Attorney Docket No.250298.000954 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 Patent Application No. 63/657,211, filed June 7, 2024, U.S. Provisional Patent Application No. 63/702,752, filed October 3, 2024, and U.S. Provisional Patent Application No. 63/804,176, filed May 12, 2025, the contents of each of which is hereby incorporated by reference in its entirety for all purposes. 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 May 30, 2025, is named 250298_000954_SL.xml and is 1,536,977 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 ^ ^
Attorney Docket No.250298.000954 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 a multispecific antibody, or a multispecific antigen- binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation: a first heavy chain region of a first Fab (“Fab1”) operably linked to a first Fc domain (“Fc1”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation: a second heavy chain region of a second Fab (“Fab2”) operably linked to a second Fc domain (“Fc2”); 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”); 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 second antigen-binding domain (“ABD2”); wherein e) 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; f) Fc1 and/or Fc2 are derived from an IgG4 heavy chain constant region; and g) the first light chain and the second light chain comprise the same amino acid sequence. [0007] In some embodiments, ABD1 binds to the capsid of the AAV particle and ABD2 binds to the molecule on the cell surface. [0008] In some embodiments, ABD2 binds to the capsid of the AAV particle and ABD1 binds to the molecule on the cell surface. [0009] In some embodiments, Fc1 and Fc2 form an Fc heterodimer. [0010] In some embodiments, the Fc1 and/or Fc2 in the Fc heterodimer comprise a knob-in- hole mutation as compared to a wild type Fc domain. [0011] In some embodiments, one of Fc1 and Fc2 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 of Fc1 and Fc2 in the Fc heterodimer comprises amino acid ^ ^
Attorney Docket No.250298.000954 substitutions Y349C, T366S, L368A, and Y407V (according to EU numbering) as compared to a wild type Fc domain. [0012] In some embodiments, at least one of Fc1 and Fc2 in the Fc heterodimer comprises a star mutation as compared to a wild type Fc domain. [0013] In some embodiments, one of Fc1 and Fc2 in the Fc heterodimer comprises amino acid mutations H435R and/or Y436F (according to EU numbering) as compared to a wild type Fc domain. [0014] In some embodiments, Fc1 and/or Fc2 comprises the amino acid sequence of SEQ ID NO: 1345 or 1365, or a variant thereof. [0015] In some embodiments, the first light chain and the second light chain comprise the amino acid sequence of SEQ ID NO: 20, or a variant thereof. [0016] In some embodiments, ABD1 or ABD2 bind to the capsid of the AAV particle, and ABD1 or ABD2 comprises: h) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 52, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10; or i) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 71, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10. [0017] In some embodiments, ABD1 or ABD2 binds to the capsid of the AAV particle, and ABD1 or ABD2 comprises: j) an HCVR that comprises the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; or k) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 71, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10, or a variant thereof. [0018] In some embodiments, ABD1 or ABD2 binds to the capsid of the AAV particle, and ABD1 or ABD2 comprises: l) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or m) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and an HCDR3 comprising the ^ ^
Attorney Docket No.250298.000954 amino acid sequence of SEQ ID NO: 77; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [0019] 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). [0020] In some embodiments, the molecule on the cell surface is TfR. [0021] In some embodiments, ABD1 or ABD2 binds to TfR, and ABD1 or ABD2 comprises: n) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 501, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof; o) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 511, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof; p) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 531, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof; or q) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 552, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [0022] In some embodiments, ABD1 or ABD2 binds to TfR, and ABD1 or ABD2 comprises: r) an HCVR that comprises the amino acid sequence of SEQ ID NO: 501, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; s) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 511, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10, or a variant thereof; t) an HCVR that comprises the amino acid sequence of SEQ ID NO: 531, or a variant thereof and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; or u) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 552, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID ^ ^
Attorney Docket No.250298.000954 NO: 10, or a variant thereof. [0023] In some embodiments, ABD1 or ABD2 binds to TfR, and ABD1 or ABD2 comprises: v) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; w) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; x) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or y) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [0024] In another aspect, provided herein is a multispecific antibody or multispecific antigen- binding fragment thereof, comprising: a) a first polypeptide chain comprising, in an N- to C-terminal orientation: a first heavy chain region of a first Fab (“Fab1”) operably linked to a first Fc domain (“Fc1”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation: a second heavy chain region of a second Fab (“Fab2”) operably linked to a second Fc domain (“Fc2”); 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”); 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 second antigen-binding domain (“ABD2”), wherein e) ABD1 binds to a capsid of an AAV particle; f) ABD2 binds to TfR; g) Fc1 comprises the amino acid sequence of SEQ ID NO: 1365, or a variant thereof; ^ ^
Attorney Docket No.250298.000954 h) Fc2 comprises the amino acid sequence of SEQ ID NO: 1345, or a variant thereof; and, i) the first light chain and second light chain comprise the same amino acid sequence. [0025] In some embodiments, the first light chain and the second light chain comprise the amino acid sequence of SEQ ID NO: 20, or a variant thereof. [0026] In some embodiments, ABD1 binds to the capsid of the AAV particle, and ABD1 comprises: j) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof; or k) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 71, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [0027] In some embodiments, ABD1 binds to the capsid of the AAV particle, and ABD1 comprises: l) an HCVR that comprises the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; or m) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 71, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10, or a variant thereof. [0028] In some embodiments, ABD1 binds to the capsid of the AAV particle, and ABD1 comprises: n) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or o) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [0029] In some embodiments, ABD2 binds to TfR, and ABD2 comprises: p) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the ^ ^
Attorney Docket No.250298.000954 amino acid sequence of SEQ ID NO: 501, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof; q) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 511, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof; r) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 531, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof; or s) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 552, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [0030] In some embodiments, ABD2 binds to TfR, and ABD2 comprises: t) an HCVR that comprises the amino acid sequence of SEQ ID NO: 501, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; u) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 511, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10, or a variant thereof; v) an HCVR that comprises the amino acid sequence of SEQ ID NO: 531, or a variant thereof and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; or w) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 552, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10, or a variant thereof. [0031] In some embodiments, ABD1 or ABD2 binds to TfR, and ABD1 or ABD2 comprises: x) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; y) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and an HCDR3 comprising the ^ ^
Attorney Docket No.250298.000954 amino acid sequence of SEQ ID NO: 514; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; z) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or aa) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [0032] 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: a first heavy chain region of a first Fab (“Fab1”) operably linked to a first Fc domain (“Fc1”), said Fc1 operably linked to a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation: a third heavy chain region of a third Fab (“Fab3”) operably linked to a second Fc domain (“Fc2”); 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 f) at least one of ABD1, ABD2, and ABD3 binds to a capsid of an AAV particle, and the other(s) of ABD1, ABD2, and ABD3 bind to a molecule on a cell surface; g)^Fc1 and/or Fc2 are derived from an IgG4 heavy chain constant region; and h) the first light chain, the second light chain, and the third light chain comprise the same amino acid sequence; or the first light chain and the second light chain comprise the same amino acid sequence and the third light chain comprises a different amino acid sequence. [0033] In some embodiments, two of ABD1, ABD2, and ABD3 bind to the capsid of the AAV particle, and one of ABD1, ABD2, and ABD3 binds to the molecule on the cell surface. ^ ^
Attorney Docket No.250298.000954 [0034] In some embodiments, ABD1 and ABD2 bind to the capsid of the AAV particle, and ABD3 binds to the molecule on the cell surface. [0035] In some embodiments, ABD3 binds to the capsid of the AAV particle, and ABD1 and ABD2 bind to the molecule on the cell surface. [0036] In some embodiments, Fc1 and Fc2 form an Fc heterodimer. [0037] In some embodiments, the Fc1 and/or Fc2 in the Fc heterodimer comprise a knob-in- hole mutation as compared to a wild type Fc domain. [0038] In some embodiments, one of Fc1 and Fc2 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 of Fc1 and Fc2 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. [0039] In some embodiments, at least one of Fc1 and Fc2 in the Fc heterodimer comprises a star mutation as compared to a wild type Fc domain. [0040] In some embodiments, one of Fc1 and Fc2 in the Fc heterodimer comprises amino acid mutations H435R and/or Y436F (according to EU numbering) as compared to a wild type Fc domain. [0041] In some embodiments, Fc1 and/or Fc2 comprises the amino acid sequence of SEQ ID NO: 1345 or 1365, or a variant thereof. [0042] In some embodiments, the first light chain, the second light chain, and the third light chain comprise the amino acid sequence of SEQ ID NO: 20 or 813, or a variant thereof. [0043] In some embodiments, the first light chain and the second light chain comprise the amino acid sequence of SEQ ID NO: 20, or a variant thereof, and the third light chain comprises the amino sequence of SEQ ID NO: 813, or a variant thereof. [0044] In some embodiments, the second heavy chain region is linked to the Fc domain via a linker. [0045] In some embodiments, the linker is or comprises a multimer of GnS (SEQ ID NO: 239) or SGn (SEQ ID NO: 240), wherein n is an integer from 1 to 10. [0046] In some embodiments, the linker is or comprises a multimer of G4S (SEQ ID NO: 242). [0047] In some embodiments, the linker is G4Sx3 (SEQ ID NO: 1115). [0048] In some embodiments, at least one of ABD1, ABD2, and ABD3 binds to the capsid of the AAV particle, and ABD1, ABD2, and/or ABD3 comprises: i) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid ^ ^
Attorney Docket No.250298.000954 sequence of SEQ ID NO: 10 or 803, or a variant thereof; or j) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 71, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 803, or a variant thereof. [0049] In some embodiments, at least one of ABD1, ABD2, and ABD3 binds to the capsid of the AAV particle, and ABD1, ABD2, ABD3 comprises: k) an HCVR that comprises the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 803, or a variant thereof; or l) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 71, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10 or 803, or a variant thereof. [0050] In some embodiments, at least one of ABD1, ABD2, and ABD3 binds to the capsid of the AAV particle, and ABD1, ABD2, and/or ABD3 comprises: m) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12 or 805, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14 or 807, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16 or 809; or n) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12 or 805, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14 or 807, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16 or 809. [0051] In some embodiments, the molecule on the cell surface is ASGR1, TfR, or CACNG1. [0052] In some embodiments, the molecule on the cell surface is TfR. [0053] In some embodiments, the other(s) of ABD1, ABD2, and ABD3 binds to TfR, and ABD1, ABD2, and/or ABD3 comprises: o) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 501, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof; p) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the ^ ^
Attorney Docket No.250298.000954 amino acid sequence of SEQ ID NO: 511, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof; q) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 531, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof; or r) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 552, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [0054] In some embodiments, the other(s) of ABD1, ABD2, and ABD3 binds to TfR, and ABD1, ABD2, and/or ABD3 comprises: s) an HCVR that comprises the amino acid sequence of SEQ ID NO: 501, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; t) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 511, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10, or a variant thereof; u) an HCVR that comprises the amino acid sequence of SEQ ID NO: 531, or a variant thereof and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; or v) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 552, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10, or a variant thereof. [0055] In some embodiments, the other(s) of ABD1, ABD2, and ABD3 binds to TfR, and ABD1, ABD2, and/or ABD3 comprises: w) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; x) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID ^ ^
Attorney Docket No.250298.000954 NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; y) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or z) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [0056] In some embodiments, the molecule on the cell surface is CACNG1. [0057] In some embodiments, the other(s) of ABD1, ABD2, and ABD3 binds to CACNG1, and ABD1 or ABD2 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 1351, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [0058] In some embodiments, the other(s) of ABD1, ABD2, and ABD3 binds to CACNG1, and ABD1 or ABD2 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 1351, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [0059] In some embodiments, the other(s) of ABD1, ABD2, and ABD3 binds to CACNG1, and ABD1 or ABD2 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 801; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 809. [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: a first heavy chain region of a first Fab (“Fab1”) operably linked to a first Fc domain (“Fc1”), said Fc1 operably linked to a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation: a third heavy ^ ^
Attorney Docket No.250298.000954 chain region of a third Fab (“Fab3”) operably linked to a second Fc domain (“Fc2”); 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 f) ABD1 and ABD2 bind to a capsid of an AAV particle; g) ABD3 binds to TfR; h) Fc1 comprises the amino acid sequence of SEQ ID NO: 1365, or a variant thereof; i) Fc2 comprises the amino acid sequence of SEQ ID NO: 1345, or a variant thereof; and, j) the first light chain, the second light chain, and the third light chain comprise the same amino acid sequence. [0061] In some embodiments, the first light chain, the second light chain, and the third light chain comprise the amino acid sequence of SEQ ID NO: 20, or a variant thereof. [0062] In some embodiments, the second heavy chain region is linked to the Fc domain via a linker. [0063] In some embodiments, the linker is G4Sx3 (SEQ ID NO: 1115). [0064] In some embodiments, ABD1 and ABD2 bind to the capsid of the AAV particle, and ABD1 and ABD2 comprises: k) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 803, or a variant thereof; or l) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 71, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 803, or a variant thereof. [0065] In some embodiments, ABD1 and ABD2 bind to the capsid of the AAV particle, and ABD1 and ABD2 comprises: m) an HCVR that comprises the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; or n) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 71, or a ^ ^
Attorney Docket No.250298.000954 variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10, or a variant thereof. [0066] In some embodiments, ABD1 and ABD2 bind to the capsid of the AAV particle, and ABD1 and ABD2 comprises: o) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or p) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 73, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 75, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [0067] In some embodiments, ABD3 binds to TfR, and ABD3 comprises: q) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 501, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof; r) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 511, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof; s) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 531, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof; or t) an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 552, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [0068] In some embodiments, ABD3 binds to TfR, and ABD3 comprises: u) an HCVR that comprises the amino acid sequence of SEQ ID NO: 501, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; v) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 511, or a ^ ^
Attorney Docket No.250298.000954 variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10, or a variant thereof; w) an HCVR that comprises the amino acid sequence of SEQ ID NO: 531, or a variant thereof and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof; or x) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 552, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10, or a variant thereof. [0069] In some embodiments, ABD3 binds to TfR, and ABD3 comprises: y) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; z) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 512, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 513, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 514; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; aa) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 532, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 533, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 534; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; or bb) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 553, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 554, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 555; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [0070] 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: a first heavy chain region of a first Fab (“Fab1”) operably linked to a first Fc domain (“Fc1”), said Fc1 operably linked to a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation: a third heavy chain region of a third Fab (“Fab3”) operably linked to a second Fc domain (“Fc2”); ^ ^
Attorney Docket No.250298.000954 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 f) ABD1 and ABD2 bind to a capsid of an AAV particle; g) ABD3 binds to CACNG1; h) Fc1 comprises the amino acid sequence of SEQ ID NO: 1365, or a variant thereof; i) Fc2 comprises the amino acid sequence of SEQ ID NO: 1345, or a variant thereof; and j) the first light chain and the second light chain comprise the same amino acid sequence and the third light chain comprises an different amino acid sequence. [0071] In some embodiments, the first light chain and the second light chain comprise the amino acid sequence of SEQ ID NO: 20, or a variant thereof. [0072] In some embodiments, the third light chain comprises the amino acid sequence of SEQ ID NO: 813, or a variant thereof. [0073] In some embodiments, the second heavy chain region is linked to the Fc domain via a linker. [0074] In some embodiments, the linker is G4Sx3 (SEQ ID NO: 1115). [0075] In some embodiments, ABD1 and ABD2 bind to the capsid of the AAV particle, and ABD1 and ABD2 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 52, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10. [0076] In some embodiments, ABD1 and ABD2 bind to the capsid of the AAV particle, and ABD1 and ABD2 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [0077] In some embodiments, ABD1 and ABD2 bind to the capsid of the AAV particle, and ABD1 and ABD2 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or an LCDR1 comprising the amino acid sequence of SEQ ^ ^
Attorney Docket No.250298.000954 ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [0078] In some embodiments, ABD3 binds to CACNG1, and ABD3 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 1351, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [0079] In some embodiments, ABD3 binds to CACNG1, and ABD3 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 1351, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [0080] In some embodiments, ABD3 binds CACNG1, and ABD3 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 801; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 809. [0081] 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: a first heavy chain region of a first Fab (“Fab1”) operably linked to a first Fc domain (“Fc1”), said Fc1 operably linked to a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation: a third heavy chain region of a third Fab (“Fab3”) operably linked to a second Fc domain (“Fc2”); 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 f) ABD1 and ABD2 bind to a capsid of an AAV particle; g) ABD3 binds to CACNG1; h) Fc1 comprises the amino acid sequence of SEQ ID NO: 1365, or a variant thereof; i) Fc2 comprises the amino acid sequence of SEQ ID NO: 1345, or a variant thereof; and ^ ^
Attorney Docket No.250298.000954 j) the first light chain, the second light chain, and the third light chain comprise the same amino acid sequence. [0082] In some embodiments, the first light chain, the second light chain, and the third light chain comprise the amino acid sequence of SEQ ID NO: 813, or a variant thereof. [0083] In some embodiments, the second heavy chain region is linked to the Fc domain via a linker. [0084] In some embodiments, the linker is G4Sx3 (SEQ ID NO: 1115). [0085] In some embodiments, ABD1 and ABD2 bind to the capsid of the AAV particle, and ABD1 and ABD2 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [0086] In some embodiments, ABD1 and ABD2 bind to the capsid of the AAV particle, and ABD1 and ABD2 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [0087] In some embodiments, ABD1 and ABD2 bind to the capsid of the AAV particle, and ABD1 and ABD2 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 809. [0088] In some embodiments, ABD3 binds to CACNG1, and ABD3 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 1351, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [0089] In some embodiments, ABD3 binds to CACNG1, and ABD3 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 1351, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [0090] In some embodiments, ABD3 binds CACNG1, and ABD3 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, an HCDR2 comprising ^ ^
Attorney Docket No.250298.000954 the amino acid sequence of SEQ ID NO: 799, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 801; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 809. [0091] 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: a first heavy chain region of a first Fab (“Fab1”) operably linked to an Fc domain, said Fc domain operably linked to a first scFv comprising a first antigen-binding domain (“ABD1”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation: a second heavy chain region of a second Fab (“Fab2”) operably linked to an Fc domain, said Fc domain operably linked to 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 e) at least one of ABD1, ABD2, ABD3, and ABD4 binds to a capsid of an AAV particle, and the other(s) of ABD1, ABD2, ABD3, and ABD4 bind to CACNG1; f) the Fc domain is derived from an IgG4 heavy chain constant region; and g) the first light chain and the second light chain comprise the same amino acid sequence. [0092] In some embodiments, two of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and two of ABD1, ABD2, ABD3, and ABD4 binds to CACNG1. [0093] In some embodiments, ABD1 and ABD2 bind to the capsid of the AAV particle, and ABD3 and ABD4 binds to CACNG1. [0094] In some embodiments, ABD3 and ABD4 bind to the capsid of the AAV particle, and ABD1 and ABD2 binds to CACNG1. [0095] In some embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO: 1397, or a variant thereof. [0096] In some embodiments, the first light chain and the second light chain comprise the amino acid sequence of SEQ ID NO: 813, or a variant thereof. [0097] In some embodiments, the first scFv and/or the second scFv are linked to the Fc domain via a linker. [0098] In some embodiments, the linker is or comprises a multimer of GnS (SEQ ID NO: 239) or SGn (SEQ ID NO: 240), wherein n is an integer from 1 to 10. ^ ^
Attorney Docket No.250298.000954 [0099] In some embodiments, the linker is or comprises a multimer of G4S (SEQ ID NO: 242). [00100] In some embodiments, the linker is G4Sx3 (SEQ ID NO: 1115). [00101] In some embodiments, at least one of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 1159, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 1157, or a variant thereof. [00102] In some embodiments, at least one of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 1159, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 1157, or a variant thereof. [00103] In some embodiments, at least one of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [00104] In some embodiments, the other(s) of ABD1, ABD2, ABD3, and ABD4 binds to CACNG1, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 1351, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [00105] In some embodiments, the other(s) of ABD1, ABD2, ABD3, and ABD4 binds to CACNG1, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 1351, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [00106] In some embodiments, the other(s) of ABD1, ABD2, ABD3, and ABD4 binds CACNG1, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and an HCDR3 comprising the amino acid ^ ^
Attorney Docket No.250298.000954 sequence of SEQ ID NO: 801; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 809. [00107] 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: a first scFv comprising a first antigen-binding domain (“ABD1”) operably linked to 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: a second scFv comprising a second antigen-binding domain (“ABD2”) operably linked to 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 e) at least one of ABD1, ABD2, ABD3, and ABD4 binds to a capsid of an AAV particle, and the other(s) of ABD1, ABD2, ABD3, and ABD4 bind to CACNG1; f) the Fc domain is derived from an IgG4 heavy chain constant region; and g) the first light chain and the second light chain comprise the same amino acid sequence. [00108] In some embodiments, two of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and two of ABD1, ABD2, ABD3, and ABD4 binds to CACNG1. [00109] In some embodiments, ABD1 and ABD2 bind to the capsid of the AAV particle, and ABD3 and ABD4 binds to CACNG1. [00110] In some embodiments, ABD3 and ABD4 bind to the capsid of the AAV particle, and ABD1 and ABD2 binds to CACNG1. [00111] In some embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO: 1397, or a variant thereof. [00112] In some embodiments, the first light chain and the second light chain comprise the sequence of SEQ ID NO: 20 or 813, or a variant thereof. [00113] In some embodiments, the first Fab and/or the second Fab is linked to the Fc domain via a linker. [00114] In some embodiments, the linker is or comprises a multimer of GnS (SEQ ID NO: 239) or SGn (SEQ ID NO: 240), wherein n is an integer from 1 to 10. [00115] In some embodiments, the linker is or comprises a multimer of G4S (SEQ ID NO: ^ ^
Attorney Docket No.250298.000954 242). [00116] In some embodiments, the linker is G4Sx3 (SEQ ID NO: 1115). [00117] In some embodiments, at least one of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof. [00118] In some embodiments, at least one of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10 or 1157, or a variant thereof. [00119] In some embodiments, at least one of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [00120] In some embodiments, the other(s) of ABD1, ABD2, ABD3, and ABD4 binds to CACNG1, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 1351, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [00121] In some embodiments, the other(s) of ABD1, ABD2, ABD3, and ABD4 binds to CACNG1, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 1351, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 803 or 1352, or a variant thereof. [00122] In some embodiments, the other(s) of ABD1, ABD2, ABD3, and ABD4 binds to CACNG1, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 801; and/or an LCDR1 comprising the amino acid sequence of ^ ^
Attorney Docket No.250298.000954 SEQ ID NO: 805, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 809. [00123] 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: a first heavy chain region of a first Fab (“Fab1”) operably linked to an Fc domain, said Fc domain operably linked to a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation: a third heavy chain region of a third Fab (“Fab3”) operable liked to an Fc domain, said Fc domain operably linked to 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 (“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 Fab4 comprises a fourth antigen-binding domain (“ABD4”); wherein g) at least one of ABD1, ABD2, ABD3, and ABD4 binds to a capsid of an AAV particle, and the other(s) of ABD1, ABD2, ABD3, and ABD4 bind to CACNG1; h) the Fc domain is derived from an IgG4 heavy chain constant region; and i) the first light chain, the second light chain, the third light chain, and the fourth light chain comprise the same amino acid sequence. [00124] In some embodiments, two of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and two of ABD1, ABD2, ABD3, and ABD4 binds to CACNG1. [00125] In some embodiments, ABD1 and ABD3 bind to the capsid of the AAV particle, and ABD2 and ABD4 binds to CACNG1. [00126] In some embodiments, ABD2 and ABD4 bind to the capsid of the AAV particle, and ABD1 and ABD3 binds to CACNG1. [00127] In some embodiments, the first light chain, the second light chain, the third light chain, and the fourth light chain comprise the amino acid sequence of SEQ ID NO: 813, or a variant thereof. [00128] In some embodiments, the Fc domain is linked to the second heavy chain region ^ ^
Attorney Docket No.250298.000954 and the fourth heavy chain region via a linker. [00129] In some embodiments, the linker is or comprises a multimer of GnS (SEQ ID NO: 239) or SGn (SEQ ID NO: 240), wherein n is an integer from 1 to 10. [00130] In some embodiments, the linker is or comprises a multimer of G4S (SEQ ID NO: 242). [00131] In some embodiments, the linker is G4Sx3 (SEQ ID NO: 1115). [00132] In some embodiments, at least one of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [00133] In some embodiments, at least one of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [00134] In some embodiments, at least one of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 809. [00135] In some embodiments, the other(s) of ABD1, ABD2, ABD3, and ABD4 binds to CACNG1, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 1351, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [00136] In some embodiments, the other(s) of ABD1, ABD2, ABD3, and ABD4 binds to CACNG1, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 1351, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 803, or a variant thereof. [00137] In some embodiments, the other(s) of ABD1, ABD2, ABD3, and ABD4 binds to ^ ^
Attorney Docket No.250298.000954 CACNG1, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 801; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 807, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 809. [00138] 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: a first heavy chain region of a first Fab (“Fab1”) operably linked to an Fc domain, said Fc domain operably linked to a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation: a third heavy chain region of a third Fab (“Fab3”) operable liked to an Fc domain, said Fc domain operably linked to 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 (“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 Fab4 comprises a fourth antigen-binding domain (“ABD4”); wherein g) at least one of ABD1, ABD2, ABD3, and ABD4 binds to a capsid of an AAV particle, and the other(s) of ABD1, ABD2, ABD3, and ABD4 bind to TfR; h) the Fc domain is derived from an IgG4 heavy chain constant region; and i) the first light chain, the second light chain, the third light chain, and the fourth light chain comprise the same amino acid sequence. [00139] In some embodiments, two of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and two of ABD1, ABD2, ABD3, and ABD4 binds to TfR. [00140] In some embodiments, ABD1 and ABD3 bind to TfR, and ABD2 and ABD4 binds to the capsid of the AAV particle. [00141] In some embodiments, ABD2 and ABD4 bind to TfR, and ABD1 and ABD3 binds to the capsid of the AAV particle. ^ ^
Attorney Docket No.250298.000954 [00142] In some embodiments, the first light chain, the second light chain, the third light chain, and the fourth light chain comprise the amino acid sequence of SEQ ID NO: 20, or a variant thereof. [00143] In some embodiments, the Fc domain is linked to the second heavy chain region and the fourth heavy chain region via a linker. [00144] In some embodiments, the linker is or comprises a multimer of GnS (SEQ ID NO: 239) or SGn (SEQ ID NO: 240), wherein n is an integer from 1 to 10. [00145] In some embodiments, the linker is or comprises a multimer of G4S (SEQ ID NO: 242). [00146] In some embodiments, the linker is G4Sx3 (SEQ ID NO: 1115). [00147] In some embodiments, at least one of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [00148] In some embodiments, at least one of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [00149] In some embodiments, at least one of ABD1, ABD2, ABD3, and ABD4 bind to the capsid of the AAV particle, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [00150] In some embodiments, the other(s) of ABD1, ABD2, ABD3, and ABD4 binds to TfR, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 501, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [00151] In some embodiments, the other(s) of ABD1, ABD2, ABD3, and ABD4 binds to TfR, and ABD1, ABD2, ABD3, and/or ABD4 comprises: ^ ^
Attorney Docket No.250298.000954 an HCVR that comprises the amino acid sequence of SEQ ID NO: 501, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [00152] In some embodiments, the other(s) of ABD1, ABD2, ABD3, and ABD4 binds to TfR, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [00153] 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: a first heavy chain region of a first Fab (“Fab1”) operably linked to a first Fc domain (“Fc1”), said Fc1 operably linked to a second heavy chain region of a second Fab (“Fab2”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation: a second Fc domain (“Fc2”), said Fc2 operably linked to a third heavy chain region of a third Fab (“Fab3”); 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”); 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 f) at least one of ABD1, ABD2, and ABD3 binds to a capsid of an AAV particle, and the other(s) of ABD1, ABD2, and ABD3 bind to TfR; g) Fc1 and/or Fc2 are derived from an IgG4 heavy chain constant region; and h) the first light chain, the second light chain, and the third light chain comprise the same amino acid sequence. [00154] In some embodiments, two of ABD1, ABD2, and ABD3 bind to the capsid of the AAV particle, and one of ABD1, ABD2, and ABD3 binds to TfR. [00155] In some embodiments, two of ABD1, ABD2, and ABD3 bind to TfR, and one of ABD1, ABD2, and ABD3 binds to the capsid of the AAV particle. [00156] In some embodiments, ABD1 binds to TfR, and ABD2 and ABD3 binds to the ^ ^
Attorney Docket No.250298.000954 capsid of the AAV particle. [00157] In some embodiments, ABD1 binds to the capsid of the AAV particle, and ABD2 and ABD3 binds to TfR. [00158] In some embodiments, Fc1 and Fc2 form an Fc heterodimer. [00159] In some embodiments, the Fc1 and/or Fc2 in the Fc heterodimer comprise a knob- in-hole mutation as compared to a wild type Fc domain. [00160] In some embodiments, one of Fc1 and Fc2 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 of Fc1 and Fc2 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. [00161] In some embodiments, at least one of Fc1 and Fc2 in the Fc heterodimer comprises a star mutation as compared to a wild type Fc domain. [00162] In some embodiments, one of Fc1 and Fc2 in the Fc heterodimer comprises amino acid mutations H435R and/or Y436F (according to EU numbering) as compared to a wild type Fc domain. [00163] In some embodiments, Fc1 and/or Fc2 comprises the amino acid sequence of SEQ ID NO: 1397 or 1511, or a variant thereof. [00164] In some embodiments, the first light chain, the second light chain, and the third light chain comprise the amino acid sequence of SEQ ID NO: 20, or a variant thereof. [00165] In some embodiments, Fc1 and/or Fc2 is linked to the second heavy chain region and the third heavy chain region via a linker. [00166] In some embodiments, the linker is or comprises a multimer of GnS (SEQ ID NO: 239) or SGn (SEQ ID NO: 240), wherein n is an integer from 1 to 10. [00167] In some embodiments, the linker is or comprises a multimer of G4S (SEQ ID NO: 242). [00168] In some embodiments, the linker is G4Sx3 (SEQ ID NO: 1115). [00169] In some embodiments, at least one of ABD1, ABD2, and ABD3 bind to the capsid of the AAV particle, and ABD1, ABD2, and/or ABD3 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [00170] In some embodiments, at least one of ABD1, ABD2, and ABD3 bind to the capsid of the AAV particle, and ABD1, ABD2, and/or ABD3 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 52, or a variant thereof, ^ ^
Attorney Docket No.250298.000954 and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [00171] In some embodiments, at least one of ABD1, ABD2, and ABD3 bind to the capsid of the AAV particle, and ABD1, ABD2, and/or ABD3 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [00172] In some embodiments, the other(s) of ABD1, ABD2, and ABD3 binds to TfR, and ABD1, ABD2, and/or ABD3 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 501, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [00173] In some embodiments, the other(s) of ABD1, ABD2, and ABD3 binds to TfR, and ABD1, ABD2, ABD3, and/or ABD4 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 501, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [00174] In some embodiments, the other(s) of ABD1, ABD2, and ABD3 binds to TfR, and ABD1, ABD2, and/or ABD3 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 14. [00175] In some embodiments, i) ABD1 binds to TfR; j) ABD2 and ABD3 bind to the capsid of the AAV particle; k) Fc1 comprises the amino acid sequence of SEQ ID NO: 1397, or a variant thereof; and l) Fc2 comprises the amino acid sequence of SEQ ID NO: 1511, or a variant thereof. [00176] 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: a first heavy chain region of a first Fab (“Fab1”) operably linked to a first Fc domain (“Fc1”); b) a second polypeptide chain comprising, in an N- to C-terminal orientation: a second heavy ^ ^
Attorney Docket No.250298.000954 chain region of a second Fab (“Fab2”) operably linked to a second Fc domain (“Fc2”), said Fc2 operably linked to a third heavy chain region of a third Fab (“Fab3”); 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 f) at least one of ABD1, ABD2, and ABD3 binds to a capsid of an AAV particle, and the other(s) of ABD1, ABD2, and ABD3 bind to TfR; g) Fc1 and/or Fc2 are derived from an IgG4 heavy chain constant region; and h) the first light chain, the second light chain, and the third light chain comprise the same amino acid sequence. [00177] In some embodiments, two of ABD1, ABD2, and ABD3 bind to the capsid of the AAV particle, and one of ABD1, ABD2, and ABD3 binds to TfR. [00178] In some embodiments, two of ABD1, ABD2, and ABD3 bind to TfR, and one of ABD1, ABD2, and ABD3 binds to the capsid of the AAV particle. [00179] In some embodiments, ABD2 and ABD3 bind to the capsid of the AAV particle, and ABD1 binds to TfR. [00180] In some embodiments, ABD2 and ABD3 bind to TfR, and ABD1 binds to the capsid of the AAV particle. [00181] In some embodiments, Fc1 and Fc2 form an Fc heterodimer. [00182] In some embodiments, the Fc1 and/or Fc2 in the Fc heterodimer comprise a knob- in-hole mutation as compared to a wild type Fc domain. [00183] In some embodiments, one of Fc1 and Fc2 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 of Fc1 and Fc2 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. [00184] In some embodiments, at least one of Fc1 and Fc2 in the Fc heterodimer comprises a star mutation as compared to a wild type Fc domain. [00185] In some embodiments, one of Fc1 and Fc2 in the Fc heterodimer comprises amino acid mutations H435R and/or Y436F (according to EU numbering) as compared to a wild type Fc domain. ^ ^
Attorney Docket No.250298.000954 [00186] In some embodiments, Fc1 and/or Fc2 comprises the amino acid sequence of SEQ ID NO: 1397 or 1511, or a variant thereof. [00187] In some embodiments, the first light chain, the second light chain, and the third light chain comprise the amino acid sequence of SEQ ID NO: 20, or a variant thereof. [00188] In some embodiments, Fc2 is linked to the third heavy chain region via a linker. [00189] In some embodiments, the linker is or comprises a multimer of GnS (SEQ ID NO: 239) or SGn (SEQ ID NO: 240), wherein n is an integer from 1 to 10. [00190] In some embodiments, the linker is or comprises a multimer of G4S (SEQ ID NO: 242). [00191] In some embodiments, the linker is G4Sx3 (SEQ ID NO: 1115). [00192] In some embodiments, at least one of ABD1, ABD2, and ABD3 bind to the capsid of the AAV particle, and ABD1, ABD2, and/or ABD3 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [00193] In some embodiments, at least one of ABD1, ABD2, and ABD3 bind to the capsid of the AAV particle, and ABD1, ABD2, and/or ABD3 comprises: an HCVR that comprises the amino acid sequence of SEQ ID NO: 52, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [00194] In some embodiments, at least one of ABD1, ABD2, and ABD3 bind to the capsid of the AAV particle, and ABD1, ABD2, and/or ABD3 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 54, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16. [00195] In some embodiments, the other(s) of ABD1, ABD2, and ABD3 binds to TfR, and ABD1, ABD2, and/or ABD3 comprises: an HCVR that comprises an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence of SEQ ID NO: 501, or a variant thereof, and/or an LCVR that comprises an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [00196] In some embodiments, the other(s) of ABD1, ABD2, and ABD3 binds to TfR, and ABD1, ABD2, and/or ABD3 comprises: ^ ^
Attorney Docket No.250298.000954 an HCVR that comprises the amino acid sequence of SEQ ID NO: 501, or a variant thereof, and an LCVR that comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof. [00197] In some embodiments, the other(s) of ABD1, ABD2, and ABD3 binds to TfR, and ABD1, ABD2, and/or ABD3 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 502, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 503, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 504; and/or an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 13, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 14. [00198] In some embodiments, i) ABD1 binds to TfR; j) ABD2 and ABD3 bind to the capsid of the AAV particle; k) Fc1 comprises the amino acid sequence of SEQ ID NO: 1397, or a variant thereof; and l) Fc2 comprises the amino acid sequence of SEQ ID NO: 1511, or a variant thereof. [00199] In some embodiments, the AAV is wild type. [00200] In some embodiments, the AAV particle comprises one or more mutations in one or more AAV capsid proteins inhibiting the natural tropism of said AAV particle. [00201] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment is a bispecific antibody or bispecific antigen-binding fragment thereof. [00202] In another aspect, provided herein is a pharmaceutical composition comprising the multispecific antibodies or multispecific antigen-binding fragments as described herein, and a pharmaceutically acceptable carrier or excipient. [00203] 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 as described herein. [00204] In some embodiments, the AAV particle comprises one or more mutations in one or more AAV capsid proteins inhibiting the natural tropism of said AAV particle. [00205] In another aspect, provided herein is a pharmaceutical composition comprising the molecular complex as described herein and a pharmaceutically acceptable carrier or excipient. [00206] In another aspect, provided herein is a method of preparing the molecular complex as described herein, comprising incubating the AAV particle in the presence of the 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. [00207] In another aspect, provided herein is a method for targeting an AAV particle to a ^ ^
Attorney Docket No.250298.000954 cell expressing a molecule on the cell surface, comprising contacting the cell with the molecular complex as described herein, or the pharmaceutical composition as 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. [00208] 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 the molecular complex as described herein or the pharmaceutical composition as 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. [00209] In some embodiments, the cell is in a subject and the molecular complex is administered to the subject. [00210] In some embodiments, the AAV particle does not target the cell in the absence of the one or more multispecific antibodies and/or multispecific antigen-binding fragments. [00211] 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. [00212] Other embodiments will become apparent from a review of the ensuing detailed description. BRIEF DESCRIPTION OF THE DRAWINGS [00213] 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. [00214] 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)/mass spectrometry (MS) methods (Figures 2A-2F) and by anti-AAV antibodies derived from hybridoma (Figures 2G-2J) described herein for various AAV serotypes. [00215] 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., ^). ^ ^
Attorney Docket No.250298.000954 [00216] Figure 4 displays a description of alternative format bispecific antibody molecules described herein. [00217] Figure 5 illustrates an example rationale for anti-AAV antibody selection. [00218] Figures 6A-6J depict graphs of binding affinities of alternative format antibodies described herein (e.g., anti-AAV x anti-ASGR1 [also called AAV x ASGR1, and the like, herein] bispecific antibodies) to an AAV2 heparin binding mutant (HBM) serotype. The AAV2-HBM serotype contains R585A, R588A mutations. RLU, relative light units. [00219] 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. [00220] 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. [00221] Figure 9 shows a schematic representation of anti-AAV x anti-CACNG1 (also called AAV x CACNG1, and the like, herein) alternative format (AF) antibodies AF70 and AF71.^AF70 comprises anti-AAV#70 scFv fused to the N-terminus of anti-CACNG1 REGN10717 hIgG1 N297G antibody. AF71 comprises anti-AAV#70 scFv fused to the C-terminus of anti-CACNG1 REGN10717 hIgG1 N297G antibody. Disulfide bonds are indicated by S-S. [00222] 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 (mCACNG1). 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. [00223] 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 (mCACNG1). 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). [00224] Figure 12 shows flow cytometry data illustrating co-incubation of AAV9 W503A with ^ ^
Attorney Docket No.250298.000954 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 (hCACNG1). 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. [00225] 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 (hCACNG1). 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). [00226] 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. [00227] 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. [00228] 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. [00229] 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. [00230] Figures 18A-18B show non-limiting examples of anti-AAV x anti-mTfR (also called AAV x mTfR, and the like, herein) 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., ^). [00231] Figure 19 shows an example experimental setup used to test alternative format antibodies binding to AAV9W503A virus by ELISA. [00232] Figure 20 depicts ELISA data for anti-AAV x anti-mTfR alternative format antibodies binding to AAV9W503A. [00233] 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. ^ ^
Attorney Docket No.250298.000954 [00234] Figure 22 shows a line graph of data generated in experiments testing AAV9W503A retargeting using anti-AAV x anti-mTfR alternative format antibodies on mTfR293T cells. [00235] Figures 23A-23C illustrate a retargeting assay using AAV9 scCBH.eGFP. [00236] Figures 24A-24B show in vitro test infection results for in vivo injection samples. [00237] Figures 25A-25F depict anti-AAV x anti-mTfR liver and brain (hippocampus, cortex, and cerebellum) green fluorescent protein (GFP) staining for control groups (Figure 25A) and alternative format designs, anti-AAV x anti-mTfR AF1 (Figure 25B), anti-AAV x anti-mTfR AF3 (Figure 25C), anti-AAV x anti-mTfR AF5 (Figure 25D), anti-AAV x anti-mTfR AF7 (Figure 25E), and anti-AAV x anti-mTfR AF9 (Figure 25F). [00238] Figure 26 shows relative RNA expression of GFP in liver samples as determined by RT-qPCR. [00239] Figure 27 shows RNA expression of GFP in brain samples as determined by RT- qPCR. [00240] 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 anti-AAV x anti-mTfR alternative format AF7 at AAV vector genome (VG) to antibody (Ab) ratios (VG:Ab ratios) of 1:9 and 1:3. [00241] Figures 29A-29I depict anti-AAV x anti-mTfR alternative format designs AF3 and AF7. Figure 29A provides a description of anti-AAV x anti-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 anti-AAV x anti-mTfR AF3 amino acid sequences (Figure 29B) and corresponding nucleotide sequences (Figures 29C-29E). Figures 29F-29I show examples of anti-AAV x anti-mTfR AF7 amino acid sequences (Figure 29F) and corresponding nucleotide sequences (Figures 29G- 29I). Figure discloses “3xG4S” as SEQ ID NO: 1115. [00242] Figures 30A-30G depict anti-AAV x anti-CACNG1 alternative format designs AF70 and AF71. Figure 30A provides a description of anti-AAV x anti-CACNG1 alternative format designs AF70 and AF71. Figures 30B-30G show examples of anti-AAV x anti-CACNG1 AF70 amino acid sequences (Figure 30B) and corresponding nucleotide sequences (Figures 30C- 30D). Figures 30E-30G show examples of anti-AAV x anti-CACNG1 AF71 amino acid sequences (Figure 30E) and corresponding nucleotide sequences (Figures 30F-30G). Figure discloses “3xG4S” as SEQ ID NO: 1115 and “4xG4S” as SEQ ID NO: 1161. [00243] Figure 31 illustrates anti-AAV x anti-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). ^ ^
Attorney Docket No.250298.000954 [00244] Figure 32 depicts an example of a study design for testing Hu37 complexed with anti-AAV x anti-CACNG12x2 antibodies in D2.MDX mice. [00245] Figure 33 shows in vitro transduction in HEK293-hCACNG1 of complexes prepared for in vivo study.^ [00246] Figures 34A-34C illustrate improved Hu37 transduction in muscle tissues when complexed with an 2x2 anti-AAV x anti-CACNG1 alternative format antibody. [00247] Figures 35A-35B illustrate bispecific antibody enhancement of Hu37 transduction into skeletal muscle. [00248] Figures 36A-36B depict anti-AAV x anti-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 anti-AAV x anti- ASGR alternative format designs AF21 (REGN16199), AF22 (REGN16200), AF29, AF30 (REGN16204), and AF32 (REGN16202). Figure 36B provides a description of anti-AAV x anti-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. [00249] Figures 37A-37B depict IVIS (In Vivo Imaging Instrument, Perkin Elmer) data illustrating retargeting of AAV to liver with AF30 and AF32. [00250] Figure 38 depicts IVIS data that demonstrate retargeting of multiple serotypes to liver with AF30. [00251] 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. [00252] Figures 40A-40C depict IVIS, PK qPCR, & ELISA data that demonstrate antibody can effectively retarget AAV when dosed prior to AAV administration. [00253] Figures 41A-41B depict IVIS & PK qPCR data that demonstrate retargeting of REGN16199 with and without Fc. [00254] Figures 42A-42F depict IVIS, PK qPCR, & RNA Taqman data that demonstrate successful targeting with linear Fab formats. [00255] Figure 43 depicts PK qPCR data of serum samples 24 hours after administration of various antibody formats complexed with AAV. [00256] Figure 44 depicts IVIS data that demonstrate retargeting of AAV with a variety of different antibody formats. [00257] Figure 45 depicts IVIS data that demonstrate retargeting of AAV with antibody comprised of one anti-AAV arm and one anti-ASGR1 arm. [00258] Figures 46A-46I depict anti-AAV x anti-ASGR alternative format designs AF1, AF5, and AF9. Figures 46A-46C show examples of anti-AAV x anti-ASGR AF1 amino acid sequences (Figure 46A) and corresponding nucleotide sequences (Figures 46B-46C). ^ ^
Attorney Docket No.250298.000954 Figures 46D-46F show examples of anti-AAV x anti-ASGR AF5 amino acid sequences (Figure 46D) and corresponding nucleotide sequences (Figures 46E-46F). Figures 46G-46I show examples of anti-AAV x anti-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. [00259] Figures 47A-47I depict anti-AAV x anti-mTfR alternative format designs AF1, AF5, and AF9. Figures 47A-47C show examples of anti-AAV x anti-mTfR AF1 amino acid sequences (Figure 47A) and corresponding nucleotide sequences (Figures 47B-47C). Figures 47D-47F show examples of anti-AAV x anti-mTfR AF5 amino acid sequences (Figure 47D) and corresponding nucleotide sequences (Figures 47E-47F). Figures 47G-47I show examples of anti-AAV x anti-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. [00260] Figure 48^shows a schematic representation of anti-AAV x anti-CACNG1 alternative format (AF) antibodies AF70, AF71, AF71x, AF72a, AF72b, AF73, AF74A, AF74B, and AF76. Star mutations are depicted with an asterisk (*) and knob-in-hole (KiH) mutations are depicted with a triangle (^).Figure discloses “3xG4S” as SEQ ID NO: 1115, “G4S” as SEQ ID NO: 242, and “4xG4S” as SEQ ID NO: 1161. [00261] Figures 49A-49B show flow cytometry data illustrating that co-incubation of AAV Hu37 with AF71, AF71x, AF72a, AF73, AF74A, and AF74B resulted in improved transduction efficiency over control AAV without antibody on HEK 293 cells overexpressing human CACNG1 (hCACNG1). 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 49A) and Median Fluorescence Intensity (MFI) (Figure 49B). [00262] Figures 50A-50E^ illustrate bispecific antibody enhancement of Hu37 transduction into skeletal muscle. Transduction levels are shown for the following skeletal muscles: tongue (Figure 50A), gastrocnemius (gastroc)/soleus (Figure 50B), and tibialis anterior (TA) (Figure 50C). Transduction levels for the heart (Figure 50D) and liver (Figure 50E) are also depicted. [00263] Figures 51A-51C depict examples of amino acid sequences (Figure 51A) and corresponding nucleotide sequences (Figures 51B-51C) for anti-AAV x anti-CACNG1 alternative format design AF71x. [00264] Figures 52A-52C depict examples of amino acid sequences (Figure 52A) and corresponding nucleotide sequences (Figures 52B-52C) for anti-AAV x anti-CACNG1 alternative format design AF72a. [00265] Figures 53A-53C depict examples of amino acid sequences (Figure 53A) and ^ ^
Attorney Docket No.250298.000954 corresponding nucleotide sequences (Figures 53B-53C) for anti-AAV x anti-CACNG1 alternative format design AF72b. [00266] Figures 54A-54C depict examples of amino acid sequences (Figure 54A) and corresponding nucleotide sequences (Figures 54B-54C) for anti-AAV x anti-CACNG1 alternative format design AF73. [00267] Figures 55A-55E depict examples of amino acid sequences (Figures 55A-55B) and corresponding nucleotide sequences (Figures 55C-55E) for anti-AAV x anti-CACNG1 alternative format design AF74A. [00268] Figures 56A-56D depict examples of amino acid sequences (Figure 56A) and corresponding nucleotide sequences (Figures 56B-56D) for anti-AAV x anti-CACNG1 alternative format design AF74B. [00269] Figures 57A-57C depict examples of amino acid sequences (Figure 57A) and corresponding nucleotide sequences (Figures 57B-57C) for anti-AAV x anti-CACNG1 alternative format design AF76. [00270] Figures 58A-58B^ show schematic representations of anti-AAV x anti-human transferrin receptor (hTfR) (also called AAV x hTfR herein) antibodies DB7035B, DB7043B, DB7045B, DB7047B, DB8035B, DB8043B, DB8045B, and DB8047B (Davis body orientation), as well as alternative format (AF) (i.e., Altibody) antibodies AF7035B, AF7043B, AF7045B, AF7047B, AF8035B, AF8043B, AF8045B, and AF8047B. Star mutations are depicted with an asterisk (*) and knob-in-hole (KiH) mutations are depicted with a triangle ^). Figure 58B discloses “3xG4S” as SEQ ID NO: 1115. [00271] Figures 59A-59B show flow cytometry data illustrating co-incubation of AAV9 with DB7035B, DB7043B, DB7045B, DB7047B, DB8035B, DB8043B, DB8045B, and DB8047B, resulted in improved transduction efficiency over control AAV9 without antibody on 3T3 cells overexpressing human TfR (hTfR). Transduction efficiency was assessed by percent (%) GFP positive cells (Figure 59A) and Median Fluorescence Intensity (MFI) (Figure 59B). [00272] Figures 60A-60B show flow cytometry data illustrating co-incubation of AAV9 with AF7035B, AF7043B, AF7045B, AF7047B, AF8035B, AF8043B, AF8045B, and AF8047B, resulted in improved transduction efficiency over control AAV9 without antibody on 3T3 cells overexpressing human TfR (hTfR). Transduction efficiency was assessed by percent (%) GFP positive cells (Figure 60A) and Median Fluorescence Intensity (MFI) (Figure 60B). [00273] Figures 61A-61D illustrate bispecific antibody enhancement of AAV9 transduction into different brain areas. Bispecific antibody enhancement of AAV9 transduction into the hippocampus, cerebellum, and cortex are shown in Figures 61A-61C, respectively.^In addition to hippocampus (CA2 region), cerebellum, and cortex, Figure 61D illustrates bispecific antibody AF7045B enhancement of AAV9 transduction into medulla, olfactory bulb, thalamus, ^ ^
Attorney Docket No.250298.000954 striatum, hypothalamus, and midbrain. [00274] Figure 62 illustrates quantification of green fluorescent protein (GFP) in the cortex of hTfR mice (7229KO) by measuring the percent (%) GFP area. [00275] Figures 63A-63C illustrate quantification of mRNA levels in the brain (Figure 63A), liver (Figure 63B), and heart (Figure 63C) of hTfR mice (7229KO). [00276] Figures 64A-64D depict examples of amino acid sequences (Figure 64A) and corresponding nucleotide sequences (Figures 64B-64D) for anti-AAV x anti-hTFR Davis body design DB7035B. [00277] Figures 65A-65D depict examples of amino acid sequences (Figure 65A) and corresponding nucleotide sequences (Figures 65B-65D) for anti-AAV x anti-hTFR Davis body design DB7043B. [00278] Figures 66A-66D depict examples of amino acid sequences (Figure 66A) and corresponding nucleotide sequences (Figures 66B-66D) for anti-AAV x anti-hTFR Davis body design DB7045B. [00279] Figures 67A-67D depict examples of amino acid sequences (Figure 67A) and corresponding nucleotide sequences (Figures 67B-67D) for anti-AAV x anti-hTFR Davis body design DB7047B. [00280] Figures 68A-68D depict examples of amino acid sequences (Figure 68A) and corresponding nucleotide sequences (Figures 68B-68D) for anti-AAV x anti-hTFR Davis body design DB8035B. [00281] Figures 69A-69D depict examples of amino acid sequences (Figure 69A) and corresponding nucleotide sequences (Figures 69B-69D) for anti-AAV x anti-hTFR Davis body design DB8043B. [00282] Figures 70A-70D depict examples of amino acid sequences (Figure 70A) and corresponding nucleotide sequences (Figures 70B-70D) for anti-AAV x anti-hTFR Davis body design DB8045B. [00283] Figures 71A-71D depict examples of amino acid sequences (Figure 71A) and corresponding nucleotide sequences (Figures 71B-71D) for anti-AAV x anti-hTFR Davis body design DB8047B. [00284] Figures 72A-72D depict examples of amino acid sequences (Figure 72A) and corresponding nucleotide sequences (Figures 72B-72D) for anti-AAV x anti-hTFR alternative format design AF7035B. [00285] Figures 73A-73D depict examples of amino acid sequences (Figure 73A) and corresponding nucleotide sequences (Figures 73B-73D) for anti-AAV x anti-hTFR alternative format design AF7043B. [00286] Figures 74A-74D depict examples of amino acid sequences (Figure 74A) and ^ ^
Attorney Docket No.250298.000954 corresponding nucleotide sequences (Figures 74B-74D) for anti-AAV x anti-hTFR alternative format design AF7045B. [00287] Figures 75A-75D depict examples of amino acid sequences (Figure 75A) and corresponding nucleotide sequences (Figures 75B-75D) for anti-AAV x anti-hTFR alternative format design AF7047B. [00288] Figures 76A-76D depict examples of amino acid sequences (Figure 76A) and corresponding nucleotide sequences (Figures 76B-76D) for anti-AAV x anti-hTFR alternative format design AF8035B. [00289] Figures 77A-77D depict examples of amino acid sequences (Figure 77A) and corresponding nucleotide sequences (Figures 77B-77D) for anti-AAV x anti-hTFR alternative format design AF8043B. [00290] Figures 78A-78D depict examples of amino acid sequences (Figure 78A) and corresponding nucleotide sequences (Figures 78B-78D) for anti-AAV x anti-hTFR alternative format design AF8045B. [00291] Figures 79A-79D depict examples of amino acid sequences (Figure 79A) and corresponding nucleotide sequences (Figures 79B-79D) for anti-AAV x anti-hTFR alternative format design AF8047B. [00292] Figures 80A-80B^show examples of structures of multispecific binding molecules (MBMs) of the disclosure. Figure 80A shows the structure of a MBM comprising: i) a first polypeptide chain comprising (in an N- to C-terminal orientation) a^single domain antibody (sdAb) (e.g., VHH), an optional linker, a CH2 domain, a CH3 domain, an optional linker, a variable heavy (VH) domain, and a CH1 domain; ii) a second polypeptide chain comprising (in an N- to C-terminal orientation) a variable light (VL) domain and a constant domain of a light chain (CL) associated with the VH and CH1 domains; iii) a third polypeptide chain comprising (in an N- to C-terminal orientation) a^single-chain Fv (scFv), an optional linker, a CH2 domain, a CH3 domain, an optional linker, a VH domain, and a CH1 domain; and iv) a fourth polypeptide chain comprising (in an N- to C-terminal orientation) a VL domain and a CL domain associated with the VH and CH1 domains. Figure 80B shows the structure of a MBM comprising:^i) a first polypeptide chain comprising (in an N- to C-terminal orientation) a sdAb (e.g., VHH), an optional linker, a CH2 domain, a CH3 domain, an optional linker, a VH domain, and a CH1 domain; ii) a second polypeptide chain comprising (in an N- to C-terminal orientation) a VL domain and a CL domain associated with the VH and CH1 domains; iii) a third polypeptide chain comprising (in an N- to C-terminal orientation) a sdAb (e.g., VHH), an optional linker, a CH2 domain, a CH3 domain, an optional linker, a VH domain, and a CH1 domain; and iv) a fourth polypeptide chain comprising (in an N- to C-terminal orientation) a VL domain and a CL domain associated with the VH and CH1 domains. ^ ^
Attorney Docket No.250298.000954 [00293] Figures 81A-81B^show examples of structures of^anti-AAV x anti-TfR alternative format designs REGN23091 (also referred to as AF7 herein) (Figure 81A) and REGN22198 (Figure 81B). [00294] Figures 82A-82B^ show examples of structures of^ anti-AAV x anti-CACNG1 alternative format designs REGN20586 (also referred to as AF71 herein) (Figure 82A) and REGN22008 (also referred to as AF71x herein) (Figure 82B). [00295] Figure 83 illustrates bispecific antibody enhancement of AAV9 transduction into the brain using different AAV and antibody complexing conditions along with sequential dosing of antibody and AAV. F/T, freeze and thaw. [00296] Figure 84 illustrates anti-AAV x anti-CACNG1 bispecific antibody enhancement of AAV9 W503A transduction into skeletal muscle. Transduction levels are shown for the following skeletal muscles: gastrocnemius and quadriceps. Transduction level for the heart and liver are also depicted. [00297] Figure 85 shows improved transduction efficiency of AAV9 with AFT5 and AFT8 alternative format antibodies over control AAV9 without antibody on 3T3 cells overexpressing human TfR (hTfR). The left panel depicts transduction as percent GFP expression. The right panel depicts transduction in terms of median fluorescence intensity (MFI). [00298] Figures 86A-86B show schematics of AFT5 (Figure 86A) and AFT8 (Figure 86B). [00299] Figures 87A-87D depict examples of amino acid sequences (Figure 87A) and corresponding nucleotide sequences (Figures 87B-87D) for anti-AAV x anti-hTFR alternative format design AFT8. [00300] Figures 88A-88C depict examples of amino acid sequences (Figure 88A) and corresponding nucleotide sequences (Figures 88B-88C) for anti-AAV x anti-hTFR alternative format design AFT5. [00301] Figures 89A-89D depict examples of amino acid sequences (Figure 89A) and corresponding nucleotide sequences (Figures 89B-89D) for anti-AAV x anti-hTFR REGN22198. DETAILED DESCRIPTION [00302] 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. ^ ^
Attorney Docket No.250298.000954 [00303] 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 [00304] 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.).^ [00305] 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. [00306] 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. [00307] 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. [00308] 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). ^ ^
Attorney Docket No.250298.000954 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). [00309] 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. [00310] 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. [00311] 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, ^ ^
Attorney Docket No.250298.000954 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. [00312] 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 “antigen- binding fragment,” as used herein. [00313] 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 VL 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 VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain. [00314] 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 ^ ^
Attorney Docket No.250298.000954 (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)). [00315] 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. [00316] 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). [00317] 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. [00318] The term “single domain antibody” or “sdAb” as used herein can refer to an antibody or antigen binding fragment thereof comprising a single binding domain (e.g., heavy chain variable region) capable of binding a target molecule without pairing with a corresponding CDR-containing polypeptide (e.g., a light chain). An sdAb or sdAb fragment can be derived from a VHH or from a non-antibody scaffold protein, for example a designed ankyrin repeat protein (darpin), an avimer, an anticalin/lipocalin, a centyrin, or a fynomer. A ^^^ ^
Attorney Docket No.250298.000954 sdAb typically lacks a CH1 domain and thus cannot associate with a light chain. [00319] The term “VHH” refers to a variable region of an antibody consisting of only a heavy chain, e.g., an antibody of camelid or cartilaginous fish origin. A VHH variable region can bind to a target molecule in the absence of a light chain. A basic VHH has the following structure from the N-terminus to the C-terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3. [00320] 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. [00321] 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 VL 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. [00322] 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.” [00323] 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 ^ ^
Attorney Docket No.250298.000954 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, e.g., via a knob-in-hole interaction and/or for purification, e.g., via star mutations. [00324] 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. [00325] 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 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 5x10-2M, less than 10-3 M, less than 5x10-4 M, less than 10-4M, less than 5x10-5M, less than 10-5M, less than 5x10-6M, less than 10-6 M, less than 5x10-7M, less than 10-7M, less than 5x10-8M, less than 10-8M, less than 5x10-9M, less than 10-9M, or less than 10-10 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. [00326] 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. [00327] 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. [00328] 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 ^ ^
Attorney Docket No.250298.000954 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, phenylalanine- tyrosine, 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. [00329] 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 ^ ^
Attorney Docket No.250298.000954 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. [00330] 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 [00331] 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 antigen- binding 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 antigen- binding fragment thereof, described herein. [00332] “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, non- enveloped, 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. [00333] 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; ^ ^
Attorney Docket No.250298.000954 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. [00334] “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. [00335] 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 ^ ^
Attorney Docket No.250298.000954 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. [00336] 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 serotype- specific 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. [00337] 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). [00338] 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. [00339] 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 ^ ^
Attorney Docket No.250298.000954 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. [00340] 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. [00341] 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. [00342] 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. [00343] In some embodiments, a Cap protein, e.g., a VP1 capsid protein as described herein, a VP2 capsid protein as described herein, and/or a VP3 capsid protein as described herein, can be modified to comprise any number of various capsid modifications, e.g., one or more of a point mutation (e.g., amino acid substitutions, deletions, and/or insertions), a ^ ^
Attorney Docket No.250298.000954 detectable label, a member of a protein:protein binding pair, etc. [00344] In some embodiments, the one or more point mutation(s) in a capsid protein (e.g., a VP1, VP2, and/or VP3 capsid protein) described herein can result in detargeting a viral particle comprising the mutant capsid protein from its natural target cell. Detargeting of a viral particle from its natural target cell can be important especially if systemic versus local or loco-regional administration of the viral particles is intended, as uptake of the viral particles by the natural target cell can limit the effective dose of the viral particles. Accordingly, point mutations can be those that reduce the transducing activity of a viral particle which is mediated by the natural receptor of the viral particle by at least 50%, preferably at least 80%, especially at least 95%. In some embodiments, detargeting mutations disclosed herein can involve deletion or replacement of one or more an amino acids which can be involved in binding of the respective viral particle to its natural receptor. Such point mutations can enable an efficient detargeting of the viral particle from cells expressing the natural receptor or, for targeting purposes, can increase specificity of the respective mutant viral particle for a new target cell. [00345] In some embodiments, a capsid protein (e.g., a VP1, VP2, and/or VP3 capsid protein) of the present disclosure can be modified to comprise an inserted heterologous amino acid sequence (e.g., a peptide insertion described herein or an additional peptide insertion, such as a peptide comprising, consisting essentially of, or consisting of any of various targeting molecules described herein) capable of retargeting or redirecting a viral particle described herein. “Retargeting” or “redirecting” may include a scenario in which a wild-type viral particle targets several cells within a tissue and/or several organs within an organism, and general targeting of the cells, tissues, and/or organs is reduced or abolished by insertion of a heterologous amino acid sequence, and retargeting the viral particle to more a specific cell in the tissue or a specific organ in the organism is achieved with the inserted heterologous amino acid sequence which can, e.g., bind a marker expressed by a specific cell. Such retargeting or redirecting may also include a scenario in which the wild- type viral particle targets a tissue, and targeting of the tissue is reduced or abolished by insertion of the heterologous amino acid sequence, and retargeting to a completely different tissue is achieved with the inserted heterologous amino acid sequence. [00346] One or more of detargeting and/or retargeting mutation(s) and/or insertion(s) can be introduced into capsid proteins of any of various AAV serotypes disclosed herein. Such detargeting and/or retargeting mutation(s) and/or insertion(s) can result in detargeting and/or retargeting of an AAV particle comprising a mutant capsid protein from or to specific cells within a tissue and/or organs within an organism. For example, cells, tissues, and/or organs which may be detargeted and/or detargeted by AAV particles comprising mutant capsids ^ ^
Attorney Docket No.250298.000954 may include or be derived from, without limitation, liver, skeletal muscle, vascular and/or smooth muscle, cardiac muscle, nervous system (e.g., brain, spinal cord, neurons, glia, ependymal cells), eye (e.g., retina and retinal cells including photoreceptors such as rods and cones, RPE, etc.), lung, heart, pancreas, kidney, and epithelium. [00347] In various embodiments, an AAV2 serotype is preferred for use in the compositions and/or methods of the present disclosure. In some embodiments the capsid of the AAV2 particle can comprise one or more amino acid mutations within a heparan sulfate proteoglycan (HSPG) binding domain of the AAV2 capsid. In some embodiments, the capsid of the AAV2 particle can comprise one or more amino acid mutations within a laminin receptor (LamR) binding domain, e.g., a 37/67-kDa LamR binding domain, of the AAV2 capsid. In some embodiments, the capsid of the AAV2 particle can comprise one or more mutations at an amino acid position(s) selected from amino acid position(s) R484, R487, R585, R588, and K532 (VP1 numbering), and a combination thereof, relative to a wild-type AAV2 capsid. In certain embodiments, the capsid of the AAV2 particle comprises a mutation at amino acid position R585 and/or R588. In some embodiments, the capsid of the AAV2 particle comprises one or more amino acid substitutions at an amino acid position(s) selected from R484A, R487A, R487G, K532A, K532D, R585A, R585S, R585Q, R588A, and R588T, and any combination thereof, relative to a wild-type AAV2 capsid. In some embodiments, the capsid of the AAV2 particle comprises an amino acid substitution R585A and/or R588A. AAV2 R585 corresponds to AAV9 S586 and AAV8 Q588 and AAV2 R588 corresponds to AAV9 A589 and AAV8 T591. Thus, when AAV9 is used, the capsid of the AAV9 particle can comprise a mutation at amino acid position S586 and/or A589. Similarly, when AAV8 is used, the capsid of the AAV8 particle can comprise a mutation at amino acid position Q588 and/or T591. In some embodiments, the capsid of the AAV2 particle comprises one or more insertion(s) at amino acid position G453 or N587, or a combination thereof. [00348] In some embodiments, an AAV9 serotype is used in the compositions and/or methods of the present disclosure. In some embodiments, the capsid of the AAV9 particle can comprise one or more amino acid mutations within a galactose binding domain of the AAV9 capsid. In some embodiments, the capsid of the AAV9 particle can comprise one or more mutations at an amino acid position(s) selected from amino acid position(s) D271, N272, Y446, S469, N470, A742, V473, W503, E500, P504, and Q590 (VP1 numbering), and a combination thereof, relative to a wild-type AAV9 capsid. In certain embodiments, the capsid of the AAV9 particle comprises a mutation at amino acid position N272 and/or W503. In some embodiments, the capsid of the AAV9 particle comprises one or more amino acid substitutions selected from K532A, K532D, R484A, R487A, R585A, R585S, R585Q, R487G, ^ ^
Attorney Docket No.250298.000954 R588A, and R588T, and any combination thereof, relative to a wild-type AAV2 capsid. In some embodiments, the capsid of the AAV9 particle comprises an amino acid substitution N272A and/or W503A, relative to a wild-type AAV9 capsid. In some embodiments, the capsid of the AAV9 particle comprises one or more insertion(s) at amino acid position G453, A587, or A589, or a combination thereof. [00349] In some embodiments, an AAV1 serotype is used in the compositions and/or methods of the present disclosure. In some embodiments, the capsid of the AAV1 particle can comprise one or more amino acid mutations within a sialic acid binding domain, e.g., an N-linked sialic acid binding domain, of the AAV1 capsid. In some embodiments, the capsid of the AAV1 particle can comprise one or more amino acid mutations within a binding domain of the AAV1 capsid essential for binding adeno-associated virus receptor (AAVR). In some embodiments, the capsid of the AAV1 particle can comprise one or more mutations at an amino acid position(s) selected from amino acid position(s) N500 (which corresponds to AAV2 E499 and AAV9 E500), K531, and K531 (VP1 numbering), and a combination thereof, relative to a wild-type AAV1 capsid. In some embodiments, the capsid of the AAV1 particle comprises one or more amino acid substitutions selected from N500E, K531A, and K531E, and any combination thereof, relative to a wild-type AAV1 capsid. [00350] In some embodiments, an AAV6 serotype is used is used in the compositions and/or methods of the present disclosure. In some embodiments, the capsid of the AAV6 particle can comprise one or more amino acid mutations within a sialic acid binding domain, e.g., an N-linked sialic acid binding domain, of the AAV6 capsid. In some embodiments, the capsid of the AAV6 particle can comprise one or more amino acid mutations within a heparan sulfate proteoglycan (HSPG) binding domain of the AAV6 capsid. In some embodiments, the capsid of the AAV6 particle can comprise one or more amino acid mutations within an epidermal growth factor receptor (EGFR) binding domain of the AAV6 capsid. In some embodiments, the capsid of the AAV6 particle can comprise an amino acid mutation at amino acid position N500 (which corresponds to AAV2 E499 and AAV9 E500) (VP1 numbering), relative to a wild-type AAV6 capsid. In some embodiments, the capsid of the AAV6 particle comprises amino acid substitution N500E relative to a wild-type AAV6 capsid. In some embodiments, the capsid of the AAV6 particle comprises an insertion at amino acid position Q585. [00351] In some embodiments, an AAV8 serotype is used is used in the compositions and/or methods of the present disclosure. In some embodiments, the capsid of the AAV8 particle can comprise one or more amino acid mutations within a laminin receptor (LamR) binding domain, e.g., a 37/67-kDa LamR binding domain, of the AAV8 capsid. In some embodiments, the capsid of the AAV8 particle comprises an insertion at amino acid position ^ ^
Attorney Docket No.250298.000954 N590 (VP1 numbering). [00352] In some embodiments, an AAV5 serotype is used in the compositions and/or methods of the present disclosure. In some embodiments, the capsid of the AAV5 particle can comprise one or more amino acid mutations within a sialic acid binding domain, e.g., an N-linked sialic acid binding domain, of the AAV5 capsid. In some embodiments, the capsid of the AAV5 particle can comprise one or more amino acid mutations within a platelet-derived growth factor receptor (PDGFR) of the AAV5 capsid. In some embodiments, the capsid of the AAV5 particle can comprise a mutation at amino acid position T571 (VP1 numbering) relative to a wild-type AAV5 capsid. In some embodiments, the capsid of the AAV5 particle comprises an amino acid substitution T571S relative to a wild-type AAV5 capsid. [00353] In some embodiments, an avian AAV is used in the compositions and/or methods of the present disclosure. In some embodiments, the capsid of the avian AAV particle comprises an insertion at amino acid position(s) G444 or K580 (VP1 numbering), or a combination thereof. [00354] In some embodiments, an bearded dragon AAV is used in the compositions and/or methods of the present disclosure. In some embodiments, the capsid of the bearded dragon AAV particle comprises an insertion at amino acid position(s) G436 or T573 (VP1 numbering), or a combination thereof. [00355] 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. [00356] 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. [00357] 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. [00358] 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 ^ ^
Attorney Docket No.250298.000954 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. [00359] 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. [00360] 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. [00361] 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 antigen- ^ ^
Attorney Docket No.250298.000954 binding 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 IgG4 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
^^^ ^
Attorney Docket No.250298.000954
^ Table 2. Nucleic Acid Sequence Identifiers for Anti-AAV Antibodies
^^^ ^
Attorney Docket No.250298.000954
REGN13876 HCVR DNA Sequence CAGGTGCACCTGCAAGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCTCCTGCACTGTCTCTGGTGATTCCATCAGAAGTGGTGGTTACTACTGGAGTTGGAT CCGCCAGCAGCCAGGAAGGGGCCTGGAATGGATTGGTTTCATCCATCAGAGTGACAG 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 ^ ^
Attorney Docket No.250298.000954 (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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 9) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 10) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (SEQ ID NO: 11) LCDR1 Amino Acid Sequence QSISSY (SEQ ID NO: 12) LCDR2 DNA Sequence GCTGCATCC (SEQ ID NO: 13) ^ ^
Attorney Docket No.250298.000954 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 CCGCCAGCAGCCAGGAAGGGGCCTGGAATGGATTGGTTTCATCCATCAGAGTGACAG GTCCTACTATAACCCGTCCCTCATGAATCGACTCACCATGTCAGTAGACACGTCTAAGA ATCAATTCTCCCTGAAACTGACCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGT GCGAGAGATCGGGACACCATGGTTCGGGGAAGCATTACAACTTCCGGCCACTTCATTG ACTACTGGGGCCAGGGAACCCTGATCACCGTCTCCTCAGCCTCCACCAAGGGCCCATC GGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGG CTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC CCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGC AACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATG GTCCCCCATGA (SEQ ID NO: 17) HC Amino Acid Sequence QVHLQESGPGLVKPSQTLSLSCTVSGDSIRSGGYYWSWIRQQPGRGLEWIGFIHQSDRSY YNPSLMNRLTMSVDTSKNQFSLKLTSVTAADTAVYYCARDRDTMVRGSITTSGHFIDYWGQ GTLITVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP* (SEQ ID NO: 18) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA ^^^ ^
Attorney Docket No.250298.000954 CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 19) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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) ^ ^
Attorney Docket No.250298.000954 HCDR2 DNA Sequence ATCTATTACAGTGGCGGCACC (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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 9) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 10) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (SEQ ID NO: 11) LCDR1 Amino Acid Sequence QSISSY (SEQ ID NO: 12) ^ ^
Attorney Docket No.250298.000954 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 Amino Acid Sequence QVQLQESGPVLVKPSETLSLTCTVSGDSISNYYWSWIRQSPGKGLEWIGYIYYSGGTNYNP SLKSRVTISIDTSKRHFSLKLNSVIAADTAVYYCARAPVTMVRGVITYNYHYAMDVWGQGTT VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP* (SEQ ID NO: 30) LC DNA Sequence ^ ^
Attorney Docket No.250298.000954 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 19) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 20) REGN13878 HCVR DNA Sequence CAATTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA CTCTCATGTGCCGCCTCTGGATTCAGTTTCAGTAGTTATGGCATGCACTGGGTCCGCCA GACTCCAGGCAAGGGACTGGAGTGGGTGACATTTATATCATATGACGGAAGTTATGATT ACTATTTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACATTTCCAAGAACACA TTGTATTTGCAAATGAACAGCCTGAGAATTGAGGACACGGCTGTCTATTACTGTGCGAG CGGCCTCACTGGCCCTACGAGGTGGTATTTCGATCTCTGGGGCCGTGGCACCCTGGT CACTGTCTCCTCC (SEQ ID NO: 31) HCVR Amino Acid Sequence QLQLVESGGGVVQPGRSLRLSCAASGFSFSSYGMHWVRQTPGKGLEWVTFISYDGSYDY YLDSVKGRFTISRDISKNTLYLQMNSLRIEDTAVYYCASGLTGPTRWYFDLWGRGTLVTVSS (SEQ ID NO: 32) HCDR1 DNA Sequence GGATTCAGTTTCAGTAGTTATGGC (SEQ ID NO: 33) ^ ^
Attorney Docket No.250298.000954 HCDR1 Amino Acid Sequence GFSFSSYG (SEQ ID NO: 34) HCDR2 DNA Sequence ATATCATATGACGGAAGTTATGAT (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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 9) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 10) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (SEQ ID NO: 11) LCDR1 Amino Acid Sequence ^ ^
Attorney Docket No.250298.000954 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 QLQLVESGGGVVQPGRSLRLSCAASGFSFSSYGMHWVRQTPGKGLEWVTFISYDGSYDY YLDSVKGRFTISRDISKNTLYLQMNSLRIEDTAVYYCASGLTGPTRWYFDLWGRGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP* (SEQ ID NO: 40) ^ ^
Attorney Docket No.250298.000954 LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 19) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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 ^ ^
Attorney Docket No.250298.000954 (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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 9) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 10) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT ^ ^
Attorney Docket No.250298.000954 (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 SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP* ^^^ ^
Attorney Docket No.250298.000954 (SEQ ID NO: 50) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 19) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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 ^^^ ^
Attorney Docket No.250298.000954 (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 GGTGACTCCATCAGAAATGGCGGCTATTAT (SEQ ID NO: 53) HCDR1 Amino Acid Sequence GDSIRNGGYY (SEQ ID NO: 54) HCDR2 DNA Sequence ^ ^
Attorney Docket No.250298.000954 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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 9), or GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA 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 ^^^ ^
Attorney Docket No.250298.000954 (SEQ ID NO: 1157) (Cys mutation underlined in sequence above) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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 ^ ^
Attorney Docket No.250298.000954 (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 QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP* (SEQ ID NO: 60), or QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1108) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG ^ ^
Attorney Docket No.250298.000954 (SEQ ID NO: 19), or GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGT (SEQ ID NO: 1145), or GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 1500) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 20) REGN13881 HCVR DNA Sequence CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCTCCTGCACTGTCTCTCGTGGCTCCATCAGCAGTGGTGGTTACTATTGGAGCTGGAT CCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGATACATCCATTATAGTGAGAG ^^^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 9) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 10) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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 ^ ^
Attorney Docket No.250298.000954 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCTCCTGCACTGTCTCTCGTGGCTCCATCAGCAGTGGTGGTTACTATTGGAGCTGGAT CCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGATACATCCATTATAGTGAGAG GACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATGTCAGTTGACACGTCTAAGA ACCAGTTCTCCCTGAAGCTGACCTCTGTGACTGCCGCGGACACGGCCGTGTATTATTG TGCGAGAGATCGGGACACCATGGTTCGGGGAGTCATTACAACTTCCGGCCACTTCATT GACGACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCA TCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCT GCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATA TGGTCCCCCATGA (SEQ ID NO: 68) HC Amino Acid Sequence QVQLQESGPGLVKPSQTLSLSCTVSRGSISSGGYYWSWIRQHPGKGLEWIGYIHYSERTYY NPSLKSRVTMSVDTSKNQFSLKLTSVTAADTAVYYCARDRDTMVRGVITTSGHFIDDWGQ GTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP* (SEQ ID NO: 69) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 19) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 20) ^ ^
Attorney Docket No.250298.000954 REGN13882 (NAC67606) HCVR DNA Sequence GAGGTGCACTTATTGGACTCTGGCGGAGGCTTGGTTCAGTCGGGGGAGTCCCTGAGA CTCTCCTGTACAGTCTCTGGAGTCACTTTTGAAAACCTTGTCATGAACTGGGTCCGGCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCGCAAGTGTTGGAGGTCGTTATACTGGCGC GGTCTTCGCAGACTCAGTGAGGGGCCGGTTCACGATCTCCAGAGACCATTCCGAGAAT ACGCTCTTTCTGCACATGAGCAGCCTGAGAGCCGAGGACACGGCCGTTTATTTTTGTAC GAAAGATTCCTCTGTCCTGATTCGGGGAGTCATTAGTACAAACTACTTCTATAGTATGGA CGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 70) HCVR Amino Acid Sequence EVHLLDSGGGLVQSGESLRLSCTVSGVTFENLVMNWVRQAPGKGLEWVASVGGRYTGAV 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) ^ ^
Attorney Docket No.250298.000954 HCDR3 Amino Acid Sequence TKDSSVLIRGVISTNYFYSMDV (SEQ ID NO: 77) 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 CAGAGCATTAGCAGCTAT (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 ^ ^
Attorney Docket No.250298.000954 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 EVHLLDSGGGLVQSGESLRLSCTVSGVTFENLVMNWVRQAPGKGLEWVASVGGRYTGAV FADSVRGRFTISRDHSENTLFLHMSSLRAEDTAVYFCTKDSSVLIRGVISTNYFYSMDVWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP* (SEQ ID NO: 79) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 19) LC Amino Acid Sequence ^ ^
Attorney Docket No.250298.000954 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 20) REGN13883 HCVR DNA Sequence CAGGAGCAACTACAACAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCC CTCACCTGCGCTGTCCATGGTGGGTCATTCAGTGGTTACTACTGGAGTTGGATCCGCC AGCCCCCCGGGAAGGGGCTGGAGTGGATTGGGGAAATCTATCCTAGTGGAGGCACCA ACCAAAATCCGTCCCTCAAGAGTCGAGTCACCATATCACTAGACATGTCCCAGAACCAG TTCTCCCTGAGGCTGAACTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGA GACGGAATTGGGACGGATACTTTGACTTCTGGGGCCAGGGAATTAAGGTCACTGTCTC 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 ^ ^
Attorney Docket No.250298.000954 GCGAGACGGAATTGGGACGGATACTTTGACTTC (SEQ ID NO: 86) HCDR3 Amino Acid Sequence ARRNWDGYFDF (SEQ ID NO: 87) 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 CAGAGCATTAGCAGCTAT (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 ^^^ ^
Attorney Docket No.250298.000954 (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 TTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGG ACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGA (SEQ ID NO: 88) HC Amino Acid Sequence QEQLQQWGAGLLKPSETLSLTCAVHGGSFSGYYWSWIRQPPGKGLEWIGEIYPSGGTNQ NPSLKSRVTISLDMSQNQFSLRLNSVTAADTAVYYCARRNWDGYFDFWGQGIKVTVSSAS TKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP* (SEQ ID NO: 89) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 19) ^ ^
Attorney Docket No.250298.000954 LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 20) REGN13884 HCVR DNA Sequence CAGGTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA CTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATACACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCACTTATATGGTATGATGGAAGTAATAA ATACTATACAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAAGACACGGCTGTGTATTACTGTGC GAGAGATAGAGTGCGATCGTATAGCTGGAACTACTTTGACTACTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCA (SEQ ID NO: 90) HCVR Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVALIWYDGSNKY 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 ATATGGTATGATGGAAGTAATAAA (SEQ ID NO: 94) HCDR2 Amino Acid Sequence IWYDGSNK ^ ^
Attorney Docket No.250298.000954 (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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 9) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 10) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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) ^ ^
Attorney Docket No.250298.000954 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 GCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGC AACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGA (SEQ ID NO: 98) HC Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVALIWYDGSNKY YTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRVRSYSWNYFDYWGQGTLVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP* (SEQ ID NO: 99) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC ^ ^
Attorney Docket No.250298.000954 TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 19) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 20) REGN13885 HCVR DNA Sequence GAGGTGCAACTGGTGGAATCTGGAGGAGGCTTGGTCCAGCCTGGGGGTTCCCTGAGA CTCTCCTGTGCAGCCTCTGGGTTCATCGTCAGTAACAACTATATGAGATGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCGGTCATTTATAGTGGTGGTGGCACATA CTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGACACAATTCCAAGAACACG ATATATCTTCAAATGAACAGCCTGCGAATTGAGGACACGGCCGTGTATTATTGTGCGAG AGAAGATAGCCACTCGTCGGAAAGTTATGACTACTTCTACGGCATGGACGTCTGGGGC CAAGGGACCACGGTCACCGTCTCCCCA (SEQ ID NO: 100) HCVR Amino Acid Sequence EVQLVESGGGLVQPGGSLRLSCAASGFIVSNNYMRWVRQAPGKGLEWVSVIYSGGGTYY 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) ^ ^
Attorney Docket No.250298.000954 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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 9) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 10) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (SEQ ID NO: 11) LCDR1 Amino Acid Sequence QSISSY (SEQ ID NO: 12) LCDR2 DNA Sequence GCTGCATCC (SEQ ID NO: 13 LCDR2 Amino
^ ^
Attorney Docket No.250298.000954 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 EVQLVESGGGLVQPGGSLRLSCAASGFIVSNNYMRWVRQAPGKGLEWVSVIYSGGGTYY ADSVKGRFTISRHNSKNTIYLQMNSLRIEDTAVYYCAREDSHSSESYDYFYGMDVWGQGTT VTVSPASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP* (SEQ ID NO: 109) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ^^^ ^
Attorney Docket No.250298.000954 ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 19) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 20) REGN13070 HCVR DNA Sequence CAATTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA CTCTCATGTGCCGCCTCTGGATTCAGTTTCAGTAGTTATGGCATGCACTGGGTCCGCCA GACTCCAGGCAAGGGACTGGAGTGGGTGACATTTATATCATATGACGGAAGTTATGATT ACTATTTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACATTTCCAAGAACACA TTGTATTTGCAAATGAACAGCCTGAGAATTGAGGACACGGCTGTCTATTACTGTGCGAG CGGCCTCACTGGCCCTACGAGGTGGTATTTCGATCTCTGGGGCCGTGGCACCCTGGT CACTGTCTCCTCC (SEQ ID NO: 110) HCVR Amino Acid Sequence QLQLVESGGGVVQPGRSLRLSCAASGFSFSSYGMHWVRQTPGKGLEWVTFISYDGSYDY YLDSVKGRFTISRDISKNTLYLQMNSLRIEDTAVYYCASGLTGPTRWYFDLWGRGTLVTVSS (SEQ ID NO: 111) HCDR1 DNA Sequence GGATTCAGTTTCAGTAGTTATGGC (SEQ ID NO: 112) HCDR1 Amino Acid Sequence GFSFSSYG (SEQ ID NO: 113) HCDR2 DNA Sequence ATATCATATGACGGAAGTTATGAT ^ ^
Attorney Docket No.250298.000954 (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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 118) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 119) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (SEQ ID NO: 120) LCDR1 Amino Acid Sequence QSISSY (SEQ ID NO: 121) LCDR2 DNA Sequence GCTGCATCC (SEQ ID NO: 122) ^ ^
Attorney Docket No.250298.000954 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 TCTGGGAACAAAGACATATACATGTAATGTGGATCATAAGCCTTCTAATACAAAGGTGG ATAAGAGAGTGGAATCTAAGTATGGACCTCCTTGTCCTCCTTGTCCTGCTCCTGGCGGT GGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAGCCTAAGGATACACTGATGATCTCTAG AACACCTGAAGTGACATGTGTGGTGGTGGATGTGTCTCAGGAAGATCCTGAAGTGCAG TTTAATTGGTATGTGGATGGAGTGGAAGTGCATAATGCTAAGACAAAGCCTAGAGAAGA ACAGTTTAATTCTACATATAGAGTGGTGTCTGTGCTGACAGTGCTGCATCAGGATTGGC TGAATGGAAAGGAATATAAGTGTAAGGTGTCTAATAAGGGACTGCCTTCTTCTATCGAA AAGACAATCTCTAAGGCTAAGGGACAGCCTAGAGAACCTCAGGTGTATACACTGCCTC CTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTCTGACATGTCTGGTGAAGGGATTT TATCCTTCTGATATCGCTGTGGAATGGGAATCTAATGGACAGCCTGAAAATAATTATAAG ACAACACCTCCTGTGCTGGATTCTGATGGATCTTTTTTTCTGTATTCTAGACTGACAGTG GATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTTGTTCTGTGATGCATGAAGCTCT GCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTCCTGGAAAGTAG (SEQ ID NO: 126) HC Amino Acid Sequence QLQLVESGGGVVQPGRSLRLSCAASGFSFSSYGMHWVRQTPGKGLEWVTFISYDGSYDY YLDSVKGRFTISRDISKNTLYLQMNSLRIEDTAVYYCASGLTGPTRWYFDLWGRGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG ^^^ ^
Attorney Docket No.250298.000954 LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSVMHEALHNRFTQKSLSLSPGK* (SEQ ID NO: 127) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 128) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 129) REGN13071 HCVR DNA Sequence CAGGAGCAACTACAACAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCC CTCACCTGCGCTGTCCATGGTGGGTCATTCAGTGGTTACTACTGGAGTTGGATCCGCC AGCCCCCCGGGAAGGGGCTGGAGTGGATTGGGGAAATCTATCCTAGTGGAGGCACCA ACCAAAATCCGTCCCTCAAGAGTCGAGTCACCATATCACTAGACATGTCCCAGAACCAG TTCTCCCTGAGGCTGAACTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGA GACGGAATTGGGACGGATACTTTGACTTCTGGGGCCAGGGAATTAAGGTCACTGTCTC CTCA (SEQ ID NO: 130) HCVR Amino Acid Sequence ^ ^
Attorney Docket No.250298.000954 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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 118) LCVR Amino Acid Sequence ^ ^
Attorney Docket No.250298.000954 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 119) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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 ^^^ ^
Attorney Docket No.250298.000954 GGAATCTAAGTATGGACCTCCTTGTCCTCCTTGTCCTGCTCCTGGCGGTGGCGGACCT TCTGTGTTTCTGTTTCCTCCTAAGCCTAAGGATACACTGATGATCTCTAGAACACCTGAA GTGACATGTGTGGTGGTGGATGTGTCTCAGGAAGATCCTGAAGTGCAGTTTAATTGGTA TGTGGATGGAGTGGAAGTGCATAATGCTAAGACAAAGCCTAGAGAAGAACAGTTTAATT CTACATATAGAGTGGTGTCTGTGCTGACAGTGCTGCATCAGGATTGGCTGAATGGAAA GGAATATAAGTGTAAGGTGTCTAATAAGGGACTGCCTTCTTCTATCGAAAAGACAATCT CTAAGGCTAAGGGACAGCCTAGAGAACCTCAGGTGTATACACTGCCTCCTTCTCAGGA AGAAATGACAAAGAATCAGGTGTCTCTGACATGTCTGGTGAAGGGATTTTATCCTTCTG ATATCGCTGTGGAATGGGAATCTAATGGACAGCCTGAAAATAATTATAAGACAACACCT CCTGTGCTGGATTCTGATGGATCTTTTTTTCTGTATTCTAGACTGACAGTGGATAAGTCT AGATGGCAGGAAGGAAATGTGTTTTCTTGTTCTGTGATGCATGAAGCTCTGCATAATAG ATTTACACAGAAGTCTCTGTCTCTGTCTCCTGGAAAGTAG (SEQ ID NO: 138) HC Amino Acid Sequence QEQLQQWGAGLLKPSETLSLTCAVHGGSFSGYYWSWIRQPPGKGLEWIGEIYPSGGTNQ NPSLKSRVTISLDMSQNQFSLRLNSVTAADTAVYYCARRNWDGYFDFWGQGIKVTVSSAS TKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSC SVMHEALHNRFTQKSLSLSPGK* (SEQ ID NO: 139) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 128) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ ^ ^
Attorney Docket No.250298.000954 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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 GGTGACTCCATCAGAAATGGCGGCTATTAT (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 ^ ^
Attorney Docket No.250298.000954 GCGCGAGGTCGGGACACCATGGTTCGGGGATCCATTACAACTTCCGGCCACTTCATTG ACTCC (SEQ ID NO: 146) HCDR3 Amino Acid Sequence ARGRDTMVRGSITTSGHFIDS (SEQ ID NO: 147) LCVR DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 118) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 119) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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 ^ ^
Attorney Docket No.250298.000954 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 GACAGTGCTGCATCAGGATTGGCTGAATGGAAAGGAATATAAGTGTAAGGTGTCTAATA AGGGACTGCCTTCTTCTATCGAAAAGACAATCTCTAAGGCTAAGGGACAGCCTAGAGAA CCTCAGGTGTATACACTGCCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTCT GACATGTCTGGTGAAGGGATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAATG GACAGCCTGAAAATAATTATAAGACAACACCTCCTGTGCTGGATTCTGATGGATCTTTTT TTCTGTATTCTAGACTGACAGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTT GTTCTGTGATGCATGAAGCTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTC CTGGAAAGTAG (SEQ ID NO: 148) HC Amino Acid Sequence QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNRFTQKSLSLSPGK* ^ ^
Attorney Docket No.250298.000954 (SEQ ID NO: 149) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 128) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 129) REGN13073 HCVR DNA Sequence CAGGTGCAACTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA CTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATACACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCACTTATATGGTATGATGGAAGTAATAA ATACTATACAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA CGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAAGACACGGCTGTGTATTACTGTGC GAGAGATAGAGTGCGATCGTATAGCTGGAACTACTTTGACTACTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCA (SEQ ID NO: 150) HCVR Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVALIWYDGSNKY YTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRVRSYSWNYFDYWGQGTLVT VSS (SEQ ID NO: 151) HCDR1 DNA Sequence GGATTCACCTTCAGTAGCTATGGC ^ ^
Attorney Docket No.250298.000954 (SEQ ID NO: 152) HCDR1 Amino Acid Sequence GFTFSSYG (SEQ ID NO: 153) HCDR2 DNA Sequence ATATGGTATGATGGAAGTAATAAA (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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 118) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 119) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT ^ ^
Attorney Docket No.250298.000954 (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 ^^^^ ^
Attorney Docket No.250298.000954 ATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAATGGACAGCCTGAAAATAATTA TAAGACAACACCTCCTGTGCTGGATTCTGATGGATCTTTTTTTCTGTATTCTAGACTGAC AGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTTGTTCTGTGATGCATGAAG CTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTCCTGGAAAGTAG (SEQ ID NO: 158) HC Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVALIWYDGSNKY YTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRVRSYSWNYFDYWGQGTLVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNRFTQKSLSLSPGK* (SEQ ID NO: 159) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 128) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 129) REGN13074 HCVR DNA Sequence ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 118) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 119) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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 ^ ^
Attorney Docket No.250298.000954 GAGGTGCAGTTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGA CTCTCCTGTGCAGTCTCTGGATTCACCTTTAGCAACTATGCCATGAGTTGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGGTTTTAGTGGAAGTGGTGGTAGCAC ATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATACCAAGAAC ACGCTGTATCTGCAAATGAACATCCTGAGAGGCGAGGACACGGCCGTATATTATTGTG CGAAAAATCGGGTACGTGGATATAGTGGCCACCATCTTGACTACTGGGGCCAGGGAAC CCCGGTCACCGTCTCCTCAGCCTCTACAAAGGGACCTTCTGTGTTTCCTCTGGCTCCTT GTTCTAGATCTACATCTGAATCTACAGCTGCTCTGGGATGTCTGGTGAAGGATTATTTTC CTGAACCTGTGACAGTGTCTTGGAATTCTGGAGCTCTGACATCTGGAGTGCATACATTT CCTGCTGTGCTGCAGTCTTCTGGACTGTATTCTCTGTCTTCTGTGGTGACAGTGCCTTC TTCTTCTCTGGGAACAAAGACATATACATGTAATGTGGATCATAAGCCTTCTAATACAAA GGTGGATAAGAGAGTGGAATCTAAGTATGGACCTCCTTGTCCTCCTTGTCCTGCTCCTG GCGGTGGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAGCCTAAGGATACACTGATGATC TCTAGAACACCTGAAGTGACATGTGTGGTGGTGGATGTGTCTCAGGAAGATCCTGAAG TGCAGTTTAATTGGTATGTGGATGGAGTGGAAGTGCATAATGCTAAGACAAAGCCTAGA GAAGAACAGTTTAATTCTACATATAGAGTGGTGTCTGTGCTGACAGTGCTGCATCAGGA TTGGCTGAATGGAAAGGAATATAAGTGTAAGGTGTCTAATAAGGGACTGCCTTCTTCTA TCGAAAAGACAATCTCTAAGGCTAAGGGACAGCCTAGAGAACCTCAGGTGTATACACTG CCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTCTGACATGTCTGGTGAAGGG ATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAATGGACAGCCTGAAAATAATTA TAAGACAACACCTCCTGTGCTGGATTCTGATGGATCTTTTTTTCTGTATTCTAGACTGAC AGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTTGTTCTGTGATGCATGAAG CTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTCCTGGAAAGTAG (SEQ ID NO: 168) HC Amino Acid Sequence EVQLLESGGGLVQPGGSLRLSCAVSGFTFSNYAMSWVRQAPGKGLEWVSGFSGSGGSTY YADSVKGRFTISRDNTKNTLYLQMNILRGEDTAVYYCAKNRVRGYSGHHLDYWGQGTPVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNRFTQKSLSLSPGK* (SEQ ID NO: 169) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ^^^^ ^
Attorney Docket No.250298.000954 ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 128) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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 ^ ^
Attorney Docket No.250298.000954 (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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 118) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 119) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (SEQ ID NO: 120) LCDR1 Amino Acid Sequence QSISSY (SEQ ID NO: 121) LCDR2 DNA Sequence GCTGCATCC ^ ^
Attorney Docket No.250298.000954 (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 CTGTGTTTCCTCTGGCTCCTTGTTCTAGATCTACATCTGAATCTACAGCTGCTCTGGGAT GTCTGGTGAAGGATTATTTTCCTGAACCTGTGACAGTGTCTTGGAATTCTGGAGCTCTG ACATCTGGAGTGCATACATTTCCTGCTGTGCTGCAGTCTTCTGGACTGTATTCTCTGTCT TCTGTGGTGACAGTGCCTTCTTCTTCTCTGGGAACAAAGACATATACATGTAATGTGGA TCATAAGCCTTCTAATACAAAGGTGGATAAGAGAGTGGAATCTAAGTATGGACCTCCTT GTCCTCCTTGTCCTGCTCCTGGCGGTGGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAG CCTAAGGATACACTGATGATCTCTAGAACACCTGAAGTGACATGTGTGGTGGTGGATGT GTCTCAGGAAGATCCTGAAGTGCAGTTTAATTGGTATGTGGATGGAGTGGAAGTGCATA ATGCTAAGACAAAGCCTAGAGAAGAACAGTTTAATTCTACATATAGAGTGGTGTCTGTG CTGACAGTGCTGCATCAGGATTGGCTGAATGGAAAGGAATATAAGTGTAAGGTGTCTAA TAAGGGACTGCCTTCTTCTATCGAAAAGACAATCTCTAAGGCTAAGGGACAGCCTAGAG AACCTCAGGTGTATACACTGCCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCT CTGACATGTCTGGTGAAGGGATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAA TGGACAGCCTGAAAATAATTATAAGACAACACCTCCTGTGCTGGATTCTGATGGATCTTT TTTTCTGTATTCTAGACTGACAGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTC TTGTTCTGTGATGCATGAAGCTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTC TCCTGGAAAGTAG (SEQ ID NO: 177) HC Amino Acid Sequence ^ ^
Attorney Docket No.250298.000954 QVQLQESGPGLVKPSQTLSLSCTVSRGSISSGGYYWSWIRQHPGKGLEWIGYIHYSERTYY NPSLKSRVTMSVDTSKNQFSLKLTSVTAADTAVYYCARDRDTMVRGVITTSGHFIDDWGQ GTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPG GGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE QFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNRFTQKSLSLSPGK* (SEQ ID NO: 178) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 128) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 129) REGN13076 HCVR DNA Sequence GAGGTGCACTTATTGGACTCTGGCGGAGGCTTGGTTCAGTCGGGGGAGTCCCTGAGA CTCTCCTGTACAGTCTCTGGAGTCACTTTTGAAAACCTTGTCATGAACTGGGTCCGGCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCGCAAGTGTTGGAGGTCGTTATACTGGCGC GGTCTTCGCAGACTCAGTGAGGGGCCGGTTCACGATCTCCAGAGACCATTCCGAGAAT ACGCTCTTTCTGCACATGAGCAGCCTGAGAGCCGAGGACACGGCCGTTTATTTTTGTAC GAAAGATTCCTCTGTCCTGATTCGGGGAGTCATTAGTACAAACTACTTCTATAGTATGGA CGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 179) ^ ^
Attorney Docket No.250298.000954 HCVR Amino Acid Sequence EVHLLDSGGGLVQSGESLRLSCTVSGVTFENLVMNWVRQAPGKGLEWVASVGGRYTGAV 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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA ^ ^
Attorney Docket No.250298.000954 (SEQ ID NO: 118) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 119) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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 ^^^^ ^
Attorney Docket No.250298.000954 CTGGTGAAGGATTATTTTCCTGAACCTGTGACAGTGTCTTGGAATTCTGGAGCTCTGAC ATCTGGAGTGCATACATTTCCTGCTGTGCTGCAGTCTTCTGGACTGTATTCTCTGTCTTC TGTGGTGACAGTGCCTTCTTCTTCTCTGGGAACAAAGACATATACATGTAATGTGGATC ATAAGCCTTCTAATACAAAGGTGGATAAGAGAGTGGAATCTAAGTATGGACCTCCTTGT CCTCCTTGTCCTGCTCCTGGCGGTGGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAGCC TAAGGATACACTGATGATCTCTAGAACACCTGAAGTGACATGTGTGGTGGTGGATGTGT CTCAGGAAGATCCTGAAGTGCAGTTTAATTGGTATGTGGATGGAGTGGAAGTGCATAAT GCTAAGACAAAGCCTAGAGAAGAACAGTTTAATTCTACATATAGAGTGGTGTCTGTGCT GACAGTGCTGCATCAGGATTGGCTGAATGGAAAGGAATATAAGTGTAAGGTGTCTAATA AGGGACTGCCTTCTTCTATCGAAAAGACAATCTCTAAGGCTAAGGGACAGCCTAGAGAA CCTCAGGTGTATACACTGCCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTCT GACATGTCTGGTGAAGGGATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAATG GACAGCCTGAAAATAATTATAAGACAACACCTCCTGTGCTGGATTCTGATGGATCTTTTT TTCTGTATTCTAGACTGACAGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTT GTTCTGTGATGCATGAAGCTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTC CTGGAAAGTAG (SEQ ID NO: 187) HC Amino Acid Sequence EVHLLDSGGGLVQSGESLRLSCTVSGVTFENLVMNWVRQAPGKGLEWVASVGGRYTGAV FADSVRGRFTISRDHSENTLFLHMSSLRAEDTAVYFCTKDSSVLIRGVISTNYFYSMDVWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPG GGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE QFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNRFTQKSLSLSPGK* (SEQ ID NO: 188) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 128) ^ ^
Attorney Docket No.250298.000954 LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 129) REGN13220 HCVR DNA Sequence CAGGTGCACCTGCAAGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCTCCTGCACTGTCTCTGGTGATTCCATCAGAAGTGGTGGTTACTACTGGAGTTGGAT CCGCCAGCAGCCAGGAAGGGGCCTGGAATGGATTGGTTTCATCCATCAGAGTGACAG 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) ^ ^
Attorney Docket No.250298.000954 HCDR3 DNA Sequence GCGAGAGATCGGGACACCATGGTTCGGGGAAGCATTACAACTTCCGGCCACTTCATTG ACTAC (SEQ ID NO: 195) HCDR3 Amino Acid Sequence ARDRDTMVRGSITTSGHFIDY (SEQ ID NO: 196) LCVR DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 118) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 119) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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) ^ ^
Attorney Docket No.250298.000954 LCDR3 DNA Sequence CAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 124) LCDR3 Amino Acid Sequence QQSYSTPPIT (SEQ ID NO: 125) HC DNA Sequence CAGGTGCACCTGCAAGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCC CTCTCCTGCACTGTCTCTGGTGATTCCATCAGAAGTGGTGGTTACTACTGGAGTTGGAT CCGCCAGCAGCCAGGAAGGGGCCTGGAATGGATTGGTTTCATCCATCAGAGTGACAG GTCCTACTATAACCCGTCCCTCATGAATCGACTCACCATGTCAGTAGACACGTCTAAGA ATCAATTCTCCCTGAAACTGACCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGT GCGAGAGATCGGGACACCATGGTTCGGGGAAGCATTACAACTTCCGGCCACTTCATTG ACTACTGGGGCCAGGGAACCCTGATCACCGTCTCCTCAGCCTCTACAAAGGGACCTTC TGTGTTTCCTCTGGCTCCTTGTTCTAGATCTACATCTGAATCTACAGCTGCTCTGGGATG 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 AVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGG GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQE ^ ^
Attorney Docket No.250298.000954 EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNRFTQKSLSLSPGK* (SEQ ID NO: 198) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 128) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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) ^ ^
Attorney Docket No.250298.000954 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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 118) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 119) ^ ^
Attorney Docket No.250298.000954 LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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 TTTCCTCTGGCTCCTTGTTCTAGATCTACATCTGAATCTACAGCTGCTCTGGGATGTCTG GTGAAGGATTATTTTCCTGAACCTGTGACAGTGTCTTGGAATTCTGGAGCTCTGACATC TGGAGTGCATACATTTCCTGCTGTGCTGCAGTCTTCTGGACTGTATTCTCTGTCTTCTGT GGTGACAGTGCCTTCTTCTTCTCTGGGAACAAAGACATATACATGTAATGTGGATCATA AGCCTTCTAATACAAAGGTGGATAAGAGAGTGGAATCTAAGTATGGACCTCCTTGTCCT CCTTGTCCTGCTCCTGGCGGTGGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAGCCTAA GGATACACTGATGATCTCTAGAACACCTGAAGTGACATGTGTGGTGGTGGATGTGTCTC AGGAAGATCCTGAAGTGCAGTTTAATTGGTATGTGGATGGAGTGGAAGTGCATAATGCT ^^^^ ^
Attorney Docket No.250298.000954 AAGACAAAGCCTAGAGAAGAACAGTTTAATTCTACATATAGAGTGGTGTCTGTGCTGAC AGTGCTGCATCAGGATTGGCTGAATGGAAAGGAATATAAGTGTAAGGTGTCTAATAAGG GACTGCCTTCTTCTATCGAAAAGACAATCTCTAAGGCTAAGGGACAGCCTAGAGAACCT CAGGTGTATACACTGCCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTCTGAC ATGTCTGGTGAAGGGATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAATGGAC AGCCTGAAAATAATTATAAGACAACACCTCCTGTGCTGGATTCTGATGGATCTTTTTTTC TGTATTCTAGACTGACAGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTTGT TCTGTGATGCATGAAGCTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTCCT GGAAAGTAG (SEQ ID NO: 207) HC Amino Acid Sequence QVQLQESGPVLVKPSETLSLTCTVSGDSISNYYWSWIRQSPGKGLEWIGYIYYSGGTNYNP SLKSRVTISIDTSKRHFSLKLNSVIAADTAVYYCARAPVTMVRGVITYNYHYAMDVWGQGTT VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNRFTQKSLSLSPGK* (SEQ ID NO: 208) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 128) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 129) ^ ^
Attorney Docket No.250298.000954 REGN13284 HCVR DNA Sequence GAGGTGCAACTGGTGGAATCTGGAGGAGGCTTGGTCCAGCCTGGGGGTTCCCTGAGA CTCTCCTGTGCAGCCTCTGGGTTCATCGTCAGTAACAACTATATGAGATGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCGGTCATTTATAGTGGTGGTGGCACATA CTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGACACAATTCCAAGAACACG ATATATCTTCAAATGAACAGCCTGCGAATTGAGGACACGGCCGTGTATTATTGTGCGAG AGAAGATAGCCACTCGTCGGAAAGTTATGACTACTTCTACGGCATGGACGTCTGGGGC CAAGGGACCACGGTCACCGTCTCCCCA (SEQ ID NO: 209) HCVR Amino Acid Sequence EVQLVESGGGLVQPGGSLRLSCAASGFIVSNNYMRWVRQAPGKGLEWVSVIYSGGGTYY ADSVKGRFTISRHNSKNTIYLQMNSLRIEDTAVYYCAREDSHSSESYDYFYGMDVWGQGTT VTVSP (SEQ ID NO: 210) HCDR1 DNA Sequence GGGTTCATCGTCAGTAACAACTAT (SEQ ID NO: 211) 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 ^ ^
Attorney Docket No.250298.000954 AREDSHSSESYDYFYGMDV (SEQ ID NO: 216) LCVR DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 118) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 119) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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 ^ ^
Attorney Docket No.250298.000954 (SEQ ID NO: 125) HC DNA Sequence GAGGTGCAACTGGTGGAATCTGGAGGAGGCTTGGTCCAGCCTGGGGGTTCCCTGAGA CTCTCCTGTGCAGCCTCTGGGTTCATCGTCAGTAACAACTATATGAGATGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTCTCGGTCATTTATAGTGGTGGTGGCACATA CTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGACACAATTCCAAGAACACG ATATATCTTCAAATGAACAGCCTGCGAATTGAGGACACGGCCGTGTATTATTGTGCGAG AGAAGATAGCCACTCGTCGGAAAGTTATGACTACTTCTACGGCATGGACGTCTGGGGC CAAGGGACCACGGTCACCGTCTCCCCAGCCTCTACAAAGGGACCTTCTGTGTTTCCTC TGGCTCCTTGTTCTAGATCTACATCTGAATCTACAGCTGCTCTGGGATGTCTGGTGAAG GATTATTTTCCTGAACCTGTGACAGTGTCTTGGAATTCTGGAGCTCTGACATCTGGAGT GCATACATTTCCTGCTGTGCTGCAGTCTTCTGGACTGTATTCTCTGTCTTCTGTGGTGA CAGTGCCTTCTTCTTCTCTGGGAACAAAGACATATACATGTAATGTGGATCATAAGCCTT CTAATACAAAGGTGGATAAGAGAGTGGAATCTAAGTATGGACCTCCTTGTCCTCCTTGT CCTGCTCCTGGCGGTGGCGGACCTTCTGTGTTTCTGTTTCCTCCTAAGCCTAAGGATAC ACTGATGATCTCTAGAACACCTGAAGTGACATGTGTGGTGGTGGATGTGTCTCAGGAA GATCCTGAAGTGCAGTTTAATTGGTATGTGGATGGAGTGGAAGTGCATAATGCTAAGAC AAAGCCTAGAGAAGAACAGTTTAATTCTACATATAGAGTGGTGTCTGTGCTGACAGTGC TGCATCAGGATTGGCTGAATGGAAAGGAATATAAGTGTAAGGTGTCTAATAAGGGACTG CCTTCTTCTATCGAAAAGACAATCTCTAAGGCTAAGGGACAGCCTAGAGAACCTCAGGT GTATACACTGCCTCCTTCTCAGGAAGAAATGACAAAGAATCAGGTGTCTCTGACATGTC TGGTGAAGGGATTTTATCCTTCTGATATCGCTGTGGAATGGGAATCTAATGGACAGCCT GAAAATAATTATAAGACAACACCTCCTGTGCTGGATTCTGATGGATCTTTTTTTCTGTATT CTAGACTGACAGTGGATAAGTCTAGATGGCAGGAAGGAAATGTGTTTTCTTGTTCTGTG ATGCATGAAGCTCTGCATAATAGATTTACACAGAAGTCTCTGTCTCTGTCTCCTGGAAA GTAG (SEQ ID NO: 217) HC Amino Acid Sequence EVQLVESGGGLVQPGGSLRLSCAASGFIVSNNYMRWVRQAPGKGLEWVSVIYSGGGTYY ADSVKGRFTISRHNSKNTIYLQMNSLRIEDTAVYYCAREDSHSSESYDYFYGMDVWGQGTT VTVSPASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNRFTQKSLSLSPGK* (SEQ ID NO: 218) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC ^^^^ ^
Attorney Docket No.250298.000954 CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 128) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 129) [00362] 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. [00363] 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. [00364] 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 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., ^ ^
Attorney Docket No.250298.000954 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). [00365] 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. [00366] 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. [00367] 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. [00368] 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. [00369] 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. [00370] 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. [00371] In some embodiments, the anti-AAV antibodies, or antigen-binding fragments thereof, described herein comprise the amino acid sequence set forth in SEQ ID NOs: 18, 198, 30, 208, 40, 127, 50, 169, 60, 1108, 1363, 1366, 149, 1362, 1379, 69, 178, 79, 1391, 1396, 188, 1390, 89, 139, 99, 159, 109, or 218, or a variant thereof having at least 40%, ^ ^
Attorney Docket No.250298.000954 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 18, 198, 30, 208, 40, 127, 50, 169, 60, 1108, 1363, 1366, 149, 1362, 1379, 69, 178, 79, 1391, 1396, 188, 1390, 89, 139, 99, 159, 109, or 218. In certain embodiments, the nucleotide sequence that encodes the anti- AAV antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence that encodes the amino acid sequence of SEQ ID NOs: 18, 198, 30, 208, 40, 127, 50, 169, 60, 1108, 1363, 1366, 149, 1362, 1379, 69, 178, 79, 1391, 1396, 188, 1390, 89, 139, 99, 159, 109, or 218, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 18, 198, 30, 208, 40, 127, 50, 169, 60, 1108, 1363, 1366, 149, 1362, 1379, 69, 178, 79, 1391, 1396, 188, 1390, 89, 139, 99, 159, 109, or 218. In certain embodiments, the nucleotide sequence that encodes the anti-AAV antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NOs: 17, 197, 29, 207, 39, 126, 49, 168, 59, 1107, 148, 1378, 68, 177, 78, 187, 1389, 88, 138, 98, 158, 108, or 217, or a nucleotide sequence having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the nucleotide sequence of SEQ ID NOs: 17, 197, 29, 207, 39, 126, 49, 168, 59, 1107, 148, 1378, 68, 177, 78, 187, 1389, 88, 138, 98, 158, 108, or 217. In certain embodiments, the anti-AAV antibodies, or antigen- binding fragments thereof, comprise the amino acid sequence set forth in SEQ ID NOs: 18, 198, 30, 208, 40, 127, 50, 169, 60, 1108, 1363, 1366, 149, 1362, 1379, 69, 178, 79, 1391, 1396, 188, 1390, 89, 139, 99, 159, 109, or 218. In certain embodiments, the nucleotide sequence that encodes the anti-AAV antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NOs: 17, 197, 29, 207, 39, 126, 49, 168, 59, 1107, 148, 1378, 68, 177, 78, 187, 1389, 88, 138, 98, 158, 108, or 217. [00372] In some embodiments, the anti-AAV antibodies, or antigen-binding fragments thereof, described herein comprise the amino acid sequence set forth in SEQ ID NOs: 20, 129, or 813, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 20, 129, or 813. In certain embodiments, the nucleotide sequence that encodes the anti-AAV antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence that encodes the amino acid sequence of SEQ ID NOs: 20, 129, or 813, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 20, 129, or 813. In certain embodiments, the nucleotide sequence that encodes the anti-AAV antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NOs: 19, 128, 1145, or 1500, or a nucleotide sequence having ^ ^
Attorney Docket No.250298.000954 at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the nucleotide sequence of SEQ ID NOs: 19, 128, 1145, or 1500. In certain embodiments, the anti-AAV antibodies, or antigen-binding fragments thereof, comprise the amino acid sequence set forth in SEQ ID NOs: 20, 129, or 813. In certain embodiments, the nucleotide sequence that encodes the anti-AAV antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NOs: 19, 128, 1145, or 1500. [00373] 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). [00374] 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., REGN13284). [00375] In an embodiment provided herein, the anti-AAV antibody or antigen-binding ^ ^
Attorney Docket No.250298.000954 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, ^ ^
Attorney Docket No.250298.000954 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, ^ ^
Attorney Docket No.250298.000954 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. [00376] 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 ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00377] 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; ^ ^
Attorney Docket No.250298.000954 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. [00378] 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; ^ ^
Attorney Docket No.250298.000954 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. [00379] In an embodiment provided herein, the anti-AAV antibody comprises a constant region derived from IgG4 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 ^ ^
Attorney Docket No.250298.000954 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. [00380] 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 antigen- binding fragment thereof described herein may bind to a capsid of an AAV particle with a KD value of about 5x10-6 M to 1x10-6 M (e.g., 1x10-6 M, 1.5x10-6 M, 2x10-6 M, 3x10-6 M, 4x10-6 M, 5x10-6 M), about 1x10-6 M to 1x10-7 M (e.g., 1x10-7 M, 2x10-7 M, 3x10-7 M, 4x10-7 M, 5x10-7 M, 6x10-7 M, 7x10-7 M, 8x10-7 M, 9x10-7 M), about 1x10-7 M to 1x10-8 M (e.g., 1x10-8 M, 2x10- 8 M, 3x10-8 M, 4x10-8 M, 5x10-8 M, 6x10-8 M, 7x10-8 M, 8x10-8 M, 9x10-8 M), about 1x10-8 M to 1x10-9 M (e.g., 1x10-9 M, 2x10-9 M, 3x10-9 M, 4x10-9 M, 5x10-9 M, 6x10-9 M, 7x10-9 M, 8x10-9 M, 9x10-9 M), or about 1x10-9 M to 1x10-10 M (e.g., 1x10-10 M, 2x10-10 M, 3x10-10 M, 4x10-10 M, 5x10-10 M, 6x10-10 M, 7x10-10 M, 8x10-10 M, 9x10-10 M). [00381] 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 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. [00382] 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. ^ ^
Attorney Docket No.250298.000954 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. [00383] 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 antibody- binding fragment. Said value is also referred to as the koff value. [00384] 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. [00385] 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. [00386] 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. [00387] Also provided herein are nucleic acid molecules encoding anti-AAV antibodies or antigen-binding fragments thereof. [00388] 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. [00389] 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. ^ ^
Attorney Docket No.250298.000954 [00390] 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. [00391] 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. [00392] 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. [00393] 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. [00394] 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. [00395] 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. [00396] 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. [00397] 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- ^^^^ ^
Attorney Docket No.250298.000954 LCDR3 amino acid sequence set is as defined by any of the exemplary anti-AAV antibodies listed in Table 1. [00398] 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. [00399] 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. [00400] 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 ^ ^
Attorney Docket No.250298.000954 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 [00401] 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. [00402] 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. [00403] 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. [00404] 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 ^ ^
Attorney Docket No.250298.000954 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. [00405] In some embodiments, MBMs of the present disclosure may comprise 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. [00406] Single chain Fv or “scFv” antibody fragments comprise the VH and VL 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 VL chains of an scFV are the linkers are described herein. [00407] Unless specified, as used herein an scFv may have the VL and V
H 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. [00408] As a non-limiting example, an scFv comprising VL-linker-VH which may be used in accordance with the disclosure may comprise the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGG SGGGGSQVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIH YSERTSHNPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFID ^ ^
Attorney Docket No.250298.000954 SWGQGALVTVSS (SEQ ID NO: 1358), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00409] As another non-limiting example, an scFv comprising VL-linker-VH which may be used in accordance with the disclosure may comprise the amino acid sequence of DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGCGTKVEIKGGGGSGGGGSGGG GSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKCLEWVAVI WHDGSDKYYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGL GTLVTVSS (SEQ ID NO: 1355), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00410] As a non-limiting example, an scFv comprising VH-linker-VL which may be used in accordance with the disclosure may comprise the amino acid sequence of^ QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKCLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS GGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQ KPGKAPNLLIYKASNLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFG CGTKVEIK (SEQ ID NO: 1350), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00411] The scFv can comprise VL and VH sequences from any suitable species, such as murine, human, or humanized VH and VL sequences. [00412] To create an scFv-encoding nucleic acid, the VL and VH-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). [00413] 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. [00414] The Fab domains can comprise constant domain and variable region sequences from any suitable species, and thus can be murine, chimeric, human, or humanized. [00415] 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 ^ ^
Attorney Docket No.250298.000954 the two constant domains can further stabilize the Fab domain. [00416] 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
[00417] Accordingly, in certain embodiments, correct association between the two ^ ^
Attorney Docket No.250298.000954 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. [00418] 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. [00419] 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. [00420] 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. [00421] 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. [00422] 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). [00423] 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). [00424] 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 ^ ^
Attorney Docket No.250298.000954 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 VH domain and a 38R modification is introduced in the VL domain. [00425] 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). [00426] 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 VL domain and a 39K modification in the VH domain. [00427] 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 VL 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. [00428] As a non-limiting example, a universal light chain which may be used in accordance with the disclosure may comprise the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ ^ ^
Attorney Docket No.250298.000954 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20) which may be encoded by the nucleic acid sequence of GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 19). [00429] In some embodiments, MBMs of the present disclosure may comprise an antigen- binding domain which is in a single-domain antibody (sdAb) format. A sdAb describes a single antigen-binding domain capable of binding to a cognate antigen. sdAbs are often derived from heavy-chain only antibodies, however they also include single VH domains capable of binding to their cognate antigen in the absence of an associated light chain. [00430] Heavy-chain only antibodies lack both light chains and a functional CH1 domain and thus rely exclusively on a heavy chain variable domain for antigen binding. Heavy-chain only antibodies are produced naturally in the Camelidae family (e.g., camels, dromedaries, llamas, vicunas, guanaco, and alpacas) as well as in cartilaginous fish (e.g., sharks). In addition to natural sources, transgenic mammals (e.g., mice) have been engineered to express heavy-chain only antibodies. Such transgenic mammals include, for example, transgenic animals described in U.S. Patent Publications 2015/0289489 A1, 2023/0270086 A1, and 2023/0062964 A1, and 2020/0267951 A1, each of which is incorporated herein by reference. [00431] In some embodiments, a sdAb is generated by immunizing an animal that produces heavy-chain only antibodies, including a natural producer (e.g., camelids, sharks) or an engineered non-human mammal (e.g., a transgenic mouse), to obtain heavy-chain only antibodies. Such antibodies may be screened to identify those having desirable properties (e.g., target affinity). Once produced and identified, the variable region of the antibody heavy chain is cloned to construct a single domain antibody consisting of only one heavy chain variable region. ^ ^
Attorney Docket No.250298.000954 [00432] sdAbs can also be obtained by immunizing animals that generate traditional antibodies (e.g., rabbits) followed by screening for VHs having high binding affinity in the absence of their cognate light chain (see, e.g., Shinozaki et al., 2017, Scientific Reports, 7(1):5794). [00433] sdAbs can be humanized by replacing natural (e.g., camelid) framework sequences with human sequences (see, e.g., Vincke, 2009, The Journal of Biological Chemistry, 285(5):3273-3284; Murakami et al., 2022, Antibodies, 11(1):10; and U.S. Patent Publication No.2016/0237142 A1, incorporated herein by reference). [00434] Fully human sdAbs can also be obtained using human VH single domains (see, e.g., Rouet et al., 2015, The Journal of Biological Chemistry, 290(19):11905-11917). [00435] Additional methods for producing heavy-chain only antibodies and/or sdAbs are recognized in the art and include, for example, those described in Muyldermans, 2021, The FEBS journal, 288(7):2084-2102. [00436] In some cases, an sdAb is engineered to enhance certain properties. For example, in some embodiments, a disulfide bond is introduced within a VHH to increase stability (see, e.g., Hagihara et al., 2007, The Journal of Biological Chemistry, 282(50):36489–36495). [00437] 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. [00438] 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. [00439] 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 ^ ^
Attorney Docket No.250298.000954 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 (i.e., a germline sequence that is different from the germline sequence from which the antigen-binding domain was originally derived). [00440] In some embodiments, a light chain sequence within an antibody or antigen-binding molecule disclosed herein may include one or more amino acid mutations designed to reduce steric hindrance between the light chain and its paired heavy chain. In some embodiments, such amino acid mutations may enhance the stability and/or yield of the antibody or antigen-binding molecule. As a non-limiting example, a light chain amino acid sequence such as, but not limited to, DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 813) may comprise, one or more of a K50A or a A51K mutation. In some embodiments, a light chain sequence described herein comprises a K50A mutation. In some embodiments, a light chain sequence described herein comprises a A51K. In some embodiments, a light chain sequence described herein comprises a K50A mutation and a A51K mutation. [00441] 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 ^ ^
Attorney Docket No.250298.000954 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 [00442] 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. [00443] 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. [00444] 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. [00445] 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. [00446] Charged (e.g., charged hydrophilic linkers) and/or flexible linkers are particularly preferred. [00447] 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 al., 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 ^ ^
Attorney Docket No.250298.000954 of GnS (SEQ ID NO: 239) or SGn (SEQ ID NO: 240), wherein n is an integer from 1 to 10, e.g., 1, 2, 3, 4, 5, 6, 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), wherein n is an integer from 1 to 10, e.g., 1, 2, 3, 4, 5, 6, 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). [00448] 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). [00449] 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). [00450] Non-limiting examples of linker sequences are set forth in Table L below. A MBM of the disclosure may comprise one or more linkers of Table L. Table L. Linker Sequences
^ ^
Attorney Docket No.250298.000954
^^^^ ^
Attorney Docket No.250298.000954
Constant Regions [00451] 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. [00452] 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 lgG1, 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 lgG1. In one embodiment the Fc domain is derived from lgG4. [00453] In some embodiments, a heavy chain constant region of a human IgG1 which may be used in accordance with the disclosure may comprise the amino acid sequence of ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 259) which may be encoded by the nucleic acid sequence of GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC AGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGG CACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG ^ ^
Attorney Docket No.250298.000954 AAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGA ACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGC CGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGC ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC AGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT GTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC CTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCAT GCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTC TCCGGGTAAA (SEQ ID NO: 260). [00454] In some embodiments, a heavy chain constant region of a human IgG1 which may be used in accordance with the disclosure may comprise the amino acid sequence of ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1164) which may be encoded by the nucleic acid sequence of GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC AGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGG CACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG AAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGA ACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGC CGCGGGAGGAGCAGTACGGCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGC ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC AGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT GTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA ^ ^
Attorney Docket No.250298.000954 GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC CTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCAT GCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTC TCCGGGTAAA (SEQ ID NO: 1163). [00455] In some embodiments, a heavy chain constant region of a human IgG1 which may be used in accordance with the disclosure may comprise the amino acid sequence of ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKN 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 ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC AGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT GTGCACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGTCCTG CGCCGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC CTCGTGAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTCAT GCTCCGTGATGCATGAGGCTCTGCACAACAGATTCACGCAGAAGTCCCTCTCCCTGTC TCCGGGTAAA (SEQ ID NO: 1142) or GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC AGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGG CACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG ^ ^
Attorney Docket No.250298.000954 AAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGA ACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGC CGCGGGAGGAGCAGTACGGTAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGC ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC AGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT GTGCACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGTCCTG CGCCGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC CTCGTGAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTCAT GCTCCGTGATGCATGAGGCTCTGCACAACAGATTCACGCAGAAGTCCCTCTCCCTGTC TCCGGGTAAA (SEQ ID NO: 1143). [00456] In some embodiments, a heavy chain constant region of a human IgG1 which may be used in accordance with the disclosure may comprise the amino acid sequence of ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTSKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRD 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 ^ ^
Attorney Docket No.250298.000954 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) [00457] In some embodiments, a heavy chain constant region of a human IgG4, hIgG4us, which may be used in accordance with the disclosure may comprise the amino acid sequence of ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 261) which may be encoded by the nucleic acid sequence of GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCC GAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGG ^ ^
Attorney Docket No.250298.000954 GCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAA GAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCAGGCGGTGG CGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGA CCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGT TCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTG GCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTG CCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAAC AACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGA TGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAA (SEQ ID NO: 262). [00458] In some embodiments, a heavy chain constant region of a human IgG4, hIgG4us, which may be used in accordance with the disclosure may comprise the amino acid sequence of ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS LSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSRWQEGNVFS CSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 1364), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00459] In some embodiments, a heavy chain constant region of a human IgG4, hIgG4us, which may be used in accordance with the disclosure may comprise the amino acid sequence of ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS LWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 1377), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00460] In some embodiments, a heavy chain Fc region of a human IgG4, hIgG4us, which may be used in accordance with the disclosure may comprise the amino acid sequence of ^ ^
Attorney Docket No.250298.000954 ESKYGPPCPPCPAPGGGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 1397), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00461] In some embodiments, a heavy chain Fc region of a human IgG4, hIgG4us, which may be used in accordance with the disclosure may comprise the amino acid sequence of ESKYGPPCPPCPAPGGGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLVSRLTVDKSRWQEGNVFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 1365), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00462] In some embodiments, a heavy chain Fc region of a human IgG4, hIgG4us, which may be used in accordance with the disclosure may comprise the amino acid sequence of^ ESKYGPPCPPCPAPGGGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 1345), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00463] In some embodiments, a heavy chain Fc region of a human IgG4, hIgG4us, which may be used in accordance with the disclosure may comprise the amino acid sequence of^ ESKYGPPCPPCPAPGGGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 1511), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00464] Hinge Regions [00465] 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. [00466] 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 ^ ^
Attorney Docket No.250298.000954 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. [00467] A number of modified hinge regions have already been described for example, in U.S. Patent No.5,677,425, WO9915549, WO2005003170, WO2005003169, WO2005003170, WO9825971, and WO2005003171, and these are incorporated herein by reference. [00468] 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. [00469] 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. [00470] In some embodiments, the MBMs of the disclosure comprise a modified hinge domain that reduces binding affinity for an Fc^ receptor relative to a wild-type hinge domain of the same isotype (e.g., human lgG1 or human lgG4). [00471] 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. [00472] 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 lgG1 that contains the sequence CPPC (SEQ ID NO: 251). [00473] 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 ^ ^
Attorney Docket No.250298.000954 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 lgG1 allows complete formation of inter-chain disulfides in the lgG4 hinge region, thus reducing heterogeneity in the purified product. [00474] The hinge region can be a chimeric hinge region. [00475] 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. [00476] 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 WO2014/121087, which is incorporated by reference in its entirety herein), ESKYGPPCPPCPAPPVA (SEQ ID NO: 254) (see, e.g., SEQ ID NO: 9 of WO2014/121087), or ESKYGPPCPPCPAPGGG (SEQ ID NO: 1371) (see, e.g., SEQ ID NO: 9 of^ WO2021/226444, which is incorporated by reference in its entirety herein). [00477] . 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. [00478] In further embodiments, the hinge region can be modified to reduce effector function, for example as described in WO2016161010, 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 WO2016161010A2). These segments can be represented as GGG-, GG-, G — or – with representing an unoccupied position. [00479] 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 WO2016161010A2). [00480] 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 lgG1 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. [00481] Exemplary hinge regions have residues 226-236, sometimes referred to as middle ^ ^
Attorney Docket No.250298.000954 (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 WO2016161010A2), CPPCPAPGG-GPSVF (SEQ ID NO: 256) (see, e.g., SEQ ID NO:2 of WO2016161010A2), CPPCPAPG— GPSVF (SEQ ID NO: 257) (see, e.g., SEQ ID NO:3 of WO2016161010A2), or CPPCPAP — GPSVF (SEQ ID NO: 258) (see, e.g., SEQ ID NO:4 of WO2016161010A2). [00482] 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 lgG1, lgG2, or lgG3 or hybrids thereof in which domains are of different isotypes. Exemplary sequences of human lgG1, lgG2, and lgG4 are shown in FIGS.2-4 of WO2016161010A2. [00483] 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). [00484] Fc Domains [00485] 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. [00486] In some embodiments, MBMs disclosed herein can have, e.g., fully human variable regions but can have mouse constant regions (e.g., a mouse IgG1 Fc or a mouse IgG2 Fc (a or b isotype)) or human constant regions (e.g., a human IgG1 Fc or a human IgG4 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 IgG1 Fc can be converted to an antibody with a human IgG4, 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. [00487] 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 lgG1, lgG2, lgG3, or lgG4. In one embodiment the Fc domain is derived from lgG1. In one embodiment the Fc domain is derived from lgG4. ^ ^
Attorney Docket No.250298.000954 [00488] Non-limiting examples of Fc domains derived from IgG4 are [00489] ESKYGPPCPPCPAPGGGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEV QFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 1345), and ESKYGPPCPPCPAPGGGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLVSRLTVDKSRWQEGNVFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 1365). [00490] 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. [00491] 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. [00492] 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. [00493] In some embodiments, the Fc region comprises CH2 and CH3 domains derived from lgG1. [00494] In some embodiments, the Fc region comprises CH2 and CH3 domains derived from lgG2. [00495] In some embodiments, the Fc region comprises CH2 and CH3 domains derived from lgG3. [00496] In some embodiments, the Fc region comprises CH2 and CH3 domains derived from lgG4. [00497] 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. [00498] In some embodiments, the Fc region comprises CH2 and CH3 domains derived from IgG and a CH4 domain derived from IgM. [00499] 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 ^ ^
Attorney Docket No.250298.000954 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. [00500] 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. [00501] 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. [00502] 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. [00503] 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. [00504] Non-limiting examples of Fc domain sequences are set forth in Table F-1 below. A MBM of the disclosure may comprise one or more Fc domain sequences of Table F-1. ^ ^
Attorney Docket No.250298.000954 Table F-1. Fc Domain Sequences
^ ^
Attorney Docket No.250298.000954
^ ^
Attorney Docket No.250298.000954
[00505] In some embodiments, an Fc domain comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity to any one of the sequences disclosed in Table F-1. [00506] In some embodiments, the Fc domain comprises one or more amino acid substitutions that reduces binding to an Fc receptor and/or effector function. [00507] In a particular embodiment the Fc receptor is an Fc^ 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, ^^^^ ^
Attorney Docket No.250298.000954 more specifically human FcyRIIIa, FcyRI, or FcyRIla, most specifically human FcyRIIIa. 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. [00508] 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”). [00509] 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). [00510] In one embodiment, the Fc domain is an lgG1 Fc domain, particularly a human lgG1 Fc domain. [00511] 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 ^ ^
Attorney Docket No.250298.000954 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). [00512] In one embodiment, the Fc domain is an lgG1 Fc domain, particularly a human lgG1 Fc domain. In some embodiments, the lgG1 Fc domain is a variant lgG1 comprising D265A, N297A mutations (EU numbering) to reduce effector function. [00513] 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. IgG4 Fc domains
^ ^
Attorney Docket No.250298.000954
^ ^
Attorney Docket No.250298.000954
^ ^
Attorney Docket No.250298.000954
[00514] 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 WO2014/121087, sometimes referred to herein as lgG4s or hlgG4s. [00515] 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 WO2014/121087 (or the bolded portion thereof) and SEQ ID NO:37 of WO2014/121087 (or the bolded portion thereof) or an Fc region comprising a combination of SEQ ID NO:31 of WO2014/121087 (or the bolded portion thereof) and SEQ ID NO:38 of WO2014/121087 (or the bolded portion thereof). [00516] 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. WO2009/089004A1. [00517] 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 (lgG1, lgG2, lgG3, and lgG4) class, as ^ ^
Attorney Docket No.250298.000954 described in the preceding section. [00518] 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. [00519] 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). [00520] 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. [00521] 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 ^ ^
Attorney Docket No.250298.000954 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). [00522] 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. [00523] 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. [00524] According to certain embodiments of the present disclosure, anti-AAV antigen- binding 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 ^ ^
Attorney Docket No.250298.000954 (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). [00525] 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. [00526] 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. [00527] 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 inter- ^ ^
Attorney Docket No.250298.000954 chain 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. [00528] 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 IgG4 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 IgG1 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. [00529] 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. [00530] 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 ^ ^
Attorney Docket No.250298.000954 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 (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). [00531] 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. [00532] 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 [00533] 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 antigen- ^ ^
Attorney Docket No.250298.000954 binding molecule, e.g., a bispecific antigen-binding molecule. In some embodiments the bispecific antigen-binding molecule is a bispecific antibody. [00534] 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 antigen- binding 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). [00535] 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 antigen- binding 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. [00536] 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. [00537] 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. [00538] 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., ^ ^
Attorney Docket No.250298.000954 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). [00539] 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. [00540] 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. 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- ^ ^
Attorney Docket No.250298.000954 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). [00541] 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 multi-subunit protein. Non-limiting examples cell surface molecules useful in the practice of the present disclosure include, e.g., Asialoglycoprotein Receptor 1 (ASGR1), ^^^^^^^^^^^^ ^^^^^^^^^^^^^^, and Calcium Voltage-Gated Channel Auxiliary Subunit Gamma 1 (CACNG1). [00542] 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 ^ ^
Attorney Docket No.250298.000954 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. [00543] 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 ^ ^
Attorney Docket No.250298.000954 (SEQ ID NO: 219) CAAGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC CTCACGTGCACTGTCTCTGGTGACTCCATCAGTGATTATTACTGGAACTGGATCCGGCA GTCCCCAGGAAAGTGTCTGGAGTGGATTGGGTATATCCATTATAGAGGGAGCACCAAT CACAACCCCTCCCTCAAAAGTCGAGTCACCATATCACTAGACACGTCCAAGAACCAGTT CTCCCTGAGGCTGACCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAAA GAAAGGTGGGACCTTCCCGGTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA (SEQ ID NO: 1246) CAAGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC CTCACGTGCACTGTCTCTGGTGACTCCATCAGTGATTATTACTGGAACTGGATCCGGCA GTCCCCAGGAAAGGGACTGGAGTGGATTGGGTATATCCATTATAGAGGGAGCACCAAT CACAACCCCTCCCTCAAAAGTCGAGTCACCATATCACTAGACACGTCCAAGAACCAGTT CTCCCTGAGGCTGACCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAAA GAAAGGTGGGACCTTCCCGGTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA (SEQ ID NO: 1281) HCVR Amino Acid Sequence QVQLQESGPGLVKPSETLSLTCTVSGDSISDYYWNWIRQSPGKGLEWIGYIHYRGSTNHNP SLKSRVTISLDTSKNQFSLRLTSVTAADTAVYYCAKERWDLPGFDYWGQGTLVTVSS (SEQ ID NO: 220) 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 ^ ^
Attorney Docket No.250298.000954 (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)
^
Attorney Docket No.250298.000954 (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 TATGTGGATGGAGTGGAAGTGCATAATGCTAAGACAAAGCCTAGAGAAGAACAGTTTAA TTCTACATATAGAGTGGTGTCTGTGCTGACAGTGCTGCATCAGGATTGGCTGAATGGAA AGGAATATAAGTGTAAGGTGTCTAATAAGGGACTGCCTTCTTCTATCGAAAAGACAATCT CTAAGGCTAAGGGACAGCCTAGAGAACCTCAGGTGTATACACTGCCTCCTTCTCAGGA AGAAATGACAAAGAATCAGGTGTCTCTGACATGTCTGGTGAAGGGATTTTATCCTTCTG ATATCGCTGTGGAATGGGAATCTAATGGACAGCCTGAAAATAATTATAAGACAACACCT CCTGTGCTGGATTCTGATGGATCTTTTTTTCTGTATTCTAGACTGACAGTGGATAAGTCT AGATGGCAGGAAGGAAATGTGTTTTCTTGTTCTGTGATGCATGAAGCTCTGCATAATAG ATTTACACAGAAGTCTCTGTCTCTGTCTCCTGGAAAG ^ ^
Attorney Docket No.250298.000954 (SEQ ID NO: 227) HC Amino Acid Sequence QVQLQESGPGLVKPSETLSLTCTVSGDSISDYYWNWIRQSPGKGLEWIGYIHYRGSTNHNP SLKSRVTISLDTSKNQFSLRLTSVTAADTAVYYCAKERWDLPGFDYWGQGTLVTVSSASTK GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV MHEALHNRFTQKSLSLSPGK (SEQ ID NO: 228) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 19) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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 ^ ^
Attorney Docket No.250298.000954 YADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCAKVQLNGDIFFDYWGQGTLVTVSS (SEQ ID NO: 230) HCDR1 DNA Sequence GGATTCACCTTTAGCAGGTCTGCC (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 GCGAAAGTTCAGCTAAATGGGGATATTTTCTTTGACTAC (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 CAGAGCATTAGCAGCTAT ^ ^
Attorney Docket No.250298.000954 (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) ^ ^
Attorney Docket No.250298.000954 HC Amino Acid Sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSRSAMSWVRQAPGKGLEWVSDISGSGRNTF YADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCAKVQLNGDIFFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SCSVMHEALHNRFTQKSLSLSPGK* (SEQ ID NO:238) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 19) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 20) [00544] 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. [00545] 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. ^ ^
Attorney Docket No.250298.000954 [00546] 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 1157 (e.g., REGN3954) and 230/10 (e.g., REGN3955). [00547] 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. [00548] In some embodiments, the anti-ASGR1 antibodies, or antigen-binding fragments thereof, described herein comprise the amino acid sequence set forth in SEQ ID NOs: 228 or 238, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 228 or 238. In certain embodiments, the nucleotide sequence that encodes the anti- ASGR1 antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence that encodes the amino acid sequence of SEQ ID NOs: 228 or 238, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 228 or 238. In certain embodiments, the nucleotide sequence that encodes the anti-ASGR1 antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NOs: 227 or 237, or a nucleotide sequence having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the nucleotide ^ ^
Attorney Docket No.250298.000954 sequence of SEQ ID NOs: 227 or 237. In certain embodiments, the anti-ASGR1 antibodies, or antigen-binding fragments thereof, comprise the amino acid sequence set forth in SEQ ID NOs: 228 or 238. In certain embodiments, the nucleotide sequence that encodes the anti- ASGR1 antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NOs: 227 or 237. [00549] In some embodiments, the anti-ASGR1 antibodies, or antigen-binding fragments thereof, described herein comprise the amino acid sequence set forth in SEQ ID NO: 20, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 20. In certain embodiments, the nucleotide sequence that encodes the anti-ASGR1 antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 20, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 20. In certain embodiments, the nucleotide sequence that encodes the anti-ASGR1 antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NO: 19, or a nucleotide sequence having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the nucleotide sequence of SEQ ID NO: 19. In certain embodiments, the anti-ASGR1 antibodies, or antigen-binding fragments thereof, comprise the amino acid sequence set forth in SEQ ID NO: 20. In certain embodiments, the nucleotide sequence that encodes the anti- ASGR1 antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NO: 19. [00550] 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). [00551] 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 ^ ^
Attorney Docket No.250298.000954 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. [00552] 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 multispecific 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 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
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Attorney Docket No.250298.000954
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Attorney Docket No.250298.000954
Table 8. Nucleic Acid Sequence Identifiers for Anti-TfR Antibodies
31874B HCVR (VH) Nucleotide Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCGCCTTTAGCAGCTATGCCATGACCTGGGTCCGA CAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATCAGTGGTACTGGTGGTAGT
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Attorney Docket No.250298.000954 ACACGCTGTATCTACAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTG TGCGAAAGGGGGAGCAGCTCGTAGAATGGAATACTTCCAGTACTGGGGCCAGGGCAC CCTGGTCACCGTCTCCTCA (SEQ ID NO: 269) HCVR (VH) Amino Acid Sequence EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYAMTWVRQAPGKGLEWVSVISGTGGSTY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGGAARRMEYFQYWGQGTLVTV SS (SEQ ID NO: 270) or EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYAMTWVRQAPGKGLEWVSVISGTGGSTY 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 CCATCACTTGCCGGGCGAGTCAGGGCATTAGCAATTATTTAGCCTGGTATCAGCAGAAA CCAGGGAAAGTTCCTAACCTCCTTATCTATGCTGCATCCACTTTGCAATCAGGGGTCCC ATCTCGATTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGC 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 EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYAMTWVRQAPGKGLEWVSVISGTGGSTY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGGAARRMEYFQYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG ^ ^
Attorney Docket No.250298.000954 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 974) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPNLLIYAASTLQSGVPSRF SGSGSGTDFTLTISSLQPEDVATYYCQKYNSAPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 975)
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) EVQLVESGGGLVQPGGSLRLSCAASGFTFNSYAMTWVRQAPGKGLEWVSFIGGSTGNTY 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 ^ ^
Attorney Docket No.250298.000954 CAGGGAAAGTTCCTAAGCTCCTGATCTATGCTGCATCCACTTTGCAATCAGGGGTCCCA TCTCGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGC AGCCTGAAGATGTTGCAACTTATTACTGTCAAAACCATAACAGTGTCCCTCTCACTTTCG GCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 286) LCVR (VL) Amino Acid Sequence DIQMTQSPSSLSASIGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRF SGSGSGTDFTLTISSLQPEDVATYYCQNHNSVPLTFGGGTKVEIK (SEQ ID NO: 287)
HC Amino Acid Sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFNSYAMTWVRQAPGKGLEWVSFIGGSTGNTY YAGSVKGRFTISSDNSKKTLYLQMNSLRAEDTAVYYCAKGGAARRMEYFQHWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 976) LC Amino Acid Sequence DIQMTQSPSSLSASIGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRF SGSGSGTDFTLTISSLQPEDVATYYCQNHNSVPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 977) 69348 HCVR (VH) Nucleotide Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCGTCTGGATTCACCTTCACTACCTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCTGTTATATGGTATGATGGAAGTAATA AATATTATGGAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAAC ACACTGTATCTGCAAATGAACAGCCTGAGAGTCGACGACACGGCTGTTTATTACTGTAC GAGAACCCATGGCTATACCAGGTCGTCGGACGGTTTTGACTACTGGGGCCAGGGAACC ^ ^
Attorney Docket No.250298.000954 CTGGTCACCGTCTCCTCA (SEQ ID NO: 291) HCVR (VH) Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFTTYGMHWVRQAPGKGLEWVAVIWYDGSNK YYGDSVKGRFTISRDNSKNTLYLQMNSLRVDDTAVYYCTRTHGYTRSSDGFDYWGQGTLV TVSS (SEQ ID NO: 292) or EVQLVESGGGVVQPGRSLRLSCAASGFTFTTYGMHWVRQAPGKGLEWVAVIWYDGSNKY 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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGAAATGTTTTAGGCTGGTTTCAGCAGAAA 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 QVQLVESGGGVVQPGRSLRLSCAASGFTFTTYGMHWVRQAPGKGLEWVAVIWYDGSNK YYGDSVKGRFTISRDNSKNTLYLQMNSLRVDDTAVYYCTRTHGYTRSSDGFDYWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD ^ ^
Attorney Docket No.250298.000954 ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 978) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSIRNVLGWFQQKPGKAPQRLIYAASSLQSGVPSR FSGSGSGTEFTLTISSLQPEDFATYYCLQHNFYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 979) 69340 HCVR (VH) Nucleotide Sequence GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATAAAGCCATGCACTGGGTCCGGCA AGTTCCAGGGAAGGGCCTGGAATGGATCTCAGGTATTAGTTGGAATAGTGGTACTATA GGCTATGCGGACTCTGTGAAGGGCCGATTCATCATCTCCAGAGACAACGCCAAGAACT CCCTGTATCTACAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGCGCA AAAGATGGAGATACCAGTGGCTGGTACTGGTACGGTTTGGACGTCTGGGGCCAAGGG ACCACGGTCACCGTCTCCTCA (SEQ ID NO: 302) HCVR (VH) Amino Acid Sequence EVQLVESGGGLVQPGRSLRLSCAASGFTFDDKAMHWVRQVPGKGLEWISGISWNSGTIGY ADSVKGRFIISRDNAKNSLYLQMNSLRAEDTALYYCAKDGDTSGWYWYGLDVWGQGTTVT
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 ^ ^
Attorney Docket No.250298.000954 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIHDVSNRATGIPARF SGSGSGTDFTLTISSLEPEDFVVYYCQQRSDWPITFGQGTRLEIK (SEQ ID NO: 308) or DIVMTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIHDVSNRATGIPAR FSGSGSGTDFTLTISSLEPEDFVVYYCQQRSDWPITFGQGTRLEIK (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 SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 980) LC Amino Acid Sequence EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIHDVSNRATGIPARF SGSGSGTDFTLTISSLEPEDFVVYYCQQRSDWPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 981) 69331 HCVR (VH) Nucleotide Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTATAGCCTCTGGATTCACCTTCAGTGTCTATGGCATTCACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGATGGCAGTAATATCACATGATGGAAATATTAA ACACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA CGCTGTATCTTCAAATTAACAGCCTGAGAACTGAGGACACGGCTGTGTATTACTGTGCG AAAGATACCTGGAACTCCCTTGATACTTTTGATATCTGGGGCCAAGGGACAATGGTCAC CGTCTCTTCA (SEQ ID NO: 313) HCVR (VH) Amino Acid Sequence ^ ^
Attorney Docket No.250298.000954 QVQLVESGGGVVQPGRSLRLSCIASGFTFSVYGIHWVRQAPGKGLEWMAVISHDGNIKHY 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 QVQLVESGGGVVQPGRSLRLSCIASGFTFSVYGIHWVRQAPGKGLEWMAVISHDGNIKHY ADSVKGRFTISRDNSKNTLYLQINSLRTEDTAVYYCAKDTWNSLDTFDIWGQGTMVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 982) LC Amino Acid Sequence ^ ^
Attorney Docket No.250298.000954 DIQLTQSPSSLSASVGDRVTITCWASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRF SGSGSGTEFTLTISSLQPEDFATYYCQQLNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQL KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD 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 STSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARGHNNLNYIIHWGQGTLVTVSS (SEQ ID NO: 325) or QVQLVESGPALVKPSQTLTLTCTFSGFSLNTYGMFVSWIRQPPGKALEWLAHIHWDDDKYY STSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARGHNNLNYIIHWGQGTLVTVSS (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 CCATCACTTGCCGGGCAAGTCAGGGCATTAGAAATGATTTAGGCTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCACTTTACAAAGTGGGGTC CCATCAAGGTTCAGCGGCAGTGGATCTGGCACAGATTTCACTCTCACCATCAGCAGCC TGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAAGATTACAATTACCCATTCACTTT CGGCCCTGGGACCAAAGTGGATATCAAA (SEQ ID NO: 330) LCVR (VL) Amino Acid Sequence ^ ^
Attorney Docket No.250298.000954 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 STSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARGHNNLNYIIHWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 984) LC Amino Acid Sequence AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASTLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCLQDYNYPFTFGPGTKVDIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK 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 ^ ^
Attorney Docket No.250298.000954 EVQLVESGGGLVQPGGSLRLSCAVSGFIFSSYEMNWVRQAPGKGLEWVSYISSSGSTIFYA DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCVSGVVLFDVWGQGTMVTVSS (SEQ ID NO: 337) QVQLVESGGGLVQPGGSLRLSCAVSGFIFSSYEMNWVRQAPGKGLEWVSYISSSGSTIFY ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCVSGVVLFDVWGQGTMVTVSS (SEQ ID NO: 338) HCDR1: GFIFSSYE (SEQ ID NO: 339) HCDR2: ISSSGSTI (SEQ ID NO: 340) HCDR3: VSGVVLFDV (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)
HC Amino Acid Sequence EVQLVESGGGLVQPGGSLRLSCAVSGFIFSSYEMNWVRQAPGKGLEWVSYISSSGSTIFYA DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCVSGVVLFDVWGQGTMVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT ^ ^
Attorney Docket No.250298.000954 CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 986) LC Amino Acid Sequence EIVMTQSPATLSVSPGERATLSCRASQSVSSNFAWYQQKPGQAPRLLIYSASSRATGIPVR FSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIWPRTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 987) 69329 HCVR (VH) Nucleotide Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTAACTATTGGATGACCTGGGTCCGCC AGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAAGGAAGATGGAAGTGAGA AAGACTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAA CTCACTGTATCTGCAAATGAACAGCCTGAGAGGCGAGGACACGGCTGTGTATTACTGT GCGAGAGATGGGGAGCAGCTCGTCGATTACTACTACTACTACGTTATGGACGTCTGGG GCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 348) HCVR (VH) Amino Acid Sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMTWVRQAPGKGLEWVANIKEDGSEKD YVDSVKGRFTISRDNAKNSLYLQMNSLRGEDTAVYYCARDGEQLVDYYYYYVMDVWGQG TTVTVSS (SEQ ID NO: 349) 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 ^ ^
Attorney Docket No.250298.000954 GCAGCCTGAAGATTTTGCAACTTACTATTGTCAAAAGGCTAACAGTTTCCCGTACACTTT TGGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 354) LCVR (VL) Amino Acid Sequence DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQKANSFPYTFGQGTKLEIK (SEQ ID NO: 355) or DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQKANSFPYTFGQGTKVEIK (SEQ ID NO: 356)
HC Amino Acid Sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMTWVRQAPGKGLEWVANIKEDGSEKD YVDSVKGRFTISRDNAKNSLYLQMNSLRGEDTAVYYCARDGEQLVDYYYYYVMDVWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 988) LC Amino Acid Sequence DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQKANSFPYTFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 989) 69323 HCVR (VH) Nucleotide Sequence GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGACTATGCCATGCACTGGGTCCGGCA AGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTTACATA GGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCGAGAACT CCCTACATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCA ^ ^
Attorney Docket No.250298.000954 AGAGGGGGATCTACTCTGGTTCGGGGAGTTAAGGGAGGCTACTACGGTATGGACGTCT GGGGCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 360) HCVR (VH) Amino Acid Sequence EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGYIG 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 CCATCACTTGCCGGGCAAGTCAGAGCATAAGTAGCTATTTAAATTGGTATCAGCAGAAA CCAGGTAAAGCCCCTAAGGTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTG CAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTATTCCGCTCACTTTC GGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 365) LCVR (VL) Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKVLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSIPLTFGGGTKVEIK (SEQ ID NO: 366)
HC Amino Acid Sequence EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGYIG YADSVKGRFTISRDNAENSLHLQMNSLRAEDTALYYCARGGSTLVRGVKGGYYGMDVWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 990) ^ ^
Attorney Docket No.250298.000954 LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKVLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSIPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQL KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD 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 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNK YYADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAGQLDLFFDYWGQGTLVTVSS (SEQ ID NO: 371) or EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNK 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 CCATCACTTGCCGGGCAAGTCAGAGCATTGACAGGTATTTAAATTGGTATCGGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATACTACATCCAGTTTGCAAAGTGGGGTCC CATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCCTCAGCAGTCT GCAGCCTGAAGATTTTGCAACTTACTACTGTCAGCAGAGTTACAGTCCCCCGCTCACTT TCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 376) ^ ^
Attorney Docket No.250298.000954 LCVR (VL) Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSIDRYLNWYRQKPGKAPKLLIYTTSSLQSGVPSRF SGSGSGTDFTLTLSSLQPEDFATYYCQQSYSPPLTFGGGTKVEIK (SEQ ID NO: 377)
HC Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNK YYADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAGQLDLFFDYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 992) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSIDRYLNWYRQKPGKAPKLLIYTTSSLQSGVPSRF SGSGSGTDFTLTLSSLQPEDFATYYCQQSYSPPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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 EVQLVESGGGLVQPGGSLRLSCTASGFTFSNYWMTWVRQAPGKGLEWVANIKEDGSEKE YVDSVKGRFTISRDNAKNSLYLQMNSLRGEDTAVYYCARDGEQLVDYYYYYVMDVWGQG ^ ^
Attorney Docket No.250298.000954
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 EVQLVESGGGLVQPGGSLRLSCTASGFTFSNYWMTWVRQAPGKGLEWVANIKEDGSEKE YVDSVKGRFTISRDNAKNSLYLQMNSLRGEDTAVYYCARDGEQLVDYYYYYVMDVWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 994) LC Amino Acid Sequence DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQKADSLPYAFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 995) ^ ^
Attorney Docket No.250298.000954 12795B HCVR (VH) Nucleotide Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTTCAGCCTGGGGGGTCCCTGAGA CTCTCCTGTGCAACCTCTGGATTCACCTTTACCAGCTATGACATGAAGTGGGTCCGCCA GGCTCCAGGGCTGGGCCTGGAGTGGGTCTCAGCTATTAGTGGTAGTGGTGGTAACAC ATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAGGAAC ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTA CGAGGTCCCATGACTTCGGTGCCTTCGACTACTTTGACTACTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA (SEQ ID NO: 391) HCVR (VH) Amino Acid Sequence EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYDMKWVRQAPGLGLEWVSAISGSGGNTY 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 CCATCACTTGCCGGGCAAGTCAGGGCATTAGAGATCATTTTGGCTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTGCACAGTGGGGTC CCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCT TGCAGCCTGAAGATTTTGCAACCTATTACTGTCTACAGTATGATACTTACCCGCTCACTT TCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 397) LCVR (VL) Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQGIRDHFGWYQQKPGKAPKRLIYAASSLHSGVPSR FSGSGSGTEFTLTISSLQPEDFATYYCLQYDTYPLTFGGGTKVEIK (SEQ ID NO: 398) or DIQLTQSPSSLSASVGDRVTITCRASQGIRDHFGWYQQKPGKAPKRLIYAASSLHSGVPSR FSGSGSGTEFTLTISSLQPEDFATYYCLQYDTYPLTFGGGTKVEIK (SEQ ID NO: 399) ^ ^
Attorney Docket No.250298.000954
HC Amino Acid Sequence EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYDMKWVRQAPGLGLEWVSAISGSGGNTY YADSVKGRFTISRDNSRNTLYLQMNSLRAEDTAVYYCTRSHDFGAFDYFDYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 996) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQGIRDHFGWYQQKPGKAPKRLIYAASSLHSGVPSR FSGSGSGTEFTLTISSLQPEDFATYYCLQYDTYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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 EVQLVESGGDLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSATRV YADSVKGRFTISRDNAKNFLYLQMNSLRSEDTALYHCAKDMDISLGYYGLDVWGQGTTVTV SS (SEQ ID NO: 404) HCDR1: GFTFDDYA (SEQ ID NO: 405) HCDR2: ISWNSATR (SEQ ID NO: 406) ^ ^
Attorney Docket No.250298.000954 HCDR3: AKDMDISLGYYGLDV (SEQ ID NO: 407) LCVR (VL) Nucleotide Sequence GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGACTGTTAGCAGCAACTTAGCCTGGTATCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTTCATCCTCCAGGGCCACTGGTATC CCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCC TGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCTCCCTACA 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 EVQLVESGGDLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSATRV YADSVKGRFTISRDNAKNFLYLQMNSLRSEDTALYHCAKDMDISLGYYGLDVWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 998) LC Amino Acid Sequence EIVMTQSPATLSVSPGERATLSCRASQTVSSNLAWYQQKPGQAPRLLIYGSSSRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPYTFGQGTKLEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 999) 12799B HCVR (VH) Nucleotide Sequence CAGATCACCTTGAAGGAGTCTGGTCCTACGCTGGTGAAACCCACACAGACCCTCACGC ^ ^
Attorney Docket No.250298.000954 TGACCTGCACCTTCTCTGGGTTCTCACTCAGCACTAGTGGAGTGGGTGTGGTCTGGAT CCGTCAGCCCCCCGGAAAGGCCCTGGAGTGGCTTGCACTCATTTATTGGAATGATCAT AAGCGGTACAGCCCATCTCTGGGGAGCAGGCTCACCATCACCAAGGACACCTCCAAAA ACCAGGTGGTCCTTACAATGACCAACATGGACCCTGTGGACACAGCCACATATTACTGT GCACACTACAGTGGGAGCTATTCCTACTACTACTATGGTTTGGACGTCTGGGGCCAAG GGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 413) HCVR (VH) Amino Acid Sequence QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVVWIRQPPGKALEWLALIYWNDHKRYS PSLGSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHYSGSYSYYYYGLDVWGQGTTVTV
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 QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVVWIRQPPGKALEWLALIYWNDHKRYS PSLGSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHYSGSYSYYYYGLDVWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS ^ ^
Attorney Docket No.250298.000954 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1000) LC Amino Acid Sequence DIQMTQSPSSVSASVGDRVTITCRASQGIASWLAWYQQKPGKAPELLIYAASSLQGGVPSR FSGSGSGTDFTLTISSLQPEDFAIYYCQQANYFPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1001)
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) 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 ^ ^
Attorney Docket No.250298.000954 CCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCC TGCGGCCTGAAGATTTTGCAACTTTTTACTGTCTACAGTATAATAGTTACCCGCTCACTT TCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 429) LCVR (VL) Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQGIRTDLGWYQQKPGKAPKRLIYAASSLQSGVPSR FSGSGSGTEFTLTISSLRPEDFATFYCLQYNSYPLTFGGGTKVEIK (SEQ ID NO: 430) or DIQMTQSPSSLSASVGDRVTITCRASQGIRTDLGWYQQKPGKAPKRLIYAASSLQSGVPSR FSGSGSGTEFTLTISSLRPEDFATFYCLQYNSYPLTFGGGTKVDIK (SEQ ID NO: 431)
HC Amino Acid Sequence EVQLLESGGALVQPGGSLRLSCAASGFTFTSYAMHWVRQAPGKGLEWVSSIRGSGGGTY SADSVKGRFTISRDNSRDTLYLQMNSVRAEDTAVYYCARSHDYGAFDFFDYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1002) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQGIRTDLGWYQQKPGKAPKRLIYAASSLQSGVPSR FSGSGSGTEFTLTISSLRPEDFATFYCLQYNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1003) 12802B HCVR (VH) Nucleotide Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTTCATGAGCTGGATCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTACTGGTAGTACCATA AATTATGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAATGTCAAGAATTC ^ ^
Attorney Docket No.250298.000954 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)
HC Amino Acid Sequence QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYFMSWIRQAPGKGLEWVSYISSTGSTINYA DSVKGRFTISRDNVKNSLYLQMTSLRVEDTAVYYCTRDNWNYEYWGQGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1004) ^ ^
Attorney Docket No.250298.000954 LC Amino Acid Sequence EIVMTQSPATLSVSPGERATLSCRASQSVSINLAWYQQKPGQAPRLLIFVASTRATGIPARF SGSGSGTEFTLTISSLQSEDFATYYCQQYDIWPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQL KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1005) 12808B HCVR (VH) Nucleotide Sequence CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC CTCACCTGCACTGTGTCTGGTGAATCCATCAGCAGTAATACTTACTACTGGGGCTGGAT 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 CCATCAATTGCCGGGCAAGTCAGGGCATTAGAAATGATTTAGGCTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CATTAAGGTTCAGTGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAACAACCTG CAGCCTGAAGATTTTGCAACTTATTACTGTCTATCGCATAATAGTTACCCGTGGACGTTC GGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 451) ^ ^
Attorney Docket No.250298.000954 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 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1006) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTINCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPLR FSGSGSGTEFTLTINNLQPEDFATYYCLSHNSYPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1007)
Nucleotide Sequence CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAGG GTCTCCTGCAAGGCTTCTAGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGAC AGGCCCCTGGACAAGGCCTTGAGTGGATGGGAGGGATCATCCCCATCTTTGGTACAGC AAACTACGCACAGAAGTTCCTGGCCAGAGTCACGATTACCGCGGACGAATCCACGAGC ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTG CGAGAGAGAAGGGGTGGAACTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCG TCTCCTCA (SEQ ID NO: 456) HCVR (VH) Amino Acid Sequence QVQLVQSGAEVKKPGSSVRVSCKASRGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANY ^ ^
Attorney Docket No.250298.000954 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 CCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCC TGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTAACAGTTTCCCTCGGACG 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 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1008) LC Amino Acid Sequence DIQMTQSPPSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPRTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1009) ^ ^
Attorney Docket No.250298.000954
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 CCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATGGTAATGGATACAACTATTTGACT TGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTTGGGTTCTAATCG GGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTG AAAATAAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTCTACA AACTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 472) LCVR (VL) Amino Acid Sequence DIVMTQSPLSLPVTPGEPASISCRSSQSLLHGNGYNYLTWYLQKPGQSPQLLIYLGSNRAS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYTFGQGTKLEIK (SEQ ID NO: 473) or ^ ^
Attorney Docket No.250298.000954 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 SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1010) LC Amino Acid Sequence DIVMTQSPLSLPVTPGEPASISCRSSQSLLHGNGYNYLTWYLQKPGQSPQLLIYLGSNRAS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST 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 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVIFISYDGSDKY YADSVKGRFAISRDSSKNTLYLQMNSLRAEDTAVYYCAKENGILTDSYGMDVWGQGTTVT ^ ^
Attorney Docket No.250298.000954 VSS (SEQ ID NO: 479) EVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVIFISYDGSDKYY 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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA 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 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVIFISYDGSDKY YADSVKGRFAISRDSSKNTLYLQMNSLRAEDTAVYYCAKENGILTDSYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1012) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF ^ ^
Attorney Docket No.250298.000954 SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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
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 ^ ^
Attorney Docket No.250298.000954 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 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1014) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013) 12835B HCVR (VH) Nucleotide Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGATACAACCTGGAGGGTCCCTGAGA CTCTCCTGTGAAGCCTCTGGATTCACCTTCAGAAATTATGAAATGAATTGGGTCCGCCA 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) ^ ^
Attorney Docket No.250298.000954 HCDR2: ISSSGNMK (SEQ ID NO: 503) HCDR3: ARDEFPYGMDV (SEQ ID NO: 504) LCVR (VL) Nucleotide Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA 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 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1015) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013) 12847B HCVR (VH) Nucleotide Sequence ^ ^
Attorney Docket No.250298.000954 GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTTCAGCCTGGCAGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGAACTGGGTCCGGCA AGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAGTAGTGGTAGCATG GACTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAAAACT CCCTGTATCTGCAAATGAACAGTCTGAGAACTGAGGACACGGCCTTATATTACTGTGCA AAAGCTAGGGAAGTTGGAGACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACG GTCACCGTCTCCTCA (SEQ ID NO: 510) HCVR (VH) Amino Acid Sequence EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMNWVRQAPGKGLEWVSGISWSSGSM DYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCAKAREVGDYYGMDVWGQGTTVT VSS (SEQ ID NO: 511) HCDR1: GFTFDDYA (SEQ ID HCDR2: ISWSSGSM (SEQ ID HCDR3: AKAREVGDYYGMDV
LCVR (VL) Nucleotide Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA 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 EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMNWVRQAPGKGLEWVSGISWSSGSM DYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCAKAREVGDYYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG ^ ^
Attorney Docket No.250298.000954 GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1016) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013) 12848B HCVR (VH) Nucleotide Sequence GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGACA CTCTCCTGTGCAGCCTCTGGATTCACCTTTGATAATTTTGGCATGCACTGGGTCCGGCA 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) ^ ^
Attorney Docket No.250298.000954 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 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1017) LC Amino Acid Sequence EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR FSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK 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 EVQLVESGGGLVQPGGSLRLSCAASGFTFNIFEMNWVRQAPGKGLEWISYISSRGTTTYYA ^ ^
Attorney Docket No.250298.000954 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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA 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 EVQLVESGGGLVQPGGSLRLSCAASGFTFNIFEMNWVRQAPGKGLEWISYISSRGTTTYYA DSVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDYEATIPFDFWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1019) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013) ^ ^
Attorney Docket No.250298.000954 12844B HCVR (VH) Nucleotide Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAAGTGTGGTACGGCCTGGGGGGTCCCTGAG ACTCTCCTGTGAAGCCTCTGGATTCACCTTTGATGATTATGGCATGAGCTGGGTCCGCC AAGATCCAGGGAAGGGGCTGGAGTGGGTCTCTGGTATTAATTGGAATGGTGATAGAAC AAATTATGCAGACTCTGTGAAGGGCCGATTCATCATTTCCAGAGACAACGCCAAGAACT CTGTGTATCTACAAATGAACAGTCTGAGAGCGGAGGACTCGGCCTTGTATCACTGTGC GAGAGATCAGGGACTCGGAGTGGCAGCTACCCTTGACTACTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA (SEQ ID NO: 540) HCVR (VH) Amino Acid Sequence EVQLVESGGSVVRPGGSLRLSCEASGFTFDDYGMSWVRQDPGKGLEWVSGINWNGDRT NYADSVKGRFIISRDNAKNSVYLQMNSLRAEDSALYHCARDQGLGVAATLDYWGQGTLVT VSS (SEQ ID NO: 541) or EVQLVESGGSVVRPGGSLRLSCEASGFTFDDYGMSWVRQDPGKGLEWVSGINWNGDRT 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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA 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) ^ ^
Attorney Docket No.250298.000954 LCDR3: QQSYSTPPIT (SEQ ID NO: 550) HC Amino Acid Sequence EVQLVESGGSVVRPGGSLRLSCEASGFTFDDYGMSWVRQDPGKGLEWVSGINWNGDRT NYADSVKGRFIISRDNAKNSVYLQMNSLRAEDSALYHCARDQGLGVAATLDYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1020) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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 EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYEMNWVRQAPGKGLEWVSYISSSTSNIYY ADSVKGRFTISRDNAENSLYLQMNSLRVEDTAVYYCVRDGIVVVPVGRGYYYYGLDVWGQ GTTVTVSS (SEQ ID NO: 552) HCDR1: GFTVSNYE (SEQ ID NO: 553) HCDR2: ISSSTSNI (SEQ ID NO: 554) HCDR3: VRDGIVVVPVGRGYYYYGLDV (SEQ ID NO: 555) ^ ^
Attorney Docket No.250298.000954 LCVR (VL) Nucleotide Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA 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) HC Amino Acid Sequence EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYEMNWVRQAPGKGLEWVSYISSSTSNIYY ADSVKGRFTISRDNAENSLYLQMNSLRVEDTAVYYCVRDGIVVVPVGRGYYYYGLDVWGQ GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1021) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013) 12839B HCVR (VH) Nucleotide Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGAAGGTCCCTGAGA CTCTCCTGCGCAGCCTCTGGATTCCCCTTTAGTAATTATGTCATGTATTGGGTCCGCCA GGCTCCAGGCAAGGGGCTGGAGTGGGTGGCTCTTATTTTTTTTGACGGAAAGAAAAAC ^ ^
Attorney Docket No.250298.000954 TATCATGCAGACTCCGTGAAGGGCCGATTCACCATAACCAGAGACAATTCCAAAAATAT GTTATATCTGCAAATGAACAGCCTGAGACCTGAGGACGCGGCTGTGTATTACTGTGCG AAAATCCATTGTCCTAATGGTGTATGTTACAAGGGGTATTACGGAATGGACGTCTGGGG CCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 561) HCVR (VH) Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFPFSNYVMYWVRQAPGKGLEWVALIFFDGKKNY 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 QVQLVESGGGVVQPGRSLRLSCAASGFPFSNYVMYWVRQAPGKGLEWVALIFFDGKKNY HADSVKGRFTITRDNSKNMLYLQMNSLRPEDAAVYYCAKIHCPNGVCYKGYYGMDVWGQ GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK ^ ^
Attorney Docket No.250298.000954 SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1022) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013)
Nucleotide Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTAAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTAACTATTGGATGAACTGGGTCCGCCA GGCTCCAGGGAAGGGACTGGAGTGGGTGGCCAATATAAAAGAAGATGGAGGTAAGAA ATTGTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACT CACTGTTTCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTATTGTGC GAGAGAAGATACAACTTTGGTTGTGGACTACTACTACTACGGTATGGACGTCTGGGGC CAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 571) HCVR (VH) Amino Acid Sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMNWVRQAPGKGLEWVANIKEDGGKKL YVDSVKGRFTISRDNAKNSLFLQMNSLRAEDTAVYYCAREDTTLVVDYYYYGMDVWGQGT TVTVSS (SEQ ID NO: 572) HCDR1: GFTFSNYW (SEQ ID NO: 573) HCDR2: IKEDGGKK (SEQ ID NO: 574) HCDR3: AREDTTLVVDYYYYGMDV (SEQ ID NO: 575) LCVR (VL) Nucleotide Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 576) LCVR (VL) Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF ^ ^
Attorney Docket No.250298.000954 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 EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMNWVRQAPGKGLEWVANIKEDGGKKL YVDSVKGRFTISRDNAKNSLFLQMNSLRAEDTAVYYCAREDTTLVVDYYYYGMDVWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1023) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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) ^ ^
Attorney Docket No.250298.000954 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 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1024) LC Amino Acid Sequence EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR FSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1018) 69261 HCVR (VH) Nucleotide Sequence ^ ^
Attorney Docket No.250298.000954 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 CCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATGGATACAACTATTTGGAT 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) ^ ^
Attorney Docket No.250298.000954 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 SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1025) LC Amino Acid Sequence DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQFLIYLGSNRAS GVPDRFSGSGSGTDFTLKINRVEAEDVGVYYCMQALQTPYTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST 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 EVQLVESGGGLVQPGRSLRLSCAVSGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGTR GYADSVKGRFTISRDNAKNSLYLQMNSLRGEDTALYYCVKDITISPNYYGMDVWGQGTTVT VSS (SEQ ID NO: 604) HCDR1: GFTFDDYA (SEQ ID NO: 605) HCDR2: ISWNSGTR (SEQ ID NO: 606) ^ ^
Attorney Docket No.250298.000954 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 EVQLVESGGGLVQPGRSLRLSCAVSGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGTR GYADSVKGRFTISRDNAKNSLYLQMNSLRGEDTALYYCVKDITISPNYYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1027) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQDISHYSAWYQQKPGKLPNLLIYAASTLQSGVPSRF SGSGSGTDFSLTTSSLQPEDVATYYCQKYNSVPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1028) ^ ^
Attorney Docket No.250298.000954 8D3 HCVR (VH) Nucleotide Sequence GAAGTACAGCTCGTCGAAAGTGGCGGTGGTCTTGTTCAGCCTGGAAACTCCCTCACCC TCTCATGTGTCGCAAGTGGATTTACTTTCTCAAATTATGGAATGCATTGGATTAGGCAAG CACCAAAAAAAGGACTTGAATGGATAGCTATGATATATTACGACTCCTCTAAAATGAATT ACGCAGATACTGTAAAAGGCAGGTTTACAATTTCTCGGGATAACTCTAAAAACACTCTTT ACCTTGAAATGAACTCTCTTAGATCCGAAGATACAGCTATGTACTATTGCGCAGTGCCA ACTAGTCATTACGTCGTCGATGTTTGGGGACAAGGCGTAAGTGTAACAGTCAGCTCA (SEQ ID NO: 1118) HCDR1: GGATTTACTTTCTCAAATTATGGAATGCAT (SEQ ID NO: 1120) HCDR2: ATGATATATTACGACTCCTCTAAAATGAATTACGCAGATACTGTAAAAGGC (SEQ ID NO: 1122) HCDR3: CCAACTAGTCATTACGTCGTCGATGTT (SEQ ID NO: 1124) HCVR (VH) Amino Acid Sequence EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSKMNY ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVSVTVSS (SEQ ID NO: 1119) HCDR1: GFTFSNYGMH (SEQ ID NO: 1121) HCDR2: MIYYDSSKMNYADTVKG (SEQ ID NO: 1123) HCDR3: PTSHYVVDV (SEQ ID NO: 1125) LCVR (VL) Nucleotide Sequence GACATTCAGATGACACAATCCCCAGCATCCCTCTCAGCATCACTCGAAGAAATCGTAAC AATCACCTGTCAAGCATCTCAAGATATCGGCAACTGGCTCGCATGGTACCAACAGAAAC CCGGCAAATCCCCTCAACTTCTTATTTATGGCGCAACATCCCTCGCAGACGGCGTTCCC TCAAGGTTCTCAGGCTCACGATCAGGCACTCAGTTCTCACTTAAAATCTCCAGAGTTCA AGTCGAAGATATAGGAATTTATTATTGTCTCCAAGCATATAACACACCATGGACATTCGG CGGCGGCACCAAACTCGAACTTAAA (SEQ ID NO: 1126) LCDR1: CAAGCATCTCAAGATATCGGCAACTGGCTCGCA (SEQ ID NO: 1128) LCDR2: GGCGCAACATCCCTCGCAGAC (SEQ ID NO: 1130) LCDR3: CAAGCATATAACACACCATGGACAT (SEQ ID NO: 1132) LCVR (VL) Amino Acid Sequence ^ ^
Attorney Docket No.250298.000954 DIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLLIYGATSLADGVPSRF SGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELK (SEQ ID NO: 1127) LCDR1: QASQDIGNWLA LCDR2: GATSLAD (SEQ LCDR3: QAYNTPWT (SE
[00553] 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, 511, 521, 531, 541, 542, 552, 562, 572, 582, 592, 593, 604, or 1119 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00554] 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. [00555] In some embodiments, provided herein are anti-AAV/anti-TfR multispecific 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., REGN12801B), 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 ^^^^ ^
Attorney Docket No.250298.000954 (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). [00556] 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. [00557] In some embodiments, the anti-TfR antibodies, or antigen-binding fragments ^ ^
Attorney Docket No.250298.000954 thereof, described herein comprise the amino acid sequence set forth in SEQ ID NOs: 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 998, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014, 1015, 1375, 1016, 1387, 1017, 1019, 1381, 1020, 1021, 1384, 1022, 1023, 1024, 1025, or 1027, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 998, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014, 1015, 1375, 1016, 1387, 1017, 1019, 1381, 1020, 1021, 1384, 1022, 1023, 1024, 1025, or 1027. In certain embodiments, the nucleotide sequence that encodes the anti-TfR antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence that encodes the amino acid sequence of SEQ ID NOs: 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 998, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014, 1015, 1375, 1016, 1387, 1017, 1019, 1381, 1020, 1021, 1384, 1022, 1023, 1024, 1025, or 1027, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 998, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014, 1015, 1375, 1016, 1387, 1017, 1019, 1381, 1020, 1021, 1384, 1022, 1023, 1024, 1025, or 1027. In certain embodiments, the anti-TfR antibodies, or antigen-binding fragments thereof, comprise the amino acid sequence set forth in SEQ ID NOs: 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 998, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014, 1015, 1375, 1016, 1387, 1017, 1019, 1381, 1020, 1021, 1384, 1022, 1023, 1024, 1025, or 1027. [00558] In some embodiments, the anti-TfR antibodies, or antigen-binding fragments thereof, described herein comprise the amino acid sequence set forth in SEQ ID NOs: 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 20, 1018, 1026, or 1028, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 20, 1018, 1026, or 1028. In certain embodiments, the nucleotide sequence that encodes the anti-TfR antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence that encodes the amino acid sequence of SEQ ID NOs: 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 20, 1018, 1026, or 1028, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 20, 1018, 1026, or 1028. In certain embodiments, the anti-TfR antibodies, ^ ^
Attorney Docket No.250298.000954 or antigen-binding fragments thereof, comprise the amino acid sequence set forth in SEQ ID NOs: 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 20, 1018, 1026, or 1028. [00559] 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., REGN12801B), 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). [00560] 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 ^^^^ ^
Attorney Docket No.250298.000954 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, ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00561] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00562] 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. [00563] 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: ^ ^
Attorney Docket No.250298.000954 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: ^ ^
Attorney Docket No.250298.000954 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: ^ ^
Attorney Docket No.250298.000954 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. [00564] 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. [00565] 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. [00566] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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, ^
Attorney Docket No.250298.000954 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: ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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: ^ ^
Attorney Docket No.250298.000954 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 ^
Attorney Docket No.250298.000954 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, ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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, ^ ^
Attorney Docket No.250298.000954 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; ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00567] 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
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[00568] 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., RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1147)); and the VH and IgG1 CH1 portion (e.g., ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1179)) or ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1112); or IgG4 CH1 (e.g., ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG (SEQ ID NO: 1171), or ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1135), or ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRV (SEQ ID NO: 1344), or ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG ^ ^
Attorney Docket No.250298.000954 LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY (SEQ ID NO: 1367)) 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 (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 IgG1 or IgG4; e.g., wherein CH1 is SEQ ID NO: 1147, 1179, 1112, 1171, 1135,1344, or 1367. [00569] 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 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA ^ ^
Attorney Docket No.250298.000954 DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 975) Fab Heavy Chain EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYAMTWVRQAPGKGLEWVSVISGTGGSTY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGGAARRMEYFQYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1061) (2) 31863B Fab Light Chain DIQMTQSPSSLSASIGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRF SGSGSGTDFTLTISSLQPEDVATYYCQNHNSVPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 977) Fab Heavy Chain EVQLVESGGGLVQPGGSLRLSCAASGFTFNSYAMTWVRQAPGKGLEWVSFIGGSTGNTY YAGSVKGRFTISSDNSKKTLYLQMNSLRAEDTAVYYCAKGGAARRMEYFQHWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1062) (3) 69348 Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSIRNVLGWFQQKPGKAPQRLIYAASSLQSGVPSR FSGSGSGTEFTLTISSLQPEDFATYYCLQHNFYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 979) Fab Heavy Chain QVQLVESGGGVVQPGRSLRLSCAASGFTFTTYGMHWVRQAPGKGLEWVAVIWYDGSNK YYGDSVKGRFTISRDNSKNTLYLQMNSLRVDDTAVYYCTRTHGYTRSSDGFDYWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1063) ^ ^
Attorney Docket No.250298.000954 (4) 69340 Fab Light Chain EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIHDVSNRATGIPARF SGSGSGTDFTLTISSLEPEDFVVYYCQQRSDWPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 981) Fab Heavy Chain EVQLVESGGGLVQPGRSLRLSCAASGFTFDDKAMHWVRQVPGKGLEWISGISWNSGTIGY ADSVKGRFIISRDNAKNSLYLQMNSLRAEDTALYYCAKDGDTSGWYWYGLDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1064) (5) 69331 Fab Light Chain DIQLTQSPSSLSASVGDRVTITCWASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRF SGSGSGTEFTLTISSLQPEDFATYYCQQLNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQL KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 983) Fab Heavy Chain QVQLVESGGGVVQPGRSLRLSCIASGFTFSVYGIHWVRQAPGKGLEWMAVISHDGNIKHY ADSVKGRFTISRDNSKNTLYLQINSLRTEDTAVYYCAKDTWNSLDTFDIWGQGTMVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1065) (6) 69332 Fab Light Chain AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASTLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCLQDYNYPFTFGPGTKVDIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 985) ^ ^
Attorney Docket No.250298.000954 Fab Heavy Chain QVTLRESGPALVKPSQTLTLTCTFSGFSLNTYGMFVSWIRQPPGKALEWLAHIHWDDDKYY STSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARGHNNLNYIIHWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1066) (7) 69326 Fab Light Chain EIVMTQSPATLSVSPGERATLSCRASQSVSSNFAWYQQKPGQAPRLLIYSASSRATGIPVR FSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIWPRTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 987) Fab Heavy Chain EVQLVESGGGLVQPGGSLRLSCAVSGFIFSSYEMNWVRQAPGKGLEWVSYISSSGSTIFYA DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCVSGVVLFDVWGQGTMVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1067) (8) 69329 Fab Light Chain DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQKANSFPYTFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 989) Fab Heavy Chain EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMTWVRQAPGKGLEWVANIKEDGSEKD YVDSVKGRFTISRDNAKNSLYLQMNSLRGEDTAVYYCARDGEQLVDYYYYYVMDVWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1068) (9) 69323 ^ ^
Attorney Docket No.250298.000954 Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKVLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSIPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQL KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 991) Fab Heavy Chain EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGYIG YADSVKGRFTISRDNAENSLHLQMNSLRAEDTALYYCARGGSTLVRGVKGGYYGMDVWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1069) (10) 69305 Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSIDRYLNWYRQKPGKAPKLLIYTTSSLQSGVPSRF SGSGSGTDFTLTLSSLQPEDFATYYCQQSYSPPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 993) Fab Heavy Chain QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNK YYADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAGQLDLFFDYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1070) (11) 69307 Fab Light Chain DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQKADSLPYAFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 995) Fab Heavy Chain ^ ^
Attorney Docket No.250298.000954 EVQLVESGGGLVQPGGSLRLSCTASGFTFSNYWMTWVRQAPGKGLEWVANIKEDGSEKE YVDSVKGRFTISRDNAKNSLYLQMNSLRGEDTAVYYCARDGEQLVDYYYYYVMDVWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1071) (12) 12795B Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQGIRDHFGWYQQKPGKAPKRLIYAASSLHSGVPSR FSGSGSGTEFTLTISSLQPEDFATYYCLQYDTYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 997) Fab Heavy Chain EVQLVESGGGLVQPGGSLRLSCATSGFTFTSYDMKWVRQAPGLGLEWVSAISGSGGNTY YADSVKGRFTISRDNSRNTLYLQMNSLRAEDTAVYYCTRSHDFGAFDYFDYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1072) (13) 12798B Fab Light Chain EIVMTQSPATLSVSPGERATLSCRASQTVSSNLAWYQQKPGQAPRLLIYGSSSRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPYTFGQGTKLEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 999) Fab Heavy Chain EVQLVESGGDLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSATRV YADSVKGRFTISRDNAKNFLYLQMNSLRSEDTALYHCAKDMDISLGYYGLDVWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1073); EVQLVESGGDLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSATRV YADSVKGRFTISRDNAKNFLYLQMNSLRSEDTALYHCAKDMDISLGYYGLDVWGQGTTVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS ^ ^
Attorney Docket No.250298.000954 SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG (SEQ ID NO: 1074); or EVQLVESGGDLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSATRV YADSVKGRFTISRDNAKNFLYLQMNSLRSEDTALYHCAKDMDISLGYYGLDVWGQGTTVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1075) (14) 12799B Fab Light Chain DIQMTQSPSSVSASVGDRVTITCRASQGIASWLAWYQQKPGKAPELLIYAASSLQGGVPSR FSGSGSGTDFTLTISSLQPEDFAIYYCQQANYFPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1001) Fab Heavy Chain QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVVWIRQPPGKALEWLALIYWNDHKRYS PSLGSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHYSGSYSYYYYGLDVWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1076); QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVVWIRQPPGKALEWLALIYWNDHKRYS PSLGSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHYSGSYSYYYYGLDVWGQGTTVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG (SEQ ID NO: 1077); or QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVVWIRQPPGKALEWLALIYWNDHKRYS PSLGSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHYSGSYSYYYYGLDVWGQGTTVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1078) (15) 12801B Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQGIRTDLGWYQQKPGKAPKRLIYAASSLQSGVPSR FSGSGSGTEFTLTISSLRPEDFATFYCLQYNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ ^ ^
Attorney Docket No.250298.000954 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1003) Fab Heavy Chain EVQLLESGGALVQPGGSLRLSCAASGFTFTSYAMHWVRQAPGKGLEWVSSIRGSGGGTY SADSVKGRFTISRDNSRDTLYLQMNSVRAEDTAVYYCARSHDYGAFDFFDYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1079) (16) 12802B Fab Light Chain EIVMTQSPATLSVSPGERATLSCRASQSVSINLAWYQQKPGQAPRLLIFVASTRATGIPARF SGSGSGTEFTLTISSLQSEDFATYYCQQYDIWPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQL KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1005) Fab Heavy Chain QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYFMSWIRQAPGKGLEWVSYISSTGSTINYA DSVKGRFTISRDNVKNSLYLQMTSLRVEDTAVYYCTRDNWNYEYWGQGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1080) (17) 12808B Fab Light Chain DIQMTQSPSSLSASVGDRVTINCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPLR FSGSGSGTEFTLTINNLQPEDFATYYCLSHNSYPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1007) Fab Heavy Chain QLQLQESGPGLVKPSETLSLTCTVSGESISSNTYYWGWIRQPPGKGLEWIGSIDYSGTTNY NPSLKSRVTISVDTSRNHFSLRLRSVTAADTAVYYCAREWGNYGYYYGMDVWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1081) ^ ^
Attorney Docket No.250298.000954 (18) 12812B Fab Light Chain DIQMTQSPPSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPRTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1009) Fab Heavy Chain QVQLVQSGAEVKKPGSSVRVSCKASRGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANY AQKFLARVTITADESTSTAYMELSSLRSEDTAVYYCAREKGWNYFDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1082) (19) 12816B Fab Light Chain DIVMTQSPLSLPVTPGEPASISCRSSQSLLHGNGYNYLTWYLQKPGQSPQLLIYLGSNRAS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPYTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1011) Fab Heavy Chain QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMNWIRQAPGKGLEWVSYISSSGTTIYYA DSVKGRFTISRDNAKKSLYLEMNSLRAEDTAVYYCAREGYGNDYYYYGIDVWGQGTTVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1083) (20) 12833B Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013) Fab Heavy Chain ^ ^
Attorney Docket No.250298.000954 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVIFISYDGSDKY YADSVKGRFAISRDSSKNTLYLQMNSLRAEDTAVYYCAKENGILTDSYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1084) (21) 12834B Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013) Fab Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISVYHGNTN YAQKFQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAREGYYDFWSGYYPFDYWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1085) (22) 12835B Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20) Fab Heavy Chain ^ ^
Attorney Docket No.250298.000954 EVQLVESGGGLIQPGGSLRLSCEASGFTFRNYEMNWVRQAPGKGLEWVSYISSSGNMKD YAESVKGRFTISRDNVKNSLQLQMNSLRVEDTAVYYCARDEFPYGMDVWGQGTTVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1086) EVQLVESGGGLIQPGGSLRLSCEASGFTFRNYEMNWVRQAPGKGLEWVSYISSSGNMKD YAESVKGRFTISRDNVKNSLQLQMNSLRVEDTAVYYCARDEFPYGMDVWGQGTTVTVSSA STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRV (SEQ ID NO: 1376) (23) 12847B Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013); or DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20) Fab Heavy Chain EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMNWVRQAPGKGLEWVSGISWSSGSM DYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCAKAREVGDYYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1087); EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMNWVRQAPGKGLEWVSGISWSSGSM DYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCAKAREVGDYYGMDVWGQGTTVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG (SEQ ID NO: 1088); or EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMNWVRQAPGKGLEWVSGISWSSGSM ^^^^ ^
Attorney Docket No.250298.000954 DYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCAKAREVGDYYGMDVWGQGTTVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1089); EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMNWVRQAPGKGLEWVSGISWSSGSM DYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTALYYCAKAREVGDYYGMDVWGQGTTVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRV (SEQ ID NO: 1388) (24) 12848B Fab Light Chain EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR FSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1018) Fab Heavy Chain EVQLVESGGGLVQPGRSLTLSCAASGFTFDNFGMHWVRQGPGKGLEWVSGLTWNSGVIG YADSVKGRFTISRDNAKNSLYLQMNSLRPEDTALYYCAKDIRNYGPFDYWGQGTLVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1090) (25) 12843B Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013) or DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ ^ ^
Attorney Docket No.250298.000954 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20) Fab Heavy Chain EVQLVESGGGLVQPGGSLRLSCAASGFTFNIFEMNWVRQAPGKGLEWISYISSRGTTTYYA DSVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDYEATIPFDFWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1091); EVQLVESGGGLVQPGGSLRLSCAASGFTFNIFEMNWVRQAPGKGLEWISYISSRGTTTYYA DSVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDYEATIPFDFWGQGTLVTVSSAST KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG (SEQ ID NO: 1092); or EVQLVESGGGLVQPGGSLRLSCAASGFTFNIFEMNWVRQAPGKGLEWISYISSRGTTTYYA DSVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDYEATIPFDFWGQGTLVTVSSAST KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1093); or EVQLVESGGGLVQPGGSLRLSCAASGFTFNIFEMNWVRQAPGKGLEWISYISSRGTTTYYA DSVRGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDYEATIPFDFWGQGTLVTVSSAST KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRV (SEQ ID NO: 1382) (26) 12844B Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013) Fab Heavy Chain ^ ^
Attorney Docket No.250298.000954 EVQLVESGGSVVRPGGSLRLSCEASGFTFDDYGMSWVRQDPGKGLEWVSGINWNGDRT NYADSVKGRFIISRDNAKNSVYLQMNSLRAEDSALYHCARDQGLGVAATLDYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1094) (27) 12845B Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013); or DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20) Fab Heavy Chain EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYEMNWVRQAPGKGLEWVSYISSSTSNIYY ADSVKGRFTISRDNAENSLYLQMNSLRVEDTAVYYCVRDGIVVVPVGRGYYYYGLDVWGQ GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1095); EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYEMNWVRQAPGKGLEWVSYISSSTSNIYY ADSVKGRFTISRDNAENSLYLQMNSLRVEDTAVYYCVRDGIVVVPVGRGYYYYGLDVWGQ GTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG (SEQ ID NO: 1096); or EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYEMNWVRQAPGKGLEWVSYISSSTSNIYY ADSVKGRFTISRDNAENSLYLQMNSLRVEDTAVYYCVRDGIVVVPVGRGYYYYGLDVWGQ GTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1097); or ^ ^
Attorney Docket No.250298.000954 EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYEMNWVRQAPGKGLEWVSYISSSTSNIYY ADSVKGRFTISRDNAENSLYLQMNSLRVEDTAVYYCVRDGIVVVPVGRGYYYYGLDVWGQ GTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRV (SEQ ID NO: 1385) (28) 12839B Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013) Fab Heavy Chain QVQLVESGGGVVQPGRSLRLSCAASGFPFSNYVMYWVRQAPGKGLEWVALIFFDGKKNY HADSVKGRFTITRDNSKNMLYLQMNSLRPEDAAVYYCAKIHCPNGVCYKGYYGMDVWGQ GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1098); QVQLVESGGGVVQPGRSLRLSCAASGFPFSNYVMYWVRQAPGKGLEWVALIFFDGKKNY HADSVKGRFTITRDNSKNMLYLQMNSLRPEDAAVYYCAKIHCPNGVCYKGYYGMDVWGQ GTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG (SEQ ID NO: 1099) QVQLVESGGGVVQPGRSLRLSCAASGFPFSNYVMYWVRQAPGKGLEWVALIFFDGKKNY HADSVKGRFTITRDNSKNMLYLQMNSLRPEDAAVYYCAKIHCPNGVCYKGYYGMDVWGQ GTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1100) (29) 12841B Fab Light Chain ^ ^
Attorney Docket No.250298.000954 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1013) Fab Heavy Chain EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMNWVRQAPGKGLEWVANIKEDGGKKL YVDSVKGRFTISRDNAKNSLFLQMNSLRAEDTAVYYCAREDTTLVVDYYYYGMDVWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1101) (30) 12850B Fab Light Chain EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR FSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1018) Fab Heavy Chain QVQLVQSGAEVKKPGSSVKVSCKASGGTFNTYAITWVRQAPGQGLEWMGGIIPISGIAEYA QKFQGRVTITTDDSSTTAYMELNSLRSEDTAVYYCASWNYALYYFYGMDVWGRGTTVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1102) (31) 69261 Fab Light Chain DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQFLIYLGSNRAS GVPDRFSGSGSGTDFTLKINRVEAEDVGVYYCMQALQTPYTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1026) Fab Heavy Chain QVQLVESGGGLVKPGGSLRLSCAASGFTFSVYYMNWIRQAPGKGLEWVSYISSSGSTIYYA ^ ^
Attorney Docket No.250298.000954 DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCGREGYSGTYSYYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1103) (32) 69263 Fab Light Chain DIQMTQSPSSLSASVGDRVTITCRASQDISHYSAWYQQKPGKLPNLLIYAASTLQSGVPSRF SGSGSGTDFSLTTSSLQPEDVATYYCQKYNSVPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1028) Fab Heavy Chain EVQLVESGGGLVQPGRSLRLSCAVSGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGTR GYADSVKGRFTISRDNAKNSLYLQMNSLRGEDTALYYCVKDITISPNYYGMDVWGQGTTVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1104) [00570] 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 antigen- binding 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 antigen- binding 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. [00571] 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 multispecific antigen-binding molecules disclosed herein, or variants thereof, including nucleic acid ^ ^
Attorney Docket No.250298.000954 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
^ ^
Attorney Docket No.250298.000954
Table 11. Nucleic Acid Sequence Identifiers for Anti-CACNG1 Antibodies
^ ^
Attorney Docket No.250298.000954
H2aM31929N/REGN10728 HCVR DNA Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTACAGCGTCTGGAATCACCTTCAGAAATTATGGCATGCACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAA GTACTATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGGTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAA GGGGCACTATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCCTCA (SEQ ID NO: 614) HCVR Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNK 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 ^ ^
Attorney Docket No.250298.000954 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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 622) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 623) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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 ^ ^
Attorney Docket No.250298.000954 QQSYSTPPIT (SEQ ID NO: 629) HC DNA Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTACAGCGTCTGGAATCACCTTCAGAAATTATGGCATGCACTGGGTCCGCC 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 QVQLVESGGGVVQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNK YYADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS ^ ^
Attorney Docket No.250298.000954 CSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 631) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 632) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 633) H2aM31944N HCVR DNA Sequence CAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGA CTCTCCTGTGAAGCGTCTGGAATCACCTTCAGAAACTATGGCATGCACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAA ATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA CGGTGTATCTGCAAATGAACAGCCTGAGAGCCGAAGACACGGCTGTGTATTACTGTGC GAGACGGGGTCATATAGCAACAGCTGCTCCCTTTGACTACTGGGGCCAGGGAACCCTG GTCACCGTCTCCTCA (SEQ ID NO: 634) HCVR Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCEASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNK YYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARRGHIATAAPFDYWGQGTLVTV SS (SEQ ID NO: 635) ^ ^
Attorney Docket No.250298.000954 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) ^ ^
Attorney Docket No.250298.000954 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 TCTGACCTGCATGGTCACAGACTTCATGCCTGAAGACATTTACGTGGAGTGGACCAACA ACGGGAAAACAGAGCTAAACTACAAGAACACTGAACCAGTCCTGGACTCTGATGGTTCT TACTTCATGTACAGCAAGCTGAGAGTGGAAAAGAAGAACTGGGTGGAAAGAAATAGCTA ^ ^
Attorney Docket No.250298.000954 CTCCTGTTCAGTGGTCCACGAGGGTCTGCACAATCACCACACGACTAAGAGCTTCTCC CGGACTCCGGGTAAATGA (SEQ ID NO: 650) HC Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCEASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNK YYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARRGHIATAAPFDYWGQGTLVTV SSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQS DLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGP SVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLR VVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQ VTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNS YSCSVVHEGLHNHHTTKSFSRTPGK (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 QLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTK DEYERHNSYTCEATHKTSTSPIVKSFNRGEC (SEQ ID NO: 653) H4H31265P2/REGN5972 HCVR DNA Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ^ ^
Attorney Docket No.250298.000954 ACTCTCCTGTACAGCGTCTGGATTCACCTTCCGTTCCTATGGCATGCACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGTCAGTTATTTGGATTGATGGAAATAATAT ATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACA CGCTGTATCTGCAAATGGACAGCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGC GAGAAGACTGGCTATAACATCAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCCTG GTCACCGTCTCCTCA (SEQ ID NO: 654) HCVR Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCTASGFTFRSYGMHWVRQAPGKGLEWVSVIWIDGNNIY 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 CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA ^ ^
Attorney Docket No.250298.000954 CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 662) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 663) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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 GAGAAGACTGGCTATAACATCAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCCTG GTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCT CCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCC CCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCT TCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCC CTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAAC ^ ^
Attorney Docket No.250298.000954 ACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAG CACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACAC TCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGA AGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAG ACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACC GTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAG GCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCC ACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCT GACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAA TGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTC CTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTC CCTGTCTCTGGGTAAATGA (SEQ ID NO: 670) HC Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCTASGFTFRSYGMHWVRQAPGKGLEWVSVIWIDGNNIY YADSVKGRFTISRDNSKNTLYLQMDSLRAEDTAVYYCARRLAITSAAPFDYWGQGTLVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK* (SEQ ID NO: 671) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA ^ ^
Attorney Docket No.250298.000954 GAGTGTTAG (SEQ ID NO: 672) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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 ^ ^
Attorney Docket No.250298.000954 GCGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTT (SEQ ID NO: 680) HCDR3 Amino Acid Sequence ARKGHYGSGTYYNPFGFDF (SEQ ID NO: 681) LCVR DNA Sequence GAAATTATGTTGATGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCAC CCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGACA 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) ^ ^
Attorney Docket No.250298.000954 HC DNA Sequence CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAG GTCTCCTGCAAGGCTTCTGGTTACGCCTTCACCACCTATGGTATCACCTGGGTGCGAC AGGCCCCTGGACAAGGACTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAATAC AAACTATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAAT ACAGCCTACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGTG CGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTGG GGCCAAGGGACAATGGTCACCGTCTCTTCAGCCAAAACGACACCCCCATCTGTCTATC CACTGGCCCCTGGATCTGCTGCCCAAACTAACTCCATGGTGACCCTGGGATGCCTGGT CAAGGGCTATTTCCCTGAGCCAGTGACAGTGACCTGGAACTCTGGATCCCTGTCCAGC GGTGTGCACACCTTCCCAGCTGTCCTGCAGTCTGACCTCTACACTCTGAGCAGCTCAG TGACTGTCCCCTCCAGCACCTGGCCCAGCGAGACCGTCACCTGCAACGTTGCCCACCC GGCCAGCAGCACCAAGGTGGACAAGAAAATTGTGCCCAGGGATTGTGGTTGTAAGCCT TGCATATGTACAGTCCCAGAAGTATCATCTGTCTTCATCTTCCCCCCAAAGCCCAAGGA TGTGCTCACCATTACTCTGACTCCTAAGGTCACGTGTGTTGTGGTAGACATCAGCAAGG ATGATCCCGAGGTCCAGTTCAGCTGGTTTGTAGATGATGTGGAGGTGCACACAGCTCA GACGCAACCCCGGGAGGAGCAGTTCAACAGCACTTTCCGCTCAGTCAGTGAACTTCCC ATCATGCACCAGGACTGGCTCAATGGCAAGGAGTTCAAATGCAGGGTCAACAGTGCAG CTTTCCCTGCCCCCATCGAGAAAACCATCTCCAAAACCAAAGGCAGACCGAAGGCTCC ACAGGTGTACACCATTCCACCTCCCAAGGAGCAGATGGCCAAGGATAAAGTCAGTCTG ACCTGCATGATAACAGACTTCTTCCCTGAAGACATTACTGTGGAGTGGCAGTGGAATGG GCAGCCAGCGGAGAACTACAAGAACACTCAGCCCATCATGGACACAGATGGCTCTTAC TTCGTCTACAGCAAGCTCAATGTGCAGAAGTCCAACTGGGAGGCAGGAAATACTTTCAC CTGCTCTGTGTTACATGAGGGCCTGCACAACCACCATACTGAGAAGTCCCTCTCCCACT CTCCTGGTAAATGA (SEQ ID NO: 690) HC Amino Acid Sequence QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNTN YAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWGQ GTMVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHT FPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEV SSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNST FRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKD KVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGN TFTCSVLHEGLHNHHTEKSLSHSPGK (SEQ ID NO: 691) ^ ^
Attorney Docket No.250298.000954 LC DNA Sequence GAAATTATGTTGATGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCAC CCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGACA TCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAG ACTGGAGCCTGAAGATTTTGCAGTTTATTTCTGTCAGCAGTATTATGGCTCACCTTGGA CGTTCGGCCAAGGGACCAAGGTGGAAATCAAGCGAGCTGATGCTGCACCAACTGTATC CATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCT TGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGA CAAAATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCA TGAGCAGCACCCTCACGTTGACCAAGGACGAGTATGAACGACATAACAGCTATACCTG TGAGGCCACTCACAAGACATCAACTTCACCCATTGTCAAGAGCTTCAACAGGGGAGAG TGTTGA (SEQ ID NO: 692) LC Amino Acid Sequence EIMLMQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATDIPD RFSGSGSGTDFTLTISRLEPEDFAVYFCQQYYGSPWTFGQGTKVEIKRADAAPTVSIFPPSS EQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLT KDEYERHNSYTCEATHKTSTSPIVKSFNRGEC (SEQ ID NO: 693) REGN7660 HCVR DNA Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCGGGGGGGTCCCTGAA ACTCTCCTGTACAGCCTCTGGGTTGACCCTCAGTGACTCTGCTATGCACTGGGTCCGC CAGGCTTCCGGGAAAGGGCTGGAGTGGGTTGGCCGTATAAGAAATAAGGCTAATAGGT ACGCGACAGAATATGCTGCGTCGGTGAAAGGCAGGTTCACCATTTCAAGAGATGATTC AAAGAACACGGCGTATCTACAAATGAACAGCCTGAAAACCGAGGACACGGCCGTGTAT TATTGTACTAGAAACTGGAAGATTTTCCTCTTTGACTACTGGGGCCAGGGAACCCTGGT CACCGTCTCCTCA (SEQ ID NO: 694) HCVR Amino Acid Sequence EVQLVESGGGLVQPGGSLKLSCTASGLTLSDSAMHWVRQASGKGLEWVGRIRNKANRYA TEYAASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRNWKIFLFDYWGQGTLVTVSS (SEQ ID NO: 695) HCDR1 DNA Sequence ^ ^
Attorney Docket No.250298.000954 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 CCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGCAGCAAATACTTAGCCTGGTTCCAGCA 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 ^ ^
Attorney Docket No.250298.000954 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) ^ ^
Attorney Docket No.250298.000954 HC Amino Acid Sequence EVQLVESGGGLVQPGGSLKLSCTASGLTLSDSAMHWVRQASGKGLEWVGRIRNKANRYA TEYAASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRNWKIFLFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 711) LC DNA Sequence GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGACTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGCAGCAAATACTTAGCCTGGTTCCAGCA GAAACGTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGACCAGTGG CATCCCCGACAGGATCAGTGGCAGTGGGTCAGGGACAGACTTCACTCTCACCATCAGC AGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGAAGTTCACCCTG GACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTC TTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCT GCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACA GCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGC CTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTAG (SEQ ID NO: 712) LC Amino Acid Sequence EIVLTQSPGTLTLSPGERATLSCRASQSVGSKYLAWFQQKRGQAPRLLIYGASSRTSGIPDR ISGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 713) REGN9909 HCVR DNA Sequence GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCGGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCTTTAACAACTATGGCATGAGCTGGGTCCGCC AGGGTCCAGGGAAGGGGCTGGAGTGGGTCTCATCTATTAGTGGTAGTGGTGGTACCA ^ ^
Attorney Docket No.250298.000954 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 ATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAATAATTATATATACTGGTACCAGCG GCTCCCAGGAACGACCCCCAAACTCCTCATCTATAGGAATAATCAGCGGCCCTCAGGG GTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTG GGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACACCCTGAG TGGGTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA (SEQ ID NO: 722) ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 GCAAGCAGCACCAAGGTGGACAAGAAAATTGAGCCCAGAGGGCCCACAATCAAGCCCT GTCCTCCATGCAAATGCCCAGCACCTAACCTCTTGGGTGGACCATCCGTCTTCATCTTC CCTCCAAAGATCAAGGATGTACTCATGATCTCCCTGAGCCCCATAGTCACATGTGTGGT GGTGGATGTGAGCGAGGATGACCCAGATGTCCAGATCAGCTGGTTTGTGAACAACGTG GAAGTACACACAGCTCAGACACAAACCCATAGAGAGGATTACAACAGTACTCTCCGGG TGGTCAGTGCCCTCCCCATCCAGCACCAGGACTGGATGAGTGGCAAGGAGTTCAAATG CAAGGTCAACAACAAAGACCTCCCAGCGCCCATCGAGAGAACCATCTCAAAACCCAAA GGGTCAGTAAGAGCTCCACAGGTATATGTCTTGCCTCCACCAGAAGAAGAGATGACTA AGAAACAGGTCACTCTGACCTGCATGGTCACAGACTTCATGCCTGAAGACATTTACGTG GAGTGGACCAACAACGGGAAAACAGAGCTAAACTACAAGAACACTGAACCAGTCCTGG ACTCTGATGGTTCTTACTTCATGTACAGCAAGCTGAGAGTGGAAAAGAAGAACTGGGTG GAAAGAAATAGCTACTCCTGTTCAGTGGTCCACGAGGGTCTGCACAATCACCACACGA CTAAGAGCTTCTCCCGGACTCCGGGTAAATGA (SEQ ID NO: 730) HC Amino Acid Sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFNNYGMSWVRQGPGKGLEWVSSISGSGGTTF YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWGQG TTVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFP AVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPN LLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDY NSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEE MTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNW VERNSYSCSVVHEGLHNHHTTKSFSRTPGK (SEQ ID NO: 731) LC DNA Sequence CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACC ATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAATAATTATATATACTGGTACCAGCG GCTCCCAGGAACGACCCCCAAACTCCTCATCTATAGGAATAATCAGCGGCCCTCAGGG GTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTG GGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACACCCTGAG TGGGTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTACGAGCTGATGCTGCACCA ACTGTATCCATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGT GTGCTTCTTGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCA GTGAACGACAAAATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCAC CTACAGCATGAGCAGCACCCTCACGTTGACCAAGGACGAGTATGAACGACATAACAGC TATACCTGTGAGGCCACTCACAAGACATCAACTTCACCCATTGTCAAGAGCTTCAACAG ^ ^
Attorney Docket No.250298.000954 GGGAGAGTGTTGA (SEQ ID NO: 732) LC Amino Acid Sequence QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNYIYWYQRLPGTTPKLLIYRNNQRPSGVPD RFSGSKSGTSASLAISGLRSEDEADYYCAAWDDTLSGYVFGTGTKVTVLRADAAPTVSIFP PSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTL TLTKDEYERHNSYTCEATHKTSTSPIVKSFNRGEC (SEQ ID NO: 733) REGN10713 HCVR DNA Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTTACCAGCCATGCCATGAACTGGGTCCGCC 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 ^ ^
Attorney Docket No.250298.000954 GCGAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTAC (SEQ ID NO: 740) HCDR3 Amino Acid Sequence AKGLYDSGNYYIDY (SEQ ID NO: 741) LCVR DNA Sequence CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACC ATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTTTCCTGGTACCAGCA 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) ^ ^
Attorney Docket No.250298.000954 HC DNA Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTTACCAGCCATGCCATGAACTGGGTCCGCC AGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTACTGGTAGAGGTTTTGACAC ACACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACATTTCCAAAAACA CGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTACTGTGC GAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTACTGGGGCCAGGGAACCCTGG TCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTC CAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC CGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC TCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACA CCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGC ACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACT CTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAA GACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGA CAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCG TCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGG CCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCA CAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTG ACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT GGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCC TTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCT TCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCC CTGTCTCTGGGTAAATGA (SEQ ID NO: 750) HC Amino Acid Sequence EVQLVESGGNLVQPGGSLRLSCAASGFTFTSHAMNWVRQAPGKGLEWVSVITGRGFDTH YADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAKGLYDSGNYYIDYWGQGTLVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK* (SEQ ID NO: 751) ^ ^
Attorney Docket No.250298.000954 LC DNA Sequence CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACC ATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTTTCCTGGTACCAGCA GCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGA TTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGG ACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATCTCAGCCTGAGT 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 ^ ^
Attorney Docket No.250298.000954 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 TCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGC 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 CTCTGGGTAAATGA (SEQ ID NO: 770) HC Amino Acid Sequence QVQLQQWGAGLLKPSATLSRTCAVYGGSFSGYYWNWIRQSPGKGLEWIGEILHSGRTNY NPSLKSRVTISVDTSKNQFSLKLTSVTAADTAVYYCAGRIAARHGWFDPWGQGTLVTVSSA STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSVMHEALHNHYTQKSLSLSLGK* (SEQ ID NO: 771) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCAC CATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAAAC CAGGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTCCCT TCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGC AGCCTGAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACTTTTG GCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTT CCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATA ACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGG TAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGC AGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAG TCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTA G (SEQ ID NO: 772) LC Amino Acid Sequence DIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 773) REGN10716 HCVR DNA Sequence CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC ^ ^
Attorney Docket No.250298.000954 CTCACCTGCACTGTCTCTGGTGACTCCATCAATAATTACTACTGGACCTGGCTCCGGCA 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 CCCTCTCCTGCAGGGCCAGTCAGACTATTAACCACAACAACTTAGCCTGGTACCAGCA GAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGCC ATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCA GACTGGAGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGCTC ^ ^
Attorney Docket No.250298.000954 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 CTCACCTGCACTGTCTCTGGTGACTCCATCAATAATTACTACTGGACCTGGCTCCGGCA GCCCCCAGGGAAGGGACTGGAGTGGATTGGTTATATCTATTACAGTGGGAGCGCCAAC TACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTT CTCCCTGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGA GGGGCGGTCAAGTACTTCCGGCATTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCC GAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGG GCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAA ^ ^
Attorney Docket No.250298.000954 GAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTG GGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCC GGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCC AGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGG AGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCC ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCC TGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAA AGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAA CAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGC AGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTG ATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAA ATGA (SEQ ID NO: 790) HC Amino Acid Sequence QVQLQESGPGLVKPSETLSLTCTVSGDSINNYYWTWLRQPPGKGLEWIGYIYYSGSANYN PSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARGAVKYFRHWGQGTLVTVSSASTKG PSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVM HEALHNHYTQKSLSLSLGK* (SEQ ID NO: 791) LC DNA Sequence GAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGACTATTAACCACAACAACTTAGCCTGGTACCAGCA GAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGCC ATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCA GACTGGAGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGCTC ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCT TCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTG CTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCC AATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACA GCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGC CTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG ^ ^
Attorney Docket No.250298.000954 AGAGTGTTAG (SEQ ID NO: 792) LC Amino Acid Sequence EIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPDR FSGSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 793) REGN10717 HCVR DNA Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGAT AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAA CACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTG CGAGAAGGGGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCAC CGTCTCCTCA (SEQ ID NO: 794) HCVR Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 CGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTAC AGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCA GGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGA CTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCC GTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 1170) LC Constant Light (CL) Domain Amino Acid Sequence RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD 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), ^ ^
Attorney Docket No.250298.000954 CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGAT AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAA CACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTG CGAGAAGGGGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCAC CGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG GCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAA GGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGG ACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCA CGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTACGGCAGCACGTACCGTGTGGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACA AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA ACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAG CCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGG CTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAAC GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCT CTCCCTGTCTCCGGGTAAA (SEQ ID NO: 1172) HC Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SCSVMHEALHNHYTQKSLSLSLGK* (SEQ ID NO: 811), or ^ ^
Attorney Docket No.250298.000954 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN 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 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 813) REGN10783 HCVR DNA Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGACGTCCCTGAG ACTCTCCTGTGCAGCGTCAGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGATTGATGGAAGTAATA AATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTG ^ ^
Attorney Docket No.250298.000954 CGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCC TGGTCACCGTCTCCTCA (SEQ ID NO: 814) HCVR Amino Acid Sequence QVQLVESGGGVVQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIVVAAPFDYWGQGTLVTVS 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 ARRGGIVVAAPFDY (SEQ ID NO: 821) LCVR DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 822) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF ^ ^
Attorney Docket No.250298.000954 SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 823) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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 ^ ^
Attorney Docket No.250298.000954 AGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAA AGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAG CCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGC CTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGC AATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGC TCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATG TCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTC TCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 830) HC Amino Acid Sequence QVQLVESGGGVVQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIVVAAPFDYWGQGTLVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK* (SEQ ID NO: 831) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 832) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF ^ ^
Attorney Docket No.250298.000954 SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 AAACTATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAAT ACAGCCTACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGTG CGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTGG GGCCAAGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCC CCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGG TCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCA GCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAG CGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGAT CACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCAT GCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCC AAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTG GACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAG GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTG GTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGC AAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAG GGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCA AGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGT GGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGG CAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACA CACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 850) HC Amino Acid Sequence QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNTN YAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWGQ GTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEF LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE QFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 851) LC DNA Sequence GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACA GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGG ^ ^
Attorney Docket No.250298.000954 CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC AGACTGGAGCCTGAAGATTTTGCTTTGTATTTCTGTCAGCAGTATTATGGCTCACCTTG GACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTC TTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCT GCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACA GCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGC CTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTAG (SEQ ID NO: 852) LC Amino Acid Sequence EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR FSGSGSGTDFTLTISRLEPEDFALYFCQQYYGSPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK 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) ^ ^
Attorney Docket No.250298.000954 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) ^ ^
Attorney Docket No.250298.000954 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 GCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAA GGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC 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 ^ ^
Attorney Docket No.250298.000954 STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 871) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCAC CATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAAAC CAGGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTCCCT TCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGC AGCCTGAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACTTTTG GCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTT CCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATA ACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGG TAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGC AGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAG TCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTA G (SEQ ID NO: 872) LC Amino Acid Sequence DIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 873) REGN14571 HCVR DNA Sequence CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCC CTCACCTGCACTGTCTCTGGTGACTCCATCAATAATTACTACTGGACCTGGCTCCGGCA GCCCCCAGGGAAGGGACTGGAGTGGATTGGTTATATCTATTACAGTGGGAGCGCCAAC TACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTT CTCCCTGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGA GGGGCGGTCAAGTACTTCCGGCATTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 874) ^ ^
Attorney Docket No.250298.000954 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) ^ ^
Attorney Docket No.250298.000954 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 CTCACCTGCACTGTCTCTGGTGACTCCATCAATAATTACTACTGGACCTGGCTCCGGCA GCCCCCAGGGAAGGGACTGGAGTGGATTGGTTATATCTATTACAGTGGGAGCGCCAAC TACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTT CTCCCTGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGA GGGGCGGTCAAGTACTTCCGGCATTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC AGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGG CACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG AAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGA ACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGC CGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGC ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCC ^ ^
Attorney Docket No.250298.000954 AGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT GTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC CTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCAT GCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTC TCCGGGTAAATGA (SEQ ID NO: 890) HC Amino Acid Sequence (N297Q is indicated in bold) QVQLQESGPGLVKPSETLSLTCTVSGDSINNYYWTWLRQPPGKGLEWIGYIYYSGSANYN PSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARGAVKYFRHWGQGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 891) LC DNA Sequence GAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGACTATTAACCACAACAACTTAGCCTGGTACCAGCA GAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGCC ATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCA GACTGGAGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGCTC ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCT TCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTG CTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCC AATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACA GCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGC CTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGG AGAGTGTTAG (SEQ ID NO: 892) LC Amino Acid Sequence EIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPDR FSGSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ^ ^
Attorney Docket No.250298.000954 ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 893) REGN14572 HCVR DNA Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGAT AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAA CACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTG CGAGAAGGGGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCAC CGTCTCCTCA (SEQ ID NO: 894) HCVR Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK 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 ^ ^
Attorney Docket No.250298.000954 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCA CCCTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAAA 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 ^ ^
Attorney Docket No.250298.000954 CGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG GCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAA GGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGG ACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCA CGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACA AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA ACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAG CCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGG CTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAAC GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCT CTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 910) HC Amino Acid Sequence (N297Q is indicated in bold) QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 911) LC DNA Sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCA CCCTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCT GCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACGTT CGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATC ^ ^
Attorney Docket No.250298.000954 TTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAA TAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCG GGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCG AAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT GTTAG (SEQ ID NO: 912) LC Amino Acid Sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 913) REGN14573 HCVR DNA Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTTACCAGCCATGCCATGAACTGGGTCCGCC 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) ^ ^
Attorney Docket No.250298.000954 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 ATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTTTCCTGGTACCAGCA 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 ^ ^
Attorney Docket No.250298.000954 GGAACATGGGATCTCAGCCTGAGTTTCAATTGGGTG (SEQ ID NO: 928) LCDR3 Amino Acid Sequence GTWDLSLSFNWV (SEQ ID NO: 929) HC DNA Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAGA CTCTCCTGTGCAGCCTCTGGATTCACCTTTACCAGCCATGCCATGAACTGGGTCCGCC 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 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP ^ ^
Attorney Docket No.250298.000954 SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 931) LC DNA Sequence CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACC ATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTTTCCTGGTACCAGCA GCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGA TTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGG ACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATCTCAGCCTGAGT TTCAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGCCAGCCCAAGGCC GCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCTGCAGGCCAACAAGGCC ACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGTGACCGTGGCCTGGAAG GCCGACTCCTCCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCTCCAAGCAGTCC AACAACAAGTACGCCGCCTCCTCCTACCTGTCCCTGACCCCCGAGCAGTGGAAGTCCC ACCGGTCCTACTCCTGCCAGGTGACCCACGAGGGCTCCACCGTGGAGAAGACCGTGG CCCCCACCGAGTGCTCCTGA (SEQ ID NO: 932) LC 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 ^ ^
Attorney Docket No.250298.000954 QVQLVESGGGVVQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIVVAAPFDYWGQGTLVTVS 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 ARRGGIVVAAPFDY (SEQ ID NO: 941) LCVR DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 942) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 943) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (SEQ ID NO: 944) ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 AGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTG GGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTC CGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGA AGTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 950) HC Amino Acid Sequence (N297Q is indicated in bold) QVQLVESGGGVVQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIVVAAPFDYWGQGTLVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 951) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 952) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 953) ^ ^
Attorney Docket No.250298.000954 REGN14647 HCVR DNA Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTACAGCGTCTGGAATCACCTTCAGAAATTATGGCATGCACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAA GTACTATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGGTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAA GGGGCACTATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCCTCA (SEQ ID NO: 954) HCVR Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNK 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 ^ ^
Attorney Docket No.250298.000954 CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 962) LCVR Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 963) LCDR1 DNA Sequence CAGAGCATTAGCAGCTAT (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 ACTCTCCTGTACAGCGTCTGGAATCACCTTCAGAAATTATGGCATGCACTGGGTCCGCC AGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAA GTACTATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGGTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAA GGGGCACTATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCAC CGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA ^ ^
Attorney Docket No.250298.000954 CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG GCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAA GGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC CCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGG ACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCA CGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACA AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA ACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAG CCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGG CTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAAC GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCT CTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 970) HC Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNK YYADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 971) LC DNA Sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTT CATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGC TGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA ^ ^
Attorney Docket No.250298.000954 ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCC TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGA GAGTGTTAG (SEQ ID NO: 972) LC Amino Acid Sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 973) ^ REGN10712 HCVR DNA Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACATTCAGTACCTATGGCATGTACTGGGTCCGCC AGACTCCAGGCAAGGGGCTGGAGTGGGTGACAGTTATATCATTTGATGGAAATAAAAAA TACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAAAACAC GCTGTTTCTGCAAATGAACAGCCTGAAAACTGAGGACACGGCTGTATATTACTGTGCGA AATCTTCTAACTGGAACTACGGTTCTTTTGATATATGGGGCCAAGGGACAATGGTCACC GTCTCTTCA (SEQ ID NO: 1180) HCVR Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMYWVRQTPGKGLEWVTVISFDGNKKY 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:1184) ^ ^
Attorney Docket No.250298.000954 HCDR2 Amino Acid Sequence ISFDGNKK (SEQ ID NO: 1185) HCDR3 DNA Sequence GCGAAATCTTCTAACTGGAACTACGGTTCTTTTGATATA (SEQ ID NO: 1186) HCDR3 Amino Acid Sequence AKSSNWNYGSFDI (SEQ ID NO:1187) LCVR DNA Sequence CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACC ATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTACC AGCAGCTTCCAGGCACAGCCCCCAGACTCCTCATCTCTTATAACAGCAATCGGCCCTC AGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATC ACTGGGCTCCAGGCTGAGGATGAGGCTGACTATTACTGCCAGTCCTATGACAGAAGCC TGAGTGGTTCTGTGTTCGGAGGAGGCACCCAGCTGACCGTCCTC (SEQ ID NO: 1188) LCVR Amino Acid Sequence QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPRLLISYNSNRPSGVP DRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRSLSGSVFGGGTQLTVL (SEQ ID NO: 1189) LCDR1 DNA Sequence AGCTCCAACATCGGGGCAGGTTATGAT (SEQ ID NO: 1190) LCDR1 Amino Acid Sequence SSNIGAGYD (SEQ ID NO: 1191) LCDR2 DNA Sequence TATAACAGC (SEQ ID NO: 1192) LCDR2 Amino Acid Sequence YNS (SEQ ID NO: 1193) LCDR3 DNA Sequence CAGTCCTATGACAGAAGCCTGAGTGGTTCTGTG (SEQ ID NO: 1194) ^ ^
Attorney Docket No.250298.000954 LCDR3 Amino Acid Sequence QSYDRSLSGSV (SEQ ID NO: 1195) HC DNA Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACATTCAGTACCTATGGCATGTACTGGGTCCGCC AGACTCCAGGCAAGGGGCTGGAGTGGGTGACAGTTATATCATTTGATGGAAATAAAAAA TACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAAAACAC GCTGTTTCTGCAAATGAACAGCCTGAAAACTGAGGACACGGCTGTATATTACTGTGCGA AATCTTCTAACTGGAACTACGGTTCTTTTGATATATGGGGCCAAGGGACAATGGTCACC GTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGA GCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAAC CGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGG CTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAG CAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAG GTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTG AGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCAT GATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCC CGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAG CCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTG CACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCC CGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGT GTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC CTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCAT GCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTC TCTGGGTAAATGA (SEQ ID NO: 1196) HC Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMYWVRQTPGKGLEWVTVISFDGNKKY YADSVKGRFTISRDNSKNTLFLQMNSLKTEDTAVYYCAKSSNWNYGSFDIWGQGTMVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR ^ ^
Attorney Docket No.250298.000954 VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 1197) HC constant, hlgG4 (S108P) DNA Sequence GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCC GAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGG GCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAA GAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTG GGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCC GGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCC AGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGG AGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCC ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCC TGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAA AGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAA CAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGC AGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTG ATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAA ATGA (SEQ ID NO: 1198) HC constant, hlgG4 (S108P) Amino Acid Sequence ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 1199) LC DNA Sequence CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACC ATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTACC AGCAGCTTCCAGGCACAGCCCCCAGACTCCTCATCTCTTATAACAGCAATCGGCCCTC ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 ATGTGTGGTGGTGGATGTGTCTGAAGATGATCCTGATGTGCAGATCTCTTGGTTTGTGA ATAATGTGGAAGTGCATACAGCTCAGACACAGACACATAGAGAAGATTATAATTCTACA ATCAGAGTGGTGTCTACACTGCCTATCCAGCATCAGGATTGGATGTCTGGAAAGGAATT TAAGTGTAAGGTGAATAATAAGGATCTGCCTTCTCCTATCGAAAGAACAATCTCTAAGAT CAAGGGACTGGTGAGAGCTCCTCAGGTGTATATCCTGCCTCCTCCTGCTGAACAGCTG TCCAGAAAGGATGTGTCTCTGACATGTCTGGTGGTGGGATTTAATCCTGGAGATATCTC TGTGGAATGGACATCTAATGGACATACAGAAGAAAATTATAAGGATACAGCTCCTGTGC TGGATTCTGATGGATCTTATTTTATCTATTCTAAGCTGAATATGAAGACATCTAAGTGGG AAAAGACAGATTCTTTTTCTTGTAATGTGAGACATGAAGGACTGAAGAATTATTATCTGA AGAAGACAATCTCCAGATCTCCTGGAAAGTGA (SEQ ID NO: 1220) HC Amino Acid Sequence EVQLLESGGGLAQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSVSGSGGTTY YAASVKGRFTVSRDNSKKTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWGQ GTTVTVSAAKTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVHTF PALLQSGLYTMSSSVTVPSSTWPSQTVTCSVAHPASSTTVDKKLEPSGPISTINPCPPCKEC HKCPAPNLEGGPSVFIFPPNIKDVLMISLTPKVTCVVVDVSEDDPDVQISWFVNNVEVHTAQ TQTHREDYNSTIRVVSTLPIQHQDWMSGKEFKCKVNNKDLPSPIERTISKIKGLVRAPQVYIL PPPAEQLSRKDVSLTCLVVGFNPGDISVEWTSNGHTEENYKDTAPVLDSDGSYFIYSKLNM KTSKWEKTDSFSCNVRHEGLKNYYLKKTISRSPGK (SEQ ID NO: 1221) HC constant, mIgG2b DNA Sequence GCCAAGACAACACCTCCTTCTGTGTATCCTCTGGCTCCTGGATGTGGAGATACAACAG GATCTTCTGTGACACTGGGATGTCTGGTGAAGGGATATTTTCCTGAATCTGTGACAGTG ACATGGAACTCTGGATCTCTGTCTTCTTCTGTGCATACATTTCCTGCTCTGCTGCAGTCT GGACTGTATACAATGTCTTCTTCTGTGACAGTGCCTTCTTCTACATGGCCTTCTCAGACA GTGACATGTTCTGTGGCTCATCCTGCTTCTTCTACAACAGTGGATAAGAAGCTGGAACC TTCTGGACCTATCTCTACAATCAATCCTTGTCCTCCTTGTAAGGAATGTCATAAGTGTCC TGCTCCTAATCTGGAAGGAGGACCTTCTGTGTTTATCTTTCCTCCTAATATCAAGGATGT GCTGATGATCTCTCTGACACCTAAGGTGACATGTGTGGTGGTGGATGTGTCTGAAGAT GATCCTGATGTGCAGATCTCTTGGTTTGTGAATAATGTGGAAGTGCATACAGCTCAGAC ACAGACACATAGAGAAGATTATAATTCTACAATCAGAGTGGTGTCTACACTGCCTATCCA GCATCAGGATTGGATGTCTGGAAAGGAATTTAAGTGTAAGGTGAATAATAAGGATCTGC CTTCTCCTATCGAAAGAACAATCTCTAAGATCAAGGGACTGGTGAGAGCTCCTCAGGTG TATATCCTGCCTCCTCCTGCTGAACAGCTGTCCAGAAAGGATGTGTCTCTGACATGTCT GGTGGTGGGATTTAATCCTGGAGATATCTCTGTGGAATGGACATCTAATGGACATACAG ^ ^
Attorney Docket No.250298.000954 AAGAAAATTATAAGGATACAGCTCCTGTGCTGGATTCTGATGGATCTTATTTTATCTATT CTAAGCTGAATATGAAGACATCTAAGTGGGAAAAGACAGATTCTTTTTCTTGTAATGTGA GACATGAAGGACTGAAGAATTATTATCTGAAGAAGACAATCTCCAGATCTCCTGGAAAG TGA (SEQ ID NO: 1222) HC constant, mIgG2b Amino Acid Sequence AKTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVHTFPALLQSGL YTMSSSVTVPSSTWPSQTVTCSVAHPASSTTVDKKLEPSGPISTINPCPPCKECHKCPAPN LEGGPSVFIFPPNIKDVLMISLTPKVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHRED YNSTIRVVSTLPIQHQDWMSGKEFKCKVNNKDLPSPIERTISKIKGLVRAPQVYILPPPAEQL SRKDVSLTCLVVGFNPGDISVEWTSNGHTEENYKDTAPVLDSDGSYFIYSKLNMKTSKWEK 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 PPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLT LTARAWERHSSYSCQVTHEGHTVEKSLSRADCS (SEQ ID NO: 1225) LC constant, mLambda DNA Sequence GGCCAACCTAAATCATCTCCATCCGTTACTCTCTTCCCCCCATCTTCAGAAGAACTCGA AACCAATAAAGCCACACTCGTTTGCACCATTACAGATTTCTATCCAGGAGTAGTTACAGT ^ ^
Attorney Docket No.250298.000954 CGATTGGAAAGTAGACGGAACACCAGTTACACAGGGTATGGAAACCACACAACCATCT AAGCAGTCTAATAACAAATACATGGCCTCATCATACCTCACTCTTACCGCCCGCGCATG GGAAAGACATTCATCATATTCTTGCCAGGTAACCCACGAAGGACACACAGTTGAAAAAT CTTTGAGTAGAGCAGATTGTAGTTGA (SEQ ID NO: 1226) LC constant, mLambda Amino Acid Sequence GQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQ SNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS (SEQ ID NO: 1227) [00572] 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. [00573] 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. [00574] 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., H2aM31941N), 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). [00575] In some embodiments, provided herein are anti-AAV/anti-CACNG1 multispecific ^ ^
Attorney Docket No.250298.000954 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. [00576] In some embodiments, the anti-CACNG1 antibodies, or antigen-binding fragments thereof, described herein comprise the amino acid sequence set forth in SEQ ID NOs: 631, 651, 671, 691, 711, 731, 751, 771, 791, 811, 1342, 1369, 831, 851, 871, 891, 911, 931, 951, 971, 1197, or 1221, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 631, 651, 671, 691, 711, 731, 751, 771, 791, 811, 1342, 1369, 831, 851, 871, 891, 911, 931, 951, 971, 1197, or 1221. In certain embodiments, the nucleotide sequence that encodes the anti-CACNG1 antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence that encodes the amino acid sequence of SEQ ID NOs: 631, 651, 671, 691, 711, 731, 751, 771, 791, 811, 1342, 1369, 831, 851, 871, 891, 911, 931, 951, 971, 1197, or 1221, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 631, 651, 671, 691, 711, 731, 751, ^ ^
Attorney Docket No.250298.000954 771, 791, 811, 1342, 1369, 831, 851, 871, 891, 911, 931, 951, 971, 1197, or 1221. In certain embodiments, the nucleotide sequence that encodes the anti-CACNG1 antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NOs: 630, 650, 670, 690, 710, 730, 750, 770, 790, 810, 830, 850, 870, 890, 910, 930, 950, 970, 1196, or 1220, or a nucleotide sequence having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the nucleotide sequence of SEQ ID NOs: 630, 650, 670, 690, 710, 730, 750, 770, 790, 810, 830, 850, 870, 890, 910, 930, 950, 970, 1196, or 1220. In certain embodiments, the anti-CACNG1 antibodies, or antigen-binding fragments thereof, comprise the amino acid sequence set forth in SEQ ID NOs: 631, 651, 671, 691, 711, 731, 751, 771, 791, 811, 1342, 1369, 831, 851, 871, 891, 911, 931, 951, 971, 1197, or 1221. In certain embodiments, the nucleotide sequence that encodes the anti-CACNG1 antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NOs: 630, 650, 670, 690, 710, 730, 750, 770, 790, 810, 830, 850, 870, 890, 910, 930, 950, 970, 1196, or 1220. [00577] In some embodiments, the anti-CACNG1 antibodies, or antigen-binding fragments thereof, described herein comprise the amino acid sequence set forth in SEQ ID NOs: 633, 653, 673, 693, 713, 733, 753, 773, 793, 813, 20, 833, 853, 873, 893, 913, 933, 953, 973, 1201, or 1223, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 633, 653, 673, 693, 713, 733, 753, 773, 793, 813, 20, 833, 853, 873, 893, 913, 933, 953, 973, 1201, or 1223. In certain embodiments, the nucleotide sequence that encodes the anti-CACNG1 antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence that encodes the amino acid sequence of SEQ ID NOs: 633, 653, 673, 693, 713, 733, 753, 773, 793, 813, 20, 833, 853, 873, 893, 913, 933, 953, 973, 1201, or 1223, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 633, 653, 673, 693, 713, 733, 753, 773, 793, 813, 20, 833, 853, 873, 893, 913, 933, 953, 973, 1201, or 1223. In certain embodiments, the nucleotide sequence that encodes the anti-CACNG1 antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NOs: 632, 652, 672, 692, 712, 732, 752, 772, 792, 812, 1346, 1368, 19, 832, 852, 872, 892, 912, 932, 952, 972, 1200, or 1224, or a nucleotide sequence having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the nucleotide sequence of SEQ ID NOs: 632, 652, 672, 692, 712, 732, 752, 772, 792, 812, 1346, 1368, 19, 832, 852, 872, 892, 912, 932, 952, 972, 1200, or 1224. In certain embodiments, the anti-CACNG1 antibodies, or antigen-binding fragments thereof, comprise the amino acid sequence set forth in SEQ ID NOs: 633, 653, 673, 693, ^ ^
Attorney Docket No.250298.000954 713, 733, 753, 773, 793, 813, 20, 833, 853, 873, 893, 913, 933, 953, 973, 1201, or 1223. In certain embodiments, the nucleotide sequence that encodes the anti-CACNG1 antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NOs: 632, 652, 672, 692, 712, 732, 752, 772, 792, 812, 1346, 1368, 19, 832, 852, 872, 892, 912, 932, 952, 972, 1200, or 1224. [00578] 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., H2aM31941N), 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). [00579] 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-CACNG1 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. ^ ^
Attorney Docket No.250298.000954 [00580] 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-CACNG1 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00581] 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-CACNG1 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00582] 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; ^ ^
Attorney Docket No.250298.000954 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. [00583] 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. [00584] 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. [00585] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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, ^ ^
Attorney Docket No.250298.000954 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: ^
Attorney Docket No.250298.000954 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 ^
Attorney Docket No.250298.000954 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: ^ ^
Attorney Docket No.250298.000954 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 ^
Attorney Docket No.250298.000954 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, ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 (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; ^ ^
Attorney Docket No.250298.000954 (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. [00586] In some embodiments, an scFv fragment that binds specifically to CACNG1 comprises the sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGCGTKVEIKGGGGSGGGGSGGG GSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKCLEWVAVI WHDGSDKYYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGL GTLVTVSS (SEQ ID NO: 1355), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00587] In some embodiments, an scFv fragment that binds specifically to CACNG1 comprises the sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKCLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS GGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQ KPGKAPNLLIYKASNLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFG CGTKVEIK (SEQ ID NO: 1350), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00588] 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., RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1147)); and the VH and IgG1 CH1 portion (e.g., ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG ^ ^
Attorney Docket No.250298.000954 LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 1179) or ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1112)); or IgG4 CH1 (e.g., ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPLLQGSG (SEQ ID NO: 1171), ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1135), ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRV (SEQ ID NO: 1344), or ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY (SEQ ID NO: 1367)) 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; ^ ^
Attorney Docket No.250298.000954 (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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 IgG1 or IgG4; e.g., wherein CH1 is SEQ ID NO: 1147, 1179, 1112, 1171, 1135, 1344, or 1367. 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 + IgG1 CH1) DNA Sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGAT AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAA CACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTG CGAGAAGGGGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCAC CGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG GCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAA GGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACA (SEQ ID NO: 1174) (2) REGN10717 HC Fab (VH + IgG1 CH1) Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1175) HC Fab (VH + IgG4us CH1) Amino Acid Sequence ^ ^
Attorney Docket No.250298.000954 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKCLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRV (SEQ ID NO: 1343) HC Fab (VH + IgG4us CH1) Amino Acid Sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKCLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP (SEQ ID NO: 1359) QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKCLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRV (SEQ ID NO: 1370) (3) REGN10717 LC DNA Sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCA CCCTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCT GCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACGTT CGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATC TTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAA TAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCG GGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCG AAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT GTTAG (SEQ ID NO: 812) (4) REGN10717 LC Fab Amino Acid Sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ^ ^
Attorney Docket No.250298.000954 ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 813) [00589] 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. [00590] 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. [00591] 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 IgG1. In some cases, the human IgG heavy chain constant region is isotype IgG4. In various embodiments, the bispecific antibody comprises a chimeric hinge that reduces Fc^ receptor binding relative to a wild-type hinge of the same isotype. [00592] 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 antigen- binding 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 IgG1, IgG2, IgG3, and IgG4, as well as any allotype within each isotype group. [00593] 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., IgG1/IgG1, IgG2/IgG2, IgG4/IgG4. Alternatively, the first and second multimerizing domains may be of different IgG isotypes such as, e.g., IgG1/IgG2, IgG1/IgG4, IgG2/IgG4, etc. ^ ^
Attorney Docket No.250298.000954 [00594] 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 [00595] 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 ^ ^
Attorney Docket No.250298.000954 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. [00596] 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 ^ ^
Attorney Docket No.250298.000954 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. [00597] 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; ^ ^
Attorney Docket No.250298.000954 (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. [00598] 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 ^ ^
Attorney Docket No.250298.000954 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. [00599] 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 ^ ^
Attorney Docket No.250298.000954 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. [00600] 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 ^ ^
Attorney Docket No.250298.000954 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 [00601] 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 ^ ^
Attorney Docket No.250298.000954 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. [00602] 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; ^ ^
Attorney Docket No.250298.000954 (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. [00603] 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 ^ ^
Attorney Docket No.250298.000954 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. [00604] 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 ^ ^
Attorney Docket No.250298.000954 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. [00605] 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 ^ ^
Attorney Docket No.250298.000954 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. [00606] 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: l) (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 ^ ^
Attorney Docket No.250298.000954 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. [00607] 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 ^ ^
Attorney Docket No.250298.000954 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. [00608] 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; ^ ^
Attorney Docket No.250298.000954 (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. [00609] 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: [00610] 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 ^ ^
Attorney Docket No.250298.000954 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. [00611] 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 ^ ^
Attorney Docket No.250298.000954 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. [00612] 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 ^ ^
Attorney Docket No.250298.000954 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. [00613] 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: ^ ^
Attorney Docket No.250298.000954 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. [00614] 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 ^ ^
Attorney Docket No.250298.000954 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. [00615] 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 ^ ^
Attorney Docket No.250298.000954 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 [00616] 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)-Ig, Quadroma, knobs-into- holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, ^ ^
Attorney Docket No.250298.000954 CrossFab, (SEED)body, leucine zipper, Duobody, IgG1/IgG2, dual acting Fab (DAF)-IgG, 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). [00617] 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 antigen- binding 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). [00618] 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 IgG1 antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of IgG2 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 IgG4 antibodies. ^ ^
Attorney Docket No.250298.000954 [00619] 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 IgG1, human IgG2, or human IgG4 CH2 region, and part or all of a CH3 sequence derived from a human IgG1, human IgG2, or human IgG4. 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 IgG1, a human IgG2, or a human IgG4 hinge region, combined with a “lower hinge” sequence, derived from a human IgG1, a human IgG2, or a human IgG4 hinge region. A particular 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: [IgG4 CH1] - [IgG4 upper hinge] - [IgG2 lower hinge] - [IgG4 CH2] - [IgG4 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: [IgG1 CH1] - [IgG1 upper hinge] - [IgG2 lower hinge] - [IgG4 CH2] - [IgG1 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. [00620] 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 [00621] The present disclosure provides any of the multispecific antibodies, or antigen binding fragments thereof, described herein in any of various alternative formats described herein. [00622] 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 ^ ^
Attorney Docket No.250298.000954 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. [00623] 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. [00624] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [00625] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface. [00626] In some embodiments, the scFv is linked to the first heavy chain region via a linker. [00627] 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. [00628] 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. [00629] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [00630] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. [00631] In some embodiments, the scFv is linked to the Fc domain via a linker. ^ ^
Attorney Docket No.250298.000954 [00632] 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. [00633] 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. [00634] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [00635] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface. [00636] In some embodiments, the first heavy chain region is linked to the second heavy chain region via a linker. [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 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 ^ ^
Attorney Docket No.250298.000954 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. [00638] 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. [00639] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface. [00640] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. [00641] In some embodiments, the second heavy chain region is linked to the Fc domain 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 scFv comprising a first antigen- binding 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. [00643] 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. [00644] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [00645] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ^ ^
Attorney Docket No.250298.000954 ABD3 binds to a molecule on a cell surface. [00646] In some embodiments, the scFv is linked to the first heavy chain region 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) 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. [00648] 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. [00649] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [00650] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. [00651] In some embodiments, Fab2 is linked to the Fc domain via a linker. [00652] 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 ^ ^
Attorney Docket No.250298.000954 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. [00653] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00654] 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. [00655] 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 ^ ^
Attorney Docket No.250298.000954 channel auxiliary subunit gamma 1 (CACNG1). [00656] In some embodiments, the molecule on the cell surface is ASGR1. [00657] 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. [00658] 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. [00659] 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. [00660] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments, the molecule on the cell surface is TfR. [00661] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00662] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00663] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00664] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments, the molecule on the cell surface is CACNG1. [00665] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00666] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00667] 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 ^ ^
Attorney Docket No.250298.000954 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. [00668] 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. [00669] 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. [00670] 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. [00671] In some embodiments, the first heavy chain region is linked to the second heavy chain region via a linker. [00672] In another aspect, provided herein is a multispecific antibody, or a multispecific antigen-binding fragment thereof, comprising: ^ ^
Attorney Docket No.250298.000954 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. [00673] 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. [00674] 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. [00675] In some embodiments, the first scFv and/or the first heavy chain region is linked to the Fc domain via a linker. [00676] 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; ^ ^
Attorney Docket No.250298.000954 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. [00677] 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 ^ ^
Attorney Docket No.250298.000954 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. ^ ^
Attorney Docket No.250298.000954 [00678] 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. [00679] 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). [00680] In some embodiments, the molecule on the cell surface is ASGR1. [00681] 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. ^ ^
Attorney Docket No.250298.000954 [00682] 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. [00683] 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. [00684] In some embodiments, the molecule on the cell surface is TfR. [00685] 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. [00686] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. [00687] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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
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
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. [00688] In some embodiments, the molecule on the cell surface is CACNG1. [00689] 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^ ^
Attorney Docket No.250298.000954 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. ^ ^ ^
Attorney Docket No.250298.000954 [00690] 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 ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. [00691] 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 ^ ^
Attorney Docket No.250298.000954 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
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
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
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
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
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
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
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
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
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
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
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
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
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 ^ ^
Attorney Docket No.250298.000954 comprising the amino acid sequence of SEQ ID NO: 1213. [00692] 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. [00693] 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. [00694] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [00695] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface. [00696] In some embodiments, the scFv is linked to the first heavy chain region via a linker. [00697] 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 ^ ^
Attorney Docket No.250298.000954 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. [00698] 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. [00699] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [00700] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. [00701] In some embodiments, the scFv is linked to the Fc domain via a linker. [00702] 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. [00703] 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. [00704] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. ^ ^
Attorney Docket No.250298.000954 [00705] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface. [00706] In some embodiments, the first heavy chain region is linked to the second heavy chain region via a linker. [00707] 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. [00708] 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. [00709] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface. [00710] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. [00711] In some embodiments, the second heavy chain region is linked to the Fc domain via a linker. [00712] 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) ^ ^
Attorney Docket No.250298.000954 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. [00713] 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. [00714] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [00715] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. [00716] In some embodiments, the scFv is linked to the first heavy chain region via a linker. [00717] 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. [00718] In some embodiments, two of ABD1, ABD2, and ABD3 bind to a capsid of an AAV ^ ^
Attorney Docket No.250298.000954 particle, and one of ABD1, ABD2, and ABD3 binds to a molecule on a cell surface. [00719] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [00720] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. [00721] In some embodiments, the second heavy chain region is linked to the Fc domain via a linker. [00722] 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. [00723] 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. [00724] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [00725] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface. [00726] 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. [00727] 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, ^ ^
Attorney Docket No.250298.000954 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 ^^^^ ^
Attorney Docket No.250298.000954 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. [00728] 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 ^ ^
Attorney Docket No.250298.000954 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. [00729] 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 ^ ^
Attorney Docket No.250298.000954 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. [00730] 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). [00731] In some embodiments, said molecule on the cell surface is ASGR1. [00732] 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. [00733] 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. [00734] 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 ^ ^
Attorney Docket No.250298.000954 comprising the amino acid sequence of SEQ ID NO: 10. [00735] In some embodiments, the molecule on the cell surface is TfR. [00736] 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. [00737] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. [00738] 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, ^ ^
Attorney Docket No.250298.000954 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 ^ ^ ^
Attorney Docket No.250298.000954 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. [00739] In some embodiments, the molecule on the cell surface is CACNG1. [00740] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00741] 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. ^ ^
Attorney Docket No.250298.000954 [00742] 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; ^ ^
Attorney Docket No.250298.000954 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. [00743] 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 (“Fab2”), 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. [00744] 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. [00745] 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. [00746] 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. [00747] 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. [00748] 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 ^ ^
Attorney Docket No.250298.000954 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. [00749] 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. [00750] 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. [00751] 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. [00752] In some embodiments, the first scFv and/or second scFv is linked to the Fc domain via a linker. [00753] 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 ^ ^
Attorney Docket No.250298.000954 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. [00754] 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. [00755] 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. [00756] 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. [00757] 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. [00758] 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. [00759] In some embodiments, two of ABD1, ABD2, ABD3, and ABD4 bind to a capsid of an ^ ^
Attorney Docket No.250298.000954 AAV particle, and two of ABD1, ABD2, ABD3, and ABD4 binds to a molecule on a cell surface. [00760] 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. [00761] 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. [00762] 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. [00763] 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. [00764] 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. [00765] 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. [00766] 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. [00767] 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. [00768] 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. [00769] In some embodiments, one or more light chains comprise the same light chain variable region. [00770] In some embodiments, the first light chain, the second light chain, the third light chain, and/or the fourth light chain comprise the same light chain variable region. [00771] In some embodiments, the first light chain, the second light chain, the third light chain, and/or the fourth light chain are universal light chains. [00772] 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 ^ ^
Attorney Docket No.250298.000954 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. [00773] 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. [00774] 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. [00775] 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. [00776] 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. [00777] 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 ^ ^
Attorney Docket No.250298.000954 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. [00778] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 comprising the amino acid sequence of SEQ ID NO: 16. [00779] 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. [00780] 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). [00781] In some embodiments, the molecule on the cell surface is ASGR1. [00782] 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 ^ ^
Attorney Docket No.250298.000954 LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10. [00783] 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. [00784] 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. [00785] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments, the molecule on the cell surface is TfR. [00786] 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. [00787] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. [00788] In some embodiments, the other(s) of ABD1, ABD2, ABD3, and ABD4 which binds ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00789] In some embodiments of the above-described multispecific antibodies, or multispecific antigen-binding fragments, the molecule on the cell surface is CACNG1. [00790] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [00791] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 NO: 1217, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219. [00792] 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 ^ ^
Attorney Docket No.250298.000954 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. [00793] 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. [00794] 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. [00795] 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. [00796] 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. [00797] In some embodiments, the linker is 5 amino acids to 25 amino acids in length. ^ ^
Attorney Docket No.250298.000954 [00798] In some embodiments, the linker is 10 amino acids to 60 amino acids in length. [00799] In some embodiments, the linker is 20 amino acids to 50 amino acids in length. [00800] In some embodiments, the linker is 25 to 35 amino acids in length. [00801] In some embodiments, the linker is or comprises a multimer of GnS (SEQ ID NO: 239) or SGn (SEQ ID NO: 240), wherein n is an integer from 1 to 10. [00802] In some embodiments, the linker is or comprises a multimer of G4S (SEQ ID NO: 242). [00803] 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)). [00804] In some embodiments, one or more light chains are universal light chains. [00805] 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. [00806] In some embodiments, the multispecific antibody or multispecific antigen-binding comprises an Fc heterodimer. [00807] In some embodiments, the Fc domains in the Fc heterodimer comprise knob-in- hole mutations as compared to a wild type Fc domain. [00808] 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. [00809] In some embodiments, at least one Fc domain in the Fc heterodimer comprises a star mutation as compared to a wild type Fc domain. [00810] 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. [00811] In some embodiments, one Fc domain can comprise knob mutation T366W and the other Fc domain can comprise hole mutations T366S, L368A, and Y407V; optionally, one or both Fc domains can comprise star mutations H435R and Y436F. [00812] In some embodiments, the capsid comprises one or more wild-type AAV capsid polypeptides. [00813] In some embodiments, the capsid comprises one or more non-wild-type AAV capsid polypeptides. ^ ^
Attorney Docket No.250298.000954 [00814] In some embodiments, the multispecific antibody or multispecific antigen-binding fragment is a bispecific antibody or bispecific antigen-binding fragment thereof. [00815] 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. [00816] 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. [00817] 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. [00818] In another aspect, provided herein is a pharmaceutical composition comprising a molecular complex described herein and a pharmaceutically acceptable carrier or excipient. [00819] 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. [00820] 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. [00821] 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. [00822] In another aspect, provided herein is a pharmaceutical composition comprising a molecular complex described herein and a pharmaceutically acceptable carrier or excipient. [00823] 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. [00824] 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. [00825] 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 ^ ^
Attorney Docket No.250298.000954 and bound to one or more multispecific antibodies and/or multispecific antigen-binding fragments which bind to said molecule on the cell surface. [00826] In some embodiments, said cell is in a subject and said molecular complex is administered to the subject. [00827] 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. [00828] 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 antigen- binding 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. [00829] 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. [00830] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [00831] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. [00832] 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 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTGGGGSGG GGSGGGGSEVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIY ^ ^
Attorney Docket No.250298.000954 YDSSKMNYADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGV SVTVSSGGGGSGGGGSGGGGSDIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQK PGKSPQLLIYGATSLADGVPSRFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGG TKLELKGGGGSKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA 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. [00833] In some embodiments, the first heavy chain region of the first Fab (Fab1) can comprise the amino acid sequence QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (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. [00834] In some embodiments, the scFv can comprise the amino acid sequence EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSKMNY ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVSVTVSSGG 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 ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVSVTVSS (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 ^ ^
Attorney Docket No.250298.000954 SKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ 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. [00835] 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 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSR 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. [00836] In some embodiments, the second heavy chain region of the second Fab (Fab2) can comprise the amino acid sequence QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (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. 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 CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ 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. [00837] In some embodiments of the above-described multispecific antibody, or ^ ^
Attorney Docket No.250298.000954 multispecific antigen-binding fragment thereof, the third polypeptide chain can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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. [00838] 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 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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. [00839] 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 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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. ^ ^
Attorney Docket No.250298.000954 [00840] 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 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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. [00841] 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). [00842] 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 ^ ^
Attorney Docket No.250298.000954 virus (AAV) particle, and the other(s) of ABD1, ABD2, and ABD3 bind to a molecule on a cell surface. [00843] 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. [00844] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [00845] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. [00846] In some embodiments, Fab2 is linked to the Fc domain via a linker. [00847] 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 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSR DELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSR WQQGNVFSCSVMHEALHNRFTQKSLSLSPGKGGGGSGGGGSGGGGSQVHLQESGPGL VMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSHNPSLQSRVIMSI DTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGALVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 1151), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00848] In some embodiments, the first heavy chain region of the first Fab (Fab1) can comprise the amino acid sequence QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (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. [00849] In some embodiments, the Fc domain can comprise the amino acid sequence CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN ^ ^
Attorney Docket No.250298.000954 AKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVS KLTVDKSRWQQGNVFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 1141). [00850] In some embodiments, the second heavy chain region of the second Fab (Fab2) can comprise the amino acid sequence QVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIHYSERTSH NPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFIDSWGQGA LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (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. [00851] 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 ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVSVTVSSGG GGSGGGGSGGGGSDIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLL IYGATSLADGVPSRFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELKGG GGSKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1149), or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. [00852] In some embodiments, the scFv can comprise the amino acid sequence EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSKMNY ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVSVTVSSGG 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 ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVSVTVSS (SEQ ID NO: 1119), or a substantially similar sequence thereof having at least 90%, at least ^ ^
Attorney Docket No.250298.000954 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 SKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1137). [00853] 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 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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. [00854] 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 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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 ^ ^
Attorney Docket No.250298.000954 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. [00855] 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 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA 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. [00856] 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). [00857] 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; ^ ^
Attorney Docket No.250298.000954 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. [00858] 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. [00859] 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. [00860] 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. [00861] In some embodiments, the first scFv is linked to Fab1 and/or the second scFv is linked to Fab2 via a linker. [00862] 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 SWGQGALVTVSSGGGGSGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFST YGMHWVRQAPGKGLEWVAVIWHDGSDKYYVDSVKGRFSIARDNSKNTLYLQMNSLRVED TGIYYCARRGIRGTVFDHWGLGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA 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. [00863] In some embodiments, the first scFv can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF ^ ^
Attorney Docket No.250298.000954 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. [00864] In some embodiments, the first scFv can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGG SGGGGSQVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIH YSERTSHNPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFID SWGQGALVTVSS (SEQ ID NO: 1358), 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. [00865] In some embodiments, the first heavy chain region of the first Fab (Fab1) can comprise the amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (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 CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1167). ^ ^
Attorney Docket No.250298.000954 [00866] 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 SWGQGALVTVSSGGGGSGGGGSGGGGSQVQLVESGGGVVQPGRSLRLSCAASGFTFST YGMHWVRQAPGKGLEWVAVIWHDGSDKYYVDSVKGRFSIARDNSKNTLYLQMNSLRVED TGIYYCARRGIRGTVFDHWGLGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA 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. [00867] 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 can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGG SGGGGSQVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIH YSERTSHNPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFID SWGQGALVTVSS (SEQ ID NO: 1358), 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 ^ ^
Attorney Docket No.250298.000954 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. [00868] In some embodiments, the second heavy chain region of the second Fab (Fab2) can comprise the amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (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 CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ 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. [00869] 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 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK 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. [00870] 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 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ^ ^
Attorney Docket No.250298.000954 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 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK 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. [00871] 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 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK 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 [00872] 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 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK 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 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK 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 ^ ^
Attorney Docket No.250298.000954 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. [00873] 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). [00874] 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. [00875] 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. [00876] 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. [00877] 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. [00878] In some embodiments, the first scFv and/or second scFv is linked to the Fc domain via a linker. [00879] In some embodiments of the above-described multispecific antibody, or multispecific antigen-binding fragment thereof, the first polypeptide chain can comprise the ^ ^
Attorney Docket No.250298.000954 amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN 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. [00880] In some embodiments, the first heavy chain region of the first Fab (Fab1) can comprise the amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (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 CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ 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. [00881] In some embodiments, the first scFv can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGG SGGGGSQVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKCLEWIGHIH YSERTSHNPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFID ^ ^
Attorney Docket No.250298.000954 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 can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGG SGGGGSQVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIH YSERTSHNPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFID SWGQGALVTVSS (SEQ ID NO: 1158), 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. [00882] 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 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN 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. ^ ^
Attorney Docket No.250298.000954 [00883] In some embodiments, the second heavy chain region of the second Fab (Fab2) can comprise the amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (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 CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ 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. [00884] 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 can comprise the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGCGTRLEIKGGGGSGGGGSGGGG SGGGGSQVHLQESGPGLVMPSQILSLSCVISGDSIRNGGYYWTWTRQQPGKGLEWIGHIH YSERTSHNPSLQSRVIMSIDTSENKFSLKLTSVTVADTAIYYCARGRDTMVRGSITTSGHFID SWGQGALVTVSS (SEQ ID NO: 1358), 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 ^ ^
Attorney Docket No.250298.000954 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. [00885] 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 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK 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. [00886] 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 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK 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 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK 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. [00887] 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 ^ ^
Attorney Docket No.250298.000954 FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK 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. [00888] 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 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK 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 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK 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. [00889] In some embodiments, the anti-AAV x anti-mTfR antibodies, the anti-AAV x anti-^ CACNG1 antibodies, or the anti-AAV x anti-ASGR antibodies, or antigen-binding fragments thereof, described herein comprise the amino acid sequence set forth in SEQ ID NOs: 1106, 1139, 20, 1149, 1151, 1153, 1173, 1169, 813, 1228, 1232, 1234, 1236, 1237, 1238, 1328, 1330, 1332, 1341, 1506, 1348, 1354, 1357, 1361, 1362, 1369, 1373, 1342, 1375, 1379, 1381, 1384, 1387, 1390, 1393, 1395, 1502, 1504, 1508, or 1510, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 1106, 1139, 20, 1149, 1151, 1153, 1173, 1169, 813, 1228, 1232, 1234, 1236, 1237, 1238, 1328, 1330, 1332, 1341, 1506, 1348, 1354, 1357, 1361, 1362, 1369, 1373, 1342, 1375, 1379, 1381, 1384, 1387, 1390, 1393, 1395, 1502, 1504, 1508, or 1510. In certain embodiments, the nucleotide sequence that encodes the anti-AAV x anti-mTfR antibodies, the anti-AAV x anti-^CACNG1 ^ ^
Attorney Docket No.250298.000954 antibodies, or the anti-AAV x anti-ASGR antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence that encodes the amino acid sequence of SEQ ID NOs: 1106, 1139, 20, 1149, 1151, 1153, 1173, 1169, 813, 1228, 1232, 1234, 1236, 1237, 1238, 1328, 1330, 1332, 1341, 1506, 1348, 1354, 1357, 1361, 1362, 1369, 1373, 1342, 1375, 1379, 1381, 1384, 1387, 1390, 1393, 1395, 1502, 1504, 1508, or 1510, or a variant thereof having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NOs: 1106, 1139, 20, 1149, 1151, 1153, 1173, 1169, 813, 1228, 1232, 1234, 1236, 1237, 1238, 1328, 1330, 1332, 1341, 1506, 1348, 1354, 1357, 1361, 1362, 1369, 1373, 1342, 1375, 1379, 1381, 1384, 1387, 1390, 1393, 1395, 1502, 1504, 1508, or 1510. In certain embodiments, the nucleotide sequence that encodes the anti-AAV x anti-mTfR antibodies, the anti-AAV x anti-^CACNG1 antibodies, or the anti-AAV x anti-ASGR antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NOs: 19, 1105, 1138, 1145, 1500, 1148, 1498, 1150, 1499, 1152, 1172, 1168, 1505, 812, 1240, 1258, 1265, 1269, 1287, 1298, 1316, 1329, 1331, 1333, 1340, 1346, 1347, 1353, 1356, 1360, 1368, 1372, 1374, 1378, 1380, 1383, 1386, 1389, 1392, 1394, 1501, 1503, 1507, or 1509, or a nucleotide sequence having at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity with the nucleotide sequence of SEQ ID NOs: 19, 1105, 1138, 1145, 1500, 1148, 1498, 1150, 1499, 1152, 1172, 1168, 1505, 812, 1240, 1258, 1265, 1269, 1287, 1298, 1316, 1329, 1331, 1333, 1340, 1346, 1347, 1353, 1356, 1360, 1368, 1372, 1374, 1378, 1380, 1383, 1386, 1389, 1392, 1394, 1501, 1503, 1507, or 1509. In certain embodiments, the anti-AAV x anti-mTfR antibodies, the anti-AAV x anti-^CACNG1 antibodies, or the anti-AAV x anti-ASGR antibodies, or antigen-binding fragments thereof, comprise the amino acid sequence set forth in SEQ ID NOs: 1106, 1139, 20, 1149, 1151, 1153, 1173, 1169, 813, 1228, 1232, 1234, 1236, 1237, 1238, 1328, 1330, 1332, 1341, 1506, 1348, 1354, 1357, 1361, 1362, 1369, 1373, 1342, 1375, 1379, 1381, 1384, 1387, 1390, 1393, 1395, 1502, 1504, 1508, or 1510. In certain embodiments, the nucleotide sequence that encodes the anti-AAV x anti-mTfR antibodies, the anti-AAV x anti-^CACNG1 antibodies, or the anti-AAV x anti-ASGR antibodies, or antigen-binding fragments thereof, comprises the nucleotide sequence set forth in SEQ ID NOs: 19, 1105, 1138, 1145, 1500, 1148, 1498, 1150, 1499, 1152, 1172, 1168, 1505, 812, 1240, 1258, 1265, 1269, 1287, 1298, 1316, 1329, 1331, 1333, 1340, 1346, 1347, 1353, 1356, 1360, 1368, 1372, 1374, 1378, 1380, 1383, 1386, 1389, 1392, 1394, 1501, 1503, 1507, or 1509. [00890] 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) ^ ^
Attorney Docket No.250298.000954 and/or the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO: 1115). Epitope Mapping and Related Technologies [00891] 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). [00892] 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. [00893] 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., ^ ^
Attorney Docket No.250298.000954 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. [00894] 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). [00895] 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). [00896] Likewise, 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. [00897] 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, ^ ^
Attorney Docket No.250298.000954 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 antigen- binding 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. [00898] 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 antigen- binding 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. ^ ^
Attorney Docket No.250298.000954 Preparation of Antigen-Binding Domains and Construction of Bispecific Molecules [00899] Antigen-binding domains specific for particular antigens can be prepared by any antibody generating technology known in the art. Once obtained, two different antigen- binding 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. [00900] Genetically engineered animals may be used to make human bispecific antigen- binding 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 ^ ^
Attorney Docket No.250298.000954 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 [00901] 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. [00902] 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. [00903] In one embodiment, two antigen-binding proteins are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency. [00904] 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. [00905] 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. [00906] 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 ^ ^
Attorney Docket No.250298.000954 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. [00907] 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 antigen- binding 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. Nucleic Acids [00908] The disclosure also provides nucleic acids encoding the multispecific binding molecules of the disclosure. In some embodiments, the multispecific binding molecules are encoded by a single nucleic acid. In other embodiments, for example in the case of a heterodimeric molecule or a molecule comprising a component composed of more than one polypeptide chain, the multispecific binding molecules can be encoded by a plurality (e.g., two, three, four, or more) nucleic acids. [00909] A single nucleic acid can encode a multispecific binding molecule that comprises a single polypeptide chain, a multispecific binding molecule that comprises two or more polypeptide chains, or a portion of a multispecific binding molecule that comprises more than two polypeptide chains (for example, a single nucleic acid can encode two polypeptide chains of a multispecific binding molecule comprising three, four, or more polypeptide chains, or three polypeptide chains of a multispecific binding molecule comprising four or more polypeptide chains). For separate control of expression, the open reading frames encoding two or more polypeptide chains can be under the control of separate transcriptional regulatory elements (e.g., promoters and/or enhancers). The open reading frames encoding two or more polypeptides can also be controlled by the same transcriptional regulatory elements, and separated by internal ribosome entry site (IRES) sequences allowing for translation into separate polypeptides. [00910] In some embodiments, a multispecific binding molecule comprising two or more polypeptide chains is encoded by two or more nucleic acids. The number of nucleic acids ^ ^
Attorney Docket No.250298.000954 encoding a multispecific binding molecule can be equal to or less than the number of polypeptide chains in the multispecific binding molecule (for example, when more than one polypeptide chains are encoded by a single nucleic acid). [00911] The nucleic acids of the disclosure can be DNA (e.g., plasmid) or RNA (e.g., mRNA). Cells [00912] The disclosure also provides host cells comprising a nucleic acid of the disclosure. [00913] In one embodiment, the host cells are genetically engineered to comprise one or more nucleic acids described herein. [00914] 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. [00915] The disclosure also provides host cells comprising the vectors described herein. [00916] 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 [00917] 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. [00918] 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 ^ ^
Attorney Docket No.250298.000954 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. [00919] 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 antigen- binding 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). [00920] 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 1×105 plaque forming units (pfu) to about 1×1015 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 1×108 pfu to about 1×1015 pfu, or from about 1×1010 pfu to about 1×1015 pfu, or from about 1×108 pfu to about 1×1012 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 1×108 pfu to about 1×1010 pfu, while an adult human subject can receive a dose from about 1×1010 pfu to about 1×1012 pfu. [00921] In some embodiments, for the methods disclosed herein, the dose of the multispecific antibodies or multispecific antigen-binding fragments (or pharmaceutical compositions thereof) administered to the subject is between about 1x105 vector genomes ^ ^
Attorney Docket No.250298.000954 (vg) to about 1x1016 vg. In certain embodiments, for the methods disclosed herein, the dose of the multispecific antibodies or multispecific antigen-binding fragments administered to the subject is between about 1x106 vg to about 1x109 vg, about 1x107 vg to about 1x1010 vg, about 1x108 vg to about 1x1011 vg, about 1x109 vg to about 1x1012 vg, about 1x1010 vg to about 1x1013 vg, about 1x1011 vg to about 1x1014 vg, about 1x1012 vg to about 1x1015 vg, about 1x1013 vg to about 1x1016 vg, or about 1x1014 vg to about 1x1016 vg. In certain embodiments, for the methods disclosed herein, the dose of the multispecific antibodies or multispecific antigen-binding fragments administered to the subject is between about 1x1010 vg to about 1x1016 vg. In certain embodiments, for the methods disclosed herein, the dose of the multispecific antibodies or multispecific antigen-binding fragments administered to the subject is at least about 1x106 vg, at least about 1x107 vg, at least about 1x108 vg, at least about 1x109 vg, at least about 1x1010 vg, at least about 1x1011 vg, at least about 1x1012 vg, at least about 1x1012 vg, at least about 1x1013 vg, at least about 1x1014 vg, or at least about 1x1015 vg. In certain embodiments, the vg is total vector genome per subject. In certain embodiments, for the methods disclosed herein, the dose of the multispecific antibodies or multispecific antigen-binding fragments administered to the subject is about 1x106 vg, about 1x107 vg, about 1x108 vg, about 2x108 vg, about 3x108 vg, about 4x108 vg, about 5x108 vg, about 6x108 vg, about 7x108 vg, about 8x108 vg, about 9x108 vg, about 1x109 vg, about 2x109 vg, about 3x109 vg, about 4x109 vg, about 5x109 vg, about 6x109 vg, about 7x109 vg, about 8x109 vg, about 9x109 vg, about 1x1010 vg, about 2x1010 vg, about 3x1010 vg, about 4x1010 vg, about 5x1010 vg, about 6x1010 vg, about 7x1010 vg, about 8x1010 vg, about 9x1010 vg, about 1x1011 vg, about 2x1011 vg, about 3x1011 vg, about 4x1011 vg, about 5x1011 vg, about 6x1011 vg, about 7x1011 vg, about 8x1011 vg, about 9x1011 vg, about 1x1012 vg, about 2x1012 vg, about 3x1012 vg, about 4x1012 vg, about 5x1012 vg, about 6x1012 vg, about 7x1012 vg, about 8x1012 vg, about 9x1012 vg, about 1x1013 vg, about 2x1013 vg, about 3x1013 vg, about 4x1013 vg, about 5x1013 vg, about 6x1013 vg, about 7x1013 vg, about 8x1013 vg, about 9x1013 vg, about 1x1014 vg, about 2x1014 vg, about 3x1014 vg, about 4x1014 vg, about 5x1014 vg, or about 1x1015 vg. In certain embodiments, the vg is total vector genome per subject. [00922] In some embodiments, for the methods disclosed herein, the dose of the multispecific antibodies or multispecific antigen-binding fragments (or pharmaceutical compositions thereof) administered to the subject is about 1x1012, 1x1013, 1x1014, 1x1015, and 1x1016 vg/mL. Further examples of doses of multispecific antibodies or multispecific antigen-binding fragments include about 1x1012, about 1x1013, about 1x1014, about 1x1015, and about 1x1016 vg/mL, or between about 1x1012 to about 1x1016, between about 1x1012 to about 1x1015, between about 1x1012 to about 1x1014, between about 1x1012 to about 1x1013, between about 1x1013 to about 1x1016, between about 1x1014 to about 1x1016, between ^ ^
Attorney Docket No.250298.000954 about 1x1015 to about 1x1016, or between about 1x1013 to about 1x1015 vg/mL. [00923] In some embodiments, for the methods disclosed herein, an AAV is dosed or incubated in combination with the multispecific antibodies or multispecific antigen-binding fragments (or pharmaceutical compositions thereof) described herein. In some embodiments, the AAV viral genome to the antibody molar ratio (e.g., the VG:Ab ratio or AAV:Ab ratio) is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49, 1:50, 1:51, 1:52, 1:53, 1:54, 1:55, 1:56, 1:57, 1:58, 1:59, 1:60, 1:61, 1:62, 1:63, 1:64, 1:65, 1:66, 1:67, 1:68, 1:69, 1:70, 1:71, 1:72, 1:73, 1:74, 1:75, 1:76, 1:77, 1:78, 1:79, 1:80, 1:81, 1:82, 1:83, 1:84, 1:85, 1:86, 1:87, 1:88, 1:89, 1:90, 1:91, 1:92, 1:93, 1:94, 1:95, 1:96, 1:97, 1:98, 1:99, 1:100, 1:105, 1:110, 1:115, 1:120, 1:125, 1:130, 1:135, 1:140, 1:145, 1:150, 1:155, 1:160, 1:165, 1:170, 1:175, 1:180, 1:185, 1:190, 1:195, 1:200, 1:205, 1:210, 1:215, 1:220, 1:225, 1:230, 1:235, 1:240, 1:243, 1:245, 1:250, 1:260, 1:270, 1:280, 1:290, 1:300, 1:310, 1:320, 1:330, 1:340, 1:350, 1:360, 1:370, 1:380, 1:390, 1:400, 1:410, 1:420, 1:430, 1:440, 1:450, 1:460, 1:470, 1:480, 1:490, 1:500, 1:510, 1:520, 1:530, 1:540, 1:550, 1:560, 1:570, 1:580, 1:590, 1:600, 1:610, 1:620, 1:630, 1:640, 1:650, 1:660, 1:670, 1:680, 1:690, 1:700, 1:710, 1:720, 1:729, 1:730, 1:740, 1:750, 1:775, 1:800, 1:825, 1:850, 1:875, 1:900, 1:925, 1:950, 1:975, 1:1000, 1:1025, 1:1050, 1:1075, 1:1100, 1:1125, 1:1150, 1:1175, 1:1200, 1:1225, 1:1250, 1:1275, 1:1300, 1:1325, 1:1350, 1:1375, 1:1400, 1:1425, 1:1450, 1:1475, 1:1500, 1:1525, 1:1550, 1:1575, 1:1600, 1:1625, 1:1650, 1:1675, 1:1700, 1:1725, 1:1750, 1:1775, 1:1800, 1:1825, 1:1850, 1:1875, 1:1900, 1:1925, 1:1950, 1:1975, 1:2000, 1:2025, 1:2050, 1:2075, 1:2100, 1:2125, 1:2150, 1:2175, 1:2187, 1:2200, 1:2300, 1:2400, 1:2500, 1:2600, 1:2700, 1:2800, 1:2900, 1:3000, 1:3100, 1:3200, 1:3300, 1:3400, 1:3500, 1:3600, 1:3700, 1:3800, 1:3900, 1:4000, 1:4100, 1:4200, 1:4300, 1:4400, 1:4500, 1:4600, 1:4700, 1:4800, 1:4900, or 1:5000. In some embodiments, the AAV viral genome to the antibody molar ratio (e.g., the VG:Ab ratio or AAV:Ab ratio) is 1:1, 1:3, 1:9, 1:27, 1:81, 1:243, 1:729, or 1:2187. In some embodiments, the AAV viral genome to the antibody molar ratio (e.g., the VG:Ab ratio or AAV:Ab ratio) is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, about 1:20, about 1:21, about 1:22, about 1:23, about 1:24, about 1:25, about 1:26, about 1:27, about 1:28, about 1:29, about 1:30, about 1:31, about 1:32, about 1:33, about 1:34, about 1:35, about 1:36, about 1:37, about 1:38, about 1:39, about 1:40, about 1:41, about 1:42, about 1:43, about 1:44, about 1:45, about 1:46, about 1:47, about 1:48, about 1:49, about 1:50, about 1:51, about 1:52, about 1:53, about 1:54, about 1:55, about 1:56, about 1:57, about ^ ^
Attorney Docket No.250298.000954 1:58, about 1:59, about 1:60, about 1:61, about 1:62, about 1:63, about 1:64, about 1:65, about 1:66, about 1:67, about 1:68, about 1:69, about 1:70, about 1:71, about 1:72, about 1:73, about 1:74, about 1:75, about 1:76, about 1:77, about 1:78, about 1:79, about 1:80, about 1:81, about 1:82, about 1:83, about 1:84, about 1:85, about 1:86, about 1:87, about 1:88, about 1:89, about 1:90, about 1:91, about 1:92, about 1:93, about 1:94, about 1:95, about 1:96, about 1:97, about 1:98, about 1:99, about 1:100, about 1:105, about 1:110, about 1:115, about 1:120, about 1:125, about 1:130, about 1:135, about 1:140, about 1:145, about 1:150, about 1:155, about 1:160, about 1:165, about 1:170, about 1:175, about 1:180, about 1:185, about 1:190, about 1:195, about 1:200, about 1:205, about 1:210, about 1:215, about 1:220, about 1:225, about 1:230, about 1:235, about 1:240, about 1:243, about 1:245, about 1:250, about 1:260, about 1:270, about 1:280, about 1:290, about 1:300, about 1:310, about 1:320, about 1:330, about 1:340, about 1:350, about 1:360, about 1:370, about 1:380, about 1:390, about 1:400, about 1:410, about 1:420, about 1:430, about 1:440, about 1:450, about 1:460, about 1:470, about 1:480, about 1:490, about 1:500, about 1:510, about 1:520, about 1:530, about 1:540, about 1:550, about 1:560, about 1:570, about 1:580, about 1:590, about 1:600, about 1:610, about 1:620, about 1:630, about 1:640, about 1:650, about 1:660, about 1:670, about 1:680, about 1:690, about 1:700, about 1:710, about 1:720, about 1:729, about 1:730, about 1:740, about 1:750, about 1:775, about 1:800, about 1:825, about 1:850, about 1:875, about 1:900, about 1:925, about 1:950, about 1:975, about 1:1000, about 1:1025, about 1:1050, about 1:1075, about 1:1100, about 1:1125, about 1:1150, about 1:1175, about 1:1200, about 1:1225, about 1:1250, about 1:1275, about 1:1300, about 1:1325, about 1:1350, about 1:1375, about 1:1400, about 1:1425, about 1:1450, about 1:1475, about 1:1500, about 1:1525, about 1:1550, about 1:1575, about 1:1600, about 1:1625, about 1:1650, about 1:1675, about 1:1700, about 1:1725, about 1:1750, about 1:1775, about 1:1800, about 1:1825, about 1:1850, about 1:1875, about 1:1900, about 1:1925, about 1:1950, about 1:1975, about 1:2000, about 1:2025, about 1:2050, about 1:2075, about 1:2100, about 1:2125, about 1:2150, about 1:2175, about 1:2187, about 1:2200, about 1:2300, about 1:2400, about 1:2500, about 1:2600, about 1:2700, about 1:2800, about 1:2900, about 1:3000, about 1:3100, about 1:3200, about 1:3300, about 1:3400, about 1:3500, about 1:3600, about 1:3700, about 1:3800, about 1:3900, about 1:4000, about 1:4100, about 1:4200, about 1:4300, about 1:4400, about 1:4500, about 1:4600, about 1:4700, about 1:4800, about 1:4900, or about 1:5000. In some embodiments, the AAV viral genome to the antibody molar ratio (e.g., the VG:Ab ratio or AAV:Ab ratio) is about 1:1, about 1:3, about 1:9, about 1:27, about 1:81, about 1:243, about 1:729, or about 1:2187. In some embodiments, the AAV viral genome to the antibody molar ratio (e.g., the VG:Ab ratio or AAV:Ab ratio) is less than about 1:1, about 1:1 to about 1:2, about 1:2 to ^ ^
Attorney Docket No.250298.000954 about 1:3, about 1:3 to about 1:4, about 1:4 to about 1:5, about 1:5 to about 1:6, about 1:6 to about 1:7, about 1:7 to about 1:8, about 1:8 to about 1:9, about 1:9 to about 1:10, about 1:10 to about 1:11, about 1:11 to about 1:12, about 1:12 to about 1:13, about 1:13 to about 1:14, about 1:14 to about 1:15, about 1:15 to about 1:16, about 1:16 to about 1:17, about 1:17 to about 1:18, about 1:18 to about 1:19, about 1:19 to about 1:20, about 1:20 to about 1:21, about 1:21 to about 1:22, about 1:22 to about 1:23, about 1:23 to about 1:24, about 1:24 to about 1:25, about 1:25 to about 1:26, about 1:26 to about 1:27, about 1:27 to about 1:28, about 1:28 to about 1:29, about 1:29 to about 1:30, about 1:30 to about 1:31, about 1:31 to about 1:32, about 1:32 to about 1:33, about 1:33 to about 1:34, about 1:34 to about 1:35, about 1:35 to about 1:36, about 1:36 to about 1:37, about 1:37 to about 1:38, about 1:38 to about 1:39, about 1:39 to about 1:40, about 1:40 to about 1:41, about 1:41 to about 1:42, about 1:42 to about 1:43, about 1:43 to about 1:44, about 1:44 to about 1:45, about 1:45 to about 1:46, about 1:46 to about 1:47, about 1:47 to about 1:48, about 1:48 to about 1:49, about 1:49 to about 1:50, about 1:50 to about 1:51, about 1:51 to about 1:52, about 1:52 to about 1:53, about 1:53 to about 1:54, about 1:54 to about 1:55, about 1:55 to about 1:56, about 1:56 to1:57, about 1:57 to about 1:58, about 1:58 to about 1:59, about 1:59 to about 1:60, about 1:60 to about 1:61, about 1:61 to about 1:62, about 1:62 to about 1:63, about 1:63 to about 1:64, about 1:64 to about 1:65, about 1:65 to about 1:66, about 1:66 to about 1:67, about 1:67 to about 1:68, about 1:68 to about 1:69, about 1:69 to about 1:70, about 1:70 to about 1:71, about 1:71 to about 1:72, about 1:72 to about 1:73, about 1:73 to about 1:74, about 1:74 to about 1:75, about 1:75 to about 1:76, about 1:76 to about 1:77, about 1:77 to about 1:78, about 1:78 to about 1:79, about 1:79 to about 1:80, about 1:80 to about 1:81, about 1:81 to about 1:82, about 1:82 to about 1:83, about 1:83 to about 1:84, about 1:84 to about 1:85, about 1:85 to about 1:86, about 1:86 to about 1:87, about 1:87 to about 1:88, about 1:88 to about 1:89, about 1:89 to about 1:90, about 1:90 to about 1:91, about 1:91 to about 1:92, about 1:92 to about 1:93, about 1:93 to about 1:94, about 1:94 to about 1:95, about 1:95 to about 1:96, about 1:96 to about 1:97, about 1:97 to about 1:98, about 1:98 to about 1:99, about 1:99 to about 1:100, about 1:100 to about 1:105, about 1:105 to about 1:110, about 1:110 to about 1:115, about 1:115 to about 1:120, about 1:120 to about 1:125, about 1:125 to about 1:130, about 1:130 to about 1:135, about 1:135 to about 1:140, about 1:140 to about 1:145, about 1:145 to about 1:150, about 1:150 to about 1:155, about 1:155 to about 1:160, about 1:160 to about 1:165, about 1:165 to about 1:170, about 1:170 to about 1:175, about 1:175 to about 1:180, about 1:180 to about 1:185, about 1:185 to about 1:190, about 1:190 to about 1:195, about 1:195 to about 1:200, about 1:200 to about 1:205, about 1:205 to about 1:210, about 1:210 to about 1:215, about 1:215 to about 1:220, about 1:220 to about 1:225, about 1:225 to about 1:230, about 1:230 to about 1:235, about ^ ^
Attorney Docket No.250298.000954 1:235 to about 1:240, about 1:240 to about 1:243, about 1:243 to about 1:245, about 1:245 to about 1:250, about 1:250 to about 1:260, about 1:260 to about 1:270, about 1:270 to about 1:280, about 1:280 to about 1:290, about 1:290 to about 1:300, about 1:300 to about 1:310, about 1:310 to about 1:320, about 1:320 to about 1:330, about 1:330 to about 1:340, about 1:340 to about 1:350, about 1:350 to about 1:360, about 1:360 to about 1:370, about 1:370 to about 1:380, about 1:380 to about 1:390, about 1:390 to about 1:400, about 1:400 to about 1:410, about 1:410 to about 1:420, about 1:420 to about 1:430, about 1:430 to about 1:440, about 1:440 to about 1:450, about 1:450 to about 1:460, about 1:460 to about 1:470, about 1:470 to about 1:480, about 1:480 to about 1:490, about 1:490 to about 1:500, about 1:500 to about 1:510, about 1:510 to about 1:520, about 1:520 to about 1:530, about 1:530 to about 1:540, about 1:540 to about 1:550, about 1:550 to about 1:560, about 1:560 to about 1:570, about 1:570 to about 1:580, about 1:580 to about 1:590, about 1:590 to about 1:600, about 1:600 to about 1:610, about 1:610 to about 1:620, about 1:620 to about 1:630, about 1:630 to about 1:640, about 1:640 to about 1:650, about 1:650 to about 1:660, about 1:660 to about 1:670, about 1:670 to about 1:680, about 1:680 to about 1:690, about 1:690 to about 1:700, about 1:700 to about 1:710, about 1:710 to about 1:720, about 1:720 to about 1:729, about 1:729 to about 1:730, about 1:730 to about 1:740, about 1:740 to about 1:750, about 1:750 to about 1:775, about 1:775 to about 1:800, about 1:800 to about 1:825, about 1:825 to about 1:850, about 1:850 to about 1:875, about 1:875 to about 1:900, about 1:900 to about 1:925, about 1:925 to about 1:950, about 1:950 to about 1:975, about 1:975 to about 1:1000, about 1:1000 to about 1:1025, about 1:1025 to about 1:1050, about 1:1050 to about 1:1075, about 1:1075 to about 1:1100, about 1:1100 to about 1:1125, about 1:1125 to about 1:1150, about 1:1150 to about 1:1175, about 1:1175 to about 1:1200, about 1:1200 to about 1:1225, about 1:1225 to about 1:1250, about 1:1250 to about 1:1275, about 1:1275 to about 1:1300, about 1:1300 to about 1:1325, about 1:1325 to about 1:1350, about 1:1350 to about 1:1375, about 1:1375 to about 1:1400, about 1:1400 to about 1:1425, about 1:1425 to about 1:1450, about 1:1450 to about 1:1475, about 1:1475 to about 1:1500, about 1:1500 to about 1:1525, about 1:1525 to about 1:1550, about 1:1550 to about 1:1575, about 1:1575 to about 1:1600, about 1:1600 to about 1:1625, about 1:1625 to about 1:1650, about 1:1650 to about 1:1675, about 1:1675 to about 1:1700, about 1:1700 to about 1:1725, about 1:1725 to about 1:1750, about 1:1750 to about 1:1775, about 1:1775 to about 1:1800, about 1:1800 to about 1:1825, about 1:1825 to about 1:1850, about 1:1850 to about 1:1875, about 1:1875 to about 1:1900, about 1:1900 to about 1:1925, about 1:1925 to about 1:1950, about 1:1950 to about 1:1975, about 1:1975 to about 1:2000, about 1:2000 to about 1:2025, about 1:2025 to about 1:2050, about 1:2050 to about 1:2075, about 1:2075 to about 1:2100, about 1:2100 to about 1:2125, about 1:2125 to about 1:2150, about 1:2150 to about 1:2175, about ^ ^
Attorney Docket No.250298.000954 1:2175 to about 1:2187, about 1:2187 to about 1:2200, about 1:2200 to about 1:2300, about 1:2300 to about 1:2400, about 1:2400 to about 1:2500, about 1:2500 to about 1:2600, about 1:2600 to about 1:2700, about 1:2700 to about 1:2800, about 1:2800 to about 1:2900, about 1:2900 to about 1:3000, about 1:3000 to about 1:3100, about 1:3100 to about 1:3200, about 1:3200 to about 1:3300, about 1:3300 to about 1:3400, about 1:3400 to about 1:3500, about 1:3500 to about 1:3600, about 1:3600 to about 3700, about 1:3700 to about 1:3800, about 1:3800 to about 1:3900, about 1:3900 to about 1:4000, about 1:4000 to about 1:4100, about 1:4100 to about 1:4200, about 1:4200 to about 1:4300, about 1:4300 to about 1:4400, about 1:4400 to about 1:4500, about 1:4500 to about 1:4600, about 1:4600 to about 1:4700, about 1:4700 to about 1:4800, about 1:4800 to about 1:4900, about 1:4900 to about 1:5000, or at least about 1:5000. In some embodiments, the AAV viral genome to the antibody molar ratio (e.g., the VG:Ab ratio or AAV:Ab ratio) is less than about 1:1, about 1:1 to about 1:3, about 1:3 to about 1:9, about 1:9 to about 1:27, about 1:27 to about 1:81, about 1:81 to about 1:243, about 1:243 to about 1:729, about 1:729 to about 1:2187, or at least about 1:2187. [00924] 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. [00925] 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 ^ ^
Attorney Docket No.250298.000954 discarded. [00926] 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 SURECLICKTM Autoinjector (Amgen, Thousand Oaks, CA), the PENLETTM (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRATM Pen (Abbott Labs, Abbott Park IL), to name only a few. [00927] 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 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ (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. [00928] 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, ^ ^
Attorney Docket No.250298.000954 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. [00929] 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 [00930] The present disclosure includes methods of using the any of antigen-binding molecules as disclosed herein or a pharmaceutically acceptable carrier or diluent. [00931] 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. [00932] 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. [00933] 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. [00934] 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. [00935] 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. ^ ^
Attorney Docket No.250298.000954 [00936] 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. [00937] 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. [00938] 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. [00939] 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. [00940] 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 [00941] 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 antigen- binding molecule and an AAV particle may be administered as a molecular complex described herein. [00942] 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. [00943] 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 ^ ^
Attorney Docket No.250298.000954 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. [00944] 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”). [00945] In one exemplary embodiment of the present disclosure, each secondary and/or tertiary dose is administered 1 to 26 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½, 15, 15½, 16, 16½, 17, 17½, 18, 18½, 19, 19½, 20, 20½, 21, 21½, 22, 22½, 23, 23½, 24, 24½, 25, 25½, 26, 26½, 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 antigen- binding 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. [00946] 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, ^ ^
Attorney Docket No.250298.000954 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. [00947] 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. [00948] 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 ^ ^
Attorney Docket No.250298.000954 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 [00949] 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^^^ bispecific antigen-binding molecule (e.g., pharmaceutical formulation thereof) set forth herein. The vessel or injection device may be packaged into a kit. [00950] 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., pre- filled 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. [00951] 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. [00952] 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.), ^ ^
Attorney Docket No.250298.000954 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 Ill.), to name only a few. [00953] 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 [00954] 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. [00955] 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. [00956] 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). Non-limiting Examples of Embodiments [00957] In one embodiment, provided herein is an antibody, or an antigen-binding fragment ^ ^
Attorney Docket No.250298.000954 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 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; ^ ^
Attorney Docket No.250298.000954 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. [00958] 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 ^ ^
Attorney Docket No.250298.000954 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. [00959] 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; ^ ^
Attorney Docket No.250298.000954 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. [00960] In another embodiment, 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. [00961] 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. [00962] 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, I261, 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, ^ ^
Attorney Docket No.250298.000954 T719, and E720. [00963] 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, I671, 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. [00964] In some embodiments, said antibody, or said antigen-binding fragment thereof, binds to a capsid of an AAV1 particle comprising amino acid substitution N500E. In some embodiments, said antibody, or said antigen-binding fragment thereof, binds to a capsid of an AAV2 particle comprising amino acid substitution(s) R585A and/or R588A. In some embodiments, said antibody, or said antigen-binding fragment thereof, binds to a capsid of an AAV5 particle comprising amino acid substitution T571S. In some embodiments, said antibody, or said antigen-binding fragment thereof, binds to a capsid of an AAV6 particle comprising amino acid substitution(s) N500E, K531A, and/or K531E. In some embodiments, said antibody, or said antigen-binding fragment thereof, binds to a capsid of an AAV9 particle comprising amino acid substitution(s) N272A and/or W503A. [00965] 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 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 ^ ^
Attorney Docket No.250298.000954 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10. [00966] 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. [00967] 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. [00968] 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, ^ ^
Attorney Docket No.250298.000954 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. [00969] In some embodiments, said antibody, or said antigen-binding fragment thereof, comprises an IgG1, IgG2, IgG3, or IgG4 constant region, or a variant thereof. [00970] In some embodiments, said antibody, or said antigen-binding fragment thereof, comprises an IgG1 constant region, or a variant thereof. [00971] In some embodiments, the IgG1 constant region comprises the amino acid sequence of SEQ ID NO: 259^or 1164. [00972] In some embodiments, said antibody, or said antigen-binding fragment thereof, comprises an IgG4 constant region, or a variant thereof. [00973] In some embodiments, the IgG4 variant comprises a hinge domain modified to reduce binding to Fc^ receptors. [00974] In some embodiments, the IgG4 constant region comprises the amino acid sequence of SEQ ID NO: 261. [00975] In some embodiments, said antigen-binding fragment is a Fab fragment. [00976] In some embodiments, said antigen-binding fragment is an scFv fragment. [00977] 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. [00978] 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. [00979] In some embodiments, said capsid comprises one or more wild-type AAV capsid polypeptides. [00980] In some embodiments, said capsid comprises one or more non-wild-type AAV capsid polypeptides. [00981] In some embodiments, rein binding of said antibody or antigen-binding fragment thereof to said AAV particle capsid does not neutralize said AAV particle. [00982] In another embodiment, 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 antigen-binding fragments. [00983] In another embodiment, provided herein is an antibody, or an antigen-binding ^ ^
Attorney Docket No.250298.000954 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. [00984] In another embodiment, provided herein is a pharmaceutical composition comprising any of the above-described antibodies or antigen-binding fragments and a pharmaceutically acceptable carrier or excipient. [00985] In another embodiment, 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; ^ ^
Attorney Docket No.250298.000954 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. [00986] 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 ^ ^
Attorney Docket No.250298.000954 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. [00987] 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; ^ ^
Attorney Docket No.250298.000954 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. [00988] In another embodiment, 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. [00989] 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; ^ ^
Attorney Docket No.250298.000954 and/or d) N254, L256, Q263, S264, V323, T324, Q325, S655, A667, S668, F669, I670, T671, G328, G546, E548, T716, and N717. [00990] 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, I261, 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. [00991] 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, I671, 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. [00992] 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 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 ^ ^
Attorney Docket No.250298.000954 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10. [00993] 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. [00994] 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 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. [00995] 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 ^^^^ ^
Attorney Docket No.250298.000954 subunit gamma 1 (CACNG1). [00996] In some embodiments, the molecule on the cell surface is ASGR1. [00997] 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. [00998] 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. [00999] 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. [001000] In some embodiments, the molecule on the cell surface is TfR. [001001] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001002] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001003] 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. [001004] In some embodiments, the molecule on the cell surface is CACNG1. [001005] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001006] 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 ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001007] 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; 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 ^ ^
Attorney Docket No.250298.000954 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. [001008] In another embodiment, 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. [001009] 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. [001010] 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. [001011] In some embodiments, the first heavy chain region is linked to the second heavy chain region via a linker. [001012] In another embodiment, 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 ^ ^
Attorney Docket No.250298.000954 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. [001013] 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. [001014] 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. [001015] In some embodiments, the first scFv and/or the first heavy chain region is linked to the Fc domain via a linker. [001016] 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; ^ ^
Attorney Docket No.250298.000954 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. [001017] 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 ^ ^
Attorney Docket No.250298.000954 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. ^ ^
Attorney Docket No.250298.000954 [001018] 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. [001019] 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). [001020] In some embodiments, the molecule on the cell surface is ASGR1. [001021] 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. ^ ^
Attorney Docket No.250298.000954 [001022] 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. [001023] 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. [001024] In some embodiments, the molecule on the cell surface is TfR. [001025] 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. [001026] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001027] 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. [001028] In some embodiments, the molecule on the cell surface is CACNG1. [001029] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 acid sequence of SEQ ID NO: 1213. [001030] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001031] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 comprising the amino acid sequence of SEQ ID NO: 1213. [001032] In another embodiment, 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. [001033] 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. [001034] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [001035] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface. [001036] In some embodiments, the scFv is linked to the first heavy chain region via a linker. [001037] In another embodiment, 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 ^ ^
Attorney Docket No.250298.000954 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. [001038] 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. [001039] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [001040] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. [001041] In some embodiments, the scFv is linked to the Fc domain via a linker. [001042] In another embodiment, 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. [001043] 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. [001044] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [001045] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface. ^ ^
Attorney Docket No.250298.000954 [001046] In some embodiments, the first heavy chain region is linked to the second heavy chain region via a linker. [001047] In another embodiment, 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. [001048] 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. [001049] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface. [001050] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. [001051] In some embodiments, the second heavy chain region is linked to the Fc domain via a linker. [001052] In another embodiment, 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 ^ ^
Attorney Docket No.250298.000954 (“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. [001053] 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. [001054] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [001055] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ABD3 binds to a molecule on a cell surface. [001056] In some embodiments, the scFv is linked to the first heavy chain region via a linker. [001057] In another embodiment, 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. [001058] 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. [001059] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [001060] In some embodiments, ABD1 and ABD2 bind to a capsid of an AAV particle, and ^ ^
Attorney Docket No.250298.000954 ABD3 binds to a molecule on a cell surface. [001061] In some embodiments, the second heavy chain region is linked to the Fc domain via a linker. [001062] In another embodiment, 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. [001063] 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. [001064] In some embodiments, ABD2 and ABD3 bind to a capsid of an AAV particle, and ABD1 binds to a molecule on a cell surface. [001065] In some embodiments, ABD1 and ABD3 bind to a capsid of an AAV particle, and ABD2 binds to a molecule on a cell surface. [001066] 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. [001067] 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 ^ ^
Attorney Docket No.250298.000954 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. ^ ^
Attorney Docket No.250298.000954 [001068] 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 ^ ^
Attorney Docket No.250298.000954 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. [001069] 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 ^ ^
Attorney Docket No.250298.000954 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. [001070] 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). [001071] In some embodiments, said molecule on the cell surface is ASGR1. [001072] 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. [001073] 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. [001074] 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. [001075] In some embodiments, the molecule on the cell surface is TfR. [001076] In some embodiments, the other(s) of ABD1, ABD2, and ABD3 which binds to ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001077] 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 ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001078] 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. [001079] In some embodiments, the molecule on the cell surface is CACNG1. [001080] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001081] 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; ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001082] 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 ^ ^
Attorney Docket No.250298.000954 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. [001083] In another embodiment, 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 ^^^^ ^
Attorney Docket No.250298.000954 molecule on a cell surface. [001084] 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. [001085] 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. [001086] 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. [001087] 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. [001088] In another embodiment, 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. [001089] 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. [001090] 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. [001091] 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. [001092] In some embodiments, the first scFv and/or second scFv is linked to the Fc domain via a linker. [001093] In another embodiment, provided herein is a multispecific antibody, or a ^ ^
Attorney Docket No.250298.000954 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. [001094] 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. [001095] 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. [001096] 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. [001097] 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. [001098] 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; ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 10. [001099] 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 ^ ^
Attorney Docket No.250298.000954 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. [001100] 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 ^ ^
Attorney Docket No.250298.000954 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. [001101] 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). [001102] In some embodiments, said molecule on the cell surface is ASGR1. [001103] 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. [001104] 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. [001105] 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. [001106] In some embodiments, said molecule on the cell surface is TfR. ^ ^
Attorney Docket No.250298.000954 [001107] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001108] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001109] 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 ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001110] In some embodiments, said molecule on the cell surface is CACNG1. [001111] 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; ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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. [001112] 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 ^ ^
Attorney Docket No.250298.000954 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; ^ ^
Attorney Docket No.250298.000954 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 ^ ^
Attorney Docket No.250298.000954 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. [001113] 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; ^ ^
Attorney Docket No.250298.000954 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. [001114] 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. [001115] 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; amino acids to 25 amino acids in length; or amino acids to 20 amino acids in length. In some embodiments, the linker is: amino acids to 50 amino acids in length;
amino acids to 45 amino acids in length; ^ ^
Attorney Docket No.250298.000954 (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. [001117] 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; amino acids to 30 amino acids in length; amino acids to 25 amino acids in length; amino acids to 20 amino acids in length. In some embodiments, the linker is 5 amino acids to 25 amino acids in length. In some embodiments, the linker is 10 amino acids to 60 amino acids in length. In some embodiments, the linker is 20 amino acids to 50 amino acids in length. In some embodiments, the linker is 25 to 35 amino acids in length. In some embodiments, the linker is or comprises a multimer of GnS (SEQ ID NO: (SEQ ID NO: 240), wherein n is an integer from 1 to 10. In some embodiments, the linker is or comprises a multimer of G4S (SEQ ID NO:
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)). [001125] In some embodiments, one or more light chains are universal light chains. [001126] 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. [001127] In some embodiments of any of the above-described multispecific antibodies or multispecific antigen-binding fragments, the multispecific antibodies or multispecific antigen- binding fragments comprise an Fc heterodimer. [001128] In some embodiments, the Fc domains in the Fc heterodimer comprise knob-in- hole mutations as compared to a wild-type Fc domain. [001129] 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 ^ ^
Attorney Docket No.250298.000954 to a wild-type Fc domain. [001130] In some embodiments, at least one Fc domain in the Fc heterodimer comprises a star mutation as compared to a wild-type Fc domain. [001131] 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. [001132] In some embodiments, said capsid comprises one or more wild-type AAV capsid polypeptides. [001133] In some embodiments, said capsid comprises one or more non-wild-type AAV capsid polypeptides. [001134] 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. [001135] In another embodiment, provided herein is a pharmaceutical composition comprising a multispecific antibody or multispecific antigen-binding fragment described herein, and a pharmaceutically acceptable carrier or excipient. [001136] In another embodiment, provided herein is a molecular complex comprising an AAV particle bound to one or more antibodies and/or antigen-binding fragments described herein. [001137] 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. [001138] In another aspect, provided herein is a pharmaceutical composition comprising a molecular complex described herein and a pharmaceutically acceptable carrier or excipient. [001139] In another embodiment, 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. [001140] In another embodiment, 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. [001141] 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. [001142] In another embodiment, provided herein is a pharmaceutical composition comprising a molecular complex described herein and a pharmaceutically acceptable carrier or excipient. ^ ^
Attorney Docket No.250298.000954 [001143] In another embodiment, 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. [001144] In another embodiment, 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. [001145] In another embodiment, 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. [001146] In some embodiments, said cell is in a subject and said molecular complex is administered to the subject. [001147] 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. EXAMPLES [001148] 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 [001149] 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 ^ ^
Attorney Docket No.250298.000954 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). [001150] Table 12 shows a description of identifiers for anti-AAV antibodies of the present Example. Table 12. Anti-AAV Antibody Identifiers
[001151] Anti-AAV mAbs of the present Example (HDQQ06E09-0017, HDQQ06F06-0018, HDPV07D04-0065, 4059311_ULC1-39_38741_MS, 3842258_ULC1-3, _79284_MS, 4059310_ULC1-39_48703_MS, 4059311_ULC1-39_31283_MS, 4059311_ULC1- 39_36126_MS, 4059311_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 µg/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 anti- human 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. ^ ^
Attorney Docket No.250298.000954 [001152] 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, REGN13074) 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 [001153] 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. [001154] Table 13 shows a description of identifiers for anti-AAV antibodies of the present Example. Table 13. Anti-AAV Antibody Identifiers
^^^^ ^
Attorney Docket No.250298.000954
REGN13885-L1 [001155] Table 14 shows a description of the reagents used in the present Example. Table 14. Description of Reagents
^ [001156] 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 NaCl, 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 µL/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. [001157] 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 (kd) 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 (t½) were calculated from the kinetic rate constants as:
^ [001158] The association and dissociation rate constants (ka and kd), the dissociative half- lives (t1/2) 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. ^ ^
Attorney Docket No.250298.000954 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 [001159] 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. [001160] 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 IgG1, and can be expressed on cell lines to capture antibodies on cell surface. As described herein, monoclonal antibodies (mAbs) to ^ ^
Attorney Docket No.250298.000954 AAV were generated and the ability of these mAbs to enhance or neutralize transduction was explored. [001161] Table 17 shows a description of identifiers for anti-AAV antibodies of the present Example. Table 17. Anti-AAV Antibody Identifiers
[001162] Anti-AAV mAbs of the present Example (HDQQ06E09-0017, HDQQ06F06-0018, HDPV07D04-0065, 4059311_ULC1-39_38741_MS, 3842258_ULC1-3, _79284_MS, 4059310_ULC1-39_48703_MS, 4059311_ULC1-39_31283_MS, 4059311_ULC1- 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 NanoGlo Luciferase assay system. Luminescence was detected using a plate reader (Tecan Infinite M200 Pro) and analyzed using GraphPad Prism. [001163] 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, ^^^^ ^
Attorney Docket No.250298.000954 4059310_ULC1-39_48703_MS, 4059310_ULC1-39_51231_MS, 4059311_ULC1- 39_31283_MS, HDQQ06F06-0018) required a greater quantity of antibody for enhancement of transduction. Example 4. Cryo-electron Microscopy (Cryo-EM) [001164] Cryo-EM sample preparation and data collection [001165] 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 µL 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 Å pixel size) and a defocus range of -0.8~-1.6 µm. Each movie contained 46 dose fractions over a 2 second exposure, and the total acquired dose per Å2 was ~40 electrons. Data collection statistics are summarized in Table 18. [001166] Cryo-EM data processing and map generation [001167] 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. [001168] Model building and refinement [001169] 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 ^ ^
Attorney Docket No.250298.000954 refinement with secondary structure and non-crystallographic symmetry (NCS) restraints in Phenix. [001170] Results summary and conclusions: [001171] Cryo-EM structure of AAV2 HBM in complex with REGN13878 [001172] A 3.08 Å 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. [001173] 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. REGN13878 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. [001174] Cryo-EM structure of AAV2 HBM in complex with REGN13883 [001175] A 3.07 Å 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. ^ ^
Attorney Docket No.250298.000954 [001176] 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 REGN13883 contacts a patch of residues in VP3-3d VR-IX (K706, S707) to stabilize the binding. [001177] Cryo-EM structure of AAV2 HBM in complex with REGN13880 [001178] A 3.10 Å 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 REGN13880. Since the epitope of REGN13880 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. [001179] Cryo-EM structure of AAV8 in complex with REGN13880 ^ ^
Attorney Docket No.250298.000954 [001180] A 2.99 Å cryo-EM structure of AAV8 in complex with the anti-AAV antibody Fab REGN13880 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-REGN13880 structure. REGN13880 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, I261, 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. [001181] Cryo-EM structure of AAV9 in complex with REGN13880 [001182] A 3.10 Å cryo-EM structure of AAV9 in complex with the anti-AAV antibody Fab REGN13880 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. REGN13880 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, I671, 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. [001183] Cryo-EM structure of AAV2 HBM in complex with REGN13882 [001184] A 2.91 Å 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, ^ ^
Attorney Docket No.250298.000954 REGN13882 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 REGN13882 is primarily located at conserved regions of VP3, allowing this Fab to bind other AAV serotypes including AAV8 and AAV9 as described below. [001185] Cryo-EM structure of AAV8 in complex with REGN13882 [001186] A 3.10 Å cryo-EM structure of AAV8 in complex with the anti-AAV antibody Fab REGN13882 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 REGN13882 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. [001187] Cryo-EM structure of AAV9 in complex with REGN13882 [001188] A 2.96 Å cryo-EM structure of AAV9 in complex with the anti-AAV antibody Fab REGN13882 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 REGN13882 is solely mediated by its heavy chain contacting VP3-5a and VP3-5b. The long ^ ^
Attorney Docket No.250298.000954 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 REGN13882 is further stabilized by CDRs H2 and H3 contacting VP3-5b VR-II (G330) and an additional residue, E718. [001189] 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
^ [001190] 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 Å 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. ^ ^
Attorney Docket No.250298.000954 Table 19. Summary of REGN13878 Residues Contacting AAV2 HBM VP3 Residues
[001191] 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 Å of non-hydrogen atoms of antibody.^Residues corresponding to ^ ^
Attorney Docket No.250298.000954 REGN13883 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
[001192] Table 21 shows^a summary of REGN13880 residues contacting AAV2 HBM VP3 residues.^Contacting residues are defined as amino acids with non-hydrogen atoms within 4 Å of non-hydrogen atoms of antibody. Table 21. Summary of REGN13880 Residues Contacting AAV2 HBM VP3 Residues
^ ^
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[001193] 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 Å of non-hydrogen atoms of antibody. ^ ^
Attorney Docket No.250298.000954 Table 22. Summary of REGN13880 Residues Contacting AAV8 VP3 Residues
^ ^
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[001194] 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 Å of non-hydrogen atoms of antibody. Table 23. Summary of REGN13880 Residues Contacting AAV9 VP3 Residues
^^^^ ^
Attorney Docket No.250298.000954 [001195] Table 24 shows a^summary of REGN13882 residues contacting AAV2 HBM VP3 residues. Contacting residues are defined as amino acids with non-hydrogen atoms within 4 Å of non-hydrogen atoms of antibody. Table 24. Summary of REGN13882 Residues Contacting AAV2 HBM VP3 Residues
^ [001196] Table 25 shows summary of REGN13882 residues contacting AAV8 VP3 residues. Contacting residues are defined as amino acids with non-hydrogen atoms within 4 Å of non- hydrogen atoms of antibody. ^ ^
Attorney Docket No.250298.000954 Table 25. Summary of REGN13882 Residues Contacting AAV8 VP3 Residues
^ [001197] 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 Å of non-hydrogen atoms of antibody. Table 26. Summary of REGN13882 Residues Contacting AAV9 VP3 Residues
^ ^
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Example 5. Anti-AAV x anti-ASGR1 Alternative Format Design and Binding Enzyme- linked immunosorbent assay (ELISA) [001198] A schematic representation of alternative format antibody designs for anti-AAV x anti-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 5, IgG1 versions of anti-AAV mAbs comprising binding arms of REGN13072 (4059311_ULC1- 39_38741_MS) and REGN13221 (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. [001199] Table 27 shows a description of identifiers for the anti-AAV antibodies of the present Example. Table 27. Anti-AAV Antibody Identifiers
[001200] 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. ^ ^
Attorney Docket No.250298.000954 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 µg/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 4059310_ULC1- 39_51231_MS binding arms. Example 6. Bispecific antibodies can effectively retarget adeno-associated virus (AAV) to the central nervous system (CNS) [001201] 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. ^ ^
Attorney Docket No.250298.000954 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 anti-AAV x anti-CACNG1 bispecific antibodies [001202] Adeno-associated viruses (AAV) are members of the Parvovirus family of non- enveloped 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. [001203] Anti-AAV x anti-CACNG1 bispecific antibodies of the present disclosure (AF70: anti-AAV#70 scFv fused to N-terminal of anti-CACNG1 REGN10717 hIgG1 N297G antibody; AF71: anti-AAV#70 scFv fused to C-terminal of anti-CACNG1 REGN10717 hIgG1 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 L 1xPBS. ^ ^
Attorney Docket No.250298.000954 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 L 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 L of BSA Stain Buffer and spun down for 2 minutes at 800xg. After the last wash, 100 L 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. [001204] 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 (1E5 viral genomes per cell) as described above. VVT885 (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 1:100 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. [001205] 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 ^ ^
Attorney Docket No.250298.000954 antibody (VVT885), 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 anti-AAV x anti-mTfR alternative format (AF) antibodies binding to AAV9W503A virus by ELISA [001206] The present Example was designed to test the binding of anti-AAV x anti-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 g/ml. A description the anti-AAV x anti-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 ^-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 anti-AAV x anti-mTfR AF antibodies with NGS/MS #70 arm bind well to AAV9W503A Ubc.Fluc at high concentrations. Anti-AAV x anti-mTfR AF Abs with anti NGS/MS #64 arm had a lower affinity to AAV9W503A Ubc.Fluc. Anti-AAV x anti-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 [001207] 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 ^ ^
Attorney Docket No.250298.000954 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. [001208] For the FLuc assay read-out protocol, the plate was spun at 1500 RPM for 1 minute and then the supernatant was discarded.50 l lysis buffer was added per well (Glo- Lysis, Promega E2661) for 5 minutes. Then, 100 l 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 anti- AAV x anti-mTfR alternative format (AF) antibodies with anti-AAV NGS/MS #70 retarget AAV9W503A at low ratios and have higher peak when compared to anti-AAV x anti- 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 anti-AAV x anti-mTfR alternative format antibodies tested (Figures 20, 22).^Anti-AAV x anti-mTfR alternative format antibodies with NGS/MS#70 bind better and retarget AAV9W503A at lower ratios as compared to anti-AAV x anti-mTfR alternative format antibodies with NGS/MS#64. Example 10. Retargeting assay using AAV9 and an eGFP reporter [001209] 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 ^ ^
Attorney Docket No.250298.000954 incubated for 72 hours at 37°C. After the 72-hour incubation period, a GFP read-out protocol was performed to measure fluorescence. [001210] 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 L of TrypLE™ Select Enzyme (1X), no phenol red, and incubated for 4-5 minutes in 37°C.100 L 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 L of BSA Stain Buffer and spun down for 2 minutes at 800xg. After the last wash, 100 L 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. [001211] 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 anti-AAV x anti-mTfR alternative format antibodies [001212] The present Example tested in vivo retargeting of AAV9 using various anti-AAV x anti-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 anti-AAV x anti-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, AAV91/8 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 5x10-11 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. [001213] On Day 0, 200 L 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. ^ ^
Attorney Docket No.250298.000954 [001214] For tissue 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. [001215] 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
[001216] For the liver, the Abcam rabbit green fluorescent protein (GFP) antibody staining protocol comprised a rabbit monoclonal antibody [EPR14104] to GFP (Abcam, 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 anti-AAV x anti-mTfR control groups 16-19 (AAV9 scCBH.eGFP, AAV91/8 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 anti-AAV x anti-mTfR AF1 (Figure 25B), anti-AAV x anti-mTfR AF3 (Figure 25C), anti-AAV x anti-mTfR AF5 (Figure 25D), anti-AAV x anti-mTfR AF7 (Figure 25E), and^anti-AAV x anti-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. [001217] Transduction was also assessed by Taqman qPCR of GFP mRNA expression in Liver (Figure 26) and Brain (Figure 27). Consistent with immunohistochemistry data, AAV ^ ^
Attorney Docket No.250298.000954 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 anti-AAV x anti- mTfR alternative format antibodies [001218] The present Example tested in vivo retargeting of AAV9 versus AAV9W503A using anti-AAV x anti-mTfR alternative format antibodies. A goal of the experiments described herein was to test^anti-AAV x anti-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 AAV91/8 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. [001219] On Day 0, 200 L 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. ^ [001220] For tissue 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. [001221] 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
^ ^
Attorney Docket No.250298.000954 [001222] For the liver and heart, the Abcam rabbit green fluorescent protein (GFP) antibody staining protocol comprised a rabbit monoclonal antibody [EPR14104] to GFP (Abcam, 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 anti-AAV x anti-mTfR AF7 in Figures 28A-28D. [001223] 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 anti-AAV x anti-CACNG1 bispecific antibodies [001224] Anti-AAV x anti-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 anti-AAV x anti-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 µL (1E11 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 ^ ^
Attorney Docket No.250298.000954 hCACNG1 at different MOI; cells were analyzed by flow for eGFP expression three day post- transduction (Figure 33). HEK 293 cells overexpressing human CACNG1 (hCACNG1) 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 (hCACNG1) 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 anti-AAV x anti-CACNG1 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 REGN10717 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 Hu371:0 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 Hu371:0 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 Hu371:0 condition. Overall in skeletal muscles (Figure 35B), compared to Hu371:0 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 Hu371:0 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 ^ ^
Attorney Docket No.250298.000954 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 [001225] 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. hASGR1 expressing (7303KO) female mice were then retro-orbitally injected with 200 µL (1E10 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 hASGR1 mice with anti-AAV x anti-ASGR1 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 (REGN16202) with low affinity AAV arm can retarget the AAV to the liver. Example 15. Comparing retargeting efficacy of different detargeted AAV variants [001226] 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. hASGR1 mice (7303KO) and control (50500) female mice were then retro- orbitally injected with 200 µL (1E10 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 hASGR1 mice and background control mice with anti-AAV x anti-ASGR1 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 [001227] Ubc fLuc-expressing virus (AAV2 HBM) and appropriate ratio of antibody ^ ^
Attorney Docket No.250298.000954 (REGN16210, REGN13136) were mixed, followed by incubation for 1 hour at 37°C. hASGR1 mice (7303KO) and control (50500) female mice were then retro-orbitally injected with 200 µL (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 hASGR1 & background control mice with anti-AAV x anti-ASGR1 altibody REGN16210 (AF29) and anti-AAV x anti- ASGR1 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 hASGR1 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 hASGR1 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 [001228] 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. hASGR1 mice (7303KO) female mice were then retro-orbitally injected with 200 µL (1E10 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 hASGR1 mice with anti-AAV x anti-ASGR1 altibody ^ ^
Attorney Docket No.250298.000954 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. Anti-AAV x anti-ASGR1 Fab’2 clearance evaluation [001229] Ubc fLuc-expressing virus (AAV2 HBM) and appropriate ratio of antibody (REGN16199, REGN16199-!Fc) were mixed, followed by incubation for 1 hour at 37°C. hASGR1 (7303KO) female mice were then retro-orbitally injected with 200 µL (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 41A-41B). Quantitation of radiance at week-3 post-AAV+antibody complex injection indicates AAV2 HBM transgene expression/retargeting to livers of hASGR1 mice with REGN16199 (AF21) and REGN16199-!Fc 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 for the REGN16199-!Fc, 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-!Fc molecules. However, unlike REGN16199 (AF21) where transduction at ratios 1:9-1:2187 dropped to background level, REGN16199-!Fc ratios 1:9-1:2187 dropped slightly and maintained a constant level of transduction (Figure 41A). PK serum analysis at 24-hour bleed demonstrated clearance of AAV from serum when incubated with increasing amounts of both REGN16199 (AF21) and REGN16199-!Fc antibodies. Reduction in circulating AAV was consistent with decreased transgene expression within livers of hASGR1 mice (Figure 41B). REGN16199-!Fc generated from REGN16199 (AF21) was effective for AAV retargeting and, unlike the parental REGN16199 (AF21), retained some ^ ^
Attorney Docket No.250298.000954 transduction efficacy at higher antibody concentrations. This demonstrated a unique quality of the !Fc antibody. Example 19. Anti-AAV x anti-ASGR1 Fab’2 vs. linear Fab retargeting and clearance evaluation. [001230] Ubc fLuc-expressing virus (AAV2 HBM) and appropriate ratio of antibody (REGN16199-!Fc and AF63) were mixed, followed by incubation for 1 hour at 37°C. hASGR1 (7303KO) female mice were then retro-orbitally injected with 200 µL (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 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 hASGR1 and background control mice with REGN16199- !Fc and AF63 at a variety of virus:antibody ratios. For hASGR1 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-!Fc and AF63 antibodies. The clearance of AAV in hASGR1 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- !Fc (Figure 42E). AF63 are functional for retargeting and at low antibody concentrations can achieve similar efficacy to REGN16199-!Fc. Example 20. Measuring AAV-Antibody Complex Clearance Based on Antibody Molecules [001231] CAG eGFP-expressing virus (AAV2 HBM) was mixed with each of the following antibodies (REGN13880, AF62, AF63, REGN16203-!Fc, REGN13136, REGN16199-!Fc, and REGN16199) separately at a fixed ratio (1:2187), followed by incubation for 1 hour at ^^^^ ^
Attorney Docket No.250298.000954 37°C. Control mice (50500) female mice were then retro-orbitally injected with 200 µL (1E10 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-!Fc, and REGN16199). AAV clearance was reduced when pre- complexed with retargeting altibody with mass less than 100kDa (REGN13880, AF62, and REGN16203-!Fc). 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-!Fc. 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 [001232] Ubc fLuc-expressing virus (AAV2 HBM) and antibody (AF29, AF37, AF41, AF61A, 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. hASGR1 mice (7303KO) female mice were then retro-orbitally injected with 200 µL (1E10 total VGs) of virus+antibody complexes. IVIS 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 hASGR1 mice with anti-AAV x anti- ASGR1 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 [001233] Ubc fLuc-expressing virus (AAV2 HBM) and antibody (AF29, AF62, and REGN16203-!Fc) were mixed at ratio 1:9, 1:27, 1:81, 1:243, 1:729, and 1:2187 (for AF29, only ratio 1:3 was included), followed by incubation for 1 hour at 37°C. hASGR1 mice (7303KO) female mice were then retro-orbitally injected with 200 µL (1E10 total VGs) of virus+antibody complexes. IVIS imaging was then performed at Week 3 on excised livers (Figure 45). Quantification of radiance at week 3 post-AAV+antibody complex injection ^ ^
Attorney Docket No.250298.000954 indicates AAV2 HBM transgene expression/retargeting to livers of hASGR1 mice with anti- AAV x anti-ASGR1 altibodies at a variety of virus:antibody ratios. For both AF62 and REGN16203-!Fc, maximum signal was shown at a ratio of 1:81. Both AF62 and REGN16203-!Fc with single anti-AAV binding arm, single anti-ASGR binding arm, and without Fc portion are functional for retargeting. [001234] The following methods were used in the above-described Examples. [001235] Reagents used include D.Luciferin, firefly potassium salt, Cat #122799-10 (Perkin Elmer). [001236] Antibodies used include AF30 (REGN16204, IgG1), REGN16210 (AF29, IgG4US, TP/PMPD), REGN16199 (AF21, IgG1), REGN19199-!Fc, 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). [001237] Mouse strains used include 7303 (MAID ID for humanized ASGR mice, same for mixed and Bl6 background) and control mice 50500 (littermate). [001238] The overall in vivo setup included the following steps. Detargeted AAVs were incubated with a range of anti-AAV x anti-“Target” antibody concentrations at 37°C for 1 hour. Mice (hASGR1, control mice) were then retro-orbitally injected with 200 µL 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. [001239] Additional antibody description is provided herein. [001240] ^Fc alternative format descriptions. REGN16199-^Fc was generated by treating REGN16199 (AF21) with protease specific for the removal of Fc from immunoglobulin. The desired REGN16199-^Fc was purified from the starting material and by-products using affinity capture chromatography followed by size exclusion chromatography. REGN16203- ^Fc was also generated using similar method. [001241] REGN13136. REGN13136 comprises of anti-AAV#70 hIgG4US heavy chain and anti-ASGR 13383P2 hIgG4US heavy chain. REGN13136 was purified from the starting material using protein A column. [001242] REGN13880. REGN13880 comprises of anti-AAV#70 Fab. REGN13880 was purified from the starting material using affinity capture chromatography followed by size exclusion chromatography. [001243] 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. ^ ^
Attorney Docket No.250298.000954 [001244] 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. [001245] REGN16199 (AF21). REGN16199 comprises of one heavy chain being anti- AAV#70 Fab fused with anti-ASGR 13383P2 hIgG1 N280G Fc. The other heavy chain is anti-AAV#70 hIgG1 N280G Fc. REGN16199 was purified from the starting material using protein A column. Example 23. In vitro assessment of AAV transduction by anti-AAV x anti-CACNG1 bispecific antibodies [001246] Anti-AAV x anti-CACNG1 bispecific antibodies AF71, AF71x, AF72a, AF73, AF74A, and AF74B (see, e.g., Figures 30A-30G, 48, 51A-51C, 52A-52C, 53A-53C, 54A-54C, 55A- 55E, 56A-56D, and 57A-57D, and Tables 30-31) were assessed for their capacity to enhance transduction of AAV Hu37 particles expressing green fluorescent protein (GFP) into human CACNG1-expressing HEK 293 cells. For transduction, cells were seeded in a clear wall clear bottom 96-well plate at 12,500 cells per well using DMEM (supplemented with 10% FBS, MEM NEAA, Pen Strep) and incubated at 37°C and 5% CO2. 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 was 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 the 1-hour incubation, appropriate volumes of the viral genome to antibody complexes were added to the cells to yield an MOI of 2E+05 VG per cell.60-hours post transduction, the transduced cells were analyzed by flow cytometry. [001247] To prepare the samples for flow cytometry, the supplemented media was discarded, and the cells were washed once with 100 L 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 L 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 L of BSA Stain Buffer and spinning down the cells for 2 minutes at 800xg. After the last wash, 100 L of BSA Stain Buffer was added and the cells were resuspended in preparation for flow cytometry analysis. GFP expression was measured using a ZE5 Cell Analyzer. ^ ^
Attorney Docket No.250298.000954 [001248] The transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody and 1 AAV to 9 antibodies as assessed by percent (%) GFP positive cells (Figure 49A) and Median Fluorescence Intensity (MFI) (Figure 49B). Co-incubation of AAV Hu37 with either AF71, AF71x, AF72a, AF73, AF74A, or AF74B resulted in improved transduction efficiency over control AAV without antibody on HEK 293 cells overexpressing human CACNG1. Example 24. In vivo retargeting efficacy of anti-AAV x anti-CACNG1 bispecific antibodies [001249] To assess the in vivo retargeting efficacy of anti-AAV x anti-CACNG1 bispecific antibodies, transduction efficiency of AAV and antibody complexes were quantified in C57BL/6 mice. AAV Hu37 expressing eGFP from a CAG promoter and an appropriate ratio of antibodies AF71, AF71X, AF72a, AF73, AF74A, or AF74B (see, e.g., Figures 30A-30G, 48, 51A-51C, 52A-52C, 53A-53C, 54A-54C, 55A-55E, 56A-56D, and 57A-57D, and Tables 30-31) were mixed, followed by incubation for 1 hour at 37˚C. A mixed gender cohort of C57BL/6 mice was retro-orbitally injected with 150 µL (4E11 total VGs) of the prepared virus+antibody complexes. Liver, skeletal, and cardiac muscles were harvested at week 3. All the tissues were processed for Taqman analysis to measure RNA levels of eGFP. [001250] eGFP mRNA levels were determined for various tissues (skeletal muscles such as tongue (Figure 50A), gastrocnemius/soleus (Figure 50B), tibialis anterior (Figure 50C), as well as heart (Figure 50D) and liver (Figure 50E)). For each bar graph depicted in Figures 50A-50E, GFP mRNA level of each condition was normalized to AAV Hu37 at the 1 AAV to 1 antibody molar ratio. [001251] Overall, there was comparable transduction of AAV complexed with AF71, AF71x, AF72a, AF74A, or AF74B in the tongue (Figure 50A), gastrocnemius/soleus (Figure 50B), and tibialis anterior (Figure 50C) for matched AAV to antibody ratios. With the exception of AF73, each antibody significantly enhanced transduction of AAV over AAV Hu37 alone. For most conditions, antibodies reduced transduction in the liver as compared to AAV Hu37 alone. These data show that different antibody formats containing anti-CACNG1 and anti- AAV binding arms are capable of enhancing AAV retargeting to skeletal muscle. Example 25. In vitro assessment of AAV transduction by anti-AAV x anti-hTfR1 bispecific antibodies [001252] Anti-AAV x anti-hTfR bispecific antibodies DB7035B, DB7043B, DB7045B, DB7047B, DB8035B, DB8043B, DB8045B, DB8047B (Davis body orientation; see, e.g., Smith et al. Sci Rep.2015 Dec 11:5:17943 and U.S. Pat. No.9,309,326, which are ^ ^
Attorney Docket No.250298.000954 incorporated by reference in their entirety herein), and alternative format antibodies AF7035B, AF7043B, AF7045B, AF7047B, AF8035B, AF8043B, AF8045B, and AF8047B (see, e.g., Figures 58A-58B, 64-79, and Tables 32A-32B) were assessed for their capacity to enhance transduction of AAV9 particles expressing green fluorescent protein (GFP) from a CBH promoter genome into human TfR-expressing 3T3 mouse cells. Cells were seeded in a clear wall clear bottom 96-well plate at 10,000 cells per well using DMEM (supplemented with 10% BCS, LG/PS) and incubated at 37°C and 5% CO2. 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, 1:27,1:8,1:243,1:729, and 1:2187). AAV9 was diluted in 1xPBS + 0.001% Pluronic. AAV9 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 the 1-hour incubation, the appropriate volumes of the viral genome to antibody complexes were added to the cells to yield an MOI of 1E+05 VG per cell.54-hours post transduction, the transduced cells were analyzed by flow cytometry. [001253] To prepare the samples for flow cytometry, the supplemented media was discarded, and the cells were washed once with 100 L 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 L of BD Pharmingen™ Stain Buffer (BSA) was then added and cells were 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 L of BSA Stain Buffer and spinning down the cells for 2 minutes at 800xg. After the last wash, 100 L of BSA Stain Buffer was added and the cells were resuspended in preparation for Flow Cytometry analysis. GFP expression was measured using a ZE5 Cell Analyzer. [001254] For complexes of AAV9 with DB7035B, DB7043B, DB7045B, DB7047B, DB8035B, DB8043B, DB8045B, or DB8047B, the flow cytometry data demonstrated improved transduction efficiency over control AAV9 without antibody on 3T3 cells overexpressing human TfR (hTfR). Transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody (AAV:Ab ratio 1:1) and 1 AAV to 27 antibodies (AAV:Ab ratio 1:27) for DB7043B, DB7045B, DB7047B, DB8043B, and DB8047B. Transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody (AAV:Ab ratio 1:1) and 1 AAV to 81 antibodies (AAV:Ab ratio 1:81) for DB8035B and DB8045B. Lastly, the transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody (AAV:Ab ratio 1:1) and 1 AAV to 243 antibodies (AAV:Ab ratio 1:243) for DB7035B the as assessed by percent (%) GFP positive cells (Figure 59A). The Median Fluorescence Intensity (MFI) peak of DB7035B was between molar ratios of 1 AAV to 27 antibody (AAV:Ab ratio 1:27) and 1 AAV to 81 ^ ^
Attorney Docket No.250298.000954 antibodies (AAV:Ab ratio 1:81). The MFI peak of DB8035B and DB8045B was at the molar ratio of 1 AAV to 27 antibodies (AAV:Ab ratio 1:27). The MFI peak of DB7045B, DB8043B, and DB8047B was between molar ratios of 1 AAV to 9 antibody (AAV:Ab ratio 1:9) and 1 AAV to 27 antibodies (AAV:Ab ratio 1:27). Lastly, the MFI peak of DB7043B and DB7047B was between molar ratio of 1 AAV to 3 antibodies (AAV:Ab ratio 1:3) and 1 AAV to 9 antibodies (AAV:Ab ratio 1:9). Complexes of AAV9 with DB7035B, DB8035B, and DB8045B show the highest MFI peak among all tested antibodies at molar ratio of 1 AAV to 27 antibodies (AAV:Ab ratio 1:27) (Figure 59B). [001255] For co-incubation of AAV9 with AF7035B, AF7043B, AF7045B, AF7047B, AF8035B, AF8043B, AF8045B, or AF8047B, the flow cytometry data demonstrated improved transduction efficiency over control AAV9 without antibody on 3T3 cells overexpressing human TfR (hTfR).Transduction efficiency was optimal between molar ratios of 1 AAV to 1 antibody (AAV:Ab ratio 1:1) and 1 AAV to 27 antibodies (AAV:Ab ratio 1:27) for AF7035B, AF7043B, AF7045B, AF7047B, AF8035B, AF8043B, AF8045B, and AF8047B (Figure 60A).The Median Fluorescence Intensity (MFI) peak of AF7035B, AF7043B, AF7045B, AF7047B, AF8043B, AF8045B, and AF8047B was at molar ratio of 1 AAV to 9 antibodies (AAV:Ab ratio 1:9) while the Median Fluorescence Intensity (MFI) peak of AF8035B was at the molar ratio of 1 AAV to 27 antibodies (AAV:Ab ratio 1:27) (Figure 60B). [001256] Co-incubation of AAV9 with either 1+1 (Figures 59A-59B) (DB7035B, DB7043B, DB7045B, DB7047B, DB8035B, DB8043B, DB8045B, and DB8047B) or 2+1 antibodies (Figures 60A-60B) (AF7035B, AF7043B, AF7045B, AF7047B, AF8035B, AF8043B, AF8045B, and AF8047B) resulted in improved transduction efficiency over control AAV without antibody on 3T3 cells overexpressing human TfR. Example 26. In vivo retargeting efficacy of anti-AAV x anti-hTfR bispecific antibodies [001257] To assess the in vivo retargeting efficacy of anti-AAV x anti-hTfR bispecific antibodies, transduction efficiency of AAV and antibody complexes was quantified in hTfR mice (7229KO) male mice. AAV9 expressing GFP from CBH promoter and appropriate ratio of antibody AF7035B, AF7043B, AF7045B, and AF7047B (see, e.g., Figures 58A-58B, 72A-72D, 73A-73D, 74A-74D, 75A-75D, and Table 32B) were mixed, followed by incubation for 1 hour at 37˚C. hTfR mice (7229KO) were then retro-orbitally injected with 100 µL (1E11 total VGs) of virus+antibody complexes. Brain, liver, and heart were harvested at week 2. Brains were trimmed to include a sagittal plane in each section. Brains were sectioned using standardized plane sectioning at 4 µm thickness. Brain sections underwent standardized ER2 antigen retrieval (30 minutes) and were then treated with an antibody to eGFP (Invitrogen, A-11122) at a concentration of 1 µg/mL for 1 hour. Following secondary antibody ^^^^ ^
Attorney Docket No.250298.000954 incubation, eGFP was detected with the Leica Refine detection kit. Immunohistochemistry (IHC) was performed on the Bond Rx platform. After staining, slides were imaged on an Aperio slide scanner at 40x magnification, and image analysis was completed using HALO analysis software. [001258] AAV9 transduction was enhanced in the hippocampus (Figure 61A), cerebellum (Figure 61B), and cortex (Figure 61C), when complexed with AF7035B, AF7045B, AF7043B, and AF7047B at molar ratios of 1 AAV to 3 antibodies (AAV:Ab ratio 1:3), and to a lesser degree at molar ratios of 1 AAV to 9 antibodies (AAV:Ab ratio 1:9) when compared to AAV9 without antibodies. The extent of transduction improvement varied by TfR binding arm. At 1 AAV to 3 antibody molar ratios, the bispecific retargeting platform showed similar transduction efficiency to the respective SpyTag/SpyCatcher. [001259] Additional IHC data obtained with AF7045B (Figure 61D) showed that, in addition to hippocampus, cerebellum, and cortex, other brain areas such as medulla, olfactory bulb, thalamus, striatum, hypothalamus, and midbrain were also transduced with AAV9 expressing GFP from CBH promoter when mixed with AF7045B at a molar ratio of 1 AAV to 3 antibodies (AAV:Ab ratio 1:3). [001260] Quantitative analysis of the cortex by HALO (Figure 62) confirmed the IHC findings. AAV9 when mixed with AF7035B, AF7043B, AF7045B, and AF7047B at a molar ratio of 1 AAV to 3 antibodies (AAV:Ab ratio 1:3) and 1 AAV to 9 antibodies (AAV:Ab ratio 1:9) transduced a much higher percentage of the cortex when compared to AAV9 only. The transduction percentage of the cortex was comparable between the bispecific antibodies retargeting platform and the SpyTag/SpyCatcher platform with corresponding TfR Fab binding arms. [001261] Taqman analysis was used to measure RNA levels in the same set of tissues. Figures 63A-63C illustrate quantification of mRNA levels in the brain (Figure 63A), liver (Figure 63B), and heart (Figure 63C) of hTfR mice (7229KO). [001262] mRNA levels in the brain (Figure 63A) of hTfR male mice (7229KO) were measured by comparing fold difference in mRNA levels of tested conditions to an AAV9 only treated sample. mRNA levels of AAV9 complexed with AF7035B or AF7045B at a molar ratio of 1 AAV to 3 antibodies (AAV:Ab ratio 1:3) showed mRNA levels up to 25-fold over AAV9 only while AAV9 complexed with AF7043B or AF7047B at a molar ratio of 1 AAV to 3 antibodies (AAV:Ab ratio 1:3) showed mRNA levels between 10- to 15-fold over AAV9 only. When complexing AAV9 with AF7035B, AF7043B, AF7045B, and AF7047B at a molar ratio of 1 AAV to 9 antibodies (AAV:Ab ratio 1:9), a high level of mRNA was seen in all samples compared to AAV9 only but slightly lower as compared to the same samples with a molar ratio of 1 AAV to 3 antibodies (AAV:Ab ratio 1:3). ^^^^ ^
Attorney Docket No.250298.000954 [001263] mRNA levels in the livers (Figure 63B) and hearts (Figure 63C) of hTfR male mice (7229KO) were measured by comparing fold difference in mRNA levels of tested conditions to an AAV9 only sample. All samples tested had mRNA levels equal to or below that of the AAV9 only treated samples. [001264] Overall, AAV9 alone had a baseline transduction in different areas of the brain. When complexed with Altibody (AF7035B, AF7043B, AF7045B, and AF7047B), transduction in the brain was significantly improved as revealed by IHC and Taqman results. These data demonstrated that bispecifics targeting human TfR can effectively deliver to brain tissue and achieve comparable efficacy to the SpyTag/SpyCatcher platform. Total efficacy was dependent on the anti-TfR binding arm and the relative AAV to antibody molar ratio. Example 27. In vivo retargeting efficacy of anti-AAV x anti-hTfR bispecific antibody using dosing conditions [001265] To assess the in vivo retargeting efficacy of the anti-AAV x anti-hTfR bispecific antibody, the transduction efficiency of AAV-antibody complexes were tested under different AAV and antibody complexing conditions in hTfR mice (7229KO) mice. Ratios are depicted as AAV:antibody (Figure 83). Wild-type AAV9 expressing GFP from a^CBH promoter was used as a control. For premixed complex testing, AAV9 vectors expressing GFP from a CBH promoter and an appropriate ratio of antibody AF7035B were mixed, followed by incubation for: 1) 1 hour at room temperature; 2) 6 hours at room temperature; 3) 1 hour at 37°C, followed by 1 cycle of freeze and thaw (F/T); 4) 1 hour at 37°C followed by 2 cycles of freeze and thaw; and 5) 1 hour at 37°C. The AAV and antibody used for sequential dosing were not incubated at any temperature/time and were prepared fresh prior to injection. hTfR mice (7229KO) for groups receiving the pre-complexed AAV and antibody were then retro- orbitally injected with 200 µL (1E11 total VGs) of virus and antibody complexes. hTfR mice (7229KO) for sequential dosing group were retro-orbitally injected with 100 µL of antibody in one eye, followed immediately by 100 µL containing 1E11 total VGs of AAV in the other eye. Brain tissue was harvested at week 2 post-dosing. RT-qPCR data shows AAV9 transduction enhancement for all tested conditions as compared to wild-type AAV9. Example 28. In vivo evaluation of anti-AAV x anti-CACNG1 alternative format antibodies for skeletal muscle targeting [001266] To assess the in vivo retargeting efficacy of anti-AAV x anti-CACNG1 bispecific alternative format antibodies, the transduction efficacy of AAV and antibody complexes were quantified in C57BL/6 mice. AAV9 W503A expressing eGFP from a CAG promoter and an appropriate ratio of antibodies AF72a and AF72b (AAV:antibody; see, e.g., Figure 84) were ^ ^
Attorney Docket No.250298.000954 mixed, followed by incubation for 1 hour at room temperature. Female C57BL/6 mice were retro-orbitally injected with 150 µL (4E11 total VGs) of the prepared virus+antibody complexes. Spytagged-AAV9-W503A conjugated with CACNG1 antibody was also used as a positive control. Peak transduction efficiency of virus+antibody complex was comparable to the Spytagged-AAV controls (data not shown). Liver, skeletal, and cardiac muscles were harvested at week 3. All tissues were processed for Taqman analysis to measure RNA levels of eGFP.^WT AAV9 was used to normalize RNA Taqman data. [001267] eGFP mRNA levels were determined for various tissues (skeletal muscles such as gastrocnemius and quadriceps), as well as heart and liver. For each bar graph depicted in Figure 84, GFP mRNA level of each condition was normalized to wild-type AAV9. [001268] As shown in Figure 84, AF72a and AF72b significantly enhanced AAV transduction in gastrocnemius and quadricep over wild-type AAV9. The tested antibody complexes also reduced transduction in cardiac muscle as compared to wild-type AAV9.^ AAV9 W503A capsid reduced liver transduction, and the reduction was present when AAV9 was complexed with antibodies. These data show that different antibody formats containing anti-CACNG1 and anti-AAV binding arm can enhance AAV retargeting to skeletal muscle. Example 29. AAV9 transduction in human TfR-expressing 3T3 cells using anti-AAV x anti-hTfR alternative format antibodies AFT5 and AFT8 [001269] The capacity of anti-AAV x anti-hTfR alternative format antibodies AFT5 and AFT8 (see, e.g., Figures 86A-86B, 87A-87D, 88A-88C, and Table 32D) to enhance transduction of AAV9 particles expressing green fluorescent protein (GFP) from a CBH promoter genome into human TfR-expressing 3T3 mouse cells was tested. Cells were seeded in a clear wall clear bottom 96-well plate at 10,000 cells per well using DMEM (supplemented with 10% BCS, LG/PS) and incubated at 37°C and 5% CO2. 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). AAV9 was diluted in 1xPBS + 0.001% Pluronic. AAV9 and antibody dilutions were combined to obtain the above viral genome to antibody molar ratios and incubated for 1 hour at room temperature 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 1E5 VG per cell.54-hours post transduction, the transduced cells were analyzed by flow cytometry. [001270] To prepare the samples for flow cytometry, the supplemented media was discarded, and the cells were washed once with 100 L 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 L of BD Pharmingen™ Stain Buffer (BSA) was then added and cells ^ ^
Attorney Docket No.250298.000954 were 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 L of BSA Stain Buffer and spinning down the cells for 2 minutes at 800xg. After the last wash, 100 L of BSA Stain Buffer was added and the cells were resuspended in preparation for Flow Cytometry analysis. GFP expression was measured using a ZE5 Cell Analyzer. [001271] As shown in Figure 85, AAV9 with AFT5 and AFT8 demonstrated improved transduction efficiency over control AAV9 without antibody on 3T3 cells overexpressing human TfR (hTfR). 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) (Figure 85). The Median Fluorescence Intensity (MFI) peak was at molar ratio of 1 AAV to 9 antibodies (AAV:Ab ratio 1:9) (Figure 85). [001272] Overall, co-incubation of AAV9 with AFT5 and AFT8 resulted in improved transduction efficiency over control AAV without antibody on 3T3 cells overexpressing human TfR. ^ ^
Attorney Docket No.250298.000954 Table 30: Listing of Example Anti-AAV x anti-mTfR, Anti-AAV x Anti-CACNG1, and Anti-AAV x anti-ASGR Amino Acid and Nucleotide Sequences
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Table 31: Listing of Example Amino Acid and Nucleotide Sequences of Anti-AAV x Anti-CACNG1 bispecific antibodies AF71x, AF72a, AF72b, AF73, AF74A, AF74B, and AF76
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Table 32A: Listing of Example Amino Acid and Nucleotide Sequences of Anti-AAV x Anti-hTfR bispecific antibodies DB7035B, DB7043B, DB7045B, DB7047B, DB8035B, DB8043B, DB8045B, and DB8047B
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Table 32B: Listing of Example Amino Acid and Nucleotide Sequences of Anti-AAV x Anti-hTfR bispecific antibodies AF7035B, AF7043B, AF7045B, AF7047B, AF8035B, AF8043B, AF8045B, and AF8047B
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Table 32C: Listing of Example Amino Acid and Nucleotide Sequences of Anti-AAV x Anti-hTfR bispecific antibody REGN22198
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Table 32D: Listing of Example Amino Acid and Nucleotide Sequences of Anti-AAV x Anti-hTfR bispecific antibodies AFT5 and AFT8
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^ * * * [001273] 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. Such modifications are intended to fall within the scope of the appended claims. [001274] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification. ^ ^