex, and Cerebellum (Figures 28A and 28C). AF7 complexed with AAV9 retains liver and heart transduction (Figure 28B), but AAV9 W503A: AF7 complexes are detargeted from both heart and liver (Figure 28D). Optimal CNS transduction efficiency was observed at ratios 1 AAV: 3 antibodies and 1 AAV to 9 antibodies. Together, these data demonstrate AAV can be effectively retargeted to CNS using bispecific antibodies.
Example 13. In vivo retargeting to skeletal muscle with CACNGIxAAV bispecific antibodies
[00918] AAV x CACNG1 bispecific antibodies were validated for retargeting of Hu37 in vitro on HEK 293 cells overexpressing mouse or human CACNG1 (Figure 31). GFP expression was assessed by flow cytometry and is shown as % GFP positive cells (top panels) or MFI of GFP expressing cells (bottom panels). To assess the in vivo retargeting efficacy of AAV x CACNG1 bispecific antibodies, transduction efficiency of AAV and antibody complexes was quantified in a mouse model of Duchenne muscular dystrophy (D2.MDX mice). D2.MDX mice contain a premature stop codon mutation in the dystrophin gene that results in loss of dystrophin expression and development of muscular dystrophy. Hu37 or AAV9 W503A expressing eGFP from CAG promoter and appropriate ratio of antibody (AF71) were mixed, followed by incubation for 1 hour at 37°C. D2.MDX mice were then retro-orbitally injected with 150 L (1 E 11 total VGs) of virus+antibody complexes and Spytagged-AAV9 conjugated with CACNG1 antibody was used as a positive control (Figure 32). Liver, skeletal, and cardiac muscles were harvested at week 3. All the tissues were processed for immunohistochemistry to measure eGFP protein levels and for taqman analysis to measure RNA levels. As a quality control, on mouse injection day, the same virus+antibody complexes and control virus were added to HEK293 cells overexpressing hCACNGI at different MOI; cells were analyzed by flow for eGFP expression three day post-transduction (Figure 33). HEK 293 cells overexpressing human CACNG1 (hCACNGI) were transduced with Hu37 alone (group 2). However, transduction was enhanced when Hu37 was complexed with AF71 at molar ratio 1 :1 , 1:3, and 1 :9 (groups 3, 4, and 5, respectively) with a minimum transduction efficiency of 76.8% at MOI 2.5E4 VG per cell. A similar pattern was observed when MOI was increased 10-fold to 2.5E5 VG per cell. As a positive control, HEK 293 cells overexpressing human CACNG1 (hCACNGI) were transduced with Spytagged- AAV9 conjugated with CACNG1 spycatcher antibody REGN10717 (group 1) and AAV9 W503A complexed with AF71 (Group 6) (Figure 33). GFP IHC data at week 3 post- AAV+antibody complex injection exhibited GFP staining, indicative of Hu37 transgene expression/retargeting to various skeletal muscles - diaphragm, tongue and tibialis anterior (Figure 34A), gastrocnemius and soleus (Figure 34B), and quadriceps (Figure 34C) of D2.MDX mice with AAVxCACNGI altibody (i.e., alternative antibody format) AF71 at a variety of virus:antibody ratios (1 :1 , 1 :3, and 1:9). Hu37 virus alone transduced the heart and transduction remained when complexing the virus with AF71 (Figure 34B). Control viruses with AAV9 background (Spytagged-AAV9 conjugated with CACNG1 spycatcher antibody REGN 10717 and AAV9 W503A complexed with AF71 at virus:antibody ratio of 1 :3) transduced skeletal muscles - diaphragm, tongue and tibialis anterior (Figure 34A), gastrocnemius and soleus (Figure 34B), and quadriceps (Figure 34C). Overall, liver transduction was at a minimum or is not observed by GFP IHC in all conditions tested (Figure 34C) in D2.MDX mice. eGFP mRNA level is shown in various organs (liver and heart (Figure 35A); skeletal muscles such as gastrocnemius, quadriceps, diaphragm, soleus, tibialis anterior, and tongue (Figure 35B)). In each bar graph, GFP mRNA level of each condition was compared in relative to Hu37 1 :0 condition. In the livers (Figure 35A) in all conditions (Hu37 complexed with AF71 and control viruses in AAV9 background), the level of GFP mRNA were lower when compared with Hu37 1 :0 condition. In the hearts (Figure 35A), as the ratio increased from 1 :1 to 1:9, the level of GFP mRNA decreased and the level of GFP mRNA were lower than Hu37 1 :0 condition. Overall in skeletal muscles (Figure 35B), compared to Hu37 1 :0 condition, the GFP mRNA level was 3.82-fold to 142.55-fold higher when Hu37 was complexed with AF71 at ratio virus:antibody 1 :1 , 1 :3, and 1 :9. Also in skeletal muscles, the GFP mRNA level with control viruses in AAV9 background (Spytagged-AAV9 conjugated with CACNG1 spycatcher antibody REGN10717 and AAV9 W503A complexed with AF71 at virus:antibody ratio 1 :3) was at least 29.99-fold higher compared to Hu37 1 :0 condition. AF71 with two anti-AAV binding arm and two anti- CACNG1 arm enhanced Hu37 transduction in skeletal muscles in D2.MDX mice. Hu37 alone has a baseline transduction in cardiac and skeletal muscle. When complexed with AF71 , transduction in skeletal muscles was significantly improved as revealed by IHC and taqman results. However, the total transduction level of complexed Hu37 was lower compared to complexed AAV9-W503A or spytagged-AAV controls. Example 14. Comparison of AAV2 HBM retargeting using a high and low affinity AF Ab
[00919] Detargeted AAV2 (AAV2 HBM) expressing FLuc from UBC promoter and appropriate ratio of antibody (AF30, AF32) were mixed, followed by incubation for 1 hour at 37°C. hASGRI expressing (7303KO) female mice were then retro-orbitally injected with 200 pL (1 E10 total VGs) of virus+antibody complexes. IVIS imaging was then performed at Week 6 on excised livers (Figures 37A-37B). Quantitation of radiance at week 6 post- AAV+antibody complex injection indicates AAV2 HBM transgene expression and retargeting to livers of hASGRI mice with AAVxASGRI altibodies at a range of virus:antibody ratios. For the high anti-AAV affinity AF30 (REGN16204) (Figure 37A), maximum signal was seen at a ratio of 1 :9, whereas the low anti-AAV affinity AF32 altibody (Figure 37B) required an increased amount of antibody for peak transduction (1 :900). These data illustrate antibodies with different anti-AAV arms can achieve comparable AAV retargeting under optimal conditions for each binding arm. Both AF30 (REGN16204) with high affinity AAV arm and AF32 (REGN 16202) with low affinity AAV arm can retarget the AAV to the liver.
Example 15. Comparing retargeting efficacy of different detargeted AAV variants [00920] Ubc fLuc-expressing viruses (AAV2 HBM, AAV9 W503A, AAV6 N500E, AAV8.2) and appropriate ratio of antibody (AF30) were mixed, followed by incubation for 1 hour at 37°C. hASGRI mice (7303KO) and control (50500) female mice were then retro-orbitally injected with 200 pL (1 E10 total VGs) of virus+antibody complexes. IVIS imaging was then performed at Week 6 on excised livers (Figure 38). Quantitation of radiance at week 6 post- AAV+antibody complex indicates AAV2 HBM, AAV9 W503A, AAV8.2, and AAV6 N500E transgene expression/retargeting to livers of hASGRI mice and background control mice with AAVxASGRI altibody AF30 (REGN16204) at a variety of virus:antibody ratios. All serotypes were effectively and similarly retargeted with peak transduction at a ratio of 1 :3. The same cross-serotype binding antibody, AF30 (REGN16204), can effectively retarget different serotypes to liver with comparable efficacy.
Example 16. Comparing retargeting efficacy of bispecific antibodies and examining circulating AAV via PK qPCR
[00921] Ubc fLuc-expressing virus (AAV2 HBM) and appropriate ratio of antibody (REGN16210, REGN13136) were mixed, followed by incubation for 1 hour at 37°C. hASGRI mice (7303KQ) and control (50500) female mice were then retro-orbitally injected with 200 pL (1E10 total VGs) of virus+antibody complexes. Mice were bled at 24 hours post-injection for PK analysis. IVIS imaging was then performed at Week 3 on excised livers (Figures 39A-39D). Quantitation of radiance at week-3 post-AAV+antibody complex injection indicates AAV2 HBM transgene expression/retargeting to livers of hASGRI & background control mice with AAVxASGRI altibody REGN16210 (AF29) and AAVxASGRI bispecific REGN13136 at a variety of virus:antibody ratios. Decreased quantities of bivalent anti-AAV altibody were required for peak transduction compared to monovalent anti-AAV bispecific antibody (Figure 39A). Control mice demonstrated minimal background signal (Figure 39B). PK serum analysis at 24-hour bleed demonstrated clearance of AAV from serum when incubated with increasing amounts of both altibody and bispecific antibody (Figure 39C). Reduction in circulating AAV was consistent with decreased transgene expression within livers of hASGRI mice. Control mice exhibited reduced levels of AAV clearance in comparison (Figure 39D). At higher concentrations of antibody, a decrease in efficacy was observed. This corresponded to a decrease in serum concentration of AAV at 24 hours. This phenomenon was observed in both mice expressing hASGRI or control mice, although it was only seen at the highest antibody ratios for control mice. These data suggest both mechanisms of target dependent and independent clearance. Both REGN13136 with one AAV and one ASGR arms and REGN16210 (AF29) with two AAV and one ASGR arms can retarget AAV to the liver. Both molecules when complexed with AAV were cleared from the system at high AAV-Ab ratio but they were cleared at a different rate.
Example 17. Comparing efficacy of pre-dosing antibody prior to AAV administration [00922] This study was split into two methods by which AAV and antibody were delivered. For one set of conditions, Ubc fLuc-expressing virus (AAV2 HBM) and appropriate ratio of antibody (REGN16210, AF29) were mixed, followed by incubation for 1 hour at 37°C. hASGRI mice (7303KO) female mice were then retro-orbitally injected with 200 pL (1 E10 total VGs) of virus+antibody complexes. For the other set of conditions, differing doses of antibody were injected retro-orbitally, followed by AAV administration 24 hours later. Mice were bled at 24 hours post-injection for PK & serum antibody analysis. Antibody concentration was determined in serum at time of dosing (ELISA) and virus clearance was assessed at 24 hours post dosing via PK qPCR. IVIS imaging was then performed at Week 4 on excised livers (Figures 40A-40C). Quantitation of radiance at week-4 post AAV+antibody complex or antibody pre-dose injection indicates AAV2 HBM transgene expression/retargeting to livers of hASGRI mice with AAVxASGRI altibody REGN16210 (AF29) at a variety of virus:antibody ratios. At concentrations tested, pre-complexed AAV-Ab samples demonstrated greater peak transduction when compared to antibody pre-dosing (Figure 40A). PK serum analysis at 24-hour bleed demonstrated increased clearance of AAV when pre-complexed with retargeting altibody when compared to serum clearance with antibody pre-dosing (Figure 40B). ELISA data confirmed presence of circulating antibody in serum at 24 hours. Increased presence of circulating antibody was witnessed under pre- dosing conditions when compared to pre-complexed AAV-Ab (Figure 40C). Data points at lower concentrations were below the limit of detection. Effective transduction was achieved when administering antibody in advance of AAV. These data indicate that antibody:AAV complexes formed in circulation and without pre-complexation. The results indicated that Mice can retarget AAV to the liver. AAV-Ab complexation methods can be adjusted to therapeutic needs.
Example 18. AAV x ASGR1 Fab’2 clearance evaluation
[00923] Ubc fLuc-expressing virus (AAV2 HBM) and appropriate ratio of antibody (REGN16199, REGN16199-AFC) were mixed, followed by incubation for 1 hour at 37°C. hASGRI (7303KO) female mice were then retro-orbitally injected with 200 pL (1 E10 total VGs) of virus+antibody complexes. Mice were bled at 24 hours post-injection for PK analysis. IVIS imaging was then performed at Week 3 on excised livers (Figures 41A-41B). Quantitation of radiance at week-3 post-AAV+antibody complex injection indicates AAV2 HBM transgene expression/retargeting to livers of hASGRI mice with REGN16199 (AF21) and REGN16199-AFc at a variety of virus:antibody ratios. The graph shows that REGN16199 (AF21), when complexed with AAV2 HBM at 1 :3 virus:antibody ratio, enhanced the transduction efficiency of the virus in liver while all the other virus:antibody ratios dropped to background level. As forthe REGN16199-AFc, the highest transduction efficiency was observed also at the 1 :3 virus:antibody ratio while other ratios dropped to lower levels. When comparing the two molecules, it was found that that AAV2 HBM transduced liver cells better at 1 :3 virus:antibody ratios with a slight advantage for the REGN16199-AFC molecules. However, unlike REGN16199 (AF21) where transduction at ratios 1:9-1:2187 dropped to background level, REGN16199-AFC ratios 1 :9-1 :2187 dropped slightly and maintained a constant level of transduction (Figure 41 A). PK serum analysis at 24-hour bleed demonstrated clearance of AAV from serum when incubated with increasing amounts of both REGN16199 (AF21) and REGN16199-AFC antibodies. Reduction in circulating AAV was consistent with decreased transgene expression within livers of hASGRI mice (Figure 41B). REGN16199-AFC generated from REGN16199 (AF21) was effective for AAV retargeting and, unlike the parental REGN16199 (AF21), retained some transduction efficacy at higher antibody concentrations. This demonstrated a unique quality of the AFc antibody.
Example 19. AAV x ASGR1 Fab’2 vs. linear Fab retargeting and clearance evaluation.
[00924] Ubc fLuc-expressing virus (AAV2 HBM) and appropriate ratio of antibody (REGN16199-AFC and AF63) were mixed, followed by incubation for 1 hour at 37°C. hASGRI (7303KO) female mice were then retro-orbitally injected with 200 L (1 E10 total VGs) of virus+antibody complexes. Mice were bled at 24 hours post-injection for PK analysis. MS imaging was then performed at Week 3 on excised livers and Taqman analysis was performed to measure RNA levels in the liver (Figures 42A-42F). Quantitation of radiance at week-3 post-AAV+antibody complex injection indicates AAV2 HBM transgene expression/retargeting to livers of hASGRI and background control mice with REGN16199- AFc and AF63 at a variety of virus:antibody ratios. For hASGRI mice, both antibodies had a similar impact on AAV2 HBM liver transduction efficiency with a slight difference at higher virus:antibody ratios (Fab’2 antibody had a better retargeting efficacy at high ratios compared to linear fab) (Figure 42A). On the other hand, background control mice showed a similar trend for both antibodies across all virus:antibody ratios (Figure 42B). PK serum analysis at 24-hour bleed demonstrated clearance of AAV from serum when incubated with increasing amounts of both REGN16199-AFC and AF63 antibodies. The clearance of AAV in hASGRI mice started at low ratios slightly at 1 :4.7 virus:antibody ratio and increased more clearly at 1 :14 and higher virus:antibody ratio (Figure 42C) while AAV clearance in background control mice started at 1 :42 virus:antibody ratio and dropped to background levels at the higher ratios (Figure 42D). RNA Taqman data exhibited the measurement of RNA molecules in liver tissue for the different virus:antibody complexes compared to the RNA molecules in liver tissue of mice injected with AAV2 HBM only. The graphs showed similar RNA levels for both antibodies at low ratios and the levels started to decrease starting at 1 :42 virus:antibody ratio. However, the drop in RNA levels for AF63 (Figure 42F) was much bigger at higher ratios compared to the high virus:antibody ratios of REGN16199- AFc (Figure 42E). AF63 are functional for retargeting and at low antibody concentrations can achieve similar efficacy to REGN16199-AFc.
Example 20. Measuring AAV-Antibody Complex Clearance Based on Antibody Molecules
[00925] CAG eGFP-expressing virus (AAV2 HBM) was mixed with each of the following antibodies (REGN13880, AF62, AF63, REGN16203-AFC, REGN13136, REGN16199-AFC, and REGN16199) separately at a fixed ratio (1 :2187), followed by incubation for 1 hour at 37°C. Control mice (50500) female mice were then retro-orbitally injected with 200 pL (1 E10 total VGs) of virus+antibody complexes. Mice were bled at 24 hours post-injection for PK analysis (Figure 43). PK serum analysis at 24-hour bleed demonstrated increased clearance of AAV when pre-complexed with retargeting altibody with mass greater than 100kDa (AF63, REGN13136, REGN16199-AFC, and REGN16199). AAV clearance was reduced when precomplexed with retargeting altibody with mass less than 100kDa (REGN13880, AF62, and REGN16203-AFc). These data demonstrate that the mass of retargeting antibodies is associated with clearance of AAV from serum. Reduced serum concentrations were not observed for REGN13880, AF62, and REGN16203-AFC. This pattern indicates complexes made with antibodies <100kDa do not result in target independent clearance of AAV from circulation.
Example 21. Retargeting antibodies with two arms against ASGR1
[00926] Ubc fLuc-expressing virus (AAV2 HBM) and antibody (AF29, AF37, AF41 , AF61 A, and AF60A) were mixed at ratio 1 :1 , 1 :3, 1 :9, and 1 :27 (for AF29, only ratio 1 :1 , 1 :3, and 1 :9 were included), followed by incubation for 1 hour at 37°C. hASGRI mice (7303KO) female mice were then retro-orbitally injected with 200 pL (1 E10 total VGs) of virus+antibody complexes. MS imaging was then performed at Week 3 on excised livers (Figure 44). Quantification of radiance at week 3 post-AAV+antibody complex injection indicates AAV2 HBM transgene expression/retargeting to livers of hASGRI mice with AAVxASGRI altibodies at a variety of virus:antibody ratios. For AF29, AF37, AF41, and AF61A, liver transduction was observed at ratios 1 :1 , 1 :3, and 1 :9. For AF60A, in addition to the previous ratios, transduction was also observed at 1 :27. Altibodies bivalent for both AAV and ASGR1 are effective for retargeting. Retargeting antibodies with two arms against ASGR1 (e.g., AF37, AF41) perform with similar efficacy to antibodies with one arm against ASGR1 (e.g., AF29). These data demonstrate that a variety of different antibody formats can effectively be used for retargeting.
Example 22. Retargeting antibodies with single anti-AAV binding arm, single anti- ASGR binding arm, and no Fc
[00927] Ubc fLuc-expressing virus (AAV2 HBM) and antibody (AF29, AF62, and REGN16203-AFC) were mixed at ratio 1 :9, 1 :27, 1 :81 , 1 :243, 1 :729, and 1 :2187 (forAF29, only ratio 1 :3 was included), followed by incubation for 1 hour at 37°C. hASGRI mice (7303KO) female mice were then retro-orbitally injected with 200 pL (1E10 total VGs) of virus+antibody complexes. I VIS imaging was then performed at Week 3 on excised livers (Figure 45). Quantification of radiance at week 3 post-AAV+antibody complex injection indicates AAV2 HBM transgene expression/retargeting to livers of hASGRI mice with AAVxASGRI altibodies at a variety of virus:antibody ratios. For both AF62 and REGN16203- AFc, maximum signal was shown at a ratio of 1 :81. Both AF62 and REGN16203-AFC with single anti-AAV binding arm, single anti-ASGR binding arm, and without Fc portion are functional for retargeting.
[00928] The following methods were used in the Examples herein.
[00929] Reagents used include D. Luciferin, firefly potassium salt, Cat #122799-10 (Perkin Elmer). [00930] Antibodies used include AF30 (REGN16204, lgG1), REGN16210 (AF29, lgG4US, TP/PMPD), REGN16199 (AF21 , lgG1), REGN19199-AFC, AF63 (linear Fab with two AAV and one ASGR arm), and AF62 (linear Fab with one AAV and one ASGR arm) (see, e.g., Figures 36A-36B).
[00931] Mouse strains used include 7303 (MAID ID for humanized ASGR mice, same for mixed and BI6 background) and control mice 50500 (littermate).
[00932] The overall in vivo setup included the following steps. Detargeted AAVs were incubated with a range of AAV x ’’Target” antibody concentrations at 37°C for 1 hour. Mice (hASGRI , control mice) were then retro-orbitally injected with 200 pL of AAV:Ab complexes. After the specified amount of weeks, mice were injected subcutaneously with D. Luciferin (#122799-10, Perkin Elmer) and IVIS (In Vivo Imaging Instrument, Perkin Elmer) was ran to examine radiance indicative of AAV transgene expression in the livers.
[00933] Additional antibody description is provided herein.
[00934] AFc alternative format descriptions. REGN16199-ZlFc was generated by treating REGN16199 (AF21) with protease specific for the removal of Fc from immunoglobulin. The desired REGN16199-ZFc was purified from the starting material and by-products using affinity capture chromatography followed by size exclusion chromatography. REGN16203- 21Fc was also generated using similar method.
[00935] REGN13136. REGN13136 comprises of anti-AAV#70 hlgG4US heavy chain and anti-ASGR 13383P2 hlgG4US heavy chain. REGN13136 was purified from the starting material using protein A column.
[00936] REGN13880. REGN13880 comprises of anti-AAV#70 Fab. REGN13880 was purified from the starting material using affinity capture chromatography followed by size exclusion chromatography.
[00937] AF62. AF62 comprises of anti-AAV#70 Fab fused with (G4S)4 linker (SEQ ID NO: 1161) and anti-ASGR 13383P2 Fab. AF62 was purified from the starting material using affinity capture chromatography followed by size exclusion chromatography.
[00938] AF63. AF63 comprises of anti-AAV#70 Fab fused with (G4S)4 linker (SEQ ID NO: 1161), followed by anti-ASGR 13383P2 Fab, another (G4S)4 linker (SEQ ID NO: 1161), and finally a second anti-AAV#70 Fab. AF63 was purified from the starting material using affinity capture chromatography followed by size exclusion chromatography.
[00939] REGN16199 (AF21). REGN16199 comprises of one heavy chain being anti- AAV#70 Fab fused with anti-ASGR 13383P2 hlgG 1 N280G Fc. The other heavy chain is anti-AAV#70 h IgG 1 N280G Fc. REGN16199 was purified from the starting material using protein A column. [00940] The present disclosure is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the disclosure in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.
Table 30: Listing of Example AAV x mTfR, AAV x CACNG1 , and AAV x ASGR Amino Acid and Nucleotide Sequences

Claims

Claims
What is claimed is:
1. An antibody, or an antigen-binding fragment thereof, wherein said antibody, or said antigen-binding fragment thereof, binds to a capsid of an adeno-associated virus (AAV) particle, and wherein said antibody, or said antigen-binding fragment thereof, comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1 159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
2. The antibody or antigen-binding fragment of claim 1 , wherein said antibody, or said antigen-binding fragment thereof, comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
3. The antibody or antigen-binding fragment of claim 2 or 3, wherein said antibody, or said antigen-binding fragment thereof, comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1 159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
4. An antibody, or an antigen-binding fragment thereof, wherein said antibody, or said antigen-binding fragment thereof, binds to a capsid of an adeno-associated virus (AAV) particle, wherein said antibody, or said antigen-binding fragment thereof, binds to one or more residues in one or more viral protein 3 (VP3) polypeptides in said capsid, wherein said one or more residues are selected from the residues listed in Tables 18- 26.
5. The antibody or antigen-binding fragment of claim 4, wherein said antibody, or said antigen-binding fragment thereof, binds to a capsid of an AAV2 particle comprising amino acid substitutions R585A and R588A, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): a) S264, A266, N268, H271 , N382, S384, Q385, G512, R487, D494, K527, D529, K532, L538, D533, E555, N705, K706, V708, T450, Q457, and R459; b) S264, G265, A266, S267, N268, H271 , N382, G383, S384, R487, K527, D528, E530, E574, Q575, K706, and S707; c) N254, L256, K258, I260, S261 , Q263, Y272, E322, V323, T324, Q325, A655, A667, S668, F669, I670, T671 , I332, Q545, G546, S547, E548, K556, N717, V719, T660, and F661 ; and/or d) N254, L256, Q263, S264, V323, T324, Q325, S655, A667, S668, F669, I670, T671 , G328, G546, E548, T716, and N717.
6. The antibody or antigen-binding fragment of claim 4, wherein said antibody, or said antigen-binding fragment thereof, binds to a capsid of an AAV8 particle, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): a) N255, L257, K259, 1261 , S262, N263, S266, A269, Y275, E325, V326, T327, Q328, A658, N670, S671 , F672, I673, T674, Q548, N549, A550, A551, D559, E720, and T663; and/or b) N255, L257, S266, E325, V326, T327, Q328, N670, S671, F672, I673, T674, N549, T719, and E720.
7. The antibody or antigen-binding fragment of claim 4, wherein said antibody, or said antigen-binding fragment thereof, binds to a capsid of an AAV9 particle, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): a) N254, I260, N262, Y274, E324, V325, T326, D327, N328, R550, D665, N668, S669, F670, 1671 , T672, Q546, G547, G549, E718, and A661 ; and/or b) N254, L256, I260, N262, E324, V325, T326, D551 , N668, S669, F670, T672, G330, and E718.
8. The antibody or antigen-binding fragment of any one of claims 4-7, wherein said antibody, or said antigen-binding fragment thereof, comprises:
1) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10;
2) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157;
3) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or
4) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
9. The antibody or antigen-binding fragment of claim 8, wherein said antibody, or said antigen-binding fragment thereof, comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
10. The antibody or antigen-binding fragment of claim 8 or 9, wherein said antibody, or said antigen-binding fragment thereof, comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
11. The antibody or antigen-binding fragment of any one of claims 1-10, wherein said antibody, or said antigen-binding fragment thereof, is a humanized antibody or antigen binding fragment thereof, human antibody or antigen binding fragment thereof, murine antibody or antigen binding fragment thereof, chimeric antibody or antigen binding fragment thereof, Fab fragment, F(ab')2 fragment, F(ab)'3 fragments, single-chain fragment variable (scFv), bis-scFv, (scFv)2, diabody, minibody, nanobody, triabody, tetrabody, disulfide stabilized Fv protein (dsFv), single-domain antibody (sdAb), Ig NAR, single heavy chain antibody, bispecific antibody, trispecific antibody, or chemically modified derivative thereof. The antibody or antigen-binding fragment of any one of claims 1-11 , wherein said antibody, or said antigen-binding fragment thereof, comprises an lgG1 , lgG2, lgG3, or lgG4 constant region, or a variant thereof. The antibody or antigen-binding fragment of claim 12, wherein said antibody, or said antigen-binding fragment thereof, comprises an lgG1 constant region, or a variant thereof. The antibody or antigen-binding fragment of claim 13, wherein the lgG1 constant region comprises the amino acid sequence of SEQ ID NO: 259 or 1164. The antibody or antigen-binding fragment of claim 12, wherein said antibody, or said antigen-binding fragment thereof, comprises an lgG4 constant region, or a variant thereof. The antibody or antigen-binding fragment of claim 15, wherein the lgG4 variant comprises a hinge domain modified to reduce binding to Fey receptors. The antibody or antigen-binding fragment of claim 16, wherein the lgG4 constant region comprises the amino acid sequence of SEQ ID NO: 261. The antibody or antigen-binding fragment of any one of claims 1-11 , wherein said antigen-binding fragment is a Fab fragment. The antibody or antigen-binding fragment of any one of claims 1-11 , wherein said antigen-binding fragment is an scFv fragment. The antibody or antigen-binding fragment of any one of claims 1-19, wherein said antibody, or said antigen-binding fragment thereof, binds to AAV2 with a dissociation constant (KD) of less than about 1.5 x 10‘6 M, as measured in a surface plasmon resonance assay. The antibody or antigen-binding fragment of claim 20, wherein said antibody, or said antigen-binding fragment thereof, binds to AAV2 with a dissociation constant (KD) of less than about 20 nM, as measured in a surface plasmon resonance assay.
22. The antibody or antigen-binding fragment of any one of claims 1-21 , wherein said capsid comprises one or more wild-type AAV capsid polypeptides.
23. The antibody or antigen-binding fragment of any one of claims 1-21 , wherein said capsid comprises one or more non-wild-type AAV capsid polypeptides.
24. The antibody or antigen-binding fragment of any one of claims 1-23, wherein binding of said antibody or antigen-binding fragment thereof to said AAV particle capsid does not neutralize said AAV particle.
25. An antibody, or an antigen-binding fragment thereof, that binds to the same epitope as the antibody or antigen-binding fragment of any one of claims 1-24.
26. An antibody, or an antigen-binding fragment thereof, that competes for binding to a capsid of an adeno-associated virus (AAV) particle with the antibody or antigen-binding fragment of any one of claims 1 -24.
27. A pharmaceutical composition comprising the antibody or antigen-binding fragment of any one of claims 1-26 and a pharmaceutically acceptable carrier or excipient.
28. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: i) a first antigen-binding domain that binds to a capsid of an adeno-associated virus (AAV) particle; and ii) a second antigen-binding arm that binds to a molecule on a cell surface, wherein said first antigen-binding domain comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
29. The multispecific antibody or multispecific antigen-binding fragment of claim 28, wherein said first antigen-binding domain comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
30. The multispecific antibody or multispecific antigen-binding fragment of claim 28 or 29, wherein said first antigen-binding domain comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
31. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: i) a first antigen-binding domain that binds to a capsid of an adeno-associated virus (AAV) particle, and ii) a second antigen-binding domain that binds to a molecule on a cell surface, wherein said first antigen-binding domain binds to one or more residues in one or more viral protein 3 (VP3) polypeptides in said capsid, wherein said one or more residues are selected from the residues listed in Tables 18-26.
32. The multispecific antibody or multispecific antigen-binding fragment of claim 31 , wherein said first antigen-binding domain binds to a capsid of an AAV2 particle comprising amino acid substitutions R585A and R588A, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): a) S264, A266, N268, H271 , N382, S384, Q385, G512, R487, D494, K527, K529, K532, L538, D533, E555, N705, K706, V708, T450, Q457, and R459; b) S264, G265, A266, S267, N268, H271 , N382, G383, S384, R487, K527, D528, E530, Q574, Q575, K706, and S707; c) N254, L256, K258, I260, S261 , Q263, Y272, E322, V323, T324, Q325, A655, A667, S668, F669, I670, T671 , I332, Q545, G546, S547, E548, K556, N717, V719, T660, and F661 ; and/or d) N254, L256, Q263, S264, V323, T324, Q325, S655, A667, S668, F669, I670, T671 , G328, G546, E548, T716, and N717.
33. The multispecific antibody or multispecific antigen-binding fragment of claim 31 , wherein said first antigen-binding domain binds to a capsid of an AAV8 particle, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): e) N255, L257, K259, 1261 , S262, N263, S266, A269, Y275, E325, V326, T327, Q328, A658, N670, S671 , F672, I673, T674, Q548, N549, A550, A551 , D559, E720, and T663; and/or f) N255, L257, S266, E325, V326, T327, Q328, N670, S671 , F672, I673, T674, N549, T719, and E720.
34. The multispecific antibody or multispecific antigen-binding fragment of claim 31 , wherein said first antigen-binding domain binds to a capsid of an AAV9 particle, and wherein the said one or more residues are selected from the following residues in said VP3 polypeptides (according to VP1 numbering): g) N254, I260, N262, Y274, E324, V325, T326, D327, N328, R550, D665, N668, S669, F670, 1671 , T672, Q546, G547, G549, E718, and A661 ; and/or h) N254, L256, I260, N262, E324, V325, T326, D551 , N668, S669, F670, T672, G330, and E718.
35. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 31-34, wherein the first antigen-binding domain comprises:
1) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10;
2) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157;
3) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or
4) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
36. The multispecific antibody or multispecific antigen-binding fragment of claim 35, wherein the first antigen-binding domain comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
37. The multispecific antibody or multispecific antigen-binding fragment of claim 35 or 36, wherein the first antigen-binding domain comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; or
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
38. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 28-37, wherein said molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
39. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 28-38, wherein said molecule on the cell surface is ASGR1 .
40. The multispecific antibody or multispecific antigen-binding fragment of claim 39, wherein said second antigen-binding domain that binds to ASGR1 comprises: a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
41 . The multispecific antibody or multispecific antigen-binding fragment of claim 39 or 40, wherein said second antigen-binding domain that binds to ASGR1 comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
42. The multispecific antibody or multispecific antigen-binding fragment thereof of any one of claims 39-41 , wherein said second antigen-binding domain that binds to ASGR1 comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
43. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 28-38, wherein said molecule on the cell surface is TfR.
44. The multispecific antibody or multispecific antigen-binding fragment of claim 43, wherein said second antigen-binding domain that binds to TfR comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid nu sequence of SEQ ID NO: 298;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
1 1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399; 13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 51 1 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
45. The multispecific antibody or multispecific antigen-binding fragment of claim 43 or 44, wherein said second antigen-binding domain that binds to TfR comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
21) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
22) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
23) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
24) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
25) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
26) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
27) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560; 28) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
29) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
30) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
31) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
32) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 61 1 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
33) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1 123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1 125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1 129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
46. The multispecific antibody or multispecific antigen-binding fragment thereof of any one of claims 43-45, wherein said second antigen-binding domain that binds to TfR comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485; 21) a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
47. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 28-38, wherein said molecule on the cell surface is CACNG1.
48. The multispecific antibody or multispecific antigen-binding fragment of claim 47, wherein said second antigen-binding domain that binds to CACNG1 comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
49. The multispecific antibody or multispecific antigen-binding fragment of claim 47 or 48, wherein said second antigen-binding domain that binds to CACNG1 comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889; 15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1 185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1 187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1 191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 121 1 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.
50. The multispecific antibody or multispecific antigen-binding fragment thereof of any one of claims 47-49, wherein said second antigen-binding domain that binds to CACNG1 comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
51. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1 ”); and c) a third polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); wherein ABD1 or ABD2 binds to a capsid of an adeno-associated virus (AAV) particle, and the other of ABD1 or ABD2 binds to a molecule on a cell surface.
52. The multispecific antibody or multispecific antigen-binding fragment of claim 51 , wherein ABD1 binds to a capsid of an adeno-associated virus (AAV) particle and ABD2 binds to a molecule on the cell surface.
53. The multispecific antibody or multispecific antigen-binding fragment of claim 51 , wherein ABD2 binds to a capsid of an adeno-associated virus (AAV) particle and ABD1 binds to a molecule on the cell surface.
54. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 51-53, wherein the first heavy chain region is linked to the second heavy chain region via a linker.
55. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) an Fc domain; b) a second polypeptide chain, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an Fc domain; and c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); wherein ABD1 or ABD2 binds to a capsid of an adeno-associated virus (AAV) particle, and the other of ABD1 or ABD2 binds to a molecule on a cell surface.
56. The multispecific antibody or multispecific antigen-binding fragment of claim 55, wherein ABD1 binds to a capsid of an adeno-associated virus (AAV) particle and ABD2 binds to a molecule on the cell surface.
57. The multispecific antibody or multispecific antigen-binding fragment of claim 55, wherein ABD2 binds to a capsid of an adeno-associated virus (AAV) particle and ABD1 binds to a molecule on the cell surface.
58. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 55-57, wherein the first scFv and/or the first heavy chain region is linked to the Fc domain via a linker.
59. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 51-58, wherein the ABD1 or ABD2 which binds to a capsid of an AAV particle comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1 159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
60. The multispecific antibody or multispecific antigen-binding fragment of claim 59, wherein the ABD1 or ABD2 which binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; and/or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
61 . The multispecific antibody or multispecific antigen-binding fragment of claim 59 or 60, wherein the ABD1 or ABD2 which binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1 159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
62. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 51-61 , wherein said molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
63. The multispecific antibody or multispecific antigen-binding fragment of claim 62, wherein said molecule on the cell surface is ASGR1 .
64. The multispecific antibody or multispecific antigen-binding fragment of claim 63, wherein the other of ABD1 or ABD2 which binds to ASGR1 comprises: a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
65. The multispecific antibody or multispecific antigen-binding fragment of claim 63 or 64, wherein the other of ABD1 or ABD2 which binds to ASGR1 comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
66. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 63-65, wherein the other of ABD1 or ABD2 which binds to ASGR1 comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
67. The multispecific antibody or multispecific antigen-binding fragment of claim 62, wherein said molecule on the cell surface is TfR.
68. The multispecific antibody or multispecific antigen-binding fragment of claim 67, wherein the other of ABD1 or ABD2 which binds to TfR comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
1 1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496; 22) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 51 1 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1 119, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
69. The multispecific antibody or multispecific antigen-binding fragment of claim 67 or 68, wherein the other of ABD1 or ABD2 which binds to TfR comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 31 1 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402; 13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
21) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
22) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
23) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
24) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
25) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
26) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
27) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
28) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
29) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
30) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
31) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
32) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 61 1 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
33) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1 123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1 125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1 129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
70. The multispecific antibody or multispecific antigen-binding fragment thereof of any one of claims 67-69, wherein the other of ABD1 or ABD2 which binds to TfR comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485; 21) a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ;
32) a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
71. The multispecific antibody or multispecific antigen-binding fragment of claim 62, wherein said molecule on the cell surface is CACNG1.
72. The multispecific antibody or multispecific antigen-binding fragment of claim 71 , wherein the other of ABD1 or ABD2 which binds to CACNG1 comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
73. The multispecific antibody or multispecific antigen-binding fragment of claim 71 or 72, wherein the other of ABD1 or ABD2 which binds to CACNG1 comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889; 15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1 185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1 187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1 191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 121 1 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.
74. The multispecific antibody or multispecific antigen-binding fragment thereof of any one of claims 71-73, wherein the other of ABD1 or ABD2 which binds to CACNG1 comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
75. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) an scFv comprising a first antigen-binding domain (“ABDI”) operably linked to (ii) a first heavy chain region of a first Fab (Tab1”), said first heavy chain region operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (Tab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2, and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
76. The multispecific antibody or multispecific antigen-binding fragment of claim 75, wherein two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
77. The multispecific antibody or multispecific antigen-binding fragment of claim 76, wherein ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
78. The multispecific antibody or multispecific antigen-binding fragment of claim 76, wherein ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
79. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 43-78, wherein the scFv is linked to the first heavy chain region via a linker.
80. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) an scFv comprising a first antigen-binding domain (“ABD1”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
81. The multispecific antibody or multispecific antigen-binding fragment of claim 80, wherein two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
82. The multispecific antibody or multispecific antigen-binding fragment of claim 81 , wherein ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
83. The multispecific antibody or multispecific antigen-binding fragment of claim 81 , wherein ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
84. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 80-83, wherein the scFv is linked to the Fc domain via a linker.
85. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”), said second heavy chain region of Fab2 operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (Tab3”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1 ”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); and e) a fifth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
86. The multispecific antibody or multispecific antigen-binding fragment of claim 85, wherein two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
87. The multispecific antibody or multispecific antigen-binding fragment of claim 86, wherein ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
88. The multispecific antibody or multispecific antigen-binding fragment of claim 86, wherein ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
89. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 85-88, wherein the first heavy chain region is linked to the second heavy chain region via a linker.
90. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (“Fab3”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1 ”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); and e) a fifth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
91. The multispecific antibody or multispecific antigen-binding fragment of claim 90, wherein two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
92. The multispecific antibody or multispecific antigen-binding fragment of claim 91 , wherein ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
93. The multispecific antibody or multispecific antigen-binding fragment of claim 91 , wherein ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface.
94. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 90-93, wherein the second heavy chain region is linked to the Fc domain via a linker.
95. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an scFv comprising a first antigen-binding domain (“ABD1 ”), said scFv operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
96. The multispecific antibody or multispecific antigen-binding fragment of claim 95, wherein two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
97. The multispecific antibody or multispecific antigen-binding fragment of claim 96, wherein ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
. The multispecific antibody or multispecific antigen-binding fragment of claim 96, wherein ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. . The multispecific antibody or multispecific antigen-binding fragment of any one of claims 95-98, wherein the scFv is linked to the first heavy chain region via a linker. 0. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) an scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a second antigen-binding domain (“ABD2”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD 1 , ABD2 and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface. 1. The multispecific antibody or multispecific antigen-binding fragment of claim 100, wherein two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface. 2. The multispecific antibody or multispecific antigen-binding fragment of claim 101 , wherein ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. 3. The multispecific antibody or multispecific antigen-binding fragment of claim 101 , wherein ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. 4. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 100-103, wherein the second heavy chain region is linked to the Fc domain via a linker.
105. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”), said second heavy chain region operably linked to (iii) a third heavy chain region of a third Fab (“Fab3”); b) a second polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1 ”); and c) a third polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ABD2”); d) a fourth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); wherein at least one of ABD1 , ABD2, and ABD3 binds to a capsid of an adeno-associated virus (AAV) particle, and the other(s) of ABD1 , ABD2 and ABD3 bind to a molecule on a cell surface.
106. The multispecific antibody or multispecific antigen-binding fragment of claim 105, wherein two of ABD1 , ABD2 and ABD3 bind to a capsid of an AAV particle, and one of ABD1 , ABD2 and ABD3 binds to a molecule on a cell surface.
107. The multispecific antibody or multispecific antigen-binding fragment of claim 106, wherein ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface.
108. The multispecific antibody or multispecific antigen-binding fragment of claim 106, wherein ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface.
109. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 105-108, wherein the first heavy chain region is operably linked to the second heavy chain region and/or the second heavy chain region is operably linked to the third heavy chain region via a linker.
1 10. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 75-109, wherein the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
111. The multispecific antibody or multispecific antigen-binding fragment of claim 110, wherein the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; and/or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
112. The multispecific antibody or multispecific antigen-binding fragment of claim 110 or 111 , wherein the at least one of ABD1 , ABD2 and ABD3 which binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
1 13. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 75-112, wherein said molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
1 14. The multispecific antibody or multispecific antigen-binding fragment of claim 113, wherein said molecule on the cell surface is ASGR1 .
1 15. The multispecific antibody or multispecific antigen-binding fragment of claim 114, wherein the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises: a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
1 16. The multispecific antibody or multispecific antigen-binding fragment of claim 114 or
1 15, wherein the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
1 17. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 1 14-1 16, wherein the other(s) of ABD1 , ABD2 and ABD3 which binds to ASGR1 comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
1 18. The multispecific antibody or multispecific antigen-binding fragment of claim 113, wherein said molecule on the cell surface is TfR.
1 19. The multispecific antibody or multispecific antigen-binding fragment of claim 118, wherein the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
1 1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419; 15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 51 1 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1 119, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
120. The multispecific antibody or multispecific antigen-binding fragment of claim 118 or 119, wherein the other(s) of ABD 1 , ABD2 and ABD3 which binds to TfR comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
21) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
22) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
23) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
24) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
25) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
26) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
27) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
28) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
29) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
30) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
31) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
32) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 61 1 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
33) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1 123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1 125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1 129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
121. The multispecific antibody or multispecific antigen-binding fragment thereof of any one of claims 1 18-120, wherein the other(s) of ABD1 , ABD2 and ABD3 which binds to TfR comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 526; 25) a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ;
32) a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
122. The multispecific antibody or multispecific antigen-binding fragment of claim 113, wherein said molecule on the cell surface is CACNG1.
123. The multispecific antibody or multispecific antigen-binding fragment of claim 122, wherein the other(s) of ABD1 , ABD2 and ABD3 which binds to CACNG1 comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
124. The multispecific antibody or multispecific antigen-binding fragment of claim 122 or 123, wherein the other(s) of ABD1 , ABD2 and ABD3 which binds to CACNG1 comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769; 9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1 185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1 187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1 191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 121 1 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.
125. The multispecific antibody or multispecific antigen-binding fragment thereof of any one of claims 122-124, wherein the other(s) of ABD1 , ABD2 and ABD3 which binds to
CACNG1 comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703; 6) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
126. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first scFv comprising a first antigen-binding domain (“ABD1”) operably linked to (ii) a first heavy chain region of a first Fab (“Fab1”), said first heavy chain region of Fab1 operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second scFv comprising a second antigen-binding domain (“ABD2”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”), said second heavy chain region of Fab2 operably linked to (iii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a third antigen-binding domain (“ABD3”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a fourth antigen-binding domain (“ABD4”); wherein at least one of ABD1 , ABD2, ABD3 and ABD4 binds to a capsid of an adeno- associated virus (AAV) particle, and the other(s) of ABD1 , ABD2, ABD3, and ABD4 bind to a molecule on a cell surface.
127. The multispecific antibody or multispecific antigen-binding fragment of claim 126, wherein two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface.
128. The multispecific antibody or multispecific antigen-binding fragment of claim 127, wherein ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 and ABD4 binds to a molecule on a cell surface.
129. The multispecific antibody or multispecific antigen-binding fragment of claim 127, wherein ABD3 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD2 binds to a molecule on a cell surface.
130. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 126-129, wherein the first scFv is linked to the first heavy chain region and/or the second scFv is linked to the second heavy chain region via a linker.
131. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1 ”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a first scFv comprising a first antigen-binding domain (“ABD1 ”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a second heavy chain region of a second Fab (“Fab2”) operably linked to (ii) an Fc domain, said Fc domain operably linked to (iii) a second scFv comprising a second antigen-binding domain (“ABD2”); c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a third antigen-binding domain (“ABD3”); and d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a fourth antigen-binding domain (“ABD4”); wherein at least one of ABD1 , ABD2, ABD3 and ABD4 binds to a capsid of an adeno- associated virus (AAV) particle, and the other(s) of ABD1 , ABD2, ABD3, and ABD4 bind to a molecule on a cell surface.
132. The multispecific antibody or multispecific antigen-binding fragment of claim 131 , wherein two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface.
133. The multispecific antibody or multispecific antigen-binding fragment of claim 132, wherein ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 and ABD4 binds to a molecule on a cell surface.
134. The multispecific antibody or multispecific antigen-binding fragment of claim 132, wherein ABD3 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD2 binds to a molecule on a cell surface.
135. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 131-134, wherein the first scFv and/or second scFv is linked to the Fc domain via a linker.
136. A multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation, (i) a first heavy chain region of a first Fab (“Fab1”) operably linked to (ii) a second heavy chain region of a second Fab (“Fab2”) operably linked to (iii) an Fc domain; b) a second polypeptide chain comprising, in an N- to C-terminal orientation, (i) a third heavy chain region of a third Fab (Tab3) operable liked to (ii) a fourth heavy chain region of a fourth Fab (“Fab4”) operably linked to (iii) an Fc domain; c) a third polypeptide chain comprising a first light chain that pairs with the first heavy chain region to form Fab1 , wherein Fab1 comprises a first antigen-binding domain (“ABD1”); d) a fourth polypeptide chain comprising a second light chain that pairs with the second heavy chain region to form Fab2, wherein Fab2 comprises a second antigen-binding domain (“ADB2”); e) a fifth polypeptide chain comprising a third light chain that pairs with the third heavy chain region to form Fab3, wherein Fab3 comprises a third antigen-binding domain (“ABD3”); and f) a sixth polypeptide chain comprising a fourth light chain that pairs with the fourth heavy chain region to form Fab4, wherein Fab 4 comprises a fourth antigen-binding domain (“ABD4”); wherein at least one of ABD1 , ABD2, ABD3 and ABD4 binds to a capsid of an adeno- associated virus (AAV) particle, and the other(s) of ABD1 , ABD2, ABD3, and ABD4 bind to a molecule on a cell surface.
137. The multispecific antibody or multispecific antigen-binding fragment of claim 136, wherein two of ABD1 , ABD2, ABD3, and ABD4 bind to a capsid of an AAV particle, and two of ABD1 , ABD2, ABD3 and ABD4 binds to a molecule on a cell surface.
138. The multispecific antibody or multispecific antigen-binding fragment of claim 137, wherein ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 and ABD4 binds to a molecule on a cell surface.
139. The multispecific antibody or multispecific antigen-binding fragment of claim 137, wherein ABD2 and ABD4 bind to a capsid of an AAV particle, and ABD1 and ABD3 binds to a molecule on a cell surface.
140. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 136-139, wherein the first heavy chain region is linked to the second heavy chain region and/or the third heavy chain region is linked to fourth heavy chain region via a linker.
141. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 126-140, wherein the at least one of ABD1 , ABD2, ABD3, and ABD4 which binds to a capsid of an AAV particle comprises: a) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1159, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; f) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a heavy chain variable region (HCVR) that comprises a HCDR1 , HCDR2, and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a light chain variable region (LCVR) that comprises a LCDR1 , LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
142. The multispecific antibody or multispecific antigen-binding fragment of claim 141 , wherein the at least one of ABD1 , ABD2, ABD3, and ABD4 which binds to a capsid of an AAV particle comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 28; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 83, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 85, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 93, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 97; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; and/or j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 103, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 107; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
143. The multispecific antibody or multispecific antigen-binding fragment of claim 141 or 142, wherein the at least one of ABD1 , ABD2, ABD3, and ABD4 which binds to a capsid of an AAV particle comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 2, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 22, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 32, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 42, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 52 or 1 159, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 62, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 71 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 81 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 91 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10; and/or j) a HCVR comprising the amino acid sequence of SEQ ID NO: 101 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
144. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 126-143, wherein said molecule on the cell surface is asialoglycoprotein receptor 1 (ASGR1), transferrin receptor (TfR), or calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1).
145. The multispecific antibody or multispecific antigen-binding fragment of claim 144, wherein said molecule on the cell surface is ASGR1 .
146. The multispecific antibody or multispecific antigen-binding fragment of claim 145, wherein the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to ASGR1 comprises: a) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157; or b) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
147. The multispecific antibody or multispecific antigen-binding fragment of claim 145 or 146, wherein the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to ASGR1 comprises: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 224, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 226; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 232, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 236; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
148. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 145-147, wherein the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to ASGR1 comprises: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 220 or 1239, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1 157; or b) a HCVR comprising the amino acid sequence of SEQ ID NO: 230, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
149. The multispecific antibody or multispecific antigen-binding fragment of claim 144, wherein said molecule on the cell surface is TfR.
150. The multispecific antibody or multispecific antigen-binding fragment of claim 149, wherein the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to TfR comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344; 8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
1 1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVRthat comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 51 1 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 567;
29) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599;
32) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1 119, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
151. The multispecific antibody or multispecific antigen-binding fragment of claim 149 or 150, wherein the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to TfR comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 272, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 273, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 274; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 277, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 279;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 283, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 285; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 288, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 289, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 290;
3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 294, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 295, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 299, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 300, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 301 ;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 304, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 305, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 306; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 310, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 311 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 312;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 315, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 316, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 317; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 321, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 322, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 323;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 327, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 328, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 329; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 333, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 334, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 335;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 339, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 340, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 341 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 345, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 346, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 347;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 351 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 352, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 353; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 357, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 358, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 359; 9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 362, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 363, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 364; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 367, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 369;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 373, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 375; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 378, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 379, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 380;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 383, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 384, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 385; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 388, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 389, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 390;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 394, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 395, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 396; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 400, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 401 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 402;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 405, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 406, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 407; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 410, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 411 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 412;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 415, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 416, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 417; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 420, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 421 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 422;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 426, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 427, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 428; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 432, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 433, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 434;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 437, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 438, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 439; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 442, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 443, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 444;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 448, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 449, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 450; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 453, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 454, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 455;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 458, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 459, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 460; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 463, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 464, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 465;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 469, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 470, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 471 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 475, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 476, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 477;
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 481 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 482, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 483; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 486, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 487, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 488;
21) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 492, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 493, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 494; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 497, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 498, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 499;
22) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 507, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 508, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 509;
23) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 517, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 519;
24) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 522, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 523, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 524; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 527, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 528, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 529;
25) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 537, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 538, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 539;
26) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 543, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 544, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 545; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 548, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 550;
27) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 558, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 559, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 560;
28) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 563, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 564, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 565; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 568, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 570;
29) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 573, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 574, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 575; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 578, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 579, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 580;
30) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 583, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 585; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 588, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 589, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 590;
31) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 594, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 595, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 596; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 600, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 601 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 602;
32) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 605, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 606, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 607; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 61 1 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 612, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 613; or
33) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 121 , a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1 123, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1 125; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1 129, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1131 , and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1133.
152. The multispecific antibody or multispecific antigen-binding fragment thereof of any one of claims 149-151 , wherein the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to TfR comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 270 or 271 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 276;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 281 or 282, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 287;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 292 or 293, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 298;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 303, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 308 or 309;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 314, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 319 or 320;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 325 or 326, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 331 or 332;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 337 or 338, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 343 or 344;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 349 or 350, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 355 or 356;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 361 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 366;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 371 or 372, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 377;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 382, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 387;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 392 or 393, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 398 or 399;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 404, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 409;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 414, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 419;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 424 or 425, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 430 or 431 ;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 436, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 441 ;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 446 or 447, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 452;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 457, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 462;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 467 or 468, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 473 or 474;
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 479 or 480, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 485;
21) a HCVR comprising the amino acid sequence of SEQ ID NO: 490 or 491 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 496;
22) a HCVR comprising the amino acid sequence of SEQ ID NO: 501 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 506;
23) a HCVR comprising the amino acid sequence of SEQ ID NO: 511 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 516;
24) a HCVR comprising the amino acid sequence of SEQ ID NO: 521 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 526;
25) a HCVR comprising the amino acid sequence of SEQ ID NO: 531 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 536;
26) a HCVR comprising the amino acid sequence of SEQ ID NO: 541 or 542, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 547;
27) a HCVR comprising the amino acid sequence of SEQ ID NO: 552, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 557;
28) a HCVR comprising the amino acid sequence of SEQ ID NO: 562, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 567; 29) a HCVR comprising the amino acid sequence of SEQ ID NO: 572, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 577;
30) a HCVR comprising the amino acid sequence of SEQ ID NO: 582, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 587;
31) a HCVR comprising the amino acid sequence of SEQ ID NO: 592 or 593, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 598 or 599 ;
32) a HCVR comprising the amino acid sequence of SEQ ID NO: 604, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 609 or 610; or
33) a HCVR comprising the amino acid sequence of SEQ ID NO: 1119, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1127.
153. The multispecific antibody or multispecific antigen-binding fragment of claim 144, wherein said molecule on the cell surface is CACNG1.
154. The multispecific antibody or multispecific antigen-binding fragment of claim 153, wherein the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to CACNG1 comprises:
1) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703; 6) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR that comprises the HCDR1 , HCDR2 and HCDR3 contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR that comprises the LCDR1 , LCDR2 and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
155. The multispecific antibody or multispecific antigen-binding fragment of claim 153 or 154, wherein the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to CACNG1 comprises:
1) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 627, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629;
2) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649; 3) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 667, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;
4) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 687, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689;
5) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709;
6) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 727, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729;
7) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 747, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749;
8) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 767, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769;
9) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 787, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789;
10) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809;
11) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 821 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 827, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829;
12) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 847, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849;
13) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 867, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869;
14) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 887, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889;
15) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 907, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909;
16) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 927, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929;
17) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 947, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949;
18) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 967, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 969;
19) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1 185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1 187; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1 191 , a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1193, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; or
20) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 121 1 ; and/or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.
156. The multispecific antibody or multispecific antigen-binding fragment thereof of any one of claims 153-155, wherein the other(s) of ABD1 , ABD2, ABD3, and ABD4 which binds to CACNG1 comprises:
1) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 623;
2) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 643;
3) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 663;
4) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 683;
5) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 703;
6) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 723;
7) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 743;
8) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 763;
9) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 783;
10) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 803;
11) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;
12) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 843;
13) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 863;
14) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 883;
15) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 903;
16) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 923;
17) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 943;
18) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 963;
19) a HCVR comprising the amino acid sequence of SEQ ID NO: 1181 , and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; or
20) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and/or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.
157. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 54, 58, 79, 84, 89, 94, 99, 104, 109, 130, 135, and 140, wherein the linker is:
(a) at least 5 amino acids, at least 6 amino acids or at least 7 amino acids in length; and optionally
(b) up to 30 amino acids, up to 40 amino acids, up to 50 amino acids or up to 60 amino acids in length.
158. The multispecific antibody or multispecific antigen-binding fragment of claim 157, wherein the linker is:
(a) 5 amino acids to 50 amino acids in length;
(b) 5 amino acids to 45 amino acids in length;
(c) 5 amino acids to 40 amino acids in length;
(d) 5 amino acids to 35 amino acids in length; (e) 5 amino acids to 30 amino acids in length;
(f) 5 amino acids to 25 amino acids in length; or
(g) 5 amino acids to 20 amino acids in length.
159. The multispecific antibody or multispecific antigen-binding fragment of claim 157, wherein the linker is:
(a) 6 amino acids to 50 amino acids in length;
(b) 6 amino acids to 45 amino acids in length;
(c) 6 amino acids to 40 amino acids in length;
(d) 6 amino acids to 35 amino acids in length;
(e) 6 amino acids to 30 amino acids in length;
(f) 6 amino acids to 25 amino acids in length; or
(g) 6 amino acids to 20 amino acids in length.
160. The multispecific antibody or multispecific antigen-binding fragment of claim 157, wherein the linker is:
(a) 7 amino acids to 40 amino acids in length;
(b) 7 amino acids to 35 amino acids in length;
(c) 7 amino acids to 30 amino acids in length;
(d) 7 amino acids to 25 amino acids in length;
(e) 7 amino acids to 20 amino acids in length.
161. The multispecific antibody or multispecific antigen-binding fragment of claim 157, wherein the linker is 5 amino acids to 25 amino acids in length.
162. The multispecific antibody or multispecific antigen-binding fragment of claim 157, wherein the linker is 10 amino acids to 60 amino acids in length.
163. The multispecific antibody or multispecific antigen-binding fragment of claim 157, wherein the linker is 20 amino acids to 50 amino acids in length.
164. The multispecific antibody or multispecific antigen-binding fragment of claim 157, wherein the linker is 25 to 35 amino acids in length.
165. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 157-164, wherein the linker is or comprises a multimer of GnS (SEQ ID NO: 239) or SGn (SEQ ID NO: 240), where n is an integer from 1 to 10. The multispecific antibody or multispecific antigen-binding fragment of claim 165, wherein the linker is or comprises a multimer of G4S (SEQ ID NO: 242). The multispecific antibody or multispecific antigen-binding fragment of any one of claims 157-164, wherein the linker is or comprises two consecutive glycines (2Gly), three consecutive glycines (3Gly), four consecutive glycines (4Gly (SEQ ID NO: 243)), five consecutive glycines (5Gly (SEQ ID NO: 244)), six consecutive glycines (6Gly (SEQ ID NO: 245)), seven consecutive glycines (7Gly (SEQ ID NO: 246)), eight consecutive glycines (8Gly (SEQ ID NO: 247)) or nine consecutive glycines (9Gly (SEQ ID NO: 248)). The multispecific antibody or multispecific antigen-binding fragment of any one of claims 51-167, wherein one or more light chains are universal light chains. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 51-167, wherein a light chain constant region (CL) and a first heavy chain constant region (CH1) of one or more Fabs are in a CrossmAb arrangement. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 28-169, which comprises an Fc heterodimer. The multispecific antibody or multispecific antigen-binding fragment of claim 170, wherein the Fc domains in the Fc heterodimer comprise knob-in-hole mutations as compared to a wild type Fc domain. The multispecific antibody or multispecific antigen-binding fragment of claim 171 , wherein one Fc domain in the Fc heterodimer comprises amino acid substitutions S354C and T366W (according to EU numbering) as compared to a wild type Fc domain, and the other Fc domain in the Fc heterodimer comprises amino acid substitutions Y349C, T366S, L368A, and Y407V (according to EU numbering) as compared to a wild type Fc domain. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 170-172, wherein at least one Fc domain in the Fc heterodimer comprises a star mutation as compared to a wild type Fc domain. The multispecific antibody or multispecific antigen-binding fragment of claim 173, wherein one Fc domain in the Fc heterodimer comprises amino acid mutations H435R and/or Y436F (according to EU numbering) as compared to a wild type Fc domain. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 28-174, wherein said capsid comprises one or more wild-type AAV capsid polypeptides. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 28-174, wherein said capsid comprises one or more non-wild-type AAV capsid polypeptides. The multispecific antibody or multispecific antigen-binding fragment of any one of claims 28-176, which is a bispecific antibody or bispecific antigen-binding fragment thereof. A pharmaceutical composition comprising the multispecific antibody or multispecific antigen-binding fragment of any one of claims 28-177, and a pharmaceutically acceptable carrier or excipient. A molecular complex comprising an AAV particle bound to one or more antibodies and/or antigen-binding fragments of any one of claims 1-26. The molecular complex of claim 179, wherein said AAV particle comprises one or more mutations in one or more AAV capsid proteins inhibiting the natural tropism of said AAV particle. A pharmaceutical composition comprising the molecular complex of claim 179 or 180 and a pharmaceutically acceptable carrier or excipient. A method of preparing the molecular complex of claim 179 or 180, comprising incubating said AAV particle in the presence of said one or more antibodies and/or antigen-binding fragments under conditions allowing specific binding of said one or more antibodies and/or antigen-binding fragments to said AAV particle capsid. A molecular complex comprising an AAV particle bound to one or more multispecific antibodies and/or multispecific antigen-binding fragments of any one of claims 28-177. The molecular complex of claim 183, wherein said AAV particle comprises one or more mutations in one or more AAV capsid proteins inhibiting the natural tropism of said AAV particle. A pharmaceutical composition comprising the molecular complex of claim 183 or 184 and a pharmaceutically acceptable carrier or excipient. A method of preparing the molecular complex of claim 183 or 184, comprising incubating said AAV particle in the presence of said one or more multispecific antibodies and/or multispecific antigen-binding fragments under conditions allowing specific binding of said one or more multispecific antibodies and/or multispecific antigen-binding fragments to said AAV particle capsid. A method for targeting an AAV particle to a cell expressing a molecule on the cell surface, comprising contacting the cell with the molecular complex of claim 183 or the pharmaceutical composition of claim 185, wherein said molecular complex comprises one or more multispecific antibodies and/or multispecific antigen-binding fragments which bind to said molecule on the cell surface. A method for delivering a polynucleotide to a cell expressing a molecule on the cell surface, comprising contacting the cell with the molecular complex of claim 183 or the pharmaceutical composition of claim 185, wherein said molecular complex comprises the AAV particle comprising said polynucleotide and bound to one or more multispecific antibodies and/or multispecific antigen-binding fragments which bind to said molecule on the cell surface. The method of claim 187 or claim 188, wherein said cell is in a subject and said molecular complex is administered to the subject. The method of any one of claims 187-189, wherein said AAV particle does not target said cell in the absence of said one or more multispecific antibodies and/or multispecific antigen-binding fragments.
EP23847703.8A 2022-12-16 2023-12-15 Antigen-binding molecules that bind to aav particles and uses Pending EP4634220A2 (en)

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