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WO2025217240A1 - Anti-tnfr2 antigen-binding proteins and uses thereof - Google Patents

Anti-tnfr2 antigen-binding proteins and uses thereof

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Publication number
WO2025217240A1
WO2025217240A1 PCT/US2025/023783 US2025023783W WO2025217240A1 WO 2025217240 A1 WO2025217240 A1 WO 2025217240A1 US 2025023783 W US2025023783 W US 2025023783W WO 2025217240 A1 WO2025217240 A1 WO 2025217240A1
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WO
WIPO (PCT)
Prior art keywords
seq
amino acid
acid sequence
cdr2
cdr1
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/023783
Other languages
French (fr)
Inventor
Luigi Franchi
Anthony W. Opipari
Lee Kim Swee
Paul-Albert KÖNIG
Laura PREISS
Ferdinand Huber
Annegrit SEIFRIED
Julia KJNOPF
Tomasz PRÓCHNICKI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Odyssey Therapeutics Inc
Original Assignee
Odyssey Therapeutics Inc
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Publication date
Application filed by Odyssey Therapeutics Inc filed Critical Odyssey Therapeutics Inc
Publication of WO2025217240A1 publication Critical patent/WO2025217240A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/22—Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • T cels Regulatory T cels (Tregs) are a subset of T cels that play a crucial role in peripheral self- tolerance and the prevention of autoimmunity. Due to their potent immunosuppressive function, Tregs can be targeted for the treatment of autoimmunity.
  • Tregs are based on the ex vivo expansion of Tregs prior to autologous transfer.
  • a major limitation of the current strategies is their inability to stabilize Tregs phenotype to ensure long-lasting immunoregulation.
  • Tumor necrosis factor receptor 2 (TNFR2) signaling has been shown to induce proliferation, sustained suppressive function and FOXP3 promoter demethylation in Tregs (Tseng et al., 2019).
  • TNFR2 signaling also induces the expression of EZH2 (Urbano et al., 2018), a histone methyl transferase involved in the repression of the effector transcriptomic program and stabilization of the Treg phenotype (DuPage et al., 2015). Because of its role in Tregs biology and FOXP3 promoter demethylation, TNFR2 signaling can be leveraged to induce a stable immunosuppressive phenotype and enhance their function to the benefit of autoimmune diseases. Accordingly, there is a need in the art to develop therapeutic molecules that can effectively activate TNFR2 signaling.
  • the present disclosure provides an antigen-binding protein that specificaly binds tumor necrosis factor receptor 2 (TNFR2), comprising a complementarity determining region 3 (CDR3) comprising the amino acid sequence AADSDL(S/R)TV(V/T)VGPHDY (SEQ ID NO: 61), A(A/G)(T/A/S)(P/L)(S/T)GKAY(T/S)Y (SEQ ID NO: 4787), or (T/A/V)A(S/A)PTGRAF(T/N/A)Y (SEQ ID NO: 66), wherein one or more non-alanine residues in the CDR3 sequence are optionaly replaced with an alanine, and/or one or more alanine residues in the CDR3 sequence are optionaly replaced with a glycine.
  • CDR3 complementarity determining region 3
  • the CDR3 comprises the amino acid sequence (T/A/V)(A/G)(S/A)(A/P)(A/T)(A/G)(A/R)A(A/F)(T/N/A)(A/Y) or (A/G)(A/G)(T/A/S)(A/P/L)(A/S/T)(A/G)(A/K)(A/G)(A/Y)(A/T/S)(A/Y).
  • the CDR3 comprises an amino acid sequence selected from SEQ ID NOs: 10, 34, 4524, 4530, 4774, 18, 4727, 4810-4833, and 4835-4855.
  • the antigen-binding protein further comprises a CDR1 comprising the amino acid sequence GRTFSDYG (SEQ ID NO: 16), GRTF(G/R/S)(N/S)(Y/L)(T/F) (SEQ ID NO:73), or GFT(F/L)DD(I/Y)A (SEQ ID NO: 69).
  • the CDR1 comprises the amino acid sequence of SEQ ID NO: 16, 32 or 4061.
  • the antigen-binding protein further comprises a CDR2 comprising the amino acid sequence INWS(N/Q/E/S)(G/A)RT (SEQ ID NO: 4809), IR(W/R/Y)(T/P)G(G/L)(S/I)T (SEQ ID NO: 80), or I(Y/F)SY(S/G)(S/P)NT (SEQ ID NO: 76).
  • the CDR2 comprises an amino acid sequence selected from SEQ ID NOs: 4062, 4527, 4070, and 4788-4793.
  • the antigen-binding protein comprises i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4809, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4787; i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 69, a CDR2 comprising an amino acid sequence of SEQ ID NO: 76, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 61; 2 310886415v1 Attorney Docket No: 260525.000071 ii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4809, and a CDR3 comprising an amino acid sequence of (A/G)(A/G)(T/A/S)(A/P/L)(A/S/T)(A/G)(
  • the antigen-binding protein comprises i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10; ii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4524; iv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3
  • the antigen-binding protein is a single-domain antibody.
  • the single-domain antibody is a VHH, a VNAR, or a VH domain.
  • the VHH is a camelid VHH.
  • the VHH comprises the amino acid sequence of SEQ ID NO: 4781 or 4783, or a sequence having at least 75% identity thereto.
  • the VHH is a humanized VHH.
  • the humanized VHH comprises an amino acid sequence selected from any one of SEQ ID NOs: 4775, 4782, 4784, 4794-4808, 4857-4902, 4994-5001, or a sequence having at least 75% identity thereto.
  • the antigen-binding protein has an agonist effect upon binding to TNFR2.
  • the antigen-binding protein binds to human TNFR2.
  • the antigen-binding protein binds to human TNFR2 with a KD of about 1x10-8 M to about 2.7 x 10-6 M.
  • the antigen-binding protein binds to cyno TNFR2. [0026] In some embodiments, the antigen-binding protein binds to cyno TNFR2 with a K - D of about 3x10 8 M to about 2.4 x 10-6 M. [0027] In some embodiments, the antigen-binding protein increases expression of one or more proteins selected from a protein in the NF-kB pathway, FOXP3, HELIOS, EZH2, HLA-DR, ICAM-1, OX-40, ICOS, and CCR8.
  • the antigen-binding protein comprises one or more modifications that reduce binding of the antigen-binding protein by pre-existing antibodies found in human blood or serum.
  • the single-domain antibody comprises one or more modifications at the amino-terminus and/or the carboxy-terminus.
  • the single-domain antibody comprises the amino acid sequence VPAG (SEQ ID NO: 4698) or VAGG (SEQ ID NO: 4697) at the carboxy-terminus starting from position 111 according to Chothia.
  • the single-domain antibody comprises a substitution of amino acid residue Glu with Asp (E1D) at the first position of the amino-terminus.
  • an antigen-binding protein that specificaly binds tumor necrosis factor receptor 2 (TNFR2), comprising a means for binding an epitope within human TNFR2 8 310886415v1 Attorney Docket No: 260525.000071 bound by an antibody selected from T-004, T-004.VTV, T-007hu1 with CDR2 G/A, CDR3 T/S, T- 009Hu1_QGR, T-009Hu1_SGR, T-009Hu1_QGR_N/C, T-009Hu1_NAR_N/C, T-009Hu1_SGR_N/C, T- 007Hu1.S3.QGR, T-007Hu1.S3.EGR, T-007Hu1.S3.SGR, T-007Hu1.S3.NSR, T-007Hu1.S3.NTR, T- 007Hu1.S3.SAR, T-007Hu1.EQ.QGR
  • the present disclosure provides a fusion protein that specificaly binds tumor necrosis factor receptor 2 (TNFR2), comprising one or more of the antigen-binding proteins described herein.
  • TNFR2 tumor necrosis factor receptor 2
  • the fusion protein comprises two of the antigen-binding proteins.
  • the fusion protein comprises four of the antigen-binding proteins.
  • the one or more antigen-binding proteins bind to the same epitope on TNFR2.
  • the one or more antigen-binding proteins bind to diferent epitopes on TNFR2.
  • the one or more antigen-binding proteins are one or more single-domain antibodies.
  • the one or more single-domain antibodies are one or more VHHs.
  • the fusion protein further comprises an immunoglobulin Fc region.
  • the immunoglobulin Fc region is an Fc region of a human immunoglobulin.
  • the immunoglobulin Fc region is an Fc region of human IgG1, IgG2, IgG3 or IgG4, or a variant thereof.
  • the immunoglobulin Fc region is an Fc region of human IgG1, or a variant thereof.
  • the Fc region of human IgG1 comprises one or more mutations selected from L234A, L235A, G237A, M252Y, S254T, T256E, D265A, N297A, and/or P329A according to EU numbering.
  • the Fc region of human IgG1 comprises a set of mutations selected from 1). L234A and L235A; 2). L234A, L235A, and P329A; 3). D265A, N297A and P329A; 4). L234A, L235A, and G237A; 5).
  • the Fc region of human IgG1 comprises L234A, L235A, and P329A.
  • the Fc region of human IgG1 comprises M252Y, S254T, and T256E.
  • the immunoglobulin Fc region is an Fc region of human IgG4, or a variant thereof.
  • the Fc region of human IgG4 comprises one or more mutations selected from S228P, L235E, L235A, and/or F234A according to EU numbering.
  • the Fc region of human IgG4 comprises a set of mutations selected from 1). S228P and L235E; 2). S228P and L235A; 3). S228P, F234A, and L235E; and 4). S228P, F234A, and L235A.
  • the Fc region of human IgG4 comprises S228P and L235E.
  • the fusion protein described herein further comprises a cytokine.
  • the cytokine is IL-2, or a variant thereof.
  • the cytokine is an IL-2 variant comprising a N88D mutation.
  • the fusion protein further comprises a moiety that binds to serum albumin.
  • the fusion protein comprises the amino acid sequence of any one of SEQ ID Nos: 4772, 4773, 4776-4779, 4903, 4979, 4981, 4983, 4985, 4987, 4989, 4991, and 4993, or a sequence having at least 75% identity thereto.
  • the fusion protein has an agonist effect upon binding to TNFR2.
  • the fusion protein binds to human TNFR2.
  • the fusion protein binds to human TNFR2 with a K -12 D of about 3x10 M to about 1 x 10-7 M. [0060] In some embodiments, the fusion protein binds to cyno TNFR2. [0061] In some embodiments, the fusion protein binds to cyno TNFR2 with a K -12 D of about 1x10 M to about 5 x 10-8 M.
  • the present disclosure provides a conjugate comprising an antigen-binding protein described herein or a fusion protein described herein, wherein the antigen-binding protein or fusion protein is conjugated to a second moiety.
  • the second moiety is selected from a detectable label, a drug, a toxin, a radionuclide, an enzyme, an immunomodulatory agent, a cytokine, a cytotoxic agent, a chemotherapeutic agent, and a diagnostic agent, or a combination thereof.
  • the second moiety is a cytokine.
  • the cytokine is IL-2, or a variant thereof.
  • the cytokine is IL-2 variant comprising a N88D mutation.
  • the present disclosure provides a polynucleotide molecule encoding an antigen-binding protein described herein or a fusion protein described herein.
  • the present disclosure provides a recombinant vector comprising a polynucleotide molecule described herein.
  • the present disclosure provides a host cel comprising a polynucleotide molecule described herein, or a recombinant vector described herein.
  • the present disclosure provides a kit comprising an antigen-binding protein described herein, a fusion protein described herein, a conjugate described herein, a polynucleotide molecule described herein, or a recombinant vector described herein, and optionaly, instructions and/or packaging for the same.
  • the present disclosure provides a pharmaceutical composition comprising an antigen-binding protein described herein, a fusion protein described herein, a conjugate described herein, a polynucleotide molecule described herein, or a recombinant vector described herein, and a pharmaceuticaly acceptable carrier and/or excipient.
  • the present disclosure provides a method for preparing an antigen-binding protein or a fusion protein that specificaly binds tumor necrosis factor receptor 2 (TNFR2), comprising the steps of: 11 310886415v1 Attorney Docket No: 260525.000071 (a) culturing a host cel described herein in a culture medium under conditions suitable for expression of an antigen-binding protein described herein or a fusion protein described herein; and (b) isolating the antigen-binding protein or the fusion protein from the host cel and/or the culture medium.
  • TNFR2 tumor necrosis factor receptor 2
  • the present disclosure provides a method for promoting proliferation, activating and/or enhancing suppressive function, and/or stabilizing immunosuppressive phenotype of a population of regulatory T cels (Treg) comprising contacting the population of Treg with an antigen- binding protein described herein, a fusion protein described herein, or a conjugate described herein.
  • the contacting occurs in vitro.
  • the contacting occurs in vivo.
  • the method further comprises administering the antigen-binding protein described herein, the fusion protein described herein, or the conjugate described herein into a subject in need thereof.
  • the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject an antigen- binding protein described herein, a fusion protein described herein, or a conjugate described herein.
  • the disease or disorder is an immunological disease, inflammatory disease, cancer, cardiovascular disease, or an infertility and pregnancy-associated disease.
  • the immunological disease is selected from an autoimmune disease, a neurological condition, an alloyy, asthma, macular degeneration, muscular atrophy, a disease related to miscarriage, atherosclerosis, bone loss, a musculoskeletal disease, obesity, a graft-versus-host disease, and an alograft rejection.
  • the autoimmune disease is selected from lupus, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, bulous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Goodpastures disease, Graves' disease, Guilain-Barré, Hashimoto's thyroiditis, hypothyroidism, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), Ig
  • the lupus is systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis, neonatal lupus, or drug-induced lupus.
  • the cutaneous lupus is acute cutaneous lupus, chronic cutaneous lupus erythematosus, discoid lupus erythematosus (DLE), or subacute cutaneous lupus erythematosus.
  • the neurological condition is selected from a brain tumor, a brain metastasis, a spinal cord injury, schizophrenia, epilepsy, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's disease, Parkinson's disease, and stroke.
  • the manganese-containing compound is selected from food mediumy, seasonal manganese, calcium, magnesium, calcium, magnesium, calcium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium, magnesium magnesium, magnesium magnesium magnesium, magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium magnesium
  • the alograft rejection is selected from skin graft rejection, bone graft rejection, vascular tissue graft rejection, ligament graft rejection, and organ graft rejection.
  • the ligament graft rejection is selected from cricothyroid ligament graft rejection, caudal cruciate ligament graft rejection, periodontal ligament graft rejection, suspensory ligament of the lens graft rejection, palmar radiocarpal ligament graft rejection, dorsal radiocarpal ligament graft rejection, ulnar colateral ligament graft rejection, radial colateral ligament graft rejection, suspensory ligament of the breast graft rejection, anterior sacroiliac ligament graft rejection, posterior sacroiliac ligament graft rejection, sacrotuberous ligament graft rejection, sacrospinous ligament graft rejection, inferior pubic ligament graft rejection, superior pubic ligament graft rejection, anterior cruciate ligament graft rejection, lateral colateral ligament
  • the organ graft rejection is selected from heart graft rejection, lung graft rejection, kidney graft rejection, liver graft rejection, pancreas graft rejection, intestine graft rejection, and thymus graft rejection.
  • the graft-versus-host disease arises from a bone marrow transplant or one or more blood cels selected from B-cels, T-cels, basophils, common myeloid progenitor cels, common lymphoid progenitor cels, dendritic cels, eosinophils, hematopoietic stem cels, neutrophils, natural kiler cels, megakaryocytes, monocytes, or macrophages.
  • the inflammatory disease is acute or chronic inflammation.
  • the inflammatory disease is selected from osteoarthritis, atopic dermatitis, endometriosis, polycystic ovarian syndrome, inflammatory bowel disease, fibrotic lung disease, and cardiac inflammation.
  • the cancer is selected from adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith- Wiedemann syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer (sarcoma of bone), brain stem glioma, brain tumor, breast cancer, inflammatory breast cancer, metastatic breast cancer, male breast cancer, Carney complex, central nervous system tumors (brain and spinal cord), cervical cancer, childhood cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, desmoid tumor, desmoplastic infantile gangliogli
  • the cardiovascular disease is selected from atherosclerosis, heart failure, left heart failure with reduced ejection fraction, left heart failure with preserved ejection fraction, right ventricular failure, congestive heart failure, restrictive cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, idiopathic cardiomyopathy, and hypertension.
  • the infertility and pregnancy-associated diseases is selected from recurrent pregnancy loss, pre-eclampsia, preterm labor, fetal growth restriction, and intrauterine growth restriction.
  • the present disclosure provides a method of regenerating a tissue or an organ comprising one or more TNFR2+ cels, the method comprising contacting the tissue or the organ with an effete amount of an antigen-binding protein described herein, a fusion protein described herein, or a conjugate described herein.
  • the tissue or the organ is selected from pancreas, salivary gland, pituitary gland, kidney, heart, lung, hematopoietic system, cranial nerves, heart, aorta, olfactory gland, ear, nerve, eye, thymus, tongue, bone, liver, smal intestine, large intestine, gastrointestinal, lung, brain, skin, peripheral nervous system, central nervous system, spinal cord, breast, embryonic structures, embryo, and testes tissue.
  • the contacting occurs in vitro.
  • the contacting occurs in vivo.
  • the method further comprises administering the antigen-binding protein described herein, the fusion protein described herein, or the conjugate described herein into a subject in need thereof.
  • the present disclosure provides a method for inducing tolerance to a foreign agent and/or preventing or reducing immune response to a foreign agent in a subject in need thereof, the method comprising administering to the subject an antigen-binding protein described herein, a fusion protein described herein, or a conjugate described herein.
  • the foreign agent is a therapeutic protein or peptide, a viral vector, a bacterial vector, a fungal vector, a biochemical vector, a lipid, carbohydrate, a nucleic acid, a sperm, an oocyte, or an embryo.
  • the viral vector is a DNA or RNA vector.
  • the subject is a mammal.
  • the mammal is human.
  • Figure 1 depicts an exemplary general panning strategy for isolation of tumor necrosis factor (TNF) receptor type 2 (TNFR2)-specific variable domain of heavy chain (VHH) antibodies, also referred to herein as V-bodies (Vbs). Binders to human and rodent TNFR2 were enriched from VHH immune libraries by two rounds of phage display. BM, bone marrow.
  • Figure 2 shows VHH immune library selection for next-generation sequencing (NGS) across the phage display process. Three initial libraries, 12 samples of the first panning round, and 36 samples of the second panning round, were sequenced with 20 milion, 2 milion, and 2 milion reads, respectively.
  • NGS next-generation sequencing
  • FIG. 3 shows a schematic diagram of an exemplary NGS workflow. Folowing phage display, the VHH region of the phage eluate was amplified via polymerase chain reaction (PCR). Unique and sample-specific barcodes were then fused, and NGS was subsequently performed using the Ilumina NovaSeq platform (Genewiz). The raw data were de-multiplexed, and then processed by the NGS analysis pipeline. Forward and reverse sequence pairs were merged via overlapping regions and the VHHs, including complementarity determining regions (CDRs) were annotated.
  • PCR polymerase chain reaction
  • CDRs complementarity determining regions
  • FIG. 4A-4B illustrate human TNFR2 (hTNFR2) V-body binding validation at a fixed concentration of 1 ⁇ M V-body.
  • the bar histogram ( Figure 4A) and table ( Figure 4B) show the percentage of Alexa488-positive cels for al VHHs tested.
  • Figures 5A-5B illustrate human TNFR2 (hTNFR2) V-body binding validation at a fixed concentration of 100 nM V-body.
  • the bar histogram ( Figure 5A) and table ( Figure 5B) show the percentage of Alexa488-positive cels for al VHHs tested.
  • the black dotted line indicates background staining ( ⁇ 5%), and the gray doted line indicates two times the background level.
  • FIG. 6A-6C depict cross-specificity of V-body binding to mouse TNFR2 (mTNFR2) ( Figure 6A) and cynomolgus TNFR2 (cTNFR2) ( Figure 6B) at a fixed concentration of 100 nM.
  • the bar histograms ( Figure 6A-6B) and table ( Figure 6C) show the percentage of Alexa488-positive cels for al VHHs tested.
  • the black dotted line indicates background staining
  • the gray dotted line indicates two times the background level.
  • Figure 7 shows testing of human TNFR2 V-body binding across a range of concentrations for V- bodies T-002, T-014, T-001, T-006, T-007, T-003, and V-bodies. V-bodies were tested at molar concentrations of 100 nM, 50 nM, 12.5 nM, 6.25 nM, 3.12 nM, and 1.55 nM.
  • Figure 8 shows a schematic diagram of an exemplary experimental setup for determination of binding Ratities of the V-bodies for their respective target via surface plasmon resonance (SPR) (left panel) and a corresponding table describing the V-body candidates analyzed (right panel).
  • SPR surface plasmon resonance
  • Figures 9A-9F depict surface plasmon resonance (SPR) sensorograms of VHH binding to human, cynomolgus, and mouse TNFR2. Fitted binding curves and calculated dissociation constants (KD) are included.
  • Figure 10 shows a summary of binding Ratio (SPR) sensorograms of VHH binding to human, cynomolgus and mouse TNFR2. Cyno, cynomolgus. 17 310886415v1 Attorney Docket No: 260525.000071
  • Figure 11 demonstrates that some humanized anti-TNFR2 V-bodies targeted the epitope recognized by a MR2-1 bivalent agonist.
  • FIGS. 12A-12E show TNFR2 agonism by multivalent V-body fusion constructs.
  • Agonism of bivalent ( Figure 12A), tetravalent ( Figures 12B-12C), and IL-2 N88D fusion ( Figure 12D) anti-TNFR2 constructs were characterized on NF- ⁇ B reporter HEK293 cels stably expressing TNFR2.
  • Dot plots show a dose-dependent response of anti-TNFR2 VHHs compared to a control VHH (Ctrl).
  • Figure 12E shows that activity of T-007_2xVHH-Fc, and an IL-2 mutein, was demonstrated in reporter cel lines specific for each signaling pathway. RLU, relative luminescence unit.
  • Figure 13 depicts HEK293 TNFR2 NF- ⁇ B (Luc) reporter gene assay controls. Anti-hTNFR2 agonist MR2-1 monoclonal antibodies were tested on NF- ⁇ B reporter (Luc) HEK293 reporter cel-line stably expressing TNFR2 (clone 25) versus parental cel line (PCL). RLU, relative luminescence unit.
  • Figures 14A-14C shows HEK293 TNFR2 NF- ⁇ B (Luc) reporter gene assay samples and assay controls.
  • Figure 14A A description of reporter gene assay samples and assay controls is shown in Figure 14A.
  • a bar graph showing protein concentration (mg/mL) for the V-body constructs and respective controls is depicted in Figure 14B.
  • a bar graph showing RLUs for V-body constructs and respective controls tested on a PCL control is depicted in Figure 14C.
  • Figures 15A-15B depict concentration range curve data generated using MR2-1 ( Figure 15A) and TNF ⁇ ( Figure 15B) controls for four assay plates.
  • Figures 16A-16C show exemplary dot plots of RLUs measured across increasing concentrations (mol/L) of control (control 12) and tetravalent V-body fusion constructs comprising four V-bodies mounted onto the fragment crystalizable (Fc) region of a IgG4 variant comprising S228P, L235E and P329G mutations.
  • Figures 17A-17F show exemplary dot plots of RLUs measured across increasing concentrations (mol/L) of control (control 10) and an alternative design of tetravalent V-body fusion constructs comprising four V-bodies mounted onto the Fc region of a IgG4 variant comprising S228P, L235E and P329G mutations.
  • Figures 18A-18C show exemplary dot plots of RLUs measured across increasing concentrations (mol/L) of control (control 2) and bivalent V-body fusion constructs. Limit of detection, LOD.
  • Figures 19A-19C show exemplary dot plots of RLUs measured across increasing concentrations (mol/L) of control (control 13) and IL-2 N88D V-body fusion constructs. Limit of detection, LOD.
  • Figure 20 depicts a comparison of RLUs measured across increasing concentrations (mol/L) of monospecific construct 10 (tetravalent Fc) and construct 12 (Vb-Fc-Vb) tested on NF- ⁇ B reporter (Luc) HEK293 reporter cel-line stably expressing TNFR2 (clone 8).
  • Figure 21 depicts an exemplary experimental timeline of TNFR2 stimulation by multivalent V- body fusion constructs (e.g., tetravalent Fc, Vb-Fc-Vb, rigid bivalent no Fc) on primary human peripheral blood mononuclear cels (PBMCs) and cluster of diferentiation 4 positive (CD4+) CD25+ CD127dim regulatory T cels (Tregs).
  • PBMCs peripheral blood mononuclear cels
  • Regs CD127dim regulatory T cels
  • Figure 22 shows a bar graph of an overview of in-assay concentrations (nM) of multivalent V- body fusion constructs first wave binders. Concentrations (nM) of the VHH constructs is also shown.
  • Figure 23 illustrateates an exemplary gating strategy applied for Treg markers.
  • Treg Donor 1 is shown as an example and an identical strategy was used for Treg Donor 1 and Donor 3.
  • Live cel and CD4 gating were based on Fluorescence Minus One (FMO) FMO control determination of the cut-of point between background fluorescence and positive cel populations.
  • FMO Fluorescence Minus One
  • Forkhead box P3 FoxP3
  • HLA-DR Human Leukocyte Antigen
  • DR isotype HLA-DR
  • C-C motif chemokine motif receptor 8
  • OX-40 gating was based on the CD4 subset of IgG control-stained sample from the same donor.
  • FoxP3 the gate was set at approximately 0.2%.
  • OX-40, HLA-DR and CCR8 the gate was set at approximately 2%.
  • Figures 24A-24B demonstrate multivalent anti-TNFR2 V-body fusion constructs increased expression of the Treg suppression marker HLA-DR and CCR8. Histograms displaying expression of Treg suppression marker HLA-DR for specific T-003 binders compared to control formats ( Figure 24A). Density plots displaying expression of Treg suppression marker HLA-DR and CCR8 for specific T-003 binders compared to control formats ( Figure 24B). Fluorescein isothiocyanate, FITC; Phycoerythrin, PE. [0128] Figures 25A-25B demonstrates tetravalent anti-TNFR2 V-body fusion constructs strongly increased expression of Treg suppression marker HLA-DR on FoxP3+ Tregs.
  • the bar graphs show HLA-DR mean fluorescent intensity (MFI) measured for each of the tetravalent Fc, Vb-Fc-Vb, and rigid bivalent no Fc V-body fusion formats relative to control formats.
  • Figure 26 shows dose-response curves based on HLA-DR MFI values of CD4+ FoxP3+ Tregs for construct T-003 and control 10 for Donor 2.
  • Figure 27 shows dose-dependent induction of Treg suppression marker HLA-DR expression across various concentrations of tetravalent anti-TNFR2 V-body Fc fusion construct 10 for Donor 1 (top panel) and Donor 2 (botom panel).
  • Figure 28 shows dose-dependent induction of Treg suppression marker HLA-DR expression across various concentrations of rigid bivalent anti-TNFR2 V-body fusion construct 2 for Donor 1 (top panel) and Donor 2 (botom panel).
  • Figure 29 shows dose-dependent induction of Treg suppression marker HLA-DR expression across various concentrations of tetravalent anti-TNFR2 V-body Vb-Fc-Vb fusion construct 12 for Donor 1 (top panel) and Donor 2 (bottom panel).
  • Figure 30 shows exemplary design of multivalent anti-TNFR2 V-body fusion constructs.
  • Anti- TNFR2 V-bodies are shown as ovals, linkers are shown with flexible (e.g., GS linkers) as curved lines, rigid linkers (e.g., proline linker) as straight lines, and Fc domains as dimeric bars.
  • Figure 31 shows assessment of tetravalent-Fc VHH activity on na ⁇ ve CD4+CD25+CD45RA+ human Treg. HLA-DR and CCR8 expression on CD4+FOXP3+ and expansion after 5 day stimulation with anti-CD3/IL-2 plus VHH or MR2-1 are shown.
  • Figure 32A shows the ability of TNFR2 VHH to stabilize Treg.
  • Naive CD4+CD25+CD45RA+ human Treg from healthy donors were stimulated with IL-2 and anti-CD3 in the presence of TNFR2 agonist VHH or TNFR2 monoclonal agonist MR2-1 for 5 days.
  • Figure 32B shows the effect of TNFR2 VHH on early markers of Treg stability.
  • Naive CD4+CD25+CD45RA+ human Treg from healthy donors were stimulated with IL-2 and anti-CD3 in the presence of TNFR2 agonist VHH or IL-2 mutein for 5 days.
  • FIGS 33A-33B show additional results of in vitro treatment of human Treg (CD4+ FOXP3+) with VHH T-007_2xVHH-Fc or IL-2 mutein in the presence of anti-CD3 and IL-2.
  • T-007_2xVHH-Fc induced and expanded a Treg population with high levels of FOXP3, EZH2 (a marker of stability), CCR8, and HLA- DR (biomarkers of tissue homing and Treg immunosuppressive functionality).
  • Figures 34A-34C show the effect of TNFR2 VHH on Treg stability under inflammatory conditions.
  • Human Treg were expanded with IL-2 mutein or TNFR2 VHH in the presence of anti-CD3 and IL-2 for 5 days and then cultured with proinflammatory cytokines (IL-1b, IL-21, and IL-23 +/- TGFb) for 11 to 12 days; IL-17A or IFN ⁇ production after PMA/ionomycin stimulation was assessed together with FOXP3 by flow cytometry.
  • proinflammatory cytokines IL-1b, IL-21, and IL-23 +/- TGFb
  • IL-17A or IFN ⁇ production after PMA/ionomycin stimulation was assessed together with FOXP3 by flow cytometry.
  • the conversion of human Treg in vitro to cels that produce Th1/17 cytokines (IFN ⁇ /IL- 17A) triggered by the inflammatory cytokines shown was prevented by co-stimulation with TNFR2 VHH 20 310886415v1 Attorney Docket No: 260525.000071 but not with IL-2 mutein
  • Naive Treg were stimulated for 7 days with anti-CD3/IL-2 plus TNFR2 VHH (T-007_2xVHH-Fc), control VHH, MR2-1, control IgG, or IL- 2 mutein; after 7 days, stimuli were removed and cels were incubated with cel tracer-labeled autologous responder cels (na ⁇ ve CD4+ T cels); bar graph shows effector CD4 cel proliferation measured as % dividing CD4+FOXP3- cels; FACS histograms show dilution of the cel tracer at diferent Treg:CD4 (responder) ratios of one of four donors.
  • FIG. 36 shows the effect of TNFR2 agonist VHH on Treg population size in mice. An exemplary design of the experimental procedure is shown. CD4+FOXP3+ Treg expansion in the spleen of mice 5 days after a single injection of 2.5 mg/kg control VHH or TNFR2-specific VHH T-007_2xVHH-Fc is shown.
  • Figure 37 shows that TNFR2 agonist VHH activates Treg in vivo.
  • CCR8 is a chemokine receptor expressed on highly suppressive Treg and involved in cel migration (Whiteside et al., Immunol 2021;163:512). ICAM-1 surface adhesion molecule is required for Treg function (Gottrand et al., Immunol 2015;146(4): 657). ICOS costimulatory molecule is upregulated upon Treg activation and maintains FOXP3 expression (Landuyt et al., J Immunol 2019;202(4):1039).
  • FIG. 39 shows that TNFR2 agonist VHH increases serum level of IL-10.
  • IL-10 is a key anti- inflammatory cytokine (Saraiva et al., J Exp Med 2020;217(1):e20190418). Serum cytokine concentration 5 days after single injection of TNFR2-specific VHH T-007_2xVHH-Fc or control VHH is shown.1-way ANOVA performed for control VHH vs.
  • FIG. 40A-40B show frequency of Treg (CD4+ FOXP3+) among total immune cels (CD45+) in the spleen, blood, colon, and lung in human TNFR2 knock-in mice 5 days after single injection of T-037.
  • T-test: *** p ⁇ 0.001; **** p ⁇ 0.0001; n 4.
  • FIG. 41A-41E show T-037 selectively increases the Treg population in the spleen 5 days after a single administration compared to IL-2 N88D, a mutein that is active in mice.
  • T-007_2xVHH-Fc is more selective for Treg and induces a higher level of FOXP3 and surface markers (FOXP3, ICAM-1, OX-40, ICOS, and CCR8), consistent with superior function and stability.
  • One-way ANOVA test: **** p ⁇ 0.0001; n 4.
  • Figures 42A-42B show that Treg expansion in the spleen as wel as increased expression of FOXP3, linked to Treg stability and function, and Treg activation shown by up-regulation of ICAM-1 and ICOS.
  • Figures 43A-43C show that reduction of arthritis, measured by paw volume and arthritis score, in a model of colagen-antibody induced arthritis upon treatment with TNFR2 agonists T-037 and T-043.
  • Figures 44A-44B show Treg expansion by TNFR2 agonist without inducing proinflammatory cytokines when compared to CD28 agonist.
  • Figures 45A-45F depict surface plasmon resonance (SPR) sensorograms of VHH binding to human and cynomolgus TNFR2. Fitted binding curves and calculated dissociation constants (KD) are included.
  • Figures 46A-46J depict surface plasmon resonance (SPR) sensorograms of VHH (obtained by alanine scanning mutagenesis) binding to human and cynomolgus TNFR2. Fitted binding curves and calculated dissociation constants (KD) are included.
  • Figures 47A-47B depict surface plasmon resonance (SPR) sensorgrams of Fc-tagged bivalent V- bodies binding to human or cynomolgus TNFR2.
  • FIG. 48A-48B depict flow cytometry plots (Figure 48A) and luminescence plots (Figure 48B) upon incubation of TNFR2 HEK reporter cels with the Fc-tagged bivalent V-bodies. DETAILED DESCRIPTION OF THE INVENTION
  • Treg Regulatory T cels
  • Activation and expansion of Treg is an attractive therapeutic approach for autoimmune diseases currently being evaluated clinicaly.
  • Treg-directed therapy needs to generate cels with a stable immunosuppressive phenotype that is resistant to conversion to T effector function under inflammatory conditions.
  • Treg specificity, Treg stability, and therapeutic efficacy are not optimal (PNAS 2010;107(45):19402; clinicaltrials.gov/study/NCT03943550; clinicaltrials.gov/study/NCT04433585).
  • Optimal Treg therapy needs to (1) expand Treg population size with cels that (2) migrate to tissues where disease occurs and (3) exert immunosuppressive effects, while (4) resisting conversion to inflammatory Th1/17 cels. Therefore, improved therapeutic approaches to promote and stabilize Treg immunosuppressive activity are needed.
  • TNFR2 agonism is an alternative approach to enhance Treg function that is projected to address al objectives required for an optimal therapy, including the generation of stable Treg cels that resist conversion to Th1/17 (Front Immunol 2022;13:888274; Sci Rep 2023;13(1):13762; PNAS 2019;116(43):21666; J Immunol 2013;190:1076; Arthritis Rheumatol 2020;72(4):576).
  • the present invention provides as described herein, TNFR2 agonists to enhance Treg immunosuppressive activity using a single-domain antibody (e.g., VHH) platform.
  • the expression “about 100” includes 95 and 105 and al values in between (e.g., 96, 97, 98, 99, etc.).
  • the term “antigen” encompasses any agent (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleotide, portions thereof, or combinations thereof) that may be specificaly bound by the products of specific humoral or celular immunity, such as an antibody molecule or T-cel receptor.
  • the antigen described herein is TNFR2, including human, cynomolgus, and/or mouse TNFR2.
  • epitope can refer to an antigenic determinant on the surface of an antigen to which an antibody molecule binds.
  • a single antigen may have more than one epitope.
  • diferent antibodies may bind to diferent areas on an antigen and may have diferent biological effects (e.g., agnostic, or antagonistic effectss).
  • Epitopes may be either conformational or linear.
  • a conformational epitope is formed by spatialy juxtaposed amino acids from diferent segments of the linear polypeptide chain.
  • a linear epitope is formed by adjacent amino acid residues in a polypeptide chain.
  • an epitope may include non-peptidic moieties on the antigen, such as saccharides, phosphoryl groups, or sulfonyl groups.
  • antigen-binding protein refers in its broadest sense to a protein that specificaly binds an antigen (e.g., TNFR2).
  • an antigen-binding protein is an antibody or an antigen-binding fragment of an antibody, such as a human antibody, a humanized antibody; a camelid antibody; a chimeric antibody; a recombinant antibody; a heavy chain antibody; a single-domain antibody (e.g., VHH); a single chain antibody (e.g., single chain fragment variable (scFv); a diabody; a triabody; a tetrabody; a Fab fragment; a F(ab′) 2 fragment; an IgD antibody; an IgE antibody; an IgM antibody; an IgG1 antibody; an IgG2 antibody; an IgG3 antibody; or an IgG4 antibody, and fragments thereof.
  • an antibody such as a human antibody, a humanized antibody; a camelid antibody; a chimeric antibody; a recombinant antibody; a heavy chain antibody; a single-domain antibody (e.g., VHH); a single chain antibody (
  • antigen-binding protein also encompasses, for example, an alternative protein scafold or artificial scafold with grafted CDRs or CDR derivatives.
  • scafolds include, but are not limited to, antibody-derived scafolds comprising mutations introduced to, for example, stabilize the three-dimensional structure of the antigen-binding protein as wel as wholy synthetic scafolds comprising, for example, a biocompatible polymer.
  • peptide antibody mimetics can be used, as wel as scafolds based on antibody mimetics utilizing fibronectin components (e.g., fibronectin type II domain (FN3) as a scafold.
  • fibronectin components e.g., fibronectin type II domain (FN3)
  • antibody and “immunoglobulin” or “Ig” are used interchangeably herein, and is used in the broadest sense and encompasses, for example, individual monoclonal antibodies (including agonist, antagonist, neutralizing antibodies, ful length or intact monoclonal antibodies), antibody compositions with polyepitopic or monoepitopic specificity, polyclonal antibodies, monovalent antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific antibodies), single-domain antibodies (e.g., VHH), single chain antibodies, intrabodies, anti-idiotypic (anti-Id) antibodies, and antigen-binding fragments of antibodies, as described below.
  • an antibody can be human, humanized, camelized, recombinantly produced, chimeric, synthetic, afinity de-matured and/or afinity matured as wel as an antibody from other species, for example mouse, camel, lama, rabbit, etc.
  • the specific target antigen that can be bound by an antibody provided herein includes a TNFR2 polypeptide, TNFR2 fragment or TNFR2 epitope.
  • An “antigen-binding fragment” generaly refers a portion of an antibody heavy and/or light chain polypeptide that retains some or al of the binding activity of the antibody from which the fragment was derived.
  • Non-limiting examples of antigen-binding fragments include single-domain antibody (e.g., VHH), single-chain Fvs (scFv), Fab fragments, F(ab′) fragments, F(ab)2 fragments, F(ab′)2 fragments, disulfide-linked Fvs (sdFv), Fd fragments, Fv fragments, diabody, triabody, tetrabody and minibody, or a chemicaly modified derivative thereof.
  • antibodies provided herein include immunoglobulin molecules and molecules that contain immunologicaly active portion(s) of an immunoglobulin molecule, for example, one or more complementarity determining regions (CDRs) of an antibody that binds to TNFR2.
  • CDRs complementarity determining regions
  • Such antibody fragments can be found described in, for example, Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York (1989); Myers (ed.), Molec. Biology and Biotechnology: A Comprehensive Desk Reference, New York: VCH Publisher, Inc.; Huston et al., Cel Biophysics, 22:189- 224 (1993); Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989) and in Day, E.D., Advanced Immunochemistry, Second Ed., Wiley-Liss, Inc., New York, N.Y. (1990).
  • the antibodies provided herein can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or any subclass (e.g., IgG2a and IgG2b) of immunoglobulin molecule.
  • any class e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2
  • subclass e.g., IgG2a and IgG2b
  • the complementarity determining regions (CDRs) of a single-domain antibody are part of a single antibody variable domain.
  • single-domain antibodies include, but are not limited to, heavy chain antibodies, antibodies naturaly devoid of light chains, single domain antibodies derived from conventional four-chain antibodies, engineered antibodies, variable domains derived from the aforementioned antibodies, and single domain scafolds other than those derived from antibodies.
  • Single domain antibodies may be derived from any species including, but not limited to mouse, human, camel, lama, shark, goat, rabbit, and/or bovine.
  • a single domain antibody as used herein is a naturaly occurring single domain antibody known as heavy chain antibody devoid of light chains.
  • variable domain derived from a heavy chain antibody naturaly devoid of light chain is known herein as a VHH to distinguish it from the conventional VH of four-chain immunoglobulins.
  • VHH variable domain derived from a heavy chain antibody naturaly devoid of light chain
  • Such a VHH molecule can be derived from antibodies raised in Camelidae species, e.g., camel, lama, dromedary, alpaca, and 25 310886415v1 Attorney Docket No: 260525.000071 guanaco.
  • Other species besides Camelidae may produce heavy chain antibodies naturaly devoid of light chain, which are also within the scope of the invention.
  • cartilaginous fishes such as sharks can produce immunoglobulin-like structures known as VNAR.
  • a single-domain antibody may be obtained from a Camelidae VH domain.
  • a single-domain antibody may be obtained from human VH by camelization. See Saerens et al., Current Opinion in Pharmacology, 2008, 8:600-608, the disclosure of which being incorporated by reference, for review of single-domain antibodies.
  • the term “specificaly binds” as used herein means that an antigen-binding protein forms a complex with a target antigen that is relatively stable under physiologic conditions.
  • Specific binding can be characterized by a dissociation constant (K) of about -6 -6 D 1x10 M or less (e.g., less than 10 M, less than 5x10-7 M, less than 10-7 M, less than 5x10-8 M, less than 10-8 M, less than 5x10-9 M, less than 10-9 M, or less than 10-10 M).
  • K dissociation constant
  • an antigen-binding protein e.g., an antibody or an antibody fragment
  • a target antigen e.g., an antibody or an antibody fragment
  • surface plasmon resonance e.g., BIACORE® assays
  • bio-layer interferometry e.g., bio-layer interferometry
  • ligand binding assays e.g., enzyme-linked immunosorbent assay (ELISA)
  • ELISA enzyme-linked immunosorbent assay
  • FACS fluorescent-activated cel sorting
  • flow cytometry-based binding assays e.g., enzyme-linked immunosorbent assay (ELISA), equilibrium dialysis, fluorescent-activated cel sorting (FACS), or flow cytometry-based binding assays and the like.
  • Specific binding to a particular target antigen from a certain species does not exclude that the antigen-binding protein can also specificaly bind to the analogous target from a diferent species.
  • antigen-binding protein can also specificaly bind to TNFR2 from cynomolgus monkeys (“cyno”) or mice.
  • isolated when used in the context of antigen-binding proteins (e.g., antibodies, such as single-domain antibodies), polypeptides, polynucleotides, and vectors, means the antigen-binding proteins (e.g., antibodies, such as single-domain antibodies), polypeptides, polynucleotides and vectors are at least partialy free of other biological molecules from the cels or cel culture from which they are produced.
  • Such biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other material such as celular debris and growth medium.
  • An isolated antigen-binding protein may further be at least partialy free of expression system components such as biological molecules from a host cel or of the growth medium thereof.
  • the term "isolated” is not intended to refer to a complete absence of such biological molecules (e.g., minor, or insignificant amounts of impurity may remain) or to an absence of water, bufers, or salts or to 26 310886415v1 Attorney Docket No: 260525.000071 components of a pharmaceutical formulation that includes the antigen-binding proteins (e.g., antibodies, such as single-domain antibodies).
  • operably linked can refer to a functional relationship between two or more regions of a polypeptide chain in which the two or more regions are linked so as to produce a functional polypeptide.
  • variant e.g., antigen-binding proteins or domains thereof
  • nucleic acid or fragment thereof indicates that, when optimaly aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 95%, and more preferably at least about 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any wel-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 substantialy similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.
  • 27 310886415v1 Attorney Docket No: 260525.000071 [0167]
  • the term "substantial similarity" or “substantialy similar” means that two peptide sequences, when optimaly aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 95% sequence identity, even more preferably at least 98% or 99% sequence identity.
  • residue positions which are not identical difer by conservative amino acid substitutions are not identical difer 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).
  • R group side chain
  • a conservative amino acid substitution wil not substantialy change the functional properties of a protein.
  • the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are wel-known to those of skil 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.
  • 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.
  • Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions, and other modifications, including conservative amino acid substitutions.
  • GCG software contains programs such as Gap and Bestfit which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from diferent 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 28 310886415v1 Attorney Docket No: 260525.000071 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 diferent organisms is the computer program BLAST, especialy BLASTP or TBLASTN, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res.25:3389-402, each herein incorporated by reference.
  • the terms “enhance” or “promote,” or “increase,” or “expand,” or “improve” refer generaly to the ability of a composition contemplated herein to produce, elicit, or cause a greater physiological response (i.e., downstream effectss) compared to the response caused by either vehicle or a control molecule/composition.
  • a measurable physiological response may include an increase in immune cel expansion, activation, effector function, persistence, and/or an increase in tumor cel death kiling ability, among others apparent from the understanding in the art and the description herein.
  • an “increased” or “enhanced” amount can be a “statisticaly significant” amount, and may include an increase that is 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 or more times (e.g., 500, 1000 times) (including al integers and decimal points in between and above 1, e.g., 1.5, 1.6, 1.7.1.8, etc.) the response produced by vehicle or a control composition.
  • compositions contemplated herein to produce, elicit, or cause a lesser physiological response (i.e., downstream effects) compared to the response caused by either vehicle or a control molecule/composition.
  • a “decrease” or “reduced” amount can be a “statisticaly significant” amount, and may include a decrease that is 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 or more times (e.g., 500, 1000 times) (including al integers and decimal points in between and above 1, e.g., 1.5, 1.6, 1.7.1.8, etc.) the response (reference response) produced by vehicle or a control composition.
  • the terms “treat” or “treatment” of a state, disorder or condition include: (1) preventing, delaying, or reducing the incidence and/or likelihood of the appearance of at least one clinical or sub- clinical symptom of the state, disorder or condition developing in a subject that may be aflicted with or predisposed to the state, disorder or condition, but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, 29 310886415v1 Attorney Docket No: 260525.000071 disorder or condition or at least one of its clinical or sub-clinical symptoms.
  • the benefit to a subject to be treated is either statisticaly significant or at least perceptible to the patient or to the physician.
  • the terms “efective amount” or “therapeuticaly effete amount” refer to a quantity and/or concentration of a composition containing an active ingredient (e.g., anti-TNFR2 antigen-binding protein) that when administered into a patient either alone (i.e., as a monotherapy) or in combination with additional therapeutic agents, yields a significant decrease in disease progression as, for example, by ameliorating or eliminating symptoms and/or the cause of the disease.
  • an active ingredient e.g., anti-TNFR2 antigen-binding protein
  • An effete amount may be an amount that relieves, lessens, or aleviates at least one symptom or biological response or effect associated with a disease or disorder, prevents progression of the disease or disorder, or improves physical functioning of the patient.
  • a therapeuticaly effete amount of a composition containing an active agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the active agent to elicit a desired response in the individual.
  • a therapeuticaly effete amount is also one in which any toxic or detrimental effectss of the active agent are outweighed by the therapeuticaly beneficial effectss.
  • a therapeuticaly effete amount may be delivered in one or more administrations.
  • a therapeuticaly effete amount refers to an amount efective, at dosages and for periods of time necessary, to achieve the desired therapeutic and/or prophylactic result.
  • the terms “individual”, “subject” and “patient” are used interchangeably herein to refer to an animal, for example a mammal. The terms include human and veterinary subjects. In some embodiments, methods of treating mammals, including, but not limited to, humans, rodents, simians, felines, canines, equines, bovines, porcines, ovines, caprines, mammalian laboratory animals, mammalian farm animals, mammalian sport animals, and mammalian pets, are provided.
  • the subject can be male or female and can be any suitable age, including infant, juvenile, adolescent, adult, and geriatric subjects.
  • a subject can be a subject in need of treatment for a disease or disorder.
  • the subject is a human.
  • Anti-TNFR2 Antigen-binding Proteins e.g., antibodies, such as single-domain antibodies
  • TNFR2 is a single pass type-1 membrane protein belonging to the TNFR superfamily. It consists of an extracellular domain with four cysteine rich domains (CRD) and an intracellular domain that is involved in signaling.
  • the cysteine rich domains contain a total of 10 disulfide bonds stabilizing the 30 310886415v1 Attorney Docket No: 260525.000071 elongated structure of the protein.
  • TNFR2 is restricted on immune cels including Tregs, myeloid cels, CD8 and NK cels but also glial cels, endothelial cels, and fibroblasts (Medler and Wajant, 2019).
  • the human TNFR2 protein is encoded by the human TNF receptor superfamily member 1B (TNFRSF1B) gene (NCBI Gene ID: 7133) and has the amino acid sequence of MAPVAVWAALAVGLELWAAAHALPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCD SCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRKCRPGFGVARPG TETSDVVCKPCAPGTFSNTTSSTDICRPHQICNVVAIPGNASMDAVCTSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPE PSTAPSTSFLLPMGPSPPAEGSTGDFALPVGLIVGVTALGLLIGVVNCVIMTQVKKKPLCLQREAKVPHLPADKARGTQ GPEQQHLLITAPSSSSSSLESSASALDRRAPTRNQPQAPGVEASGAGE
  • the cyno TNFR2 protein is encoded by the Cyno TNF receptor superfamily member 1B (TNFRSF1B) gene (Gene ID: 102144224) and has the amino acid sequence of MVTRRGGDDRRRLKGHRVLGVTLEVLARRCWGGRVGGPAEAGEGRGGGVSKAGWPRPAPPRCLASGPLQRGLSLS VAAGWRAQRSLGRRRCAARARGREGRGNRIPPAPMAPAAVWAALAVGLELWAAGHALPAQVAFTPYAPEPGGTCR LREYYDQTAQMCCSKCPPGQHAKVFCTKTSDTVCDSCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRIC TCRPGWYCALSKQEGCRLCAQLRKCRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDICRPHQICHVVAIPGNASM DAVCTSTSPTRSMAPGAVHLPQPVSTRSQ
  • the mouse TNFR2 protein is encoded by the mouse TNF receptor superfamily member 1B (Tnfrsf1b) gene (Gene ID: 21938) and has the amino acid sequence of MAPAALWVALVFELQLWATGHTVPAQVVLTPYKPEPGYECQISQEYYDRKAQMCCAKCPPGQYVKHFCNKTSDTVC ADCEASMYTQVWNQFRTCLSCSSSCTTDQVEIRACTKQQNRVCACEAGRYCALKTHSGSCRQCMRLSKCGPGFGVAS SRAPNGNVLCKACAPGTFSDTTSSTDVCRPHRICSILAIPGNASTDAVCAPESPTLSAIPRTLYVSQPEPTRSQPLDQEPG PSQTPSILTSLGSTPIEQSTKGGISLPIGLIVGVTSLGLLMLGLVNCILVQRKKKPSCLQRDAKVPHVPDEKSQDAVGLEQ QHLLTTAPS
  • antigen-binding proteins of the present disclosure have an agonist effect upon binding to TNFR2.
  • an agonistic TNFR2 binder can promote or increase activation of TNFR2 and/or potentiate one or more signal transduction pathways mediated by TNFR2.
  • agonistic TNFR2 binders may promote or increase the proliferation of a population of Treg cels.
  • Agonistic TNFR2 binders may promote or increase TNFR2 activation by 31 310886415v1 Attorney Docket No: 260525.000071 binding TNFR2, e.g., to induce a conformational change that renders the receptor biologicaly active.
  • agonistic TNFR2 binders may nucleate the trimerization of TNFR2 in a manner similar to the interaction between TNFR2 and its cognate ligand, tumor necrosis factor (TNF), thus inducing TNFR2- mediated signaling.
  • TNF tumor necrosis factor
  • agonistic TNFR2 binding proteins of the present disclosure may be capable of inducing the proliferation of Treg cels (e.g., CD4+, CD25+, FOXP3+ Treg cels).
  • Agonistic TNFR2 binding proteins of the present disclosure may also be capable of suppressing the proliferation of cytotoxic T lymphocytes (e.g., CD8+ T-cels), e.g., through activation of immunomodulatory Treg cels or by directly binding TNFR2 on the surface of an autoreactive cytotoxic T- cel and inducing apoptosis.
  • antigen-binding proteins of the present disclosure upon binding to TNFR2 do not impair the binding of its cognate ligand, tumor necrosis factor (TNF), to TNFR2.
  • antigen-binding proteins of the present disclosure do not have overlapping epitopes with TNF.
  • antigen-binding proteins of the present disclosure have overlapping epitopes with TNF.
  • antigen-binding proteins of the present disclosure upon binding to TNFR2 promote or facilitate TNFR2 oligomerization (in the presence or absence of TNF, respectively).
  • antigen-binding proteins of the present disclosure upon binding to TNFR2 multimerize (e.g., dimerize) the TNFR2 trimers to induce intracellular signaling. [0181] In some embodiments, antigen-binding proteins of the present disclosure bind to human TNFR2.
  • antigen-binding proteins e.g., antibodies such as single-domain antibodies
  • a K ⁇ 6 D of less than about 1 ⁇ 10 M, for example, less than about 5 ⁇ 10 ⁇ 7 M, less than about 3 ⁇ 10 ⁇ 7 M, less than about 1 ⁇ 10 ⁇ 7 M, less than about 8 ⁇ 10 ⁇ 8 M, less than about 5 ⁇ 10 ⁇ 8 M, less than about 3 ⁇ 10 ⁇ 8 M, less than about 1 ⁇ 10 ⁇ 8 M, less than about 8 ⁇ 10 ⁇ 9 M, less than about 5 ⁇ 10 ⁇ 9 M, less than about 3 ⁇ 10 ⁇ 9 M, or less than about 1 ⁇ 10 ⁇ 9 M, or about 1 ⁇ 10 ⁇ 10 to 1 ⁇ 10 ⁇ 9 M, 1 ⁇ 10 ⁇ 10 to 5 ⁇ 10 ⁇ 9 M, about 1 ⁇ 10 ⁇ 10 to 1 ⁇ 10 ⁇ 8 M, about 1 ⁇ 10 ⁇ 10 to 5 ⁇ 10 ⁇ 8 M, about 1 ⁇ 10 ⁇ 9 to 1 ⁇ 10 ⁇ 8 M, about 1 ⁇ 10 ⁇ 9 to 5 ⁇ 10 ⁇ 8 M, about 1 ⁇ 10 ⁇ 9 to 5 ⁇ 10 ⁇ 8 M, about 1 ⁇ 10 ⁇
  • antigen-binding proteins e.g., antibodies such as single-domain antibodies
  • antigen-binding proteins (e.g., antibodies such as single-domain antibodies) of the present disclosure may bind to human TNFR2 with a K ⁇ 8 ⁇ 6 D of about 1 ⁇ 10 M to about 2.7 ⁇ 10 M.
  • antigen-binding proteins of the present disclosure bind to cynomolgus monkey (“cyno”) TNFR2.
  • antigen-binding proteins e.g., antibodies such as 32 310886415v1 Attorney Docket No: 260525.000071 single-domain antibodies
  • a KD of less than about 1 ⁇ 10 ⁇ 6 M for example, less than about 5 ⁇ 10 ⁇ 7 M, less than about 3 ⁇ 10 ⁇ 7 M, less than about 1 ⁇ 10 ⁇ 7 M, less than about 8 ⁇ 10 ⁇ 8 M, less than about 5 ⁇ 10 ⁇ 8 M, less than about 3 ⁇ 10 ⁇ 8 M, less than about 1 ⁇ 10 ⁇ 8 M, less than about 8 ⁇ 10 ⁇ 9 M, less than about 5 ⁇ 10 ⁇ 9 M, less than about 3 ⁇ 10 ⁇ 9 M, or less than about 1 ⁇ 10 ⁇ 9 M, or about 1 ⁇ 10 ⁇ 10 to 1 ⁇ 10 ⁇ 9 M, 1 ⁇ 10 ⁇ 10 to 5 ⁇ 10 ⁇ 9 M, about 1 ⁇ 10 ⁇ 10 to 1 ⁇ 10 ⁇ 8 M, about 1 ⁇ 10 ⁇ 10 to 5 ⁇ 10 ⁇ 8 M, about 1 ⁇ 10 ⁇ 9 to
  • antigen-binding proteins e.g., antibodies such as single-domain antibodies
  • antigen-binding proteins of the present disclosure may bind to cyno TNFR2 with a K of -12 ⁇ 6 D about 1x10 M to about 1 ⁇ 10 M.
  • antigen-binding proteins e.g., antibodies such as single-domain antibodies
  • antigen-binding proteins of the present disclosure bind to mouse TNFR2.
  • antigen-binding proteins of the present disclosure may bind to mouse TNFR2 with a K of less than about 1 ⁇ 10 ⁇ 6 M, fo ⁇ 7 ⁇ 7 D r example, less than about 5 ⁇ 10 M, less than about 3 ⁇ 10 M, less than about 1 ⁇ 10 ⁇ 7 M, less than about 8 ⁇ 10 ⁇ 8 M, less than about 5 ⁇ 10 ⁇ 8 M, less than about 3 ⁇ 10 ⁇ 8 M, less than about 1 ⁇ 10 ⁇ 8 M, less than about 8 ⁇ 10 ⁇ 9 M, less than about 5 ⁇ 10 ⁇ 9 M, less than about 3 ⁇ 10 ⁇ 9 M, or less than about 1 ⁇ 10 ⁇ 9 M, or about 1 ⁇ 10 ⁇ 10 to 1 ⁇ 10 ⁇ 9 M, 1 ⁇ 10 ⁇ 10 to 5 ⁇ 10 ⁇ 9 M, about 1 ⁇ 10 ⁇ 10 to 1 ⁇ 10 ⁇ 8 M, about 1 ⁇ 10 ⁇ 10 to 5 ⁇ 10 ⁇ 8 M, about 1 ⁇ 10 ⁇ 9 to 1 ⁇ 10 ⁇ 8 M, about 1 ⁇ 10 ⁇ 9 to 5 ⁇ 10 ⁇ 8 M, about 1 ⁇ 10 ⁇ 9 to 1 ⁇ 10 ⁇ 7 M
  • antigen- binding proteins of the present disclosure do not bind to mouse TNFR2.
  • anti-TNFR2 antigen-binding proteins of the present disclosure may specificaly bind TNFR2 without exhibiting specific binding for another receptor of the tumor necrosis factor receptor (TNFR) superfamily.
  • Binding afinity of a molecular interaction between two molecules can be measured via various techniques, such as surface plasmon resonance (SPR), bio-layer interferometry (BLI), enzyme-linked immunosorbent assay (ELISA), equilibrium dialysis, fluorescent-activated cel sorting (FACS), or flow cytometry binding assays and the like.
  • Surface plasmon resonance is a biosensor technique that alows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, where one molecule is immobilized on the biosensor chip and the other 33 310886415v1 Attorney Docket No: 260525.000071 molecule is passed over the immobilized molecule under flow conditions (see e.g., Ober et al.2001, Intern. Immunology 13: 1551-1559).
  • SPR can for example be performed using the BIACORE® system or Carterra LSA system.
  • Bio-layer Interferometry is a label-free optical technique that analyzes the interference pattern of light reflected from two surfaces: an internal reference layer (reference beam) and a layer of immobilized protein on the biosensor tip (signal beam).
  • reference beam an internal reference layer
  • signal beam a layer of immobilized protein on the biosensor tip
  • a change in the number of molecules bound to the tip of the biosensor causes a shift in the interference pattern, reported as a wavelength shift (nm), the magnitude of which is a direct measure of the number of molecules bound to the biosensor tip surface.
  • Antigen-binding proteins of the present disclosure can include an antibody or an antigen-binding fragment of an antibody, such as a human antibody, a humanized antibody; a camelid antibody; a chimeric antibody; a recombinant antibody; a heavy chain antibody; a single-domain antibody (e.g., VHH); a single chain antibody (e.g., single chain fragment variable (scFv); a diabody; a triabody; a tetrabody; a Fab fragment; a F(ab′) 2 fragment; an IgD antibody; an IgE antibody; an IgM antibody; an IgG1 antibody; an IgG2 antibody; an IgG3 antibody; or an IgG4 antibody, and fragments thereof.
  • an antibody or an antigen-binding fragment of an antibody such as a human antibody, a humanized antibody; a camelid antibody; a chimeric antibody; a recombinant antibody; a heavy chain antibody; a single-domain antibody
  • an antigen-binding protein that binds to TNFR2 is a single-domain antibody (also termed as “sdAb”).
  • the single-domain antibodies of the present disclosure can be derived from numerous sources, including but not limited to VHHs, VNARs, or VH domains (naturaly occurring or engineered VH domains).
  • VHHs can be generated from camelid heavy chain only antibodies and libraries thereof.
  • VNARs can be generated from cartilaginous fish heavy chain only antibodies and libraries thereof.
  • Various methods have been implemented to generate monomeric sdAbs from conventionaly heterodimeric VH and VL domains, including interface engineering and selection of 34 310886415v1 Attorney Docket No: 260525.000071 specific germline families.
  • the sdAb of the present invention are human or humanized.
  • a single-domain antibody described herein is a VHH fragment (also known as a nanobody). VHH fragments are also referred to as “V-bodies” in the present disclosure.
  • the VHH is a camelid VHH, a humanized VHH or a camelized VH.
  • a single-domain antibody described herein is a VH domain.
  • a single-domain antibody described herein is a naturaly occurring VH domain or engineered VH domain.
  • variable domain of an antigen-binding protein e.g., antibody such as a single-domain antibody
  • the variable domain comprises at least three complementarity determining regions (CDRs) which determine its binding specificity.
  • CDRs complementarity determining regions
  • FRs framework regions
  • the variable domain typicaly contains 4 framework regions interspaced by 3 CDR regions, resulting in the folowing typical antibody variable domain structure: FR1- CDR1-FR2-CDR2-FR3-CDR3-FR4.
  • CDRs and/or FRs of the single domain antibody of the invention may be fragments or derivatives from a naturaly occurring antibody variable domain or may be synthetic.
  • Table 1-1 sets forth the sequence identifiers of amino acid sequences of the complementarity determining regions (CDR1, CDR2 and CDR3), amino acid and DNA sequences of the ful-length camelid VHH antibodies, as wel as amino acid sequences of corresponding humanized VHH antibodies.
  • the sufix "-Hu1" in an antibody ID indicates a humanized version of the referenced antibody.
  • Amino acid sequences of additional exemplary anti-TNFR2 VHH antibodies and corresponding humanized VHH antibodies are provided in Table 1-2. Table 1-1.
  • GRTF(G/R/S)(N/S)(Y/L)(T/F) (SEQ ID NO: 73); 53 310886415v1 Attorney Docket No: 260525.000071 h).
  • GASLSRNA (SEQ ID NO: 40); i). GS(I/T)FRFPP (SEQ ID NO: 74); j). GFTLDDYA (SEQ ID NO: 4061); and k).
  • G(F/V)(S/T)LD(D/Y)(H/Y)T (SEQ ID NO: 4519).
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single- domain antibody) of the present disclosure comprises a complementarity determining region 2 (CDR2) comprising an amino acid sequence selected from (amino acids listed in a pair of brackets represent the possible amino acids at the particular position) a). IRSDGF(T/I) (SEQ ID NO: 75); b). I(Y/F)SY(S/G)(S/P)NT (SEQ ID NO: 76); c). I(Y/S)(S/D)DGS(E/D)T (SEQ ID NO: 77); d). INWSN(G/A)RT (SEQ ID NO: 4699); e).
  • CDR2 complementarity determining region 2
  • I(S/N)(V/T)(S/G)DGST (SEQ ID NO: 78); f). IDT(R/G)GST (SEQ ID NO: 79); g). IR(W/R/Y)(T/P)G(G/L)(S/I)T (SEQ ID NO: 80); h). IYDDGET (SEQ ID NO: 41); i). LTSGGST (SEQ ID NO: 45); j). IFSYSSNT (SEQ ID NO: 4062); k). I(N/S)SNDG(S/T)(T/V) (SEQ ID NO: 4518); and l). INWS(N/Q/E/S)(G/A)RT (SEQ ID NO: 4809).
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as a single- domain antibody
  • a complementarity determining region 3 CDR3 comprising an amino acid sequence selected from (amino acids listed in a pair of brackets represent the possible amino acids at the particular position) a).
  • (Y/F)YQ(S/A)LS(T/S)(P/A)N(Y/F)GQ(V/T)F (SEQ ID NO: 60); b). AADSDL(S/R)TV(V/T)VGPHDY (SEQ ID NO: 61); c).
  • AKDAG(S/G)WG(T/R)GPFG(Y/F)(E/D)YDY (SEQ ID NO: 62); d). AA(T/A)PSGKAY(T/S)Y (SEQ ID NO: 63); e). ATPGPY(T/S/M)YCAPYGSSWSRGYDY (SEQ ID NO: 64); f). ARV(R/G)G(T/S/A)PY(E/D)Y(N/G)Y (SEQ ID NO: 65); g).
  • the CDR3 sequence comprises the amino acid sequence: a).
  • a CDR1 comprising an amino acid sequence of SEQ ID NO: 4519, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4518, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4517; xi).
  • a CDR1 comprising an amino acid sequence of SEQ ID NO: 16
  • a CDR2 comprising an amino acid sequence of SEQ ID NO: 4699
  • a CDR3 comprising an amino acid sequence of SEQ ID NO: 4771; xii).
  • a CDR1 comprising an amino acid sequence of SEQ ID NO: 16
  • a CDR2 comprising an amino acid sequence of SEQ ID NO: 4699
  • a CDR3 comprising an amino acid sequence of SEQ ID NO: 4787; xiv).
  • a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4809, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4787; xv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4809, and a CDR3 comprising an amino acid sequence of (A/G)(A/G)(T/A/S)(A/P/L)(A/S/T)(A/G)(A/K)(A/G)(A/Y)(A/T/S)(A/Y); or xvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 73, a CDR2 comprising an amino acid sequence of SEQ ID NO: 80, and a CDR3 comprising an amino acid sequence of (T/A/V)(A/G)(S/A)(A/
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single- domain antibody) of the present disclosure comprises a) a CDR1 comprising an amino acid sequence of SEQ ID NO: 69, a CDR2 comprising an amino acid sequence of SEQ ID NO: 76, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 61; b) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4699, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 63; c) a CDR1 comprising an amino acid sequence of SEQ ID NO: 73, a CDR2 comprising an amino acid sequence of SEQ ID NO: 80, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 66; d) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR1 comprising an amino acid sequence
  • a CDR1 comprising an amino acid sequence of GRTFSDYG (SEQ ID NO: 4719), a CDR2 comprising an amino acid sequence of INWSNGRT (SEQ ID NO: 4723), and a CDR3 comprising an amino acid sequence of AATPTGKAYTY (SEQ ID NO: 4727); xii).
  • a CDR1 comprising an amino acid sequence of GRTFSDYG (SEQ ID NO: 4720), a CDR2 comprising an amino acid sequence of INWSNART (SEQ ID NO: 4724), and a CDR3 comprising an amino acid sequence of AATPTGKAYTY (SEQ ID NO: 4728); xiv).
  • a CDR1 comprising an amino acid sequence of GRTFSDYG (SEQ ID NO: 4721), a CDR2 comprising an amino acid sequence of INWSNGRT (SEQ ID NO: 4725), and a CDR3 comprising an amino acid sequence of AGTLSGKAYTY (SEQ ID NO: 4729); xv).
  • a CDR1 comprising an amino acid sequence of GRTFSDYG (SEQ ID NO: 4722), a CDR2 comprising an amino acid sequence of INWSNART (SEQ ID NO: 4726), and a CDR3 comprising an amino acid sequence of AGTLSGKAYTY (SEQ ID NO: 4730); or xvi) a CDR1 comprising an amino acid sequence of GFT(F/L)DD(I/Y)A (SEQ ID NO: 69), a CDR2 comprising an amino acid sequence of I(Y/F)SY(S/G)(S/P)NT (SEQ ID NO: 76), and a CDR3 comprising an amino acid sequence of AADSDLSTVV(V/T)GPHDY (SEQ ID NO: 4702).
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single- domain antibody) of the present disclosure comprises 58 310886415v1 Attorney Docket No: 260525.000071 a) a CDR1 comprising an amino acid sequence of GFTFDDIA (SEQ ID NO: 8), a CDR2 comprising an amino acid sequence of IYSYGPNT (SEQ ID NO: 9), and a CDR3 comprising an amino acid sequence of AADSDLSTVV(V/T)GPHDY (SEQ ID NO: 4702); b) a CDR1 comprising an amino acid sequence of GRTFSDYG (SEQ ID NO: 16), a CDR2 comprising an amino acid sequence of INWSN(G/A)RT (SEQ ID NO: 4699), and a CDR3 comprising an amino acid sequence of AA(T/A)PSGKAYSY (SEQ ID NO: 4703); c) a CDR1 comprising
  • anti-TNFR2 antigen-binding proteins e.g., antibodies such as single-domain antibodies
  • a CDR1 comprising an amino acid sequence selected from any of the CDR1 amino acid sequences listed in Table 1-1, Table 5, Table 7, or Table 8, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity.
  • an anti-TNFR2 antigen-binding protein comprises a CDR1 comprising an amino acid sequence selected from SEQ ID Nos: 1, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 4061, 4065, 4069, 4520, 4719-4722, 1128-1686, 4173-4234, and 4533-4556, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity.
  • anti-TNFR2 antigen-binding proteins e.g., antibodies such as single-domain antibodies
  • CDR2 CDR2
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 2, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 4062, 4066, 4070, 4527, 4723-4726, 1687- 2245, 4235-4296, 4557- 4580, and 4788-4793, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity.
  • anti-TNFR2 antigen-binding proteins e.g., antibodies such as single-domain antibodies
  • CDR3 CDR3
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence selected from SEQ ID Nos: 3, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 4063, 4067, 4071, 4524, 4530, 4727-4730, 2246-2804, 4297-4358, 4581-4604, 4774, 4810-4833, and 4835-4855, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity.
  • anti-TNFR2 antigen-binding proteins e.g., antibodies such as single-domain antibodies
  • anti-TNFR2 VHH antibodies comprising a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within any of the exemplary anti-TNFR2 VHH antibodies listed in Tables 1-1, Table 1-2, Table 5, Table 7, or Table 8.
  • an anti-TNFR2 antigen-binding protein comprises a) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 17, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; 68 310886415v1 Attorney Docket No: 260525.000071 b) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; c) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4530; d) a CDR1 comprising an amino acid sequence of SEQ ID NO:
  • anti-TNFR2 antigen-binding proteins e.g., antibodies such as single-domain antibodies
  • anti-TNFR2 antigen-binding proteins comprising a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within a VHH amino acid sequence as defined by any of the exemplary anti-TNFR2 VHH antibodies listed in Table 1-1, Table 1-2, Table 5, Table 7, or Table 8.
  • antibodies, or antigen-binding fragments thereof comprising the set of CDR1-CDR2-CDR3 amino acid sequences contained within a VHH amino acid sequence selected from SEQ ID Nos: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 4064, 4068, 4072, 4521, 4780, 4781, 4783, 4785, 4786, 81-92, 93-640, 4079-4125, 2805-3363, 4359-4420, 4605-4628, 4526, 4529, 4532, 4078, 4523, 4076, 4077, 4078, 4731-4734, 4775, 4782, 4784, 4794-4808, 4857-4902, and 4994-5001.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as a single- domain antibody
  • an anti-TNFR2 antigen-binding protein of the present disclosure can include a. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4; b. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7; c. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 11; d.
  • variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4078; u. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4731; v. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4732; 71 310886415v1 Attorney Docket No: 260525.000071 w. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4733; x.
  • variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4805; ss. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4806; tt. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4807; uu. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4808; vv.
  • variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4857; ww. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4858; xx. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4859; yy. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4860; zz.
  • variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4861; 73 310886415v1 Attorney Docket No: 260525.000071 aaa. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4862; bbb. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4863; ccc.
  • variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4876; 74 310886415v1 Attorney Docket No: 260525.000071 ppp. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4877; qqq. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4878; rrr.
  • variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4879; sss. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4880; ttt. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4881; uuu. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4882; vvv.
  • variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4887; aaaa. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4888; bbbb. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4889; cccc. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4890; dddd.
  • variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4891; 75 310886415v1 Attorney Docket No: 260525.000071 eeee. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4892; ff. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4893; gggg.
  • variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4902; pppp. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4994; qqqq. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4995; rrrr. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4996; ssss.
  • variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4997; 76 310886415v1 Attorney Docket No: 260525.000071 tttt. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4998; uuuu. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4999; vvvv.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as a single- domain antibody
  • an anti-TNFR2 antigen-binding protein of the present disclosure can include a). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 19; b).
  • variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4878; ccc).
  • variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4893; rrr).
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as a single-domain antibody
  • an anti-TNFR2 antigen-binding protein of the present disclosure can include a VHH amino acid sequence selected from SEQ ID Nos: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 4064, 4068, 4072, 4521, 93-640, 4079-4125, 2805-3363, 4359-4420, 4605-4628, 4653-4685, 4780, 4781, 4783, 4785, and 4786, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as a single-domain antibody
  • an anti-TNFR2 antigen-binding protein of the present disclosure can include a VHH amino acid sequence selected from SEQ ID Nos: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 4064, 4068, 4072, 4521, 4653-4685, 4732, 4780, 4781, 4783, 4785, and 4786, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as a single-domain antibody
  • an anti-TNFR2 antigen-binding protein of the present disclosure can include a humanized VHH amino acid sequence selected from SEQ ID Nos: 81-92, 4076-4078, 4523, 4526, 4529, 4532, 4731-4734, 641-1127, 4126-4172, 4775, 4782, 4784, 4794-4808, 4857-4902, and 4994-5001, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as a single-domain antibody
  • an anti-TNFR2 antigen-binding protein of the present disclosure can include a VHH amino acid sequence selected from SEQ ID Nos: 19, 4072, 4078, 4526, 4529, 4532, 4653-4685, 4732, 4775, 4782, 4784, 4780, 4781, 4783, 4785, 4786, 4794-4808, 4857-4902 and 4994-5001, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) 83 310886415v1 Attorney Docket No: 260525.000071 comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4794.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4794, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4732.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4732, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4795.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4795, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4796.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4796, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4797.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4797, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4798.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4798, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, 86 310886415v1 Attorney Docket No: 260525.000071 at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4799.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4799, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4800.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4800, 87 310886415v1 Attorney Docket No: 260525.000071 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4801.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4801, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4791.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4802.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4791, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen-binding protein 88 310886415v1 Attorney Docket No: 260525.000071 comprises the amino acid sequence of SEQ ID NO: 4802, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4792.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4803.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4792, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4803, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4793.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4804.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4793, and a CDR3 comprising an 89 310886415v1 Attorney Docket No: 260525.000071 amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4804, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 18.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4805.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4805, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 18.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4806.
  • an anti-TNFR2 antigen-binding protein comprises a CDR1 comprising an amino acid sequence of SEQ 90 310886415v1 Attorney Docket No: 260525.000071 ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4806, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 18.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4807.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4807, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4791.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4808.
  • an anti-TNFR2 antigen-binding protein (e.g., 91 310886415v1 Attorney Docket No: 260525.000071 antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4791, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4808, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4071.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4078, 4624, 4626, or 4994.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4071.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4078, 4624, 4626, or 4994, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4810.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino 92 310886415v1 Attorney Docket No: 260525.000071 acid sequence of SEQ ID NO: 4857.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4810.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4857, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4811.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4858.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4811.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4858, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4812.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of 93 310886415v1 Attorney Docket No: 260525.000071 three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4859.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4812.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4859, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4813.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4860.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4813.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4860, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4814.
  • an anti-TNFR2 antigen- 94 310886415v1 Attorney Docket No: 260525.000071 binding protein e.g., antibody such as single-domain antibody
  • binding protein e.g., antibody such as single-domain antibody
  • a set of three CDRs i.e., CDR1-CDR2-CDR3 contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4861.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4814.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4861, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4815.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4862.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4815.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4862, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 95 310886415v1 Attorney Docket No: 260525.000071 comprising an amino acid sequence of SEQ ID NO: 4816.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4863.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4816.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4863, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4817.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4864.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4817.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4864, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an 96 310886415v1 Attorney Docket No: 260525.000071 anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4818.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4865.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4818.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4865, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4819.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4866.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4819.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4866, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) 97 310886415v1 Attorney Docket No: 260525.000071 comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4820.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4867 or 4995.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4820.
  • an anti-TNFR2 antigen- binding protein comprises the amino acid sequence of SEQ ID NO: 4867 or 4995, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4821.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4868 or 4996.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4821.
  • an anti-TNFR2 antigen- binding protein comprises the amino acid sequence of SEQ ID NO: 4868 or 4996, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4822.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4869 or 4997.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4822.
  • an anti-TNFR2 antigen- binding protein comprises the amino acid sequence of SEQ ID NO: 4869 or 4997, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4823.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4870 or 4998.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4823.
  • an anti-TNFR2 antigen- binding protein comprises the amino acid sequence of SEQ ID NO: 4870 or 4998, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4824.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4871 or 4999.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4824.
  • an anti-TNFR2 antigen- binding protein comprises the amino acid sequence of SEQ ID NO: 4871 or 4999, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4825.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4872.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4825.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4872, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, 100 310886415v1 Attorney Docket No: 260525.000071 at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4826.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4873.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4826.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4873, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4827.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4874 or 5000.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4827.
  • an anti-TNFR2 antigen- binding protein comprises the amino acid sequence of 101 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 4874 or 5000, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4828.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4875.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4828.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4875, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 34.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4876.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 34.
  • an anti-TNFR2 antigen-binding protein 102 310886415v1 Attorney Docket No: 260525.000071 comprises the amino acid sequence of SEQ ID NO: 4876, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4829.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4877 or 5001.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4829.
  • an anti-TNFR2 antigen- binding protein comprises the amino acid sequence of SEQ ID NO: 4877 or 5001, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4830.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4878.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an 103 310886415v1 Attorney Docket No: 260525.000071 amino acid sequence of SEQ ID NO: 4830.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4878, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4831.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4879.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4831.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4879, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4832.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4880.
  • an anti-TNFR2 antigen-binding protein comprises a CDR1 comprising an amino acid sequence of SEQ 104 310886415v1 Attorney Docket No: 260525.000071 ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4832.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4880, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4833.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4881.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4833.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4881, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4835.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4882.
  • an anti-TNFR2 antigen-binding protein (e.g., 105 310886415v1 Attorney Docket No: 260525.000071 antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4835.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4882, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4836.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4883.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4836.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4883, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4530.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino 106 310886415v1 Attorney Docket No: 260525.000071 acid sequence of SEQ ID NO: 4532.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4530.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4532, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4837.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4884.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4837.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4884, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4838.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of 107 310886415v1 Attorney Docket No: 260525.000071 three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4885.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4838.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4885, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4839.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4886.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4839.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4886, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4840.
  • an anti-TNFR2 antigen- 108 310886415v1 Attorney Docket No: 260525.000071 binding protein e.g., antibody such as single-domain antibody
  • binding protein e.g., antibody such as single-domain antibody
  • a set of three CDRs i.e., CDR1-CDR2-CDR3 contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4887.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4840.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4887, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4841.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4888.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4841.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4888, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 109 310886415v1 Attorney Docket No: 260525.000071 comprising an amino acid sequence of SEQ ID NO: 4842.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4889.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4842.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4889, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4843.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4890.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4843.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4890, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an 110 310886415v1 Attorney Docket No: 260525.000071 anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4844.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4891.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4844.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4891, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4845.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4892.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4845.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4892, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single-domain antibody
  • 111 310886415v1 Attorney Docket No: 260525.000071 comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single-domain antibody
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4893.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4846.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4893, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4847.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4894.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4847.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4894, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4848.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4895.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4848.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4895, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4849.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4896.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4849.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4896, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4850.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4897.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4850.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4897, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4851.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4898.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4851.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4898, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, 114 310886415v1 Attorney Docket No: 260525.000071 at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4852.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4899.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4852.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4899, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4853.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4900.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4853.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4900, 115 310886415v1 Attorney Docket No: 260525.000071 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4854.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4901.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4854.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4901, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4855.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4902.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4855.
  • an anti-TNFR2 antigen-binding protein 116 310886415v1 Attorney Docket No: 260525.000071 comprises the amino acid sequence of SEQ ID NO: 4902, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4775.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4775, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 9.
  • an anti- TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4524.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4526 or 4780.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 8, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9, and a CDR3 117 310886415v1 Attorney Docket No: 260525.000071 comprising an amino acid sequence of SEQ ID NO: 4524.
  • an anti-TNFR2 antigen- binding protein comprises the amino acid sequence of SEQ ID NO: 4526 or 4780, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4781 or 4782.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4781 or 4782, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4524.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4783 or 4784.
  • an anti-TNFR2 antigen-binding protein comprises a CDR1 comprising an amino acid 118 310886415v1 Attorney Docket No: 260525.000071 sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4524.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4783 or 4784, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 4719.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4723.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4731 or 4785.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 4719, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4723, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4731 or 4785, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 4721.
  • an anti-TNFR2 antigen-binding protein comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4725.
  • an anti-TNFR2 antigen-binding protein comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4729.
  • an anti-TNFR2 antigen- binding protein e.g., antibody such as single-domain antibody described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4733 or 4786.
  • an anti-TNFR2 antigen-binding 119 310886415v1 Attorney Docket No: 260525.000071 protein comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 4721, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4725, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4729.
  • an anti-TNFR2 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 4733 or 4786, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • the present disclosure also provides an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) that competes for binding to TNFR2 with any one of the exemplary anti-TNFR2 VHH antibodies listed in Table 1-1, Table 1-2, Table 5, Table 7 , or Table 8.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as a single-domain antibody
  • the present disclosure also provides an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) that binds to the same epitope on TNFR2 as any one of the exemplary anti-TNFR2 VHH antibodies listed in Table 1-1, Table 1-2, Table 5, Table 7, or Table 8.
  • the present disclosure also provides an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) that comprises a means for binding an epitope within human TNFR2 bound by any one of the exemplary anti-TNFR2 VHH antibodies listed in Table 1-1, Table 1-2, Table 5, Table 7, or Table 8.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as a single-domain antibody
  • a single-domain antibody e.g., VHH
  • VHH can be obtained by immunization of dromedaries, camels, lamas, alpacas, or sharks with the desired antigen and subsequent isolation of the mRNA coding for heavy-chain antibodies.
  • Antigens can be purified from natural sources, or in the course of recombinant production.
  • Immunization and/or screening for immunoglobulin sequences can be performed using peptide fragments of such antigens.
  • PCR reverse transcription and polymerase chain reaction
  • Screening techniques such as phage display, yeast display, and ribosome display help to identify the clones binding the antigen.
  • Methods generation of heavy-chain antibody fragments are described in e.g., WO 94/04678; Hamers-Casterman et al.1993; Muyldermans et al.2001; and Arbabi Ghahroudi, M. et al. (1997).
  • a diferent method may use gene libraries from animals that have not been previously immunized. Such na ⁇ ve libraries usualy contain only antibodies with low afinity to the desired antigen, making it necessary to apply afinity maturation by random mutagenesis as an additional step. See e.g., Saerens, D.; et al. (2008). “Single-domain antibodies as building blocks for novel therapeutics”. Current Opinion in Pharmacology 8 (5): 600-608.
  • Afinity maturation strategies can be categorized as either targeted/rational approaches or untargeted/random approaches.
  • targeted approaches information about the VHH of interest is needed, such as hot spots for afinity maturation or structural information on the VHH:antigen complex, whereas for untargeted approaches no prior information is needed.
  • Targeted approaches that may be applied for afinity maturation of VHHs include site-directed in-vitro mutagenesis and in- silico/computational approaches.
  • Common untargeted approaches used for afinity maturation of VHHs include random in-vitro mutagenesis, CDR swapping and autonomous hypermutation yeast surface display, with the latter two being novel, emerging and very time techniques.
  • the resulting library can be screened by employing standard display techniques such as yeast, phage or ribosome display to select for the best binders.
  • standard display techniques such as yeast, phage or ribosome display to select for the best binders.
  • the choice of the display system is often guided by the library size to be displayed, with yeast display being able to handle library sizes of ⁇ 107 – 109, phage display ⁇ 108-1010 and ribosome display ⁇ 1012-1013 (Chan and Groves, 2021).
  • yeast display being able to handle library sizes of ⁇ 107 – 109
  • phage display ⁇ 108-1010 ⁇ 108-1010
  • ribosome display ⁇ 1012-1013 Choan and Groves, 2021).
  • the number of highly interactive residues such as aromatic amino acids usualy increase in the CDR regions.
  • the selected afinity matured clones may be further evaluated by a developability assessment to test for undesired properties, such as unspecific binding to of-targets or VHH instability.
  • a set of selected residues within the CDRs of a VHH may be mutated (Tiler et al., 2017; Yau et al., 2005). Pre-selection of these residues can be either performed using alanine scanning to identify hot spot residues for mutation or by using structural data of the antigen:VHH complex to identify positions to be mutated.
  • hotspots for mutations can be identified that are then submited to in vitro mutagenesis (Bert Schepens et al., 2021; Cheng et al., 2019; Inoue et al., 2013; Mahajan et al., 2018). Further, in silico methods can search al designed variants in a virtual library (1 ⁇ 040 members) in a rather short amount of time to identify a feasible number of promising candidates to be tested experimentaly. These techniques can be especialy valuable if structural data on the drug- target interaction are available.
  • Untargeted/random afinity maturation strategies that can be applied to afinity mature VHHs include random in vitro mutagenesis, CDR shufling/swapping and in vivo afinity maturation via yeast display.
  • random in vitro mutagenesis the sequence of either the entire VHH or only the CDRs are mutated randomly (Chen et al., 2021; Ye et al., 2021; Zupancic et al., 2021).
  • the most commonly used technique is error prone PCR employing a DNA polymerase that lacks proof reading activity and PCR conditions that increase the polymerase error rate even further.
  • CDR shufling or swapping is applied for VHH afinity maturation, such as described in Zupancic et al., 2021.
  • enriched libraries can be used as input material for a PCR reaction to individualy amplify the CDR of the VHHs.
  • in vivo afinity maturation via yeast display is applied for VHH afinity maturation, such as described in Welner et al., 2021.
  • the method is based on an autonomous hypermutation yeast surface display (AHEAD), which imitates somatic hypermutation during VHH selection using engineered yeast strains.
  • AHEAD autonomous hypermutation yeast surface display
  • the yeast’s error prone orthogonal DNA replication system can generate new variants during plasmid replication by randomly introducing mutations.
  • the new variants can then be displayed and selected using yeast surface display to identify the best binders.
  • This enables the production of high afinity clones in very litle time (about 2 weeks), which is significantly faster than 122 310886415v1 Attorney Docket No: 260525.000071 classical afinity maturation procedures.
  • the method can be applied using synthetic or immune libraries using unenriched libraries enriched libraries or a subset of preselected clones. [0295] In case binders with medium afinity are required, as it is the case for the anti-TNFR2 V-bodies and the afinity of the identified candidates need to be decreased, very similar techniques can be applied.
  • mutations that are aiming at lowering the afinity can be introduced using the same targeted or untargeted approaches as described for the afinity maturation.
  • the selection afterwards can be adapted accordingly.
  • the selection strategy can be adapted to enrich medium afinity binders while excluding high afinity candidates. This could, for example be a pre-panning in phage display with low antigen concentration to remove al higher afinity candidates, folowed by a selection with high antigen concentration to obtain medium afinity VHHs.
  • a kinetic of- rate characterization can be used to get immediate information about the kinetic behavior of the candidates.
  • Single-domain antibodies can also be derived from conventional antibodies. In some embodiments, single-domain antibodies can be made from conventional murine or human IgG with four chains.
  • the binding region of a conventional IgG consists of two domains (VH and VL), which tend to dimerize or aggregate because of their lipophilicity. Monomerization can be accomplished by replacing lipophilic by hydrophilic amino acids. (See e.g., Borrebaeck, C. A. K.; Ohlin, M. (2002). “Antibody evolution beyond Nature”. Nature Biotechnology 20 (12): 1189-90.) If afinity can be retained after monomerization, the single-domain antibodies can likewise be produced in E. coli, S. cerevisiae or other suitable organisms.
  • a “humanized antibody” refers to a chimeric, geneticaly engineered, antibody in which the amino acid sequences (typicaly CDRs) from an antibody (donor antibody), e.g., a camelid antibody, are grafted onto a human antibody (acceptor antibody).
  • a humanized antibody typicaly comprises 123 310886415v1 Attorney Docket No: 260525.000071 CDRs from a donor antibody and variable region framework and constant regions, when present, from a human antibody.
  • a “humanized VHH” comprises CDRs that corresponds to the CDRs of a naturaly occurring VHH domain (e.g., a camelid VHH), but that has been “humanized”.
  • Humanized VHH may be prepared by replacing one or more amino acid residues in the amino acid sequence of the naturaly occurring VHH sequence (particularly in the framework sequences) by one or more of the amino acid residues that occur at the corresponding position(s) in a VH domain from a conventional 4- chain human antibody.
  • Such humanized VHHs can be obtained in any suitable manner known to a skiled person in the art and thus not strictly limited to methods described herein. [0299] Humanization of VHHs can achieved using resurfacing or CDR grafting.
  • Resurfacing strategies have been described in e.g., Conrath et al., 2005 J Mol Biol; Kazemi-Lomedasht et al., 2018; Vincke et al., 2009 J Biol Chem, and CDR grafting strategies have been described in e.g., ben Abderrazek et al., 2011; van Faassen et al., 2020 FASEB; Li et al., 2018; Vaneycken et al., 2010; Vincke et al., 2009 J Biol Chem; and Yu et al., 2017, each of which is incorporated herein by reference in its entirety.
  • a human germline reference that is most similar to the camelid germline sequence of the selected VHH may be identified.
  • Most of the isolated camelid VHHs in literature belong to the camelid IGHV3 subfamily 2 (Nguyen et al., 2000, EMBO J) with DP-47/VH3-23 from the IGHV3 family commonly used as human reference.
  • the framework of the camelid VHH can then be compared to the human reference sequence. Surface exposed residues are substituted to their human counterpart as it is assumed that their contribution to protein stability is rather low. Buried residues however remain of camelid origin, as they likely contribute to the overal VHH stability.
  • residues H37 and H47 are known to interact with the CDR-H3 loop in many VHHs, stabilizing its conformation and thereby contributing to antigen binding afinity.
  • a significant number of VHHs use framework 2 residues H44, H45 and H47 for antigen binding (Zavrtanik et al., 2018, J Mol Biol).
  • a ful humanization of these residues hence frequently results in reduced solubility or aggregation of the VHHs and a reduced 124 310886415v1 Attorney Docket No: 260525.000071 or complete loss of binding afinity for the target antigen (van Faassen et al., 2020, Vincke et al., 2009).
  • CDR grafting Another approach that may be applied to humanize VHHs is CDR grafting. CDRs of the selected VHHs can be transplanted onto a universal VHH framework that has been partialy or fuly humanized (Saerens et al., 2009 J Biol Chem, Soler et al., 2021, Vincke et al., 2009 J Biol Chem).
  • CDR grafting has been successfuly used in some cases but failed for several others, with VHHs frequently losing their potential to bind to the desired antigen and/or becoming structuraly instable with a high tendency to aggregate (van Faassen et al., 2020, FASEB). This is mostly atributed to interactions of CDR3 with specific residues in framework 2 that are important for CDR3 conformation, general VHH stability and overal hydrophobicity, which are impaired by this approach. Sometimes camelid backmutations are introduced into the framework to compensate for these effectss (van Faassen et al., 2020, FASEB).
  • humanizing substitutions include Q108L and A14P. Such humanizing substitutions may also be suitably combined with one or more other mutations as described herein (such as with one or more mutations that reduce binding by pre-existing antibodies).
  • humanized VHH sequences stil retain the residues that are relevant for protein A binding.
  • the engineering activities during humanization may be applied to engineer protein A binding properties into a VHH that did previously not interact with protein A (Graile et al., 2000, PNAS).
  • a “camelized antibody” refers to an antibody having amino acid sequences (typicaly CDRs) from a donor antibody, e.g., a human antibody, and variable region framework and constant regions, when present, from a camelid antibody. Accordingly, a “camelized VH” comprises an amino acid sequence that corresponds to the amino acid sequence of a naturaly occurring VH domain, but that has been “camelized”.
  • Camelized VH may be prepared by replacing one or more 125 310886415v1 Attorney Docket No: 260525.000071 amino acid residues in the amino acid sequence of a naturaly occurring VH domain from a conventional 4-chain antibody by one or more of the amino acid residues that occur at the corresponding position(s) in a VHH domain of a heavy chain antibody. This can be performed in a manner, for example as described in WO 2008/020079.
  • VH sequence that is used as a starting material or starting point for generating or designing the camelized VH is a VH sequence from a mammal, or the VH sequence of a human antibody.
  • camelized VH can be obtained in any suitable manner known to a skiled person in the art and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturaly occurring VH domain as a starting material.
  • the amino acid residues of a single-domain antibody can be numbered according to the general numbering for VH domains given by Kabat et al. (“Sequence of proteins of immunological interest”, US Public Health Services, NIH Bethesda, Md., Publication No.91), as applied to VHH domains from Camelids described in Riechmann and Muyldermans, 2000 (J. Immunol.
  • the total number of amino acid residues in each of the CDRs may vary and may not correspond to the total number of amino acid residues indicated by the Kabat numbering. For example, one or more positions according to the Kabat numbering may not be occupied in the actual sequence, or the actual sequence may contain more amino acid residues than the number alowed for by the Kabat numbering. As a result, the numbering according to Kabat may or may not correspond to the actual numbering of the amino acid residues in the actual sequence.
  • the total number of amino acid residues in a VH domain and a VHH domain is usualy in the range of from 110 to 120, often between 112 and 115.
  • Determination of CDR regions in a single-domain antibody may be accomplished using diferent methods, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (“Kabat” numbering scheme); Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme); MacCalum et al., J. Mol. Biol.262:732-745 (1996), “Antibody-antigen interactions: Contact analysis and binding site topography,” J. Mol.
  • the boundaries of a given CDR or framework (FR) may vary depending on the scheme used for identification.
  • the Kabat scheme is based on structural alignments
  • the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, with insertions accommodated by insertion letters, for example, “30a,” and deletions appearing in some antibodies.
  • the two schemes place certain insertions and deletions (“indels”) at diferent positions, resulting in diferential numbering.
  • the Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme.
  • CDRs can be defined in accordance with any of the Kabat numbering scheme, the Chothia numbering scheme, a combination of Kabat and Chothia, the AbM numbering scheme, and/or the Contact numbering scheme.
  • a VHH typicaly comprises three CDRs, designated CDR1, CDR2, and CDR3.
  • Table 1-3 below, lists exemplary position boundaries of CDR-H1, CDR-H2, CDR- H3 as identified by Kabat, Chothia, AbM, and Contact schemes, respectively.
  • residue numbering is listed using both the Kabat and Chothia numbering schemes.
  • FRs are located between CDRs, for example, with FR-H1 located before CDR-H1, FR-H2 located between CDR-H1 and CDR-H2, FR- H3 located between CDR-H2 and CDR-H3 and so forth. It is noted that because the shown Kabat numbering scheme places insertions at H35A and H35B, the end of the Chothia CDR-H1 loop when numbered using the shown Kabat numbering convention varies between H32 and H34, depending on the length of the loop. Table 1-3.
  • CDRs definitions according to various numbering schemes
  • CDR Kabat Chothia AbM Contact 127 310886415v1 Attorney Docket No: 260525.000071
  • CDR Kabat Chothia AbM Contact Kabat individual specified CDRs (e.g., CDR-H1, CDR-H2, CDR-H3), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) CDR as defined by any of the above-mentioned schemes.
  • a particular CDR e.g., a CDR-H3
  • a CDR-H3 contains the amino acid sequence of a corresponding CDR in a given VHH amino acid sequence
  • a CDR has a sequence of the corresponding CDR (e.g., CDR-H3) within the VHH, as defined by any of the above-mentioned schemes.
  • specific CDR sequences are specified.
  • Exemplary CDR sequences of provided antibodies are described using various numbering schemes (see e.g., Table 1-3), although it is understood that a provided antibody can include CDRs as described according to any of the other above-mentioned numbering schemes or other numbering schemes known to a person of ordinary skil in the art.
  • the framework sequences may be any suitable framework sequences.
  • the framework sequences may be framework sequences derived from a heavy chain variable domain (e.g., a VH sequence or VHH sequence).
  • the framework sequences are either framework sequences that have been derived from a VHH sequence (in which said framework sequences may optionaly have been partialy or fuly humanized) or are conventional VH sequences (in which said framework sequences may optionaly have been partialy or fuly camelized).
  • an antigen-binding protein of the present disclosure may comprise naturaly occurring sequences (from a suitable species), recombinant sequences, or synthetic or semi-synthetic sequences.
  • nucleotide sequences encoding antigen-binding proteins of the present disclosure may comprise naturaly occurring nucleotide sequences, recombinant sequences, or synthetic or semi-synthetic sequences (for example, sequences that are prepared by PCR or isolated from a library).
  • Anti-TNFR2 antigen-binding proteins e.g., antibodies such single-domain antibodies
  • Anti-TNFR2 antigen-binding proteins 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 chain variable domains as compared to the exemplary antibody sequences provided herein. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases.
  • the antigen-binding molecules of the present disclosure may comprise antigen-binding domains which are derived from any of the exemplary amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein briefly as "germline mutations").
  • Germline mutations A person of ordinary skil in the art, starting with the heavy 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.
  • al of the framework and/or CDR residues within the VHH domains are mutated back to the residues found in the original germline sequence from which the antigen-binding domain was originaly derived.
  • 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.
  • one or more of the framework and/or CDR residue(s) are mutated to the corresponding 129 310886415v1 Attorney Docket No: 260525.000071 residue(s) of a diferent germline sequence (i.e., a germline sequence that is diferent from the germline sequence from which the antigen-binding domain was originaly derived).
  • the antigen-binding domains may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that difer from the original germline sequence are maintained or are mutated to the corresponding residue of a diferent germline sequence.
  • 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 afinity, improved, or enhanced biological properties (e.g., agonistic effect), reduced immunogenicity, etc.
  • Antigen-binding proteins comprising one or more antigen-binding domains obtained in this general manner are encompassed within the present disclosure.
  • anti-TNFR2 antigen-binding proteins comprising variants of any of the VHH and/or CDR amino acid sequences disclosed herein having one or more amino acid substitutions.
  • the present disclosure includes anti-TNFR2 antigen-binding proteins having VHH 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 amino acid substitutions relative to any of the VHH and/or CDR amino acid sequences set forth in Tables 1-1, 1-2, 5 and 7 herein.
  • Amino acid substitutions may be introduced into an antigen-binding protein of interest and the resultant variants can screened for a desired activity, for example, retained/improved antigen binding, decreased immunogenicity, or reduced ADCC or CDC.
  • Amino acids may be grouped according to common side-chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; (6) aromatic: Trp, Tyr, Phe.
  • an amino acid substitution is a conservative substitution, meaning exchanging an amino acid with another amino acid of the same class.
  • amino acid substitutions may also include a non-conservative substitution, meaning exchanging an amino acid with an amino acid of a diferent class.
  • Other exemplary amino acid substitutions are shown in Table 1-4. Table 1-4.
  • p sclosure may comprise one or more mutations to reduce oxidation levels of oxidation-labile residues such as Met (M). In certain embodiments, it may be desirable to address Met (M) oxidation liability by mutation of a Met (M) residue.
  • the single-domain antibodies (e.g., VHH) of the present disclosure may comprise one or more mutations (e.g., substitution mutations) of a Met residue to reduce oxidation.
  • a Met residue may be substituted in any of the single-domain antibodies described herein with e.g., Ile (I), Ala (A), or Leu (L), to reduce oxidation.
  • single-domain antibodies (e.g., VHH) of the present disclosure comprise one or more modifications that reduce binding of the single-domain antibodies (e.g., VHH) by pre- existing antibodies found in human blood or serum.
  • single-domain antibodies (e.g., VHHs) of the present disclosure are modified by mutation of amino acid position 11, for example Leu11Glu (L11E), Leu11Lys (L11K), or Leu11Val (L11V).
  • a single-domain antibody (e.g., VHH) of the present disclosure may comprise a valine (V) at amino acid position 11 and a leucine (L) at amino acid position 89 (according to Kabat numbering).
  • a single-domain antibody (e.g., VHH) of the present disclosure may comprise an extension of 1 to 5 (naturaly occurring) amino acids, such as a single alanine (A) extension, at the C-terminus of the single-domain antibody (e.g., VHH).
  • A alanine
  • the C-terminus of a VHH is normaly VTVSS (SEQ ID NO: 4031).
  • a single- 131 310886415v1 Attorney Docket No: 260525.000071 domain antibody (e.g., VHH) of the present disclosure comprises a lysine (K) or glutamine (Q) at position 110 (according to Kabat numbering).
  • a single-domain antibody (e.g., VHH) of the present disclosure comprises a lysine (K) or glutamine (Q) at position 112 (according to Kabat numbering).
  • the C-terminus of a single-domain antibody can be any one of VKVSS (SEQ ID NO: 4032), VQVSS (SEQ ID NO: 4033), VTVKS (SEQ ID NO: 4034), VTVQS (SEQ ID NO: 4035), VKVKS (SEQ ID NO: 4036), VKVQS (SEQ ID NO: 4037), VQVKS (SEQ ID NO: 4038), or VQVQS (SEQ ID NO: 4039).
  • single-domain antibodies e.g., VHH
  • single-domain antibodies are modified by changes in carboxy-terminal region, for example to a terminal sequence having the sequence GQGTLVTVKPGG (SEQ ID NO: 4043) or GQGTLVTVEPGG (SEQ ID NO: 4044) or modification thereof.
  • Additional modification to reduce binding by pre-existing antibodies in human serum can be found in e.g., WO2012/175741, WO2015/173325, WO2016/150845, WO2011/003622, WO2013/024059; US 11,426,468, US 10,526,397, which are incorporated herein by reference in their entities.
  • a single-domain antibody (e.g., VHH) of the present disclosure comprises at the carboxy-terminus starting from position 111 according to Chothia the amino acid sequence VAGG (SEQ ID NO: 4697) or VPAG (SEQ ID NO: 4698).
  • a single-domain antibody (e.g., VHH) of the present disclosure comprises at the carboxy-terminus starting from position 111 according to Chothia the amino acid sequence VAGG (SEQ ID NO: 4697).
  • a single-domain antibody (e.g., VHH) of the present disclosure comprises at the carboxy-terminus starting from position 111 according to Chothia the amino acid sequence VPAG (SEQ ID NO: 4698).
  • a single-domain antibody e.g., VHH
  • VHH single-domain antibody
  • a single-domain antibody comprises an amino acid sequence selected from any one of SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 132 310886415v1
  • a single-domain antibody e.g., VHH
  • VHH comprises an amino acid sequence selected from any one of SEQ ID NOs: 81-92, 4076-4078, 4523, 4526, 4529, 4532, 4731-4734, 641-1127, 4126-4172, 4775, 4782, 4784, 4794-4808, 4857-4902, and 4994-5001, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, wherein the amino acid sequence at the carboxy-terminus starting from position 111 according to Chothia comprises VAGG (SEQ ID NO: 4697) or VPAG (SEQ ID NO: 4698).
  • single-domain antibodies e.g., VHH
  • VHH single-domain antibodies
  • Single-domain antibodies e.g., VHH
  • SpA staphylococcal protein A
  • SpG streptococcal protein G
  • binding of SpA and SpG to antibodies or antibody fragments can be useful in the manufacturing process of the antibodies or antibody fragments.
  • the high-afinity interaction of the IgG Fc region with SpA and SpG has been extensively exploited and became the gold standard for monoclonal antibody purification (Björck and Kronval, 1984).
  • non-Fc containing antibody fragments such as VHHs and Fabs do not have the capacity to bind to SpA or SpG via their Fc regions.
  • sequence-dependent interaction with SpA has been demonstrated for these non-Fc containing antibody fragments(Graile et al., 2000; Henry et al., 2016). This characteristic circumvents potential use of afinity tags fused to the drug candidate for afinity chromatography that have the disadvantage as being regarded as a sequence liability, as it may impact protein immunogenicity as wel as protein structure and stability and could compromise functionality.
  • single-domain antibodies e.g., VHH
  • SpA single-domain antibodies
  • single-domain antibodies (e.g., VHH) of the present disclosure have, or are modified to have a SpA-binding motif.
  • the VHH-SpA interface has been mapped to thirteen residues, which cluster within the framework at the back side of the V-body, distant to the CDRs (Graile et al., 2000, Henry et al., 2016).
  • the thirteen residues of the VHH-SpA interface have been characterized to be intolerant to substitutions (residues Gly15, Arg19, Tyr59, Gly65, and Arg66), tolerant to specific substitutions (residues Thr/Lys/Arg57, Thr68, Gln81, Asn82a, and Ser82b) or generaly tolerant to a variety of substitutions (residues Ser17, Lys64, and Ser70) (al residue positions refer to Kabat numbering) (Henry et al., Plos One, 2016).
  • a SpA-binding motif included in a single-domain antibody (e.g., VHH) of the present disclosure may include one or more, or al of the thirteen residues.
  • single-domain antibodies (e.g., VHH) of the present disclosure comprise one or more modifications at N-terminus to prevent formation of a pyroglutamate and product heterogeneity.
  • the amino acid residue Glu at the first position of the single-domain antibodies (e.g., VHH) is replaced with Asp (E1D).
  • a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 134 310886415v1 Attorney Docket No: 260525.000071 4064, 4068, 4072, 4521, 93-640, 4079-41252805-3363, 4359-4420, 4605-4628, 4780, 4781, 4783, 4785, and 4786, or a sequence having at least 75% identity thereto, wherein the amino acid residue Glu at the first position of the single-domain antibody (e.g., VHH) is replaced with Asp (E1D).
  • SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 134 310886415v1 Attorney Docket No: 260525.000071 4064, 4068, 4072, 4521, 93-640, 4079-41252805-3363, 4359-4420, 46
  • a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 4064, 4068, 4072, 4521, 4780, 4781, 4783, 4785, and 4786, or a sequence having at least 75% identity thereto, wherein the amino acid residue Glu at the first position of the single-domain antibody (e.g., VHH) is replaced with Asp (E1D).
  • SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 4064, 4068, 4072, 4521, 4780, 4781, 4783, 4785, and 4786 or a sequence having at least 75% identity thereto, wherein the amino acid residue Glu at the first position of the single-domain antibody (e.g., VHH) is replaced with Asp (E1D).
  • a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 81-92, 4076-4078, 4523, 4526, 4529, 4532, 4731-4734, 641-1127, 4126-4172, 4775, 4782, 4784, 4794-4808, 4857-4902, and 4994-5001, or a sequence having at least 75% identity thereto, wherein the amino acid residue Glu at the first position of the single-domain antibody (e.g., VHH) is replaced with Asp.
  • a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 81-92, 4076-4078, 4523, 4526, 4529, 4731-4734, 4532, 4775, 4782, 4784, 4794-4808, and 4857-4902, or a sequence having at least 75% identity thereto, wherein the amino acid residue Glu at the first position of the single-domain antibody (e.g., VHH) is replaced with Asp (E1D).
  • SEQ ID NOs: 81-92, 4076-4078 amino acid sequence selected from any one of SEQ ID NOs: 81-92, 4076-4078, 4523, 4526, 4529, 4731-4734, 4532, 4775, 4782, 4784, 4794-4808, and 4857-4902, or a sequence having at least 75% identity thereto, wherein the amino acid residue Glu at the first position of the single-domain antibody (e.g., VHH)
  • a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 4994-5001, or a sequence having at least 75% identity thereto, wherein the amino acid residue Glu at the first position of the single-domain antibody (e.g., VHH) is replaced with Asp (E1D).
  • Alternative protein scafolds [0335] In some embodiments, anti-TNFR2 antigen-binding proteins of the present disclosure can adopt an alternative protein scafold.
  • Such alternative protein scafold may be a single chain polypeptidic framework, optionaly with a reduced size (e.g., less than about 200 amino acids), that contains a highly structured core associated with variable domains of high conformational tolerance alowing insertions, deletions, or other substitutions.
  • Such antigen-binding proteins may be generated by grafting CDRs or variable regions described herein onto a suitable protein scafold.
  • the structure of alternative scafolds may vary, but preferably are of human origin for those developed as therapeutics.
  • Alternative protein scafolds of the present disclosure can be based either on a conventional immunoglobulin (Ig) backbone, or are derived from a completely unrelated protein. These variable domains can be modified to create novel binding interfaces toward any targeted antigen.
  • Ig immunoglobulin
  • an alternative protein scafold of the present disclosure can be derived from Protein A, e.g., the Z-domain thereof (afibodies), ImmE7 (immunity proteins), BPTI/APPI (Kunitz domains), Ras- binding protein AF-6 (PDZ-domains), charybdotoxin (Scorpion toxin), CTLA-4, Min-23 (knottins), lipocalins (anticalins), neokarzinostatin, a fibronectin domain (used in “adnectin”), an ankyrin repeat (AR) domain (used in “DARPins”), avidity multimers (also known as “avimers”), or thioredoxin (Skerra, A., Curr.
  • Protein A e.g., the Z-domain thereof (afibodies), ImmE7 (immunity proteins), BPTI/APPI (Kunitz domains), Ras- binding protein AF-6 (PDZ-domains
  • Anticalins are a suitable type of non-Ig based alternative scafolds for use in the antigen-binding molecules of the present disclosure.
  • Anticalins are a class of engineered ligand-binding proteins that are based on the lipocalin scafold.
  • Lipocalins are a family of proteins that transport smal hydrophobic molecules such as steroids, bilins, retinoids, and lipids. Lipocalins have limited sequence homology, but share a common tertiary structure architecture based on eight antiparalel ⁇ -barrels. Lipocalins contain four exposed loops built on the rigid ⁇ -barrel structure. Exemplary anticalin proteins that are commonly used are about a size of about 180 amino acids and a mass of about 20 kDa. [0338] DARPins are another suitable non-Ig based alternative scafold that can be used in the antigen- binding molecules of the present disclosure.
  • DARPins are geneticaly engineered antibody mimetic proteins typicaly exhibiting highly specific and high-afinity target protein binding. They are derived from natural ankyrin repeat (AR) proteins, which usualy contain a 33 amino acid protein motif consisting of two ⁇ -helices separated by loops, which repeats mediate protein—protein interactions. DARPins can be generated using combinatorial AR libraries constructed based on the 33 amino acid AR motif with seven randomized positions. DARPin libraries can be screened using ribosome display, and library members typicaly are wel produced in Escherichia coli, do not aggregate, and display high thermodynamic stability.
  • AR ankyrin repeat
  • DARPins contain two to four of these motifs flanked by N- and C- terminal capping motifs to shield hydrophobic regions and alow increased solubility.
  • the avimer structure can also be used as a protein backbone to generate a suitable non-Ig based alternative scafold.
  • Avimers typicaly consist of two or more peptide sequences of 30 to 35 amino acids each, connected by peptide linker. The individual sequences are derived from A-domains of various 136 310886415v1 Attorney Docket No: 260525.000071 membrane receptors and have a rigid structure, stabilized by disulfide bridges and calcium. Each A- domain can bind to a certain epitope of the target protein.
  • Proteins derived from fibronectin II (FN3) domains can also be used to generate a suitable non- Ig based alternative scafold (also known as “monobody”).
  • FN3 domains proteins derived from fibronectin II domains
  • FN10 tenth fibronectin type II domain of human fibronectin corresponds to a ⁇ -sandwich with seven ⁇ -strands and three connecting loops showing structural homologies to Ig domains without disulfide bridges.
  • the connecting loops of FN10 can be randomized and the domains displayed on both phage and yeast to select for a scafold with the desirable properties.
  • AdnectinsTM is an exemplary scafold generated using 10th FN3 domains randomized and displayed in this way.
  • Another exemplary scafold comprising FN3 domains is a CentyrinTM.
  • CentryrinsTM contain the consensus sequence of FN3 domains of human Tenascin C (TNC), which is found in the extracellular matrix of various tissues.
  • CentyrinTM scafolds have loops that have structural homology to antibody variable domains (i.e., CDR1, CDR2 and CDR3), and are smal (about 10 kDa), simple, and highly stable single domain proteins that do not contain cysteine, disulfides, or glycosylated residues. CentyrinTM possess excellent biophysical properties such as stability to heat, pH, denaturant and organic solvents, reversible unfolding and monodispersity.
  • Another recent exemplary FN3-based scafold that can be used in the present disclosure is fluctuation-regulated afinity proteins (FLAPs), as described in See et al., 2020.
  • FLAPs fluctuation-regulated afinity proteins
  • Fusion Proteins and Conjugates comprising at least one anti- TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) linked, directly or indirectly, to one or more additional domains or moieties.
  • the at least one anti-TNFR2 antigen-binding protein can specificaly bind TNFR2.
  • the fusion protein or conjugate of the present disclosure comprises a single polypeptide. In other embodiments, the fusion protein or conjugate of the present disclosure comprises more than one polypeptide.
  • the fusion protein or conjugate of the present disclosure comprises two polypeptides.
  • the fusion protein or conjugate of the present disclosure comprises at least one anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) described herein.
  • the fusion protein or conjugate is multivalent.
  • the fusion 137 310886415v1 Attorney Docket No: 260525.000071 protein or conjugate of the present disclosure may be at least bivalent, but can also be e.g., trivalent, tetravalent, pentavalent, hexavalent, etc.
  • the fusion protein or conjugate is multispecific.
  • the one or more additional domain or moieties may be one or more additional binding domain that binds to one or more further antigen or protein.
  • the fusion protein or conjugate of the present disclosure may be, for example, bispecific, trispecific, tetraspecific, pentaspecific, etc.
  • the two or more anti-TNFR2 antigen-binding proteins may comprise the same sequence or may comprise diferent sequences.
  • the two or more anti-TNFR2 antigen-binding proteins may bind to the same epitope on TNFR2 or diferent epitopes on TNFR2.
  • a fusion protein or conjugate of the present disclosure may be biparatopic, e.g., if two VHHs bind two diferent epitopes on TNFR2.
  • multivalent anti-TNFR2 fusion constructs can comprise two or more anti-TNFR2 antigen-binding proteins each comprising an amino acid sequence selected from any of the CDR1, CDR2, and/or CDR3 amino acid sequences listed in Table 1-1, Table 5, Table 7, or Table 8, or any combination thereof, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity, or any combination thereof.
  • multivalent anti-TNFR2 fusion constructs can comprise two or more anti-TNFR2 antigen-binding proteins each comprising a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within any of the exemplary anti- TNFR2 VHH antibodies listed in Table 1-1, Table 1-2, Table 5, Table 7, or Table 8.
  • the two or more anti-TNFR2 antigen-binding proteins can comprise the same set of three CDRs.
  • the two or more anti-TNFR2 antigen-binding proteins can comprise diferent sets of three CDRs.
  • fusion proteins of the present disclosure bind to human TNFR2.
  • fusion proteins e.g., fusion proteins such as fusion proteins conjugated to Fc regions
  • the present disclosure may bind to human TNFR2 with a K of l ⁇ 6 D ess than about 1 ⁇ 10 M, for example, less than about 5 ⁇ 10 ⁇ 7 M, less than about 3 ⁇ 10 ⁇ 7 M, less than about 1 ⁇ 10 ⁇ 7 M, less than about 8 ⁇ 10 ⁇ 8 M, less than about 5 ⁇ 10 ⁇ 8 M, less than about 3 ⁇ 10 ⁇ 8 M, less than about 1 ⁇ 10 ⁇ 8 M, less than about 8 ⁇ 10 ⁇ 9 M, less than about 5 ⁇ 10 ⁇ 9 M, less than about 3 ⁇ 10 ⁇ 9 M, less than about 1 ⁇ 10 ⁇ 9 M, less than about 8 ⁇ 10 ⁇ 10 M, less than about 5 ⁇ 10 ⁇ 10 M, less than about 3 ⁇ 10 ⁇ 10 M, less than about 1 ⁇ 10 ⁇ 10 M, less than about 8 ⁇ 10 ⁇ 10 M, less than about 5 ⁇ 10 ⁇ 10 M, less than about 3 ⁇ 10 ⁇ 10 M, less than about 1 ⁇ 10 ⁇ 10 M, less than
  • fusion proteins e.g., fusion proteins such as fusion proteins conjugated to Fc regions
  • fusion proteins may bind to human TNFR2 with a K -12 D of about 1x10 M to about 1 ⁇ 10 ⁇ 6 M.
  • fusion proteins e.g., fusion proteins such as fusion proteins conjugated to Fc regions
  • fusion proteins may bind to human TNFR2 with a KD of about 1 ⁇ 10 ⁇ 8 M to about 2.7 ⁇ 10 ⁇ 6 M.
  • fusion proteins e.g., fusion proteins such as fusion proteins conjugated to Fc regions
  • fusion proteins of the present disclosure may bind to human TNFR2 with a K of ab ⁇ 12 ⁇ 7 D out 3 ⁇ 10 M to about 1 ⁇ 10 M.
  • fusion proteins of the present disclosure bind to cynomolgus monkey (“cyno”) TNFR2.
  • fusion proteins e.g., fusion proteins such as fusion proteins conjugated to Fc regions
  • a KD of less than about 1 ⁇ 10 ⁇ 6 M, for example, less than about 5 ⁇ 10 ⁇ 7 M, less than about 3 ⁇ 10 ⁇ 7 M, less than about 1 ⁇ 10 ⁇ 7 M, less than about 8 ⁇ 10 ⁇ 8 M, less than about 5 ⁇ 10 ⁇ 8 M, less than about 3 ⁇ 10 ⁇ 8 M, less than about 1 ⁇ 10 ⁇ 8 M, less than about 8 ⁇ 10 ⁇ 9 M, less than about 5 ⁇ 10 ⁇ 9 M, less than about 3 ⁇ 10 ⁇ 9 M, or less than about 1 ⁇ 10 ⁇ 9 M, less than about 8 ⁇ 10 ⁇ 10 M, less than about 5 ⁇ 10 ⁇ 10 M, less than about 3 ⁇ 10 ⁇ 10 M, less than about 1 ⁇ 10 ⁇ 10 M, less than about 8 ⁇ 10 ⁇ 11 M, less than about 5 ⁇ 10 ⁇ 11 M, less than about 3 ⁇ 10 ⁇ 11 M, less than about 1 ⁇ 10 ⁇ 11 M
  • fusion proteins e.g., fusion proteins such as fusion proteins conjugated to Fc regions
  • fusion 139 310886415v1 Attorney Docket No: 260525.000071 proteins (e.g., fusion proteins such as fusion proteins conjugated to Fc regions) of the present disclosure may bind to cyno TNFR2 with a K -8 ⁇ 6 D of about 3x10 M to about 2.4 ⁇ 10 M.
  • fusion proteins e.g., fusion proteins such as fusion proteins conjugated to Fc regions
  • a fusion protein or conjugate of the present disclosure comprises at least one anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) provided herein operably linked to a dimerization domain such as an immunoglobulin Fc region.
  • anti-TNFR2 antigen-binding protein e.g., antibody such as a single-domain antibody
  • an immunoglobulin Fc region may be linked indirectly or directly to the at least one anti-TNFR2 antigen- binding protein (e.g., antibody such as a single-domain antibody).
  • a fusion protein or conjugate of the present disclosure comprises one, two, three, four, five, six or more anti- TNFR2 antigen-binding proteins provided herein operably linked to an Fc region.
  • the present disclosure provides a fusion protein or conjugate that comprises (1) a means for binding an epitope within human TNFR2 bound by any one of the exemplary anti-TNFR2 VHH antibodies listed in Table 1-1, Table 1-2, Table 5, Table 7, or Table 8; and (2) an Fc region.
  • the present disclosure provides a fusion protein or conjugate that comprises (1) a means for binding an epitope within human TNFR2 bound by an antibody selected from T-004, T-004.VTV, T-007hu1 with CDR2 G/A, CDR3 T/S, T-009Hu1_QGR, T-009Hu1_SGR, T- 009Hu1_QGR_N/C, T-009Hu1_NAR_N/C, T-009Hu1_SGR_N/C, T-007Hu1.S3.QGR, T-007Hu1.S3.EGR, T- 007Hu1.S3.SGR, T-007Hu1.S3.NSR, T-007Hu1.S3.NTR, T-007Hu1.S3.SAR, T-007Hu1.EQ.QGR, T- 007Hu1.EQ.EGR, T-007Hu1.EQ.EGR, T-007Hu1.EQ.EGR, T-007Hu1.EQ.SGR
  • a “Fc region” as used herein refers to a portion of a heavy chain constant region comprising CH2 and CH3.
  • an Fc region comprises a hinge, CH2, and CH3.
  • the hinge can mediate dimerization between two Fc-containing polypeptides.
  • An Fc region included in a fusion protein or conjugate may be an Fc region from any species, or derived from any species, including, but not limited to, human, mouse, rat, monkey (e.g., cyno), camel, lama, shark, goat, rabbit, and/or bovine.
  • an Fc region included in a fusion protein or conjugate of the present disclosure is a human immunoglobulin Fc region, or is derived from a human immunoglobulin Fc region.
  • the immunoglobulin Fc region is of IgG, IgE, IgM, IgD, IgA or IgY isotype.
  • the immunoglobulin Fc region is an IgG isotype, such as IgG1, IgG2, IgG3, or IgG4 subclass.
  • the immunoglobulin Fc region may comprise a variant or fragment of a native IgG Fc region.
  • an Fc region included in a fusion protein or conjugate described herein may be a murine (e.g., a mouse or a rat) immunoglobulin Fc region, or derived from a murine immunoglobulin Fc region.
  • an Fc region included in a fusion protein or conjugate described herein may be a cyno immunoglobulin Fc region, or derived from a cyno immunoglobulin Fc region.
  • a native Fc region typicaly possesses an effector function, including but not limited to, Fc receptor binding; Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cel-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cel surface receptors (for example B-cel receptor); and B-cel activation, etc.
  • Such effector functions generaly require the Fc region to be combined with a binding domain (for example, an antibody variable domain) and can be assessed using various assays.
  • a fusion protein or conjugate of the present disclosure can comprise a dimer of Fc regions.
  • an Fc region mediates dimerization of the TNFR2-binding units at physiological conditions, such as when expressed from a cel, such that a dimer is formed that doubles the number of TNFR2 binding units.
  • a fusion polypeptide comprising one VHH domain that binds TNFR2 and an Fc region is monovalent as a monomer, but the Fc region can mediate dimerization; as a result, the fusion protein is bivalent (i.e., having two anti-TNFR2 VHH domains per molecule).
  • two anti-TNFR2 VHH domains (2x) are fused to an IgG Fc region and as a result of dimerization, the fusion protein is tetravalent (i.e., having four anti-TNFR2 VHH domains per molecule).
  • three anti-TNFR2 VHH domain (3 ⁇ ) are fused to an IgG 141 310886415v1 Attorney Docket No: 260525.000071 Fc region and as a result of dimerization, the fusion protein is hexavalent (i.e., having six anti-TNFR2 VHH domains per molecule).
  • a fusion protein or conjugate of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)n- Linker-Fc, wherein n can be any integral number (e.g., 1, 2, 3, 4, 5, etc).
  • n can be any integral number (e.g., 1, 2, 3, 4, 5, etc).
  • each anti-TNFR2 VHH may be optionaly operably linked to another anti-TNFR2 VHH via a linker.
  • a fusion protein or conjugate of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)n- Linker-Fc-(anti-TNFR2 VHH)m, wherein n and m can independently be any integral number (e.g., 1, 2, 3, 4, 5, etc).
  • n and m can independently be any integral number (e.g., 1, 2, 3, 4, 5, etc).
  • each anti-TNFR2 VHH may be optionaly operably linked to another anti- TNFR2 VHH via a linker.
  • a fusion protein or conjugate of the present disclosure is bivalent.
  • the bivalent fusion protein or conjugate of the disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker-Fc.
  • a fusion protein or conjugate of the present disclosure is tetravalent.
  • the tetravalent fusion protein or conjugate of the disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker- (anti-TNFR2 VHH)-Linker-Fc.
  • the tetravalent fusion protein or conjugate of the disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker-Fc-Linker-(anti-TNFR2 VHH).
  • the multiple linkers used in the fusion protein are not necessarily the same.
  • a fusion protein or conjugate of the disclosure is hexavalent.
  • the hexavalent fusion protein or conjugate of the disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker-(anti-TNFR2 VHH)-Linker-(anti-TNFR2 VHH)-Linker-Fc.
  • the hexavalent fusion protein or conjugate of the disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker-(anti-TNFR2 VHH)-Linker-Fc-linker-(anti-TNFR2 VHH).
  • the hexavalent fusion protein or conjugate of the disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker-Fc- Linker-(anti-TNFR2 VHH)-Linker-(anti-TNFR2 VHH).
  • the multiple linkers used in the fusion protein are not necessarily the same.
  • the CH3 domain of the Fc region can be used as homodimerization domain, such that the resulting fusion protein may be formed from two identical polypeptides.
  • the CH3 dimer interface region of the Fc region can be mutated to enable heterodimerization.
  • a heterodimerization domain can be incorporated into the fusion protein such that the construct is a heterodimeric fusion protein.
  • the first and second Fc regions may be of the same IgG isotype such as, e.g., IgG1/IgG1, IgG2/IgG2, IgG4/IgG4.
  • the first and second Fc regions may be of diferent IgG isotypes such as, e.g., IgG1/IgG2, IgG1/IgG4, IgG2/IgG4, etc.
  • the Fc region included in a fusion protein or conjugate of the present disclosure can be mutated or modified.
  • the mutations include one or more amino acid substitutions to reduce an effector function of the Fc region.
  • mutations to Fc regions to alter, such as reduce, effector function are known, including any as described below.
  • the numbering of the residues in an immunoglobulin heavy chain or portion thereof, such as an Fc region is according to the EU index as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991).
  • the human IgG Fc region is modified to alter antibody-dependent celular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC).
  • Non-limiting examples of amino acid modifications that can alter ADCC and/or CDC are described in Alegre et al, 1992 J Immunol, 148: 3461-3468; Idusogie et al., 2001 J Immunol, 166(4): 2571-5; Shields et al., 2001 JBC, 276(9): 6591-6604; Lazar et al., 2006 PNAS, 103(11): 4005-4010; Stavenhagen et al., 2007 Cancer Res, 67(18): 8882-8890; Natsume et al., 2008 Cancer Res, 68(10): 3863-72; Stavenhagen et al., 2008 Advan.
  • an Fc region included in a fusion protein or conjugate of the present disclosure exhibits reduced effector functions (such as CDC and ADCC).
  • Various in vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities.
  • Fc receptor (FcR) binding assays can be conducted to ensure that the fusion protein construct and/or cleaved components thereof lack Fc ⁇ R binding (hence likely lacking ADCC activity), but retains FcRn binding ability.
  • the primary cels for mediating ADCC are NK cels which express Fc ⁇ RII only, whereas monocytes express Fc ⁇ RI, Fc ⁇ RI and Fc ⁇ RII.
  • Non-limiting examples of in vitro assays to assess 143 310886415v1 Attorney Docket No: 260525.000071 ADCC activity of a molecule of interest are described in e.g., US 5,500,362; US 5,821,337; Helstrom. et al., Proc.
  • non- radioactive assay methods may be employed, such as ACTITM non-radioactive cytotoxicity assay for flow cytometry or CytoTox96TM non-radioactive cytotoxicity assay.
  • Useful effector cels for such assays include peripheral blood mononuclear cels (PBMC) and Natural Kiler (NK) cels.
  • ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998).
  • C1q binding assays may also be carried out to confirm that the fusion protein construct or cleaved components thereof is unable to bind C1q and hence lacks CDC activity (see, e.g., C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402).
  • a CDC assay may be performed (see, e.g., Gazzano- Santoro et al., J.
  • mutations that enhance CDC include modifications at Lys326 and Glu333.
  • the Fc region is modified at one or both of these positions, for example Lys326Ala and/or Glu333Ala (K326A and E333A) using the Kabat numbering system.
  • the Fc region of the fusion protein is altered at one or more of the folowing positions to reduce Fc receptor binding: Leu 234 (L234), Leu235 (L235), Asp265 (D265), Asp270 (D270), Ser298 (S298), Asn297 (N297), Asn325 (N325) orAla327 (A327) or Pro329 (P329).
  • Leu 234Ala (L234A), Leu235Ala (L235A), Leu235Glu (L235E), Asp265Asn (D265N), Asp265Ala (D265A), Asp270Asn (D270N), Ser298Asn (S298N), Asn297Ala (N297A), Pro329Ala (P329A) or Pro239Gly (P329G), Asn325Glu (N325E) orAla327Ser (A327S).
  • modifications within the Fc region reduce binding to Fc-receptor-gamma receptors (Fc ⁇ Rs) while have minimal impact on binding to the neonatal Fc receptor (FcRn).
  • the human IgG1 Fc region is modified at amino acid Asn297 (Kabat Numbering) to prevent glycosylation of the fusion protein, e.g., Asn297Ala (N297A) or Asn297Asp (N297D).
  • the Fc region of the fusion protein is modified at amino acid Leu235 144 310886415v1 Attorney Docket No: 260525.000071 (Kabat Numbering) to alter Fc receptor interactions, e.g., Leu235Glu (L235E) or Leu235Ala (L235A).
  • the Fc region of the fusion protein is modified at amino acid Leu234 (Kabat Numbering) to alter Fc receptor interactions, e.g., Leu234Ala (L234A).
  • the Fc region of the fusion protein is modified at amino acid Leu234 (Kabat Numbering) to alter Fc receptor interactions, e.g., Leu235Glu (L235E).
  • the Fc region of the fusion protein is altered at both amino acids 234 and 235, e.g., Leu234Ala and Leu235Ala (L234A/L235A) or Leu234Val and Leu235Ala (L234V/L235A).
  • the Fc region of the fusion protein is altered at amino acids at 234, 235, and 297, e.g., Leu234Ala, Leu235Ala, Asn297Ala (L234A/L235A/N297A).
  • the Fc region of the fusion protein is altered at amino acids at 234, 235, and 329, e.g., Leu234Ala, Leu235Ala, Pro239Ala (L234A/L235A/P329A).
  • the Fc region of the fusion protein is modified at amino acid Asp265 (Kabat Numbering) to alter Fc receptor interactions, e.g Asp265Ala (D265A).
  • the Fc region of the fusion protein is modified at amino acid Pro329 (Kabat Numbering) to alter Fc receptor interactions, e.g., Pro329Ala (P329A) or Pro329Gly (P329G).
  • the Fc region of the fusion protein is altered at both amino acids 265 and 329, e.g., Asp265Ala and Pro329Ala (D265A/P329A) or Asp265Ala and Pro329Gly (D265A/P329G).
  • the Fc region of the fusion protein is altered at amino acids at 234, 235, and 265, e.g., Leu234Ala, Leu235Ala, Asp265Ala (L234A/L235A/D265A).
  • the Fc region of the fusion protein is altered at amino acids at 234, 235, and 329, e.g., Leu234Ala, Leu235Ala, Pro329Gly (L234A/L235A/P329G). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 234, 235, 265 and 329, e.g., Leu234Ala, Leu235Ala, Asp265Ala, Pro329Gly (L234A/L235A/D265A/P329G). In some embodiments, the Fc region of the fusion protein is altered at Gly235 to reduce Fc receptor binding.
  • the human IgG1 Fc region is modified at amino acid Gly236 to enhance the interaction with CD32A, e.g., Gly236Ala (G236A).
  • the human IgG1 Fc region lacks Lys447 (EU index of Kabat et al 1991 Sequences of Proteins of Immunological Interest).
  • the Fc region of the fusion protein is altered at amino acids at 234, 235, and 236, e.g., Leu234Gly, Leu235Ser, Gly236Arg (L234G/L235S/G236R).
  • the Fc region of the fusion protein is altered at amino acids at 234, 235, and 236, e.g., Leu234Ser, Leu235Thr, Gly236Arg (L234S/L235T/G236R). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 234, 235, and 236, e.g., Leu234Ser, Leu235Val, Gly236Arg (L234S/L235V/G236R).
  • the Fc region of the fusion protein is altered at amino acids at 234, 235, and 236, e.g., 145 310886415v1 Attorney Docket No: 260525.000071 Leu234Thr, Leu235Gln, Gly236Arg (L234T/L235Q/G236R). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 234, 235, and 236, e.g., Leu234Thr, Leu235Thr, Gly236Arg (L234T/L235T/G236R).
  • the Fc region of the fusion protein fusion protein is altered at amino acids at 234, 235, and 329, e.g., Leu234Thr, Leu235Thr, Pro329Gly (L234A/L235A/P329G). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 252, 254, and 256, e.g., Met252Tyr, Ser254Thr, Thr256Glu (M252Y/S254T/T256E).
  • the Fc region of the fusion protein is lacking an amino acid at one or more of the folowing positions to reduce Fc receptor binding: Glu233 (E233), Leu234 (L234), or Leu235 (L235).
  • the Fc region of the fusion protein is lacking an amino acid at one or more of the folowing positions Glu233 (E233), Leu234 (L234), or Leu235 (L235) and is modified at one or more of the Asp265 (D265), Asn297 (N297), or Pro329 (P329) to reduce Fc receptor binding.
  • an Fc region included in a TNFR2 binding polypeptide is derived from a human Fc domain, and comprises a three amino acid deletion in the lower hinge corresponding to IgG1 E233, L234, and L235.
  • such Fc polypeptides do not engage Fc ⁇ Rs and thus are referred to as “efector silent” or “efector nul.”
  • Fc deletion of these three amino acids reduces the complement protein C1q binding.
  • a polypeptide with an Fc region with Fc deletion of these three amino acids retains binding to FcRn and therefore has extended half-life and transcytosis associated with FcRn mediated recycling.
  • the immunoglobulin Fc region of the fusion protein is a variant of human IgG1 Fc region, having an amino acid sequence: IgG1 L234A, L235A (also known as “LALA” variant) (mutations bolded in the sequence below) DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSPG (SEQ ID NO: 4045) [0372] In one embodiment, the immunoglobulin Fc region of the fusion protein is a variant of human IgG1 Fc region, having an amino acid sequence: I
  • the immunoglobulin Fc region of the fusion protein is a variant of human IgG1 Fc region, having an amino acid sequence: IgG1 D265A, N297A and P329A (also known as “DANAPA” variant) (mutations bolded in the sequence below) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYAST YRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSPG (SEQ ID NO: 4047) [0375] In one embodiment, the immunoglobulin Fc region of the fusion protein is a variant of human Ig
  • Fc mutations that enhance binding to FcRn are Met252Tyr, Ser254Thr, Thr256Glu (M252Y, S254T, T256E, respectively) (Kabat numbering, Dal'Acqua et al 2006, J.
  • the Fc region lacks or has reduced fucose attached to the N-linked glycan-chain at N297.
  • fucosylation There are numerous ways to prevent fucosylation, including but not limited to production in a FUT8 deficient cel line; addition inhibitors to the mammalian cel culture media, for example Castanospermine; and metabolic engineering of the production cel line.
  • the Fc domain included in a fusion protein or conjugate of the present disclosure is derived from a human Fc domain and comprises mutations M252Y and M428V.
  • the mutated or modified Fc polypeptide includes the folowing mutations: M252Y and M428L using the Kabat numbering system.
  • such mutations enhance binding to FcRn at the acidic pH of the endosome (near 6.5), while losing detectable binding at neutral pH (about 7.2), alowing for enhanced FcRn mediated recycling and extended half-life.
  • the Fc domain included in a fusion protein or conjugate is derived from a human Fc domain and comprises mutations to induce heterodimerization.
  • such mutations include those referred to as “knob” and “hole” mutations.
  • the “knob” Fc domain comprises the mutation T366W.
  • the “hole” Fc domain comprises mutations T366S, L368A, and Y407V.
  • Fc domains used for heterodimerization comprise additional mutations, such as the mutation S354C on a first member of a heterodimeric Fc pair that forms an asymmetric disulfide with a corresponding mutation Y349C on the second member of a heterodimeric Fc pair.
  • one member of a heterodimeric Fc pair comprises the modification H435R or H435K to prevent protein A binding while maintaining FcRn binding.
  • one member of a heterodimeric Fc pair comprises the modification H435R or H435K, while the second member of the heterodimeric Fc pair is not modified at H435.
  • the hole Fc domain comprises the modification H435R or H435K (referred to as “hole-R” in some instances when the modification is H435R), while the knob Fc domain does not.
  • the hole-R mutation improves purification of the heterodimer over homodimeric hole Fc domains that may be present.
  • the human IgG Fc region is modified to prevent dimerization.
  • the fusion proteins of the present disclosure are monomeric. For example, modification at residue Thr366 to a charged residue, e.g. Thr366Lys, Thr366Arg, Thr366Asp, or Thr366Glu (T366K, T366R, T366D, or T366E, respectively), prevents CH3-CH3 dimerization.
  • the immunoglobulin Fc region of the fusion protein is of human IgG3 isotype, or a variant thereof.
  • the IgG3 Fc region is modified at amino acid Asn297 (Kabat Numbering) to prevent to glycosylation of the antibody, e.g., Asn297Ala (N297A) or Asn297Asp (N297D).
  • the human IgG3 Fc region is modified at amino acid 435 to extend the half-life, e.g., Arg435His (R435H).
  • the human IgG3 Fc region lacks Lys447 (EU index of Kabat et al 1991).
  • the immunoglobulin Fc region of the fusion protein is of human IgG4 isotype, or a variant thereof.
  • an immunoglobulin Fc region of human IgG4 isotype may have an amino acid sequence: ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 5005) 150 310886415v1 Attorney Docket No: 260525.000071 [0391]
  • the immunoglobulin Fc region of human IgG4 isotype may comprise the amino acid sequence set forth in SEQ ID NO: 5505, or a similar sequence thereof having
  • the human IgG4 Fc region comprises one or more mutations selected from, e.g., Ser228Pro (S228P), Leu235Glu (L235E), Leu235Ala (L235A), Phe234Ala (F234A), and/or Pro329Gly (P329G) according to EU numbering.
  • the human IgG4 Fc region is modified at amino acid 235 to alter Fc receptor interactions, e.g., Leu235Glu (L235E).
  • the human IgG4 Fc region is modified at amino acid Asn297 (Kabat Numbering) to prevent to glycosylation of the antibody, e.g., Asn297Ala (N297A) or Asn297Asp (N297D).
  • the human IgG4 Fc region is lacks Lys447 (EU index of Kabat et al 1991).
  • the IgG4 Fc region of the fusion protein is altered at amino acids at 228 and 235, e.g., Ser228Pro, Leu235Glu or Leu235Ala (S228P/L235E or S228P/L235A).
  • the IgG4 Fc region of the fusion protein is altered at amino acids at 228, 234 and 235, e.g., Ser228Pro, Phe234Ala, Leu235Glu or Leu235Ala (S228P/F234A/L235E or S228P/F234A/L235A). In some embodiments, the IgG4 Fc region of the fusion protein is altered at amino acids at 228, 235, and 329, e.g., Ser228Pro, Leu235Glu and P329G (S228P/L235E/P329G).
  • the immunoglobulin Fc region of the fusion protein is a variant of human IgG4 Fc region, having an amino acid sequence: IgG4 S228P, L235E (mutations bolded in the sequence below) ESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4049) [0396] In one embodiment, the immunoglobulin Fc region of the fusion protein is a variant of human IgG4 Fc region, having an amino acid sequence:
  • the fusion protein or conjugate contains an immunoglobulin hinge region.
  • the hinge region serves as a linker to connect one or more TNFR2 binding units (e.g., VHHs) to the Fc region.
  • the fusion protein can comprise a linker in addition to the hinge region to connect the one or more TNFR2 binding units (e.g., VHHs) to the Fc region.
  • the hinge region can be selected from any of the human IgG subclasses.
  • the fusion protein may contain a modified IgG1 hinge having the sequence of EPKSSDKTHTCPPC (SEQ ID NO: 3923), wherein the Cys220 that typicaly forms a disulfide bond with the C-terminal cysteine of the light chain is mutated to serine, e.g., Cys220Ser (C220S).
  • the fusion protein contains a truncated hinge having a sequence DKTHTCPPC (SEQ ID NO: 3924).
  • the fusion protein contains a truncated hinge having a sequence DKTHTCPPCP (SEQ ID NO: 5008).
  • the fusion protein or conjugate has a modified hinge from IgG4, which is modified to prevent or reduce strand exchange, e.g., Ser228Pro (S228P), having the sequence ESKYGPPCPPC (SEQ ID NO: 3925).
  • a fusion protein or conjugate of the present disclosure may comprise sequences other than an Fc region to achieve multimerization (e.g., dimerization).
  • an amino acid sequence containing at least one cysteine residue may be included to facilitate dimerization of two polypeptides by formation of a disulfide bond between the two polypeptides.
  • such multimerizing domain may comprise one or more cysteine residues, 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.
  • Fc mutations suitable for use in the fusion proteins disclosed herein are also discussed in, e.g., Wilkinson et al., Fc-engineered antibodies with immune effector functions completely abolished.
  • a fusion protein or conjugate of the present disclosure may comprise one or more other moieties which provide the fusion protein or conjugate with increased (in vivo) half- life.
  • In vivo half-life extension means, that the fusion protein or conjugate has an increased half-life in a mammal, such as a human subject, after administration.
  • Non-limiting examples of half-life extension moieties suitable for use in the present disclosure include polyethylene glycol (PEG) molecules, serum proteins or fragments thereof, binding units that can bind to serum proteins, an Fc portion, and smal proteins or peptides that can bind to serum proteins.
  • a fusion protein or conjugate of the present disclosure may comprise a binding moiety that can bind to serum albumin, such as human serum albumin, or a serum immunoglobulin, such as IgG.
  • a fusion protein or conjugate of the present disclosure may comprise a binding moiety that can bind to human serum albumin.
  • the binding moiety is a single-domain antibody (e.g., VHH).
  • albumin binders that are described in, e.g., WO 04/041865, WO 06/122787, WO2012/175400, WO 2012/175741, WO2015/173325, WO2017/080850, WO2017/085172, WO2018/104444, WO2018/134235, WO2018/134234, each of which is incorporated 153 310886415v1 Attorney Docket No: 260525.000071 herein by reference is its entirety, can be used in the fusion protein or conjugate of the present disclosure.
  • a fusion protein or conjugate of the present disclosure may comprise one or more cytokine molecules.
  • Non-limiting exemplary cytokine molecules that may be conjugated with include interleukin-2 (IL-2), transforming growth factor beta (TGF- ⁇ ), thymic stromal lymphopoietin (TSLP), or a variant or combination thereof.
  • IL-2 interleukin-2
  • TGF- ⁇ transforming growth factor beta
  • TSLP thymic stromal lymphopoietin
  • the cytokine IL-2 plays a major role in the activation and function of Tregs. Incorporating IL-2 into the anti-TNFR2 fusion protein or conjugate of the present disclosure may enhance the ability of the anti-TNFR2 antigen-binding protein to promote Tregs expansion and stabilization.
  • a fusion protein or conjugate of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)n- Linker-Fc-(IL-2)m, where n and m is independently any integral number (e.g., 1, 2, 3, 4, 5, etc).
  • n and m is independently any integral number (e.g., 1, 2, 3, 4, 5, etc).
  • each anti-TNFR2 VHH may be optionaly operably linked to another anti-TNFR2 VHH via a linker.
  • each IL-2 may be optionaly operably linked to another IL-2 via a linker.
  • a fusion protein or conjugate of the present disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker-Fc- (IL-2).
  • IL-2 fusion proteins may be prepared as described in e.g., US 10,174,091, WO2014/023752, WO2019/246404, each of which is incorporated by reference in its entirety.
  • the IL-2 molecule used in the fusion proteins or conjugates of the present disclosure is a wild-type IL-2 having the amino acid sequence: APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR PRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSISTLT (SEQ ID NO: 3926)
  • the IL-2 molecule used in the fusion proteins or conjugates of the present disclosure is a variant of IL-2 having an amino acid sequence that is at least 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 3926.
  • the IL-2 molecule used in the fusion proteins or conjugates of the present disclosure is a variant of IL-2 with a N88D mutation (bolded in the sequence below), having the amino acid sequence: 154 310886415v1 Attorney Docket No: 260525.000071 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR PRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSISTLT (SEQ ID NO: 3927)
  • Other suitable IL-2 variants that can be used in the fusion proteins or conjugates of the present disclosure include those described in US 10,174,091, US 10,174,092, US 11,091,526, US 11,091,527, WO2016/164937, US 9,580,486, US 7,105,653, US 9,616,105, US 9,428,567, US2017/00
  • Anti-TNFR2 antigen-binding proteins may be operably linked, directly or indirectly, to a second moiety, such as but not limited to, a detectable label, a drug, a toxin, a radionuclide, an enzyme, an immunomodulatory agent, a cytokine, a cytotoxic agent, a smal molecule drug, a chemotherapeutic agent, a therapeutic agent, a diagnostic agent, or a combination thereof.
  • a conjugate of the present disclosure comprises a label, which can generate a detectable signal.
  • the label is capable of producing, either directly or indirectly, a detectable signal.
  • the label may be radio-opaque or a radioisotope (such as 3H, 14C, 32P, 35S, 123I, 125I, 131I); a fluorescent (fluorophore) or chemiluminescent (chromophore) compound (such as fluorescein isothiocyanate, rhodamine or luciferin); an enzyme (such as ⁇ - galactosidase, alkaline phosphatase, or horseradish peroxidase); an imaging agent; or a metal ion.
  • a radioisotope such as 3H, 14C, 32P, 35S, 123I, 125I, 131I
  • a fluorescent (fluorophore) or chemiluminescent (chromophore) compound such as fluorescein isothiocyanate, rhodamine or luciferin
  • an enzyme such as
  • the label is a radioactive atom for scintigraphic studies, for example 99Tc or 123I, or a spin label for nuclear magnetic resonance (NMR) imaging, such as zirconium-89, iodine-123, iodine- 131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron.
  • Zrconium-89 may also be complexed to various metal chelating agents and conjugated to antibodies, e.g., for PET imaging (WO 2011/056983).
  • Anti-TNFR2 antigen-binding proteins e.g., antibodies such as single-domain antibodies
  • another moiety such as an epitope tag, e.g., for the purpose of purification or detection.
  • epitope tag e.g., for the purpose of purification or detection.
  • Examples of such molecules that are useful in protein purification include those that present structural epitopes capable of being recognized by a second molecule. This is commonly employed in protein purification by afinity chromatography, in which a molecule is immobilized on a solid support and exposed to a heterogeneous mixture containing a target protein 155 310886415v1 Attorney Docket No: 260525.000071 conjugated to a molecule capable of binding the immobilized compound.
  • Non-limiting examples of epitope tag molecules that can be conjugated to anti-TNFR2 antigen-binding proteins (e.g., antibodies such as single-domain antibodies) of the present disclosure, e.g., for the purposes of molecular recognition include a poly-histidine tag (His-tag), a myc-tag, human influenza hemagglutinin (HA) tag, a FLAG-tag, maltose-binding protein, glutathione-S-transferase, biotin, and streptavidin.
  • Conjugates containing the epitopes presented by these molecules are capable of being recognized by complementary molecules such as maltose, glutathione, a nickel-containing complex, an anti-FLAG antibody, an anti-myc antibody, an anti-HA antibody, streptavidin, or biotin, respectively.
  • complementary molecules such as maltose, glutathione, a nickel-containing complex, an anti-FLAG antibody, an anti-myc antibody, an anti-HA antibody, streptavidin, or biotin, respectively.
  • a conjugate of the present disclosure may comprise one or more anti- TNFR2 VHH domains described herein conjugated to a therapeutic agent, which can be cytotoxic, cytostatic, or otherwise provides some therapeutic benefit.
  • the cytotoxic agent is a drug, a chemotherapeutic agent, a growth inhibitory agent, a toxin (e.g., an enzymaticaly active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (e.g., a radioconjugate).
  • a conjugate of the present disclosure comprises a toxin.
  • the toxin includes, for example, bacterial toxins such as diphtheria toxin, plant toxins such as ricin, smal molecule toxins such as geldanamycin (Mandler et al., J. Nat. Cancer Inst.
  • toxins may exert their cytotoxic and cytostatic effectss by mechanisms including tubulin binding, DNA binding, or topoisomerase inhibition.
  • anti-TNFR2 antigen-binding proteins e.g., antibodies such as single- domain antibodies
  • CNS central nervous system
  • the moiety that can facilitate delivery of an anti-TNFR2 antigen-binding protein to the central nervous system (CNS)/brain can be for example, a peptide, a polypeptide, smal molecule, a lipid, or a synthetic polymer.
  • CNS central nervous system
  • Various approaches to deliver single-domain antibodies into the brain are described in Pothin et al., Pharmaceutics 2020, 12(10), 937, which is incorporated herein by reference in its entirety.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • a moiety e.g., an antibody
  • TfR transferrin receptor
  • the transferrin receptor (TfR) is highly expressed by brain capilary endothelial cels (BCECs) forming the blood-brain barrier (BBB) and has been utilized as a target for brain drug delivery.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single-domain antibody
  • hydrophobic fatty acid moieties such as C18 faty acid (stearic acid), C16 faty acid (palmitic acid) or C8 fatty acid (octanoic acid) moieties; or amphiphilic block copolymer moieties, such as poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (pluronics or poloxamers) or poly(2-oxasolines).
  • Example methods for ataching a moiety, such as a label, to a binding protein include those described in Hunter, et al., Nature 144:945 (1962); David, et al., Biochemistry 13:1014 (1974); Pain, et al., J. Immunol. Meth.40:219 (1981); Nygren, J. Histochem.
  • the attachment between an anti-TNFR2 antigen-binding protein and a second moiety can be covalent or non-covalent, e.g., via a biotin-streptavidin non-covalent interaction.
  • a second moiety can be atached to an anti-TNFR2 antigen-binding protein using 157 310886415v1 Attorney Docket No: 260525.000071 any of various molecular biological or chemical conjugation and linkage methods known in the art and described below.
  • linkers such as peptide linkers, cleavable linkers, non-cleavable linkers, or linkers that aid in the conjugation reaction, can be used to link, or conjugate a second moiety to an anti-TNFR2 antigen-binding protein described herein.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single- domain antibody
  • one or more second moieties e.g., about 1 to about 20 moieties per molecule, optionaly via a linker.
  • the one or more second moieties can be the same or diferent.
  • the linker may be composed of one or more linker components. For covalent attachment of an antibody and the second moiety, the linker typicaly has two reactive functional groups, i.e., bivalency in a reactive sense.
  • Bivalent linker reagents which are useful to attach two or more functional or biologicaly active moieties, such as peptides, nucleic acids, drugs, toxins, antibodies, haptens, and reporter groups have been described in, e.g., Hermanson, G. T. (1996) Bioconjugate Techniques; Academic Press: New York, p 234-242.
  • a linker used in a conjugate of the present disclosure may include 6- maleimidocaproyl (“MC”), maleimidopropanoyl (“MP”), valine-citruline (“val-cit”), a alanine- phenylalanine (“ala-phe”), p-aminobenzyloxycarbonyl (“PAB”), N-Succinimidyl 4-(2- pyridylthio)pentanoate (“SPP”), N-Succinimidyl 4-(N-maleimidomethyl)cyclohexane-I carboxylate (“SMCC”), or N-Succinimidyl(4-iodo-acetyl)aminobenzoate (“STAB”), or a combination thereof.
  • MC 6- maleimidocaproyl
  • MP maleimidopropanoyl
  • val-cit valine-citruline
  • ala-phe alanine- phenyla
  • a linker used in a conjugate of the present disclosure may comprise amino acid residues.
  • Exemplary amino acid linker components include a dipeptide, a tripeptide, a tetrapeptide or a pentapeptide.
  • Exemplary dipeptides include valine-citruline (vc or val-cit), alanine- phenylalanine (af or ala-phe).
  • Exemplary tripeptides include glycine-valine-citruline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly).
  • Amino acid residues used in an amino acid linker component may include naturaly occurring amino acids, as wel as minor amino acids and non-naturaly occurring amino acid analogs, such as citruline.
  • Amino acid linker components can be designed and optimized in their selectivity for enzymatic cleavage by particular enzymes, for example, a tumor-associated protease, cathepsin B, C and D, or a plasmin protease.
  • Conjugates of an anti-TNFR2 antigen-binding protein e.g., antibody such as single-domain antibody
  • second moiety e.g., cytotoxic agent
  • bifunctional protein- coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as 158 310886415v1 Attorney Docket No: 260525.000071 disuccinimidyl substrate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p- azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)- ethylenediamine), disocyanates (such as tol
  • SPDP N-succinimi
  • Conjugates of the present disclosure can be prepared by a variety of methods.
  • the conjugation method may include: (1) reaction of a nucleophilic group of a VHH domain with a bivalent linker reagent, to form VHH-Linker, via a covalent bond, folowed by reaction with a drug moiety; or (2) reaction of a nucleophilic group of a drug moiety with a bivalent linker reagent, to form drug-linker, via a covalent bond, folowed by reaction with the nucleophilic group of a VHH domain.
  • Nucleophilic groups on proteins including antibodies include, but are not limited to: (i) N-terminal amine groups, (i) side chain amine groups (e.g., lysine), (ii) side chain thiol groups (e.g., cysteine), and (iv) sugar hydroxyl or amino groups where the antibody is glycosylated.
  • Amine, thiol, and hydroxyl groups are nucleophilic and capable of reacting to form covalent bonds with electrophilic groups on linker moieties and linker reagents including: (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides; (i) alkyl and benzyl halides such as haloacetamides; (ii) aldehydes, ketones, carboxyl, and maleimide groups.
  • active esters such as NHS esters, HOBt esters, haloformates, and acid halides
  • alkyl and benzyl halides such as haloacetamides
  • aldehydes, ketones, carboxyl, and maleimide groups are nucleophilic and capable of reacting to form covalent bonds with electrophilic groups on linker moieties and linker reagents including: (i) active esters such as NHS esters, HOBt esters, haloformat
  • Additional nucleophilic groups can be introduced into proteins (e.g., antibodies such as VHH domains) through the reaction of lysines with 2- iminothiolane (Traut's reagent) resulting in conversion of an amine into a thiol.
  • Reactive thiol groups may be introduced into a protein (e.g., antibody such as a VHH domain) by introducing one, two, three, four, or more cysteine residues.
  • Conjugates such as antibody drug conjugates, may also be produced by modification of an antibody, such as a VHH domain, to introduce electrophilic moieties, which can react with nucleophilic substituents on the linker reagent or drug.
  • the sugars of glycosylated antibodies may be oxidized, e.g., with periodate oxidizing reagents, to form aldehyde or ketone groups which may lead with the amine group of linker reagents or drug moieties.
  • the resulting imine Schif base groups may form a stable linkage, or may be reduced, e.g., by borohydride reagents to form stable amine linkages.
  • reaction of the carbohydrate portion of a glycosylated antibody with either galactose oxidase or sodium meta-periodate may yield carbonyl (aldehyde and ketone) groups in the protein that can react with appropriate groups on the drug (Hermanson, Bioconjugate Techniques).
  • proteins containing N-terminal serine or threonine residues can react with sodium meta- 159 310886415v1 Attorney Docket No: 260525.000071 periodate, resulting in production of an aldehyde in place of the first amino acid.
  • Such aldehyde can be reacted with a drug moiety or linker nucleophile.
  • nucleophilic groups on a drug moiety include, but are not limited to: amine, thiol, hydroxyl, hydrazide, oxime, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide groups capable of reacting to form covalent bonds with electrophilic groups on linker moieties and linker reagents including: (i) active esters such as NHS esters, HOBi esters, haloformates, and acid halides; (i) alkyl and benzyl halides such as haloacetamides; (ii) aldehydes, ketones, carboxyl, and maleimide groups.
  • a fusion protein containing a VHH domain and cytotoxic agent may be made, e.g., by recombinant DNA techniques or peptide synthesis.
  • a DNA sequence may be engineered to comprise respective regions encoding the two portions of the fusion protein either adjacent to one another or separated by a region encoding a linker peptide which does not impair the desired properties of the fusion protein.
  • the DNA sequence can be then transfected into a host cel that expresses the fusion protein.
  • the fusion protein can be recovered from the cel culture and purified using techniques known in the art.
  • Linkers [0436]
  • the one or more polypeptides of the fusion proteins of the present disclosure are operably linked via peptide linkers.
  • 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.
  • a peptide linker e.g., a peptide linker separating two VHH domains or an VHH 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 optionaly is up to 30 amino acids, up to 40 amino acids, up to 50 amino acids or up to 60 amino acids in length.
  • 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.
  • 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.
  • the 160 310886415v1 Attorney Docket No: 260525.000071 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.
  • charged (e.g., charged hydrophilic linkers) and/or flexible linkers are used.
  • flexible linkers that can be used in the fusion proteins of the disclosure include those disclosed by Chen et ai, 2013, Adv Drug Deliv Rev.65(10): 1357-1369 and Klein et a/., 2014, Protein Engineering, Design & Selection 27(10): 325-330.
  • GS-linker a monomer or multimer of GnS (SEQ ID NO: 4013) or SGn (SEQ ID NO: 4014), where n is an integer from 1 to 10, e.g., 12, 3, 4, 5, 6, or 7, 8, 9 or 10.
  • the linker is or comprises a monomer or multimer of repeat of G4S (SEQ ID NO: 3969), e.g., (GGGGS)n (SEQ ID NO: 4015).
  • the linker is or comprises a monomer or multimer of repeat of G3S (SEQ ID NO: 5002), e.g., (GGGS)n (SEQ ID NO: 5003).
  • G3S SEQ ID NO: 5002
  • GGGS GGGSn
  • Polyglycine linkers can suitably be used in the fusion proteins of the disclosure.
  • a peptide linker used herein comprises two consecutive glycines (2Gly), three consecutive glycines (3Gly), four consecutive glycines (4Gly) (SEQ ID NO: 4016), five consecutive glycines (5Gly) (SEQ ID NO: 4017), six consecutive glycines (6Gly) (SEQ ID NO: 4018), seven consecutive glycines (7Gly) (SEQ ID NO: 4019), eight consecutive glycines (8Gly) (SEQ ID NO: 4020), or nine consecutive glycines (9Gly) (SEQ ID NO: 4021).
  • a GS-linker used herein comprises an amino acid sequence selected from GGSGGS (SEQ ID NO: 4022), i.e., (GGS)2 (SEQ ID NO: 4022); GGSGGSGGS (SEQ ID NO: 4023), i.e., (GGS)3 (SEQ ID NO: 4023); GGSGGSGGSGGS (SEQ ID NO: 4024), i.e., (GGS)4 (SEQ ID NO: 4024); GGSGGSGGSGGSGGS, i.e., (GGS)5 (SEQ ID NO: 4025) and GGGS (SEQ ID NO: 5004).
  • the fusion proteins can include a combination of a GS-linker and a glycine linker.
  • two or more VHHs are linked via a GGGGSGGGGSGGGGS (SEQ ID NO: 3970) linker.
  • two or more VHHs are linked via a GGGGSGGGGS (SEQ ID NO: 4026) linker.
  • a VHH and an Fc region are linked via a GGGGSESKYGPPCPSCP (SEQ ID NO: 4008) linker.
  • a VHH and an Fc region are linked via a GGGGS (SEQ ID NO: 3969) linker.
  • the one or more polypeptides of the fusion proteins of the present disclosure are operably linked via a “rigid” peptide linker.
  • a “rigid” peptide linker may comprise a proline- rich peptide.
  • a rigid peptide linker comprises PAPAPAPAPAPAPAPAP (SEQ ID NO: 4009).
  • a rigid peptide linker comprises GGGGSPAPAPAPAPAPAPAPAPAPAPAPAP (SEQ ID NO: 4010).
  • a rigid peptide linker comprises PAPAPAPAPAPAPAPGGGGS (SEQ ID NO: 161 310886415v1 Attorney Docket No: 260525.000071 4011).
  • a rigid peptide linker comprises GGGGSPAPAPAPAPAPAPAPAPGGGGS (SEQ ID NO: 4012). In one embodiment, a rigid peptide linker comprises GGGGSPAPAPAPAPAPAPAPGGGS (SEQ ID NO: 5007). In one embodiment, a rigid peptide linker comprises A(EAAAK)nA (SEQ ID NO: 4027), where n is any integer, e.g., 12, 3, 4, 5, 6, or 7, 8, 9 or 10. [0444] Other exemplary peptide linkers that can be used in the fusion proteins described herein are shown in Table 2. Table 2.
  • a fusion protein of the present disclosure comprises any one of SEQ ID NOs: 3933-3964, 4483-4513, 4686-4696, 4709-4716, 4735- 4770, 4772-4773, 4776-4779, 4903, 4979, 4981, 4983, 4985, 4987, 4989, 4991, and 4993, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises any one of SEQ ID NOs: 4483-4513, 4686-4696, 4709-4716, 4735-4770, 4772-4773, 4776-4779, 4903, 4979, 4981, 4983, 4985, 4987, 4989, 4991, and 4993, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises SEQ ID NO: 4979 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises SEQ ID NO: 4981 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises SEQ ID NO: 4983 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises SEQ ID NO: 4985 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises SEQ ID NO: 4987 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises SEQ ID NO: 4989 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises SEQ ID NO: 4991 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises SEQ ID NO: 4993 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises SEQ ID NO: 4903 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at 164 310886415v1 Attorney Docket No: 260525.000071 least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises SEQ ID NO: 4483 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises SEQ ID NO: 4489 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises any one of SEQ ID NO: 4709-4716 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises any one of SEQ ID NO: 4735-4770 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises any one of SEQ ID NO: 4772-4773 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein of the present disclosure comprises any one of SEQ ID NO: 4776-4779, 4903, 4979, 4981, 4983, 4985, 4987, 4989, 4991, and 4993, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a fusion protein that specificaly binds TNFR2, comprising two polypeptides, wherein each polypeptide comprises two anti-TNFR2 antigen-binding proteins as described herein which are operably linked to each other, wherein one of the antigen- binding proteins is further operably linked to a dimerization domain (e.g., an immunoglobulin Fc region).
  • a dimerization domain e.g., an immunoglobulin Fc region
  • the two antigen-binding proteins are operably linked to each other via a peptide linker.
  • the peptide linker is a (G4S)n (SEQ ID NO: 4015) linker.
  • the peptide linker is a GGGGSGGGGSGGGGS linker (SEQ ID NO: 3970).
  • the peptide linker is a G3S (SEQ ID NO: 5002), e.g., (GGGS)n (SEQ ID NO: 5003) linker.
  • the peptide linker is GGGS (SEQ ID NO: 5004).
  • one of the two antigen-binding proteins is further operably linked to an immunoglobulin Fc region via a peptide linker.
  • the peptide linker is a (G4S)n (SEQ ID NO: 4015) linker.
  • the peptide linker is a GGGGS linker (SEQ ID NO: 3969).
  • the fusion protein described herein further comprises an immunoglobulin Fc region.
  • the immunoglobulin Fc region is an Fc region of a human immunoglobulin.
  • the immunoglobulin Fc region is an Fc region of human IgG1, IgG2, IgG3 or IgG4, or a variant thereof. [0467] In some embodiments, the immunoglobulin Fc region is an Fc region of human IgG1, or a variant thereof. In some embodiments, the Fc region of human IgG1 comprises one or more mutations selected from L234A, L235A, G237A, D265A, N297A, and/or P329A according to EU numbering. In some embodiments, the Fc region of human IgG1 comprises a set of mutations selected from 1). L234A and L235A; 2). L234A, L235A, and P329A; 3).
  • the immunoglobulin Fc region is an Fc region of human IgG1 comprising L234A, L235A, and P329A.
  • the immunoglobulin Fc region is an Fc region of human IgG4, or a variant thereof.
  • the Fc region of human IgG4 comprises one or more mutations selected from S228P, L235E, L235A, and/or F234A according to EU numbering.
  • the Fc region of human IgG4 comprises a set of mutations selected from 1).
  • the immunoglobulin Fc region is an Fc region of human IgG4 comprising S228P and L235E.
  • the exemplary fusion proteins described herein contain non-humanized VHH amino acid sequences, such non-humanized VHH amino acid sequences can be replaced with any of the humanized VHH amino acid sequences described herein (e.g., in Tables 1-1, 1- 2, 7, and 8).
  • the fusion protein described herein may further comprise a signal sequence at its N-terminus. Signal sequences may be present in the precursor molecule of the fusion protein and may be removed after the protein is secreted from the host cel during production.
  • the signal sequence is MAVMAPRTLVLLLSGALALTQTWA (SEQ ID NO: 3928) or a fragment or variant thereof.
  • the signal sequence is MYRMQLLSCIALSLALVTNS (SEQ ID NO: 3929), or a fragment or variant thereof.
  • Polynucleotide Molecules [0473] In another aspect, provided herein are polynucleotide molecules encoding the anti-TNFR2 antigen-binding proteins (e.g., antibodies including single-domain antibodies) or fusion proteins described herein. Polynucleotide molecules encoding polypeptide portion(s) of a conjugate of the present disclosure are also encompassed within the present disclosure.
  • a polynucleotide molecule of the present disclosure encodes an anti- TNFR2 VHH amino acid sequence selected from SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 4064, 4068, 4072, 4521, 93-640, 4079-41252805-3363, 4359-4420, 4605-4628, 4780, 4781, 4783, 4785, and 4786, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encoding an anti- TNFR2 VHH comprises the nucleotide sequence of any one of SEQ ID NOs: 48-59, 4073-4075, 4522, 4525, 4528, 4531, 3364-3922, 4421-4482, 4629-4652, 4904-4977, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence selected from SEQ ID NOs: 81-92, 4076, 4078, 4523, 4526, 4529, 4532, 4731-4734, 641-1127, 4126-4172, 4775, 4782, 4784, 4794-4808, 4857-4902, and 4994-5001, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4526, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • the polynucleotide molecule encoding a humanized VHH amino acid sequence of SEQ ID NO: 4526 comprises the nucleotide sequence of SEQ ID NO: 4525, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4529, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • the polynucleotide molecule encoding a humanized VHH amino acid sequence of SEQ ID NO: 4529 comprises the nucleotide sequence of SEQ ID NO: 4528, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4532, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • the polynucleotide molecule encoding a humanized VHH amino acid sequence of SEQ ID NO: 4532 comprises the nucleotide sequence of SEQ ID NO: 4531, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at 168 310886415v1 Attorney Docket No: 260525.000071 least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4775, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4782, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4784, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4780, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4781, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4783, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 169 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4785, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4786, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4794, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4732, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4795, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4796, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 170 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4797, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4798, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4799, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4800, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4801, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4802, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 171 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4803, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4804, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4805, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4806, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4807, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4808, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 172 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4857, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4858, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4859, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4860, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4861, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4862, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 173 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4863, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4864, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4865, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4866, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4867, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4868, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 174 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4869, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4870, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4871, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4872, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4873, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4874, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 175 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4875, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4876, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4877, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4878, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4879, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4880, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 176 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4881, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4882, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4883, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4532, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4884, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4885, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 177 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4886, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4887, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4888, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4889, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4890, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4891, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 178 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4892, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4893, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4894, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4895, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4896, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4897, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 179 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4898, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4899, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4900, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4901, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4902, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4994, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 180 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4995, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4996, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4997, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4998, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4999, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 5000, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 181 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 5001, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encodes a fusion protein comprising an amino acid sequence selected from SEQ ID NOs: 3933-3964, and 4483-4513, 4686-4696, 4709-4716, 4735- 4770, 4772, 4773, 4776-4779, 4903, 4979, 4981, 4983, 4985, 4987, 4989, 4991, and 4993, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule of the present disclosure encoding a fusion protein comprises the nucleotide sequence of any one of SEQ ID NOs: 4978, 4980, 4982, 4984, 4986, 4988, 4990, and 4992, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • a polynucleotide molecule may be used to transform/transfect a host cel or host organism, e.g., for expression and/or production of a polypeptide.
  • Suitable hosts or host cels for production of an anti- TNFR2 polypeptides described herein include any suitable fungal, prokaryotic, or eukaryotic cel or cel line or any suitable fungal, prokaryotic, or eukaryotic organism.
  • a host or host cel comprising a polynucleotide molecule encoding an anti-TNFR2 antigen-binding protein polypeptide or fusion protein described herein is also encompassed by the present disclosure.
  • a polynucleotide molecule may be for example DNA, RNA, or a hybrid thereof, and may also comprise (e.g., chemicaly) modified nucleotides, like locked nucleic acids (LNA) or peptide nucleic acids (PNA).
  • LNA locked nucleic acids
  • PNA peptide nucleic acids
  • the polynucleotide is single-stranded.
  • the polynucleotide is double-stranded.
  • the polynucleotide is in the form of double- stranded DNA (e.g., plasmid).
  • the polynucleotide is in the form of a single- stranded RNA (e.g., mRNA).
  • Techniques for generating polynucleotides may include, for example but not limited to, automated DNA synthesis; site-directed mutagenesis; combining two or more naturaly occurring and/or synthetic sequences (or two or more parts thereof), introduction of mutations that lead to the expression of a truncated expression product; introduction of one or more restriction sites (e.g. to create cassettes and/or regions that may easily be digested and/or ligated using suitable restriction enzymes), and/or the introduction of mutations by means of a PCR reaction using one or more “mismatched” primers.
  • polynucleotides of the present disclosure may be isolated from a suitable natural source.
  • Polynucleotide sequences encoding naturaly occurring (poly)peptides can for example be subjected to site-directed mutagenesis, to generate a polynucleotide molecule encoding polypeptide with sequence variation.
  • Vectors [0564] Also provided herein are vectors comprising the polynucleotide molecules encoding the anti- TNFR2 antigen-binding proteins (e.g., antibodies including single-domain antibodies), fusion proteins, or other relevant polypeptides of the present disclosure.
  • a “vector” as used herein is a vehicle suitable for carrying genetic material into a host cel.
  • a vector can include a nucleic acid vector, such as a plasmid or mRNA, or nucleic acids embedded into a bigger structure, such as a liposome or viral vector.
  • a vector can include one or more of the folowing elements: an origin of replication, one or more regulatory sequences (e.g., promoters, enhancers, terminators) that regulate the expression of a polypeptide of interest, and/or one or more selectable marker genes (such as, for example, antibiotic resistance genes and genes that can be used in colorimetric assays, for example, ⁇ -galactosidase).
  • the vector is an expression vector, i.e. a vector suitable for expressing an encoded polypeptide or construct under suitable conditions in a host cel.
  • polynucleotides encoding partial or ful-length polypeptide chains e.g., obtained as described above (e.g., VHH, VHH-Fc) can be inserted into expression vectors such that the genes are operatively linked to one or more transcriptional and translational control sequences.
  • the expression vector and expression control sequences are chosen to be compatible with the expression host cel used.
  • Polynucleotides encoding the two or more polypeptide chains (when present and difer from one 183 310886415v1 Attorney Docket No: 260525.000071 another) of an anti-TNFR2 antigen-binding protein or fusion protein of the present disclosure can be inserted into separate vectors, or, optionaly, incorporated into the same expression vector.
  • the recombinant expression vectors of the invention may include regulatory sequences that control the expression of genes encoding the polypeptide chain(s) in a host cel.
  • suitable regulatory sequences for mammalian host cel expression include viral elements that direct high levels of protein expression in mammalian cels, such as promoters and/or enhancers derived from cytomegalovirus (CMV), Simian Virus 40 (SV40), adenovirus, (e.g., the adenovirus major late promoter (AdMLP) and polyoma. Additional examples of viral regulatory elements, and sequences thereof, include those described in, e.g., U.S. Pat.
  • Recombinant expression vectors of the present disclosure may carry additional sequences, such as sequences that regulate replication of the vector in host cels (e.g., origins of replication) and selectable marker genes.
  • a selectable marker gene facilitates selection of host cels into which the vector has been introduced (see e.g., US4,399,216; US 4,634,665; and US 5,179,017; the disclosure of each of which is incorporated herein by reference in its entirety).
  • selectable marker gene confers resistance to antibiotics, such as ampicilin, chloramphenicol, kanamycin, or nourseothricin, or cytotoxic drugs, such as G418, puromycin, blasticidin, hygromycin or methotrexate, to a host cel into which the vector has been introduced.
  • Suitable selectable marker genes can include the dihydrofolate reductase (DHFR) gene (for use in DHFR deficient host cels with methotrexate selection/amplification) and the neo gene (for G418 selection).
  • DHFR dihydrofolate reductase
  • Vectors of the present disclosure may further include sequence elements that enhance the rate of translation of these genes or improve the stability or nuclear export of the mRNA that results from gene transcription.
  • Viral vectors can be used for the delivery of exogenous genes into the genome of a cel (e.g., a eukaryotic or prokaryotic cel). Viral vectors are particularly useful for gene delivery because the polynucleotides contained within such genomes are typicaly incorporated into the genome of a target 184 310886415v1 Attorney Docket No: 260525.000071 cel by generalized or specialized transduction.
  • a cel e.g., a eukaryotic or prokaryotic cel.
  • Viral vectors are particularly useful for gene delivery because the polynucleotides contained within such genomes are typicaly incorporated into the genome of a target 184 310886415v1 Attorney Docket No: 260525.000071 cel by generalized or specialized transduction.
  • suitable viral vectors include a retrovirus, adenovirus (e.g., Ad5, Ad26, Ad34, Ad35, and Ad48), parvovirus (e.g., adeno-associated viruses (AAV) such as AAV2, AAV8, AAV9), negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e.g., rabies and vesicular stomatitis virus), paramyxovirus (e.g.
  • a retrovirus e.g., Ad5, Ad26, Ad34, Ad35, and Ad48
  • parvovirus e.g., adeno-associated viruses (AAV) such as AAV2, AAV8, AAV9
  • AAV adeno-associated viruses
  • negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e.g., rabies and vesicular stomatitis virus), paramy
  • RNA viruses such as picornavirus and alphavirus
  • double-stranded DNA viruses including adenovirus, herpes virus (e.g., Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus), baculovirus, coronavirus, and poxvirus (e.g., vaccinia, modified vaccinia Ankara (MVA), fowlpox and canarypox).
  • herpes virus e.g., Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus
  • baculovirus e.g., vaccinia, modified vaccinia Ankara (MVA), fowlpox and canarypox.
  • VVA modified vaccinia Ankara
  • viruses useful for delivering polynucleotides encoding polypeptides of the present disclosure include, for example Norwalk virus, togavirus, flavivirus, reoviruses, papovavirus, hepadnavirus, and hepatitis virus.
  • retroviruses include, but are not limited to, avian leukosis-sarcoma, mammalian C-type, B-type viruses, D-type viruses, HTLV-BLV group, lentivirus, spumavirus (Cofin, J. M.1996. Fundamental Virology, DMKDN Fields, PM Howley, ed.
  • viral genomes useful in the compositions and methods of the present disclosure include murine leukemia viruses, murine sarcoma viruses, mouse mammary tumor virus, bovine leukemia virus, feline sarcoma virus, feline leukemia virus, avian leukemia virus, human T-cel leukemia virus, baboon endogenous virus, Gibbon ape leukemia virus, Mason Pfizer monkey virus, simian immunodeficiency virus, simian sarcoma virus, Rous sarcoma virus, and lentiviruses.
  • Host Cels [0571]
  • the present disclosure also provides host cels or host organisms that comprise the polynucleotides or vectors encoding the anti-TNFR2 antigen-binding proteins (e.g., antibodies including single-domain antibodies), fusion proteins, or other relevant polypeptides described herein.
  • Suitable host cels or host organisms can be any suitable fungal, prokaryotic, or eukaryotic cel or cel line or any suitable fungal, prokaryotic, or eukaryotic organism.
  • Host cels include progeny of a single host cel, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cel due to natural, accidental, or deliberate mutation.
  • Host cels can also include cels transfected in vivo with a polynucleotide(s) or vector provided herein.
  • a polynucleotide(s) or vector provided herein 185 310886415v1 Attorney Docket No: 260525.000071
  • Exemplary eukaryotic cels include mammalian cels, such as primate or non-primate animal cels; fungal cels, such as yeast (e.g., Saccharomyces cerevisiae or Pichia pastoris); plant cels; and insect cels.
  • Non-limiting exemplary mammalian cels include, but are not limited to, NSO cels, PER.C6® cels (Crucel), COS cels, SP2/0 cels, and 293 and CHO cels, and their derivatives, such as 293-6E, CHO-DG44, CHO-K1, CHO-S, and CHO-DS cels.
  • Exemplary prokaryotic cels include bacterial cels such as Escherichia coli.
  • Preparation Methods [0573] The present disclosure also provides methods of producing the anti-TNFR2 antigen-binding proteins (e.g., antibodies including single-domain antibodies), fusion proteins, or conjugates described herein.
  • a method may comprise transforming/transfecting a host cel or host organism with a polynucleotide encoding an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody), fusion protein, or other relevant polypeptide(s) described herein, expressing the anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody), fusion protein, or other relevant polypeptide(s) in the host, optionaly folowed by one or more isolation and/or purification steps.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single-domain antibody
  • fusion protein e.g., antibody such as single-domain antibody
  • other relevant polypeptide(s) in the host optionaly folowed by one or more isolation and/or purification steps.
  • recombinant expression vectors encoding one or more polypeptide(s) of an anti-TNFR2 antigen-binding protein e.g., antibody such as single-domain antibody
  • fusion protein, or conjugate of the present disclosure are introduced into mammalian host cels
  • the host cels are cultured for a period of time sufficient to alow for expression of the protein(s) or polypeptide(s) in the host cels or secretion of the protein(s) or polypeptide(s) into the culture medium in which the host cels are grown.
  • Protein(s) or polypeptide(s) can be recovered from the culture medium using standard protein purification methods.
  • Host cels can also be used to produce portions of intact antibodies, such as VHH domains.
  • a protein or polypeptide of the present disclosure can be purified by any method known in the art for purification of a protein or polypeptide, for example, by chromatography (e.g., ion exchange, afinity, particularly by afinity for TNFR2 after Protein A or Protein G selection, and sizing column chromatography), centrifugation, diferential solubility, or by any other standard technique for the purification of proteins.
  • chromatography e.g., ion exchange, afinity, particularly by afinity for TNFR2 after Protein A or Protein G selection, and sizing column chromatography
  • centrifugation e.g., centrifugation, diferential solubility, or by any other standard technique for the purification of proteins.
  • proteins or polypeptides of the present disclosure can be fused to heterologous polypeptide sequences described herein (e.g., His-tag) or otherwise known in the art to facilitate purification or to produce 186 310886415v1 Attorney Docket No: 260525.000071 therapeutic conjugates below).
  • heterologous polypeptide sequences described herein e.g., His-tag
  • a protein or polypeptide of the present disclosure can, if desired, be further purified, e.g., by high performance liquid chromatography, or by gel filtration chromatography, such as on a SuperdexTM column.
  • compositions and Formulations [0577]
  • the present disclosure also provides a composition comprising anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody), fusion protein, or conjugate of the present technology, at least one polynucleotide molecule encoding the same, at least one vector comprising such a polynucleotide molecule, or at least one host cel comprising the polynucleotide molecule or vector.
  • the composition may be a pharmaceutical composition.
  • the composition may further comprise at least one pharmaceuticaly acceptable carrier, diluent, or excipient and/or adjuvant, and optionaly comprise one or more further pharmaceuticaly active polypeptides and/or compounds.
  • the term “pharmaceuticaly acceptable carrier” is intended to include any and al solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, which is incorporated herein by reference. Suitable examples of such carriers or diluents include, but are not limited to, water, saline, ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. Supplementary active compounds can also be incorporated into the compositions.
  • suitable formulations include, but are not limited to, solutions, suspensions, powders, pastes, ointments, jelies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTINTM, Life Technologies, Carlsbad, CA), DNA conjugates, anhydrous absorption pastes, oil-in- water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powel et al.
  • a pharmaceutical composition of the present disclosure may be formulated according to its intended route of administration.
  • suitable routes of administration include, e.g., intravenous, subcutaneous, intratumoral, oral (e.g., buccal, sublingual), intranasal, inhalation, intraocular, intramuscular, intradermal, transdermal (i.e., topical), intraperitoneal, transmucosal, 187 310886415v1 Attorney Docket No: 260525.000071 vaginal, and rectal administration, or injection to the CNS/brain (e.g., intraspinal, intracerebral, or intrathecal administration).
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the folowing components: a sterile diluent such as water for injection, saline solution, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; fixed oils; chelating agents such as ethylenediaminetetraacetic acid (EDTA); bufers such as phosphates, acetates, or citrates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include, for example, physiological saline, bacteriostatic water, Cremophor EL®, or phosphate bufered saline (PBS).
  • the composition is preferably sterile and has a proper fluidity.
  • the composition is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, e.g., water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the contamination by microorganisms can be achieved by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients described above, as required, folowed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation include vacuum drying and/or freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions may include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, capsules, or liquid forms. Formulation in tablet and liquid forms may be used for protease insensitive VHHs. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied oraly and swished and expectorated or swalowed. Pharmaceuticaly compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pils, capsules, troches and the like can contain any of the folowing ingredients, or compounds of a similar nature: a binder such as microcrystaline celulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as coloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystaline celulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propelant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propelant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generaly known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generaly known in the art.
  • the compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • suppositories e.g., with conventional suppository bases such as cocoa butter and other glycerides
  • retention enemas for rectal delivery.
  • compounds of the present disclosure may be formulated to facilitate crossing of the blood-brain barrier.
  • anti-TNFR2 antigen-binding proteins e.g., antibody such as single-domain antibody
  • fusion proteins, or conjugates of the present disclosure may be encapsulated into brain targeted liposomes, lipid nanoparticles, lipid microparticles, or lipid microcapsules for brain 189 310886415v1 Attorney Docket No: 260525.000071 delivery.
  • Example liposomes delivery systems are described in Pothin et al., Pharmaceutics 2020, 12(10), 937, which is incorporated herein by reference in its entirety.
  • the active compounds are prepared with carriers that can protect the compound against rapid elimination from the body, such as a controled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, colagen, polyorthoesters, and polylactic acid.
  • Liposomal suspensions can also be used as pharmaceuticaly acceptable carriers. These can be prepared according to methods known to those skiled in the art, for example, as described in US 4,522,811, which is incorporated herein by reference in its entirety. [0589] It is especialy advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physicaly discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the disclosure is dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • the pharmaceutical compositions (or components thereof) can be included in a kit, container, pack, or dispenser together with instructions for administration. These pharmaceutical compositions can be included in diagnostic kits with instructions for use.
  • Pharmaceutical compositions are administered in an amount effete for treatment or prophylaxis of the specific indication.
  • the therapeuticaly effete amount is typicaly dependent on the weight of the subject being treated, the physical or health condition of the subject, the extensiveness of the condition to be treated, or the age of the subject being treated.
  • the pharmaceutical composition may be administered in an amount in the range of about 50 ⁇ g/kg body weight to about 50 mg/kg body weight per dose. In some embodiments, the pharmaceutical composition may be administered in an amount in the range of about 100 ⁇ g/kg body weight to about 50 mg/kg body weight per dose. In some embodiments, the pharmaceutical composition may be administered in an amount in the range of about 100 ⁇ g/kg body weight to about 20 mg/kg body weight per dose.
  • the pharmaceutical composition may be administered in an amount in the range of about 0.5 mg/kg body weight to about 20 mg/kg body weight per dose.
  • the frequency and the duration of the treatment can be adjusted.
  • Efective dosages and schedules for administering a pharmaceutical composition of the present disclosure may be determined empiricaly; for example, patient progress can be monitored by periodic assessment, and the dose adjusted accordingly.
  • interspecies scaling of dosages can be performed using wel- known methods in the art (e.g., Mordenti et al., 1991, Phdomainaceut. Res.8:1351).
  • the pharmaceutical composition may be administered in an amount in the range of about 10 mg to about 1,000 mg per dose. In some embodiments, the pharmaceutical composition may be administered in an amount in the range of about 20 mg to about 500 mg per dose. In some embodiments, the pharmaceutical composition may be administered in an amount in the range of about 20 mg to about 300 mg per dose. In some embodiments, the pharmaceutical composition may be administered in an amount in the range of about 20 mg to about 200 mg per dose.
  • the antigen-binding proteins of the present disclosure are administered as a viral vector (e.g., an AAV)
  • dose ranges and frequency of administration of the viral vector described herein can vary depending on the nature of the viral vector, and the medical condition, as wel as parameters of a specific patient and the route of administration used.
  • 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.
  • 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.
  • 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.
  • 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 cels 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, intraocular, epidural, intraspinal, intracerebral, intrathecal, and oral routes.
  • the composition may be administered by any 191 310886415v1 Attorney Docket No: 260525.000071 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 biologicaly active agents. Administration can be systemic or local.
  • a pharmaceutical composition of the present disclosure can be delivered subcutaneously or intravenously with a standard needle and syringe.
  • 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 generaly utilizes a replaceable cartridge that contains a pharmaceutical composition. Once al 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.
  • there is no replaceable cartridge there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefiled with the pharmaceutical composition held in a reservoir within the device.
  • the pharmaceutical composition can be delivered in a controled release system.
  • a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng.14:201).
  • polymeric materials can be used; see, Medical Applications of Controled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida.
  • a controled 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 Controled Release, supra, vol.2, pp.115-138). Other controled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.
  • the injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous, intramuscular, intratumoral, intraperitoneal, intraspinal, intracerebral, and intrathecal injections, drip infusions, etc.
  • 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 conventionaly used for injections.
  • a sterile aqueous medium or an oily medium conventionaly used 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.
  • an alcohol e.g., ethanol
  • a polyalcohol e.g., propylene glycol, polyethylene glycol
  • a nonionic surfactant
  • the oily 192 310886415v1 Attorney Docket No: 260525.000071 medium there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
  • a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
  • the injection thus prepared is preferably filed in an appropriate ampoule.
  • 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.
  • dosage forms in a unit dose include, for example, tablets, pils, capsules, injections (ampoules), suppositories, etc.
  • the amount of the antigen-binding proteins described herein may be about 5 to about 500 mg per dosage form in a unit dose; especialy in the form of injection, the antigen-binding proteins described herein may be contained in about 5 to about 100 mg and in about 10 to about 250 mg for the other dosage forms.
  • the pharmaceutical composition may be administered as needed to a subject. In some embodiments, an effete dose of the pharmaceutical composition is administered to a subject one or more times. In various embodiments, an effete dose of the pharmaceutical composition is administered to the subject once a month, less than once a month, such as, for example, every two months, every three months, or every six months.
  • an effete dose of the pharmaceutical composition is administered more than once a month, such as, for example, every two weeks, every week, twice per week, three times per week, daily, or multiple times per day.
  • An effete dose of the pharmaceutical composition is administered to the subject at least once.
  • the effete dose of the pharmaceutical composition may be administered multiple times, including for periods of at least a month, at least six months, or at least a year.
  • the pharmaceutical composition is administered to a subject as needed to aleviate one or more symptoms of a condition.
  • a pharmaceutical composition of the present disclosure may be administered to a subject at levels lower than that required to achieve the desired therapeutic effect and the dosage may be gradualy increased until the desired effect is achieved.
  • compositions of the present disclosure may be administered at a high dose and subsequently administered progressively lower doses until a therapeutic effect is achieved.
  • a suitable daily dose of an antigen-binding protein of the invention is an amount of the antibody which is the lowest dose effete to produce a therapeutic effect.
  • Pharmaceutical compositions of the present disclosure may optionaly include more than one active agent.
  • compositions of the present disclosure may contain an anti-TNFR2 antigen- 193 310886415v1 Attorney Docket No: 260525.000071 binding protein conjugated to, admixed with, or administered separately from another pharmaceuticaly active molecule, e.g., Treg cel, or an additional agent that is useful for induction of Treg cel expansion.
  • an anti-TNFR2 antigen-binding protein may be admixed with one or more additional active agents, such as IL-2 or TNF ⁇ , to treat an immunological disease, e.g., a disorder described herein.
  • additional active agents such as IL-2 or TNF ⁇
  • pharmaceutical compositions of the present disclosure may be formulated for co- administration or sequential administration with one or more additional active agents that can be used to attenuate CD8+ T-cel growth.
  • additional active agents that can be used to atenuate cytotoxic T-cel proliferation and that can be conjugated to, admixed with, or administered separately from an anti-TNFR2 antigen-binding protein of the present disclosure include cytotoxic agents, e.g., those described herein.
  • This response may also have the effect of reducing populations of cytotoxic T-lymphocytes (e.g., CD8+ T-cels) that are often associated with mounting an inappropriate immune response that can cause an immunological disorder.
  • anti-TNFR2 antigen-binding proteins, fusion proteins or conjugates of the present disclosure may synergize with existing Treg proliferating agents, such as IL-2 and TNF ⁇ .
  • anti-TNFR2 antigen-binding proteins, fusion proteins, or conjugates of the present disclosure to activate and/or enhance suppressive function (e.g. inhibition of effector T/B cel function or proliferation or antigen presenting cel function) of a population of Treg cels.
  • enhance suppressive function e.g. inhibition of effector T/B cel function or proliferation or antigen presenting cel function
  • the methods may comprise contacting the population of regulatory T cels with an anti-TNFR2 antigen-binding protein, fusion protein or conjugate described herein.
  • the methods may be carried out in vitro or in vivo.
  • the methods further comprise administering the anti-TNFR2 antigen-binding protein, fusion protein or conjugate described herein into a subject.
  • 194 310886415v1 Attorney Docket No: 260525.000071
  • Tregs are a subset of T cels that play a crucial role in peripheral self-tolerance and the prevention of autoimmunity.
  • Tregs have been identified as a CD4 subset that specificaly express CD25, the high afinity IL-2 receptor alpha chain (Sakaguchi et al., 1995). Subsequently, FOXP3 transcription factor was identified as CD4 Treg’s master regulator (Hori et al., 2003). In fact, FOXP3 deficiency leads to systemic autoimmunity in both mouse and human in which it causes the Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome due to Tregs deficiency and unregulated effector T cel function (Bennett et al., 2001).
  • IPEX Immunodysregulation polyendocrinopathy enteropathy X-linked
  • CD4 Tregs can diferentiate during T cel development (thymic “tTregs”) or in the periphery (peripheral “pTregs”) under non- inflammatory T cel receptor stimulation (Wing et al., 2019). Numerous subsets have been described including na ⁇ ve and memory Tregs (Sakaguchi et al., 2020), Th-like Tregs (Halim et al., 2017) as wel as CD8 Tregs (Mishra et al., 2021; Niederlova et al., 2021).
  • regulatory cytokines e.g., IL-10, IL-35, TGF- ⁇
  • IL-2 scavenging e.g., IL-2 scavenging
  • adenosine production e.g., direct cytotoxicity
  • dendritic cel regulation Vignali et al., 2008.
  • regulatory T cels or “Treg” as used herein are meant to encompass al the above-described subsets of regulatory T cels.
  • Tregs have enhanced afinity for MHC I-presented self-antigen peptide and have a TCR repertoire that is non-overlapping with effector CD4 T cels (Fazileau et al., 2007; Hsieh et al., 2006; Pacholczyk et al., 2006). Therefore, self-antigen recognition in the periphery can induce tTregs activation (Moran et al., 2011).
  • Tregs can suppress effector cels that have diferent antigen specificity through bystander suppression (Thornton and Shevach, 2000; Yeh et al., 2017; Yu et al., 2005) by regulating antigen presenting cels or soluble factors. [0607] It has been shown that over time, Tregs retain some plasticity and can lose FOXP3 expression. These so caled “ex-Tregs” have increased level of FOXP3 promoter methylation and lower FOXP3 expression compared to Tregs and can acquire effector function (Zhou et al., 2009).
  • Tregs the demethylation of FOXP3 promoter, particularly in the “Treg-specific demethylated region” (TSDR) (Huehn et al., 2009), stabilizes gene expression.
  • TSDR Treg-specific demethylated region
  • human Tregs exposed to IL-2 + inflammatory cytokines have been shown to lose FOXP3 expression while upregulating RORg and IL-17, a feature associated with TH17 cels.
  • Instability of the Treg phenotype in the presence of inflammatory cytokines can be referred to as “Treg fragility” and is of crucial relevance for therapeutic purpose in autoimmune diseases.
  • anti-TNFR2 antigen-binding proteins, fusion proteins or conjugates of the present disclosure may be capable of stimulating the proliferation of a population of Treg cels by between 1% and 100% relative to untreated cels (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%), as measured, e.g., by fluorescence activated cel sorting (FACS) analysis.
  • FACS fluorescence activated cel sorting
  • anti-TNFR2 antigen-binding proteins, fusion proteins or conjugates of the present disclosure may be capable of reducing the growth of a population of CD8+ T-cels, e.g., by about 10% to about 200% relative to untreated cels (e.g., 10%, 20%, 30%, 40%, 50%, 75%, 100%, 125%, 150%, 175%, or 200%).
  • anti-TNFR2 antigen-binding proteins of the present disclosure can be used to promote the proliferation of a population of Treg cels and thus enhance the immunomodulatory activity of these cels.
  • Anti-TNFR2 antigen-binding proteins of the present disclosure can therefore be used to atenuate an aberrant cel-mediated or humoral immune response associated with a variety of human diseases, such as autoimmune disorders, asthma, modic reactions, and diseases associated with alograft tolerance.
  • anti-TNFR2 antigen-binding proteins of the present disclosure may be administered to suppress cytotoxic T-cel and B-cel activity, thereby attenuating the response of a subject to a self or benign antigen.
  • Anti-TNFR2 antigen-binding proteins of the present disclosure can be administered to a mammalian subject, such as a human, to attenuate an aberrant immune response, such as a response against a self or non-threatening antigen.
  • anti-TNFR2 antigen-binding proteins of the present disclosure can be used to expand a population of Treg cels ex vivo that have been extracted, e.g., from a patient or an MHC-matched donor. After inducing proliferation of these Treg cels in culture by contacting with an anti-TNFR2 antigen-binding protein of the present disclosure, these cels can subsequently be administered to a subject, e.g., using adoptive cel transfer techniques known in the art or described herein. In this way, anti-TNFR2 antigen- binding proteins of the present disclosure may synergize with existing techniques to suppress humoral and cel-mediated immune responses as a treatment modality for patients making from a variety of immunological disorders.
  • anti-TNFR2 antigen-binding proteins of the present disclosure are capable of interacting with and promoting signal transduction events mediated by TNFR2.
  • Anti-TNFR2 antigen-binding proteins of the present disclosure may be able to induce conformational changes within 196 310886415v1 Attorney Docket No: 260525.000071 TNFR2 that lead to receptor trimerization.
  • anti-TNFR2 antigen-binding proteins of the present disclosure may be capable of increasing the transcription and/or expression of various genes.
  • anti-TNFR2 antigen-binding proteins of the present disclosure may induce the expression of one or more of Akt, cIAP2, Etk, TRAF2, VEGFR2, P13K, genes encoding proteins involved in the angiogenic pathway, IKK complexes, RIP, NIK, MAP3K, genes encoding proteins involved in the NF- ⁇ B pathway, NIK, JNK, AP-1, a MEK (e.g., MEK1, MEK7), MKK3, NEMO, IL2R, Foxp3, IL2, TNF, and lymphotoxin (e.g., lymphotoxin a and lymphotoxin ⁇ ).
  • Akt Akt
  • cIAP2 Etk e.g., Etk
  • TRAF2 VEGFR2 P13K genes encoding proteins involved in the angiogenic pathway
  • IKK complexes RIP
  • NIK MAP3K
  • genes encoding proteins involved in the NF- ⁇ B pathway e
  • anti-TNFR2 antigen-binding proteins of the present disclosure may be capable of promoting the activity of one or more proteins associated with the TNFR2 signaling pathway (or related signaling pathways that are activated as a result of TNFR2 signaling).
  • anti-TNFR2 antigen-binding proteins of the present disclosure may be capable of promoting an increase in the phosphorylation of one or more proteins, such as Akt, clAP2, Etk, TRAF2, VEGFR2, P13K, proteins involved in the angiogenic pathway, IKK complexes, RIP, NIK, MAP3K, proteins involved in the NF- ⁇ B pathway, NIK, JNK, AP-1, a MEK (e.g., MEK1, MEK7), MKK3, NEMO, IL2R, Foxp3, IL2, TNF, and lymphotoxin (e.g., lymphotoxin ⁇ and lymphotoxin ⁇ ).
  • proteins such as Akt, clAP2, Etk, TRAF2, VEGFR2, P13K, proteins involved in the angiogenic pathway, IKK complexes, RIP, NIK, MAP3K, proteins involved in the NF- ⁇ B pathway, NIK, JNK, AP-1, a
  • antigen-binding proteins of the present disclosure increases expression of one or more proteins selected from a protein in the NF-kB pathway, FOXP3, HELIOS, EZH2, HLA-DR, ICAM-1, OX-40, ICOS, and CCR8.
  • a method of inhibiting an immune response mediated by a B cel or a CD8+ T cel in a subject including the step of administering to the subject an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody), a fusion protein, a conjugate, a polynucleotide molecule, a vector, or a host cel described herein.
  • an anti-TNFR2 antigen-binding protein e.g., antibody such as single-domain antibody
  • a fusion protein e.g., a fusion protein, a conjugate, a polynucleotide molecule, a vector, or a host cel described herein.
  • anti-TNFR2 antigen-binding proteins e.g., antibody such as single-domain antibody
  • fusion proteins conjugates, polynucleotide molecules, vectors, and/or host cels described herein, or pharmaceutical compositions thereof
  • an anti- TNFR2 antigen-binding protein e.g., antibody such as single-domain antibody
  • a fusion protein e.g., a conjugate, a polynucleotide molecule, a vector, or a host cel for use as a medicament.
  • a (prophylactic and/or therapeutic) method of treating a disease or disorder comprising administering, to a subject in need thereof, a pharmaceuticaly active amount of an anti- TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody), a fusion protein, a conjugate, a polynucleotide molecule, a vector, or a host cel described herein.
  • an anti- TNFR2 antigen-binding protein e.g., antibody such as single-domain antibody
  • a fusion protein e.g., a fusion protein, a conjugate, a polynucleotide molecule, a vector, or a host cel described herein.
  • the diseases or disorder that can be treated with the compositions and methods described herein include, but are not limited to, immunological diseases (e.g., autoimmune diseases), inflammatory diseases, cancers, cardiovascular diseases (e.g., atherosclerosis, heart failure, left heart failure with reduced ejection fraction, left heart failure with preserved ejection fraction, right ventricular failure, congestive heart failure, restrictive cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, idiopathic cardiomyopathy, hypertension), and infertility and pregnancy-associated diseases (e.g., recurrent pregnancy loss, pre-eclampsia, preterm labor, fetal growth restriction, intrauterine growth restriction).
  • immunological diseases e.g., autoimmune diseases
  • inflammatory diseases e.g., cancers
  • cardiovascular diseases e.g., atherosclerosis, heart failure, left heart failure with reduced ejection fraction, left heart failure with preserved ejection fraction, right ventricular failure, congestive heart failure,
  • immunological diseases examples include, but are not limited to, autoimmune diseases, modies, asthma, neurological diseases, metabolic diseases (e.g., diabetes), macular diseases (e.g., macular degeneration), muscular atrophy, diseases related to miscarriage, vascular diseases (e.g., atherosclerosis), diseases related to bone loss (e.g., bone loss as a result of menopause or osteoporosis), blood disorders (e.g., hemophilia), musculoskeletal disorders, diseases related to growth receptor expression or activity, obesity, graft- versus-host disease (GVHD), or alograft rejections.
  • autoimmune diseases examples include, but are not limited to, autoimmune diseases, toies, asthma, neurological diseases, metabolic diseases (e.g., diabetes), macular diseases (e.g., macular degeneration), muscular atrophy, diseases related to miscarriage, vascular diseases (e.g., atherosclerosis), diseases related to bone loss (e.g., bone loss as a result of menopause or osteop
  • the compositions and methods described herein are used to treat an autoimmune disease.
  • the autoimmune disease is selected from lupus, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, bulous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold 198 310886415v1 Attorney Docket No: 260525.000071 agglutinin disease, Crohn's disease, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Goodpastures disease, Graves' disease, Guilain-Barré, Hashimoto'
  • the compositions and methods described herein are used to treat lupus.
  • the lupus is systemic lupus erythematosus (SLE), cutaneous lupus (including acute cutaneous lupus, chronic cutaneous lupus erythematosus, or discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus), lupus nephritis, neonatal lupus, or drug-induced lupus.
  • the compositions and methods described herein are used to treat monty.
  • the manganese is an organic conjunctivitis, chemical toy, cosmetic party, drug party, dust party, food party, hay fever, hives, mold complexy, pet carbony, poison ivy mangay oak manganese, or seasonal manganese.
  • the compositions and methods described herein are used to treat a neurological condition.
  • the neurological condition is a brain tumor, a brain metastasis, a spinal cord injury, schizophrenia, epilepsy, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's disease, Parkinson's disease, or stroke.
  • the compositions and methods described herein are used to treat a graft rejection.
  • anti-TNFR2 antigen-binding proteins of the present disclosure may treat graft rejections, e.g., by binding TNFR2 receptors on the surface of autoreactive CD8+ T-cels that bind antigens presented on the surface of the graft and inducing apoptosis in these CD8+ T-cels, or by inducing the expansion of Treg cels that may subsequently eliminate autoreactive CD8+ T-cels.
  • graft rejections that can be treated with the compositions and methods described herein include, without limitation, skin graft rejection, bone graft rejection, vascular tissue 199 310886415v1 Attorney Docket No: 260525.000071 graft rejection, ligament graft rejection (e.g., anterior cruciate ligament graft rejection, anterior sacroiliac ligament graft rejection, caudal cruciate ligament graft rejection, cranial cruciate ligament graft rejection, cricothyroid ligament graft rejection, dorsal radiocarpal ligament graft rejection, inferior pubic ligament graft rejection, lateral colateral ligament graft rejection, medial colateral ligament graft rejection, palmar radiocarpal ligament graft rejection, patelar ligament graft rejection, periodontal ligament graft rejection, posterior cruciate ligament graft rejection, posterior sacroiliac ligament graft rejection, radial colateral ligament graft rejection, sacrospinous ligament graft rejection, sacrotube
  • the compositions and methods described herein are used to treat a graft-versus-host disease.
  • the graft-versus-host disease arises from a bone marrow transplant or one or more blood cels such as B-cels, T-cels, basophils, common myeloid progenitor cels, common lymphoid progenitor cels, dendritic cels, eosinophils, hematopoietic stem cels, neutrophils, natural kiler cels, megakaryocytes, monocytes, or macrophages.
  • the compositions and methods described herein are used to treat an inflammatory disease.
  • the inflammatory disease may be acute or chronic inflammation.
  • the inflammatory disease is selected from osteoarthritis, atopic dermatitis, endometriosis, polycystic ovarian syndrome, inflammatory bowel disease, fibrotic lung disease, and cardiac inflammation.
  • the compositions and methods described herein are used to treat a cancer.
  • the cancer is an adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer (sarcoma of bone), brain stem glioma, brain tumor, breast cancer, inflammatory breast cancer, metastatic breast cancer, male breast cancer, Carney complex, central nervous system tumors (brain and spinal cord), cervical cancer, childhood cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, desmoid tumor, desmoplastic infantile ganglioglioma, childhood tumor, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma,
  • anti-TNFR2 antigen-binding proteins of the present disclosure can also be used to treat a patient in need of organ repair or regeneration, e.g., by inducing the proliferation of cels within a damaged tissue or organ. While not wishing to be bound by any theory, it is contemplated that agonistic TNFR2 antibodies may stimulate organ repair or regeneration, e.g., by binding TNFR2 on the surface of cels within damaged tissue to induce TRAF2/3- and/or NF- ⁇ B-mediated cel proliferation.
  • tissues and organs that may be induced to regenerate by the use of anti-TNFR2 antigen- binding proteins of the present disclosure include the blood vessels including the aorta, bone, cranial nerves, ear, eye, embryonic structures, heart, heart, hematopoietic system, kidney, smal intestine, large 201 310886415v1 Attorney Docket No: 260525.000071 intestine, liver, lung, nerves, olfactory gland, pancreas, pituitary gland, peripheral nervous system, central nervous system, spinal cord, salivary gland, structures of the head, testes, thymus, and tongue.
  • blood vessels including the aorta, bone, cranial nerves, ear, eye, embryonic structures, heart, heart, hematopoietic system, kidney, smal intestine, large 201 310886415v1 Attorney Docket No: 260525.000071 intestine, liver, lung, nerves, olfactory gland
  • Additional diseases that can be treated with the compositions and methods of the present disclosure include genetic diseases with an immunological phenotype. Exemplary genetic diseases with an immunological phenotype are described in, e.g., Table S2 of Tangye et al., Journal of Clinical Immunology volume 42, pages1473–1507 (2022), which is incorporated herein by reference in its entirety. [0627] In some embodiments, patients receiving an anti-TNFR2 treatment of the present disclosure can be monitored for their responsiveness to the treatment.
  • a physician may monitor the response of a mammalian subject (e.g., a human) to treatment with anti-TNFR2 antigen-binding proteins of the present disclosure by analyzing the quantity of IFN ⁇ secreted by CD8+ T-cels within a particular patient.
  • a composition of the present disclosure may be capable of reducing IFN ⁇ secretion by between 1% and 100% (e.g., 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%).
  • a physician may monitor the responsiveness of a subject (e.g., a human) to treatment with a composition of the present disclosure by analyzing the Treg cel population in the lymph of a particular subject.
  • a physician may withdraw a sample of blood from a mammalian subject (e.g., a human) and determine the quantity or density of a population of Treg cels (e.g., CD4+ CD25+ FOXP3+ Treg cels or CD17+ Treg cels) using established procedures, such as FACS analysis.
  • Treg cels e.g., CD4+ CD25+ FOXP3+ Treg cels or CD17+ Treg cels
  • high counts of Treg cels can be indicative of eficacious therapy
  • lower Treg cel counts may indicate that the patient is to be prescribed or administered higher dosages of the anti-TNFR2 antigen-binding protein of the present disclosure until, e.g., an ideal Treg cel count is achieved.
  • a physician of skil in the art may monitor the effect of treatment by administration of a composition of the present disclosure to a subject having from an immunological disorder, such as an autoimmune disease described herein, by analyzing the quantity of autoreactive CD8+ T-cels within a lymph sample isolated from the patient.
  • Anti-TNFR2 antigen-binding proteins of the invention may atenuate the proliferation of autoreactive T-cels, e.g., by binding TNFR2 at the surface of an autoreactive T-cel and inducing apoptosis, and/or by stimulating the expansion of Treg cels that subsequently eliminate autoreactive T lymphocytes.
  • Treatment with anti-TNFR2 antigen- binding proteins may lead to reduced quantities of autoreactive T-cels within the lymph isolated from a patient receiving treatment, and a rapid decline in the population of autoreactive T-cels in a lymph sample isolated from such a patient may indicate effete treatment.
  • a lymph sample 202 310886415v1 Attorney Docket No: 260525.000071 isolated from a patient exhibits an autoreactive T-cel count that has not declined in response to agonistic TNFR2 antibody therapy
  • a physician may prescribe the patient higher doses of the antibody or an antigen-binding fragment thereof or may administer the anti-TNFR2 antigen-binding proteins with higher frequency, e.g., multiple times per day, week, or month.
  • Anti-TNFR2 antigen-binding proteins described herein may be administered as a monotherapy or in combination with one or more additional therapeutic agents.
  • anti-TNFR2 antigen-binding proteins of the present disclosure may also be admixed, conjugated, or administered with, or administered separately from, another agent that promotes Treg cel proliferation. Additional agents that can be used to promote Treg cel expansion include, e.g., IL-2 and TNF ⁇ , the cognate ligand for TNFR2.
  • pharmaceutical compositions of the invention may be formulated for co- administration or sequential administration with one or more additional active agents that can be used to inhibit CD8+ T-cel growth.
  • cytotoxic agents examples include cytotoxic agents, e.g., those described herein.
  • Exemplary cytotoxic agents that can be conjugated to, admixed with, or administered separately from anti-TNFR2 antigen-binding protein of the present disclosure include, but not limited to, 13-cis retinoic acid, 14-hydroxy-retro-retinol, 2-chloro-2′-deoxyadenosine, 2-Chloro-2'-arabino-fluoro-2'- deoxyadenosine, 2-chlorodeoxyadenosine, 2-chlorodeoxyadenosine (2-Cda), 2'-deoxycoformycin, 3- methyl TTNEB, 6-mercaptopurine, 6-thioguanine, 9-aminocamptothecin, 9-cis retinoic acid, aclarubicin, acodazole hydrochloride, acronine, adozelesin, adozelesin, adriamycin, aldesleukin, al-trans retinoic acid, al
  • Other therapeutic agents that can be conjugated to, admixed with, or administered separately from anti-TNFR2 antigen-binding protein of the present disclosure include, but are not limited to, 2′ deoxycoformycin (DCF), 1,25 dihydroxyvitamin D3, 5-ethynyluracil, 9-dioxamycin, abiraterone, acylfulvene, adecypenol, ALL-TK antagonists, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, anagrelide, andrographolide, angiogenesis inhibitors, antagonist D, antagonist G, antarelix, antiandrogen, prostatic carcinoma, anti-dorsalizing morphogenetic protein-1, antiestrogen, antineoplaston, antisense oligonucleotides, aphidicolin glycinate, apoptosis gene modulators, apoptosis regulators, apurinic acid,
  • DCF
  • anti-TNFR2 antigen-binding proteins of the present disclosure may be admixed, conjugated, or administered with, or administered separately from, an anti-inflammatory agent.
  • anti-inflammatory agents useful in conjunction with the compositions and methods of the invention include steroids, colchicine, hydroxychloroquine, sulfasalazine, dapsone, methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, sirolimus, everolimus, azathioprine, leflunomide, mycophenolate, inhibitors of IL-1/IL-2/IL-4/IL5/IL-6/IL-13/IL-17/IL- 23/TNF/complement/BAFF/interferon/JAK/CD28/IgE/Integrins/T cel costimulation pathway or B-cel depleting agents.
  • anti-TNFR2 antigen-binding proteins of the present disclosure may be admixed, conjugated, or administered with, or administered separately from, an immunotherapy agent.
  • immunotherapy agents useful in conjunction with the compositions and methods of the invention include an anti-CTLA-4 agent, an anti-PD-1 agent, an anti-PD-L1 agent, an anti-PD-L2 agent, a TNF ⁇ cross-linking agent, a TRAIL cross-linking agent, an anti-CD27 agent, an anti-CD30 agent, an anti- CD40 agent, an anti-4-1BB agent, an anti-GITR agent, an anti-OX40 agent, an anti-TRAILR1 agent, an anti-TRAILR2 agent, an anti-TWEAKR agent, an anti-TL1A agent, an anti-LIGHT agent, an anti-BTLA agent, an anti-LAG3 agent, an anti-Siglecs agent, an anti-ICOS ligand agent, an anti-B7-H3 antibody; an anti-B
  • anti-TNFR2 antigen-binding protein of the present disclosure can also be admixed with, co-administered with, or administered separately from Bacilus Calmete-Guérin (BCG), a bacterial strain that has been used to treat a variety of immunological disorders, such as type I diabetes, multiple sclerosis, scleroderma, Sjogren's disease, systemic lupus erythematosus, Grave's disease, hypothyroidism, Crohn's disease, colititis, an autoimmune skin disease, and rheumatoid arthritis, among others.
  • BCG Bacilus Calmete-Guérin
  • anti-TNFR2 antigen-binding protein of the present disclosure may be included in a therapeutic regimen in combination with BCG for the treatment of an immunological disorder (e.g., one of those described above, such as type I diabetes or rheumatoid arthritis).
  • the anti-TNFR2 antigen- binding protein may be co-administered with BCG, e.g., by an injection route described herein.
  • the anti-TNFR2 antigen-binding protein may be administered separately from a BCG- containing composition.
  • BCG to treat immunological disorders has been described, e.g., in US 6,660,487; and US 6,599,710; the disclosures of each of which are incorporated herein by reference in its entirety.
  • Example 1 Camelid immunization
  • Three alpacas were immunized by four subcutaneous injections with recombinant human TNFR2 (10417-H08H, Sino Biologicals) and complete/incomplete Freund’s or Gerbu FAMA adjuvant using standard protocols to elicit a humoral immune response that included the generation of antigen-specific conventional and heavy-chain only (VHH) antibodies.
  • VHH conventional and heavy-chain only
  • Antibody induction was monitored by comparing antigen-specific antibody titers in the sera before and after immunization by enzyme-linked immunosorbent assay (ELISA). Briefly, 96-wel Maxisorp plates were coated with human TNFR2 (10417-H08H, Sino Biologicals), blocked, and incubated with diluted serum samples. TNFR2-specific antibodies were bound by alkaline phosphatase-conjugated goat anti-alpaca IgG (H+L) (Jackson ImmunoResearch, Cat. No.128-055-160) and detected using p-Nitrophenyl Phosphate. Example 2.
  • ELISA enzyme-linked immunosorbent assay
  • Phage library construction [0639] Four to ten days after the fourth injection in accordance with procedures described in Example 1, blood samples were colected, and four to six days after the fourth injection a bone marrow sample was aspirated. Peripheral blood mononuclear cels (PBMCs) were isolated from heparinized blood or bone marrow folowing density gradient purification with Ficol-PaqueTM Plus. Total RNA was extracted from freshly isolated PBMCs. [0640] To generate VHH immune libraries, total RNA was reverse transcribed to cDNA using random hexamer primers.
  • PBMCs Peripheral blood mononuclear cels
  • Binders to human and mouse TNFR2 were enriched from VHH immune libraries by two rounds of phage display.
  • the general panning strategy is illustrated in Figure 1 using the panning substrates listed Table 3.
  • Table 3 Panning substrates Species Modification Bufer Cat. # Lot # Vendor MW N-term.
  • Source S 3 310886415v1 Attorney Docket No: 260525.000071 Species Modification Bufer Cat.
  • Source Seq. aa Seq. 3 he first harvested bone marrow sample of the same animal were pooled in equal parts (at the phage level), resulting in three pooled input libraries per antigen. Each library was panned under four conditions (two antigen concentrations and two ways of antigen immobilization) with human TNFR2, resulting in 12 panning reactions.
  • For the second rounds of panning six output samples (enriched libraries) from the first round were chosen and served as input libraries for the second round. Preferentialy, the enriched libraries from the higher panning substrate concentration were chosen to preserve maximum diversity. Pannings of the second round were performed with three antigen concentrations of human and mouse antigen to result 24 conditions.
  • binders with lower afinity Three antigen concentrations for TNFR2 were further chosen to recover binders with lower afinity. This panning regimen was implemented to identify binders that cross- reacted with human and mouse TNFR2. [0643] In some cases, binders with medium afinity were preferred since higher valency may drive avidity. Thus, the antigen concentrations in the second panning round were the same, one tenth and one hundredth of the first round. [0644] Phages were produced according to QVQ Holding B.V. (QVQ) standard operating procedures (SOPs) and phage titers were determined to ensure at least 10-fold excess over the maximum diversity of the libraries. Panning substrates were commercialy purchased (see Table 1).
  • the panning substrates were immobilized either by direct coating on enzyme-linked immunoassay (ELISA) plates or by binding of biotinylated antigen on neutravidin-coated ELISA plate.
  • Glycerol stocks were prepared from al outputs and are stored at -80°C.
  • Panning outputs were analyzed by random clone picking/periplasmic extract (PE)-ELISA/Sanger sequencing (QVQ) and next-generation sequencing (NGS; Genewiz/PipeBio).
  • PES random clone picking/periplasmic extract
  • NGS next-generation sequencing
  • rescued outputs of the first and second panning rounds were plated out and 920 random single clones (equal numbers of colonies from each condition) were selected to create masterplates (96-wel format).
  • Next-generation sequencing [0648] Folowing two rounds of panning, phages were eluted and corresponding phagemid DNA was extracted. Identification of initial V-body candidates was performed in a parallelized fashion, employing a random colony picking, as wel as a next-generation sequencing (NGS) approach, as orthogonal techniques to yield a particularly diverse set of initial candidates. Prior to NGS techniques, random colony picking was the prevalent method for initial hit identification, which involved transformation of a phagemid pool (from a panning elution) and selection of individual bacterial colonies to isolate single clones. Folowing this approach, 920 single colonies were randomly picked from the 36 samples of the second panning round ( Figure 2).
  • the NGS raw data contained multiplexed sequencing reads, which were de-multiplexed based on the sample-specific barcodes.
  • the de-multiplexed data containing unmerged sequencing reads were then processed by employing an NGS analysis platform.
  • 211 310886415v1 Attorney Docket No: 260525.000071 brief, forward and reverse sequence pairs were merged by their overlapping sequence, thereby generating a ful VHH sequence from two half sequences ( Figure 3).
  • the framework regions, CDRs, and sequence-specific liabilities were then annotated for the merged V-body sequences.
  • V-body sequences were clustered, alowing for a detailed analysis of V- body enrichment during phage display, sequence diversity, CDR3 length distribution and cluster abundance.
  • Identified V-bodies can be classified into eleven distinct clusters, as folows: Group A, Group B, Group C, Group D, Group G, Group J, Group K, Group L, Group M, Group N, and Group O.
  • the folowing Table 4-1 to Table 4-33 display the amino acid frequency distribution at each amino acid (AA) position (IMGT) for CDR1, CDR2 and CDR3 for the eleven clusters.
  • Table 5 provides the sequence identifiers of amino acid sequences of the complementarity determining regions (CDR1, CDR2 and CDR3), amino acid and DNA sequences of the ful-length VHH domain for the identified V-bodies.
  • CDR1, CDR2 and CDR3 complementarity determining regions
  • Table 4-1 CDR1 amino acid frequency distribution for Group A Position AA 27 28 29 30 35 36 37 38 A 0 0 0 0 53 0 36
  • Position AA 56 57 58 59 63 64 65 213 310886415v1 Attorney Docket No: 260525.000071
  • Table 4-3 CDR3 amino acid frequency distribution for Group A Position AA 105 106 107 108 109 110 111 112.1 112 113 114 115 116 117 A 0 0 0 239 0 0 2 206 0 0 03 0 17 0
  • Position AA 27 28 29 30 35 36 37 38 A 214 310886415v1 Attorney Docket No: 260525
  • HEK293 cels were encoding for respective antigens. After 48 to 72 hours, binding was measured by incubation of His-tagged V-bodies with cels at various fixed concentrations, folowed by washing and detection with Alexa488 fluorophore-labeled anti-His antibodies.
  • binding to HEK293 transfected with constructs where a single CRD was exchanged for camel CRD was measured. Lack of binding to a particular construct indicated binding to the domain which was exchanged.
  • HEK293T cels were transiently transfected with a plasmid encoding human TNFR2 (hTNFR2; hTNFR2_pcDNA3.4.dna). After 48 hours, HEK293T cels were harvested and incubated with 1 ⁇ M purified His-tagged (myc-his tag) VHHs, including a control 247 310886415v1 Attorney Docket No: 260525.000071 VHH against an irrelevant antigen. VHH binding was then detected using an Alexa488-labeled anti-His tag antibody and measured by flow cytometry (iQue).
  • HEK293T cels were transiently transfected with a plasmid encoding human TNFR2 (hTNFR2; hTNFR2_pcDNA3.4.dna). After 48 hours, HEK293T cels were harvested and incubated with 100 nM purified His-tagged (myc-his tag) VHHs, including a control VHH against an irrelevant antigen. VHH binding was then detected using an Alexa488-labeled anti-His tag antibody and measured by flow cytometry (iQue).
  • HEK293T cels were transiently transfected with a plasmid encoding cynomolgus TNFR2 (cTNFR2; cTNFR2_pcDNA3.4.dna) or mouse TNFR2 (mTNFR2; mTNFR2_pcDNA3.4.dna). After 48 hours, HEK293T cels were harvested and incubated with 100 nM purified His-tagged (myc-his tag) VHHs, including a control VHH against an irrelevant antigen. VHHs binding was then detected using a Alexa488-labeled anti-His tag antibody and measured by flow cytometry (iQue).
  • Figure 7 shows testing of human TNFR2 V-body binding across a range of concentrations for T- 002, T-014, T-001, T-006, T-007, and T-003.
  • V-bodies were tested at the folowing molar concentrations: 100 nM, 50 nM, 12.5 nM, 6.25 nM, 3.12 nM, and 1.55 nM.
  • HEK293T cels were transiently transfected with a plasmid encoding human TNFR2 (hTNFR2; hTNFR2_pcDNA3.4.dna).
  • HEK293T cels were harvested and incubated with increasing molar concentrations of purified His-tagged (myc-his tag) VHHs, including a control VHH against an irrelevant antigen. VHH binding was then detected using an Alexa488-labeled anti-His tag antibody and measured by flow cytometry (iQue).
  • the bar histogram ( Figure 7) shows the percentage of Alexa488 positive cels for T-002, T-014, T-001, T-006, T-007, and T-003.
  • SPR surface plasmon resonance
  • FIG. 8 A schematic diagram depicting the experimental setup of the present Example is shown in Figure 8.
  • Afinity purified V-bodies were covalently crosslinked onto an LSA HC200M chip using EDC/Sulfo NHS.
  • the interaction with human, cynomolgus, and mouse TNFR2 (extracellular domain) (V-body coupling concentration: human, 1 ⁇ M; cynomolgus/mouse, 4 ⁇ M) was measured under physiological conditions (Running Bufer: HBST- 50 mM HEPES pH 7.4, 150 mM NaCl, 0.1 % (w/v) BSA, 0.05% (v/v) Tween20, 25°C) using eight diferent antigen concentrations (3-fold serial dilutions, start at 200 nM).
  • Figure 10 shows a 248 310886415v1 Attorney Docket No: 260525.000071 summary of binding Ratio's V-bodies including T-002, T-006, T-001, T-007, T-014, and T-003. Seven of the 16 V-body candidates tested (including T-002, T-006, T-001, T-007, T-014, and T- 003) were shown to bind human TNFR2 with 1–2-digit nM afinity.
  • V-bodies demonstrated cross-reactivity to cynomolgus TNFR2 (96% identical to hTNFR2 sequence) and mouse TNFR2 (63% identical to hTNFR2 sequence), respectively.
  • Example 6. MR2-1 competition [0657] To whether humanized TNFR2 V-bodies targeted the epitope recognized by a MR2-1 bivalent expressing HEK cels (clone 25) were incubated with or without MR2-1 (5 or 10 ⁇ g/mL) prior to (pre-) and/or during (co-) incubation with His-tagged TNFR2-specific V-bodies. After washing, V-body binding was detected by labeled anti-His antibody.
  • Binding inhibition in the presence of MR2-1 indicated binding of TNFR2 V-bodies and MR2-1 bivalent agonist to an overlapping epitope. Specificaly, T-013hu1 and T-018hu1 may recognize the same epitope as MR2-1.
  • MR2-1 binding enhanced binding of T-015hu1, T-017hu1 and T-011hu1 to TNFR2 ( Figure 11).
  • TNFR2 reporter assay [0658] HEK293 nuclear factor kappa B (NF- ⁇ B) reporter (Luc) cels stably expressing TNFR2 were established by transfection and antibiotic selection. Several clones were derived from the cel pool.
  • TNFR2 signaling was measured by NF- ⁇ B-induced expression of firefly luciferase (Luc).
  • Data showing agonism of multivalent constructs characterized on NF-kB reporter HEK293 cels stably expressing TNFR2 are displayed in Figures 12A-12D. Typicaly, luciferase activity was measured 16- to 24-hours after incubation with the V-bodies.
  • commercialy available human TNFR2 agonist MR2-1 monoclonal antibodies were tested on NF- ⁇ B reporter (Luc) HEK293 reporter cel-line stably expressing TNFR2 (clone 25) versus parental cel line (PCL) ( Figure 13).
  • Concentration range curve data generated using MR2-1 (Hycult) and TNF ⁇ controls revealed increasing RLU measured with increasing concentrations of MR2-1 (mol/L) and TNF ⁇ (ng/mL) ( Figures 15A-15B, respectively).
  • Figures 16A-16C show dot plots of RLU measured across increasing concentrations (mol/L) of control (control 12) and tetravalent V-body fusion constructs comprising four V-bodies mounted onto an Fc of a IgG4 variant comprising S228P and L235E mutations.
  • Figures 17A-17F show dot plots of RLU measured across 249 310886415v1 Attorney Docket No: 260525.000071 increasing concentrations (mol/L) of control (control 10) and tetravalent V-body fusion constructs comprising four V-bodies mounted onto an Fc of a IgG4 variant comprising S228P and L235E mutations.
  • Figures 18A-18C show dot plots of RLU measured across increasing concentrations (mol/L) of control (control 10) and tetravalent V-body fusion constructs comprising four V-bodies mounted onto an Fc of a IgG4 variant comprising S228P and L235E mutations.
  • Figures 19A-19C show exemplary dot plots of RLUs measured across increasing concentrations (mol/L) of control (control 13) and IL-2N88D V-body fusion constructs. Limit of detection is denoted as “LOD”.
  • LOD Limit of detection
  • a comparison of RLU measured across increasing concentrations (mol/L) of monospecific constructs 10 and 12 tested on NF- ⁇ B reporter (Luc) HEK293 reporter cel-line stably expressing TNFR2 (clone 8) is shown in Figure 20.
  • Example 8 A comparison of RLU measured across increasing concentrations (mol/L) of monospecific constructs 10 and 12 tested on NF- ⁇ B reporter (Luc) HEK293 reporter cel-line stably expressing TNFR2 (clone 8) is shown in Figure 20.
  • Example 8 A comparison of RLU measured across increasing concentrations (mol/L) of monospecific constructs 10 and 12 tested on NF- ⁇ B reporter (Luc) HEK293 reporter cel-line stably expressing
  • TNFR2 agonism by multivalent constructs
  • the ability to agonize TNFR2 on human regulatory T cels (Tregs) was demonstrated by Leukocyte Antigen, DR isotype (HLA-DR) and chemokine motif (C-C motif) receptor 8 (CCR8) upon activation of TNFR2.
  • HLA-DR and CCR8 are markers expressed on highly suppressive Tregs, which have been shown to be upregulated by TNFR2 agonist MR2-1.
  • Treg markers e.g., forkhead box P3 (FoxP3), HLA-DR, CCR8, and OX-40
  • Table 6 A description of established Treg markers (e.g., forkhead box P3 (FoxP3), HLA-DR, CCR8, and OX-40) useful in, e.g., screening of multivalent constructs in first wave binders on primary cels, is described in Table 6.
  • Table 6 Treg Markers for Screening Multivalent Constructs Marker Exemplary biological function(s) FoxP3 ⁇ Treg marker - g g, g y sing magnetic beads, and subsequently stimulated with anti-CD3 and anti-CD28 coated stimulation beads with IL-2, in the presence or absence of fixed or increasing concentrations of a control VHH or TNFR2- specific V-bodies.
  • FIG. 21 An exemplary experimental timeline of TNFR2 stimulation by multivalent constructs on primary human peripheral blood mononuclear cels (PBMCs) and CD4+ CD25+ CD127dim Tregs is shown in Figure 21. Briefly, on Day 0, PBMCs were isolated and selected from three donors (Donors 1-3). Tregs were positively selected for CD4+ CD25+ CD127dim (Mitlenyi Cat. No.130-094-775). Fluorescence-activated 250 310886415v1 Attorney Docket No: 260525.000071 cel sorting (FACS) analysis was used in cel quality control (QC) experiments to confirm cel populations based on CD4, CD25, CD127, FoxP3, and TNFR2 markers.
  • FACS cel quality control
  • a 96-wel plate was seeded with 2x104 cels/wel CD4+ C25+ CD127dim Tregs or PBMCs (200 ⁇ l total culture volume). Cels were activated with anti-CD3/anti-CD28 coated stimulation beads (using a ratio of 1:2 for beads:cels) and IL-2 (5 IU/mL). Multivalent constructs and controls were added to each wel at a 1:100 dilution. Controls were multivalent control V-body fusion constructs, IL-2 N88D fusion constructs, and TNFR2 agonist MR2-1.
  • FIG. 22 A bar graph of an overview of in-assay concentrations (nM) of multivalent (e.g., tetravalent Fc, Vb-Fc-Vb, rigid bivalent no Fc) binders is shown in Figure 22.
  • An exemplary gating strategy for Treg markers useful in the practice of the present Example is shown in Figure 23. Briefly, Treg Donor 1 is shown as an example and an identical strategy was used for Treg Donor 2 and Donor 3.
  • Live cel and CD4 gating were based on Fluorescence Minus One (FMO) control determination of the cut- of point between background fluorescence and positive cel populations.
  • FMO Fluorescence Minus One
  • FOXP3, HLA-DR, CCR8, and OX-40 gating was based on the CD4 subset of IgG control-stained sample from the same donor.
  • FoxP3 the gate was set at approximately 0.2%.
  • Findings from the present Example showed that multivalent anti-TNFR2 constructs increased expression of the Treg suppression marker HLA-DR ( Figures 24A-B) and CCR8 ( Figure 24B).
  • each of the multivalent formats tested herein resulted in increased HLA-DR and CCR8 expression for specific T-003 binder compared to control with formats, with 4 binders showing the strongest increase.
  • IL-2 N88D fusion constructs increased HLA-DR expression however a tetravalent anti-TNFR2 V-body formal was required for an additional increase in HLA-DR expression compared to control.
  • tetravalent anti-TNFR2 V-bodies strongly increased expression of Treg suppression marker HLA-DR on Fox P3+ Tregs ( Figures 25A-25B).
  • Vb-Fc-Vb tetravalent anti-TNFR2 V-body fusion construct 12 for Donor 1 (top panel) and Donor 2 (bottom panel) is shown in Figure 29.
  • Vb-Fc-Vb constructs demonstrated dose-dependent induction of Treg suppression marker HLA-DR expression. Maximal induction and potency was dose dependent.
  • Amino acid sequences of exemplary fusion protein constructs described in Examples 7 and 8 are provided below.
  • VHH sequences are indicated with a straight underline (e.g., VHH), Fc regions are indicated with bold letters (e.g., hIgG4-P329G SPLE or hIgG1 LALAGA), IL-2 N88D sequence is indicated with italic letters (e.g., IL2N88D), linker sequences are indicated with a wavy underline (e.g., Linker), and hinge regions are indicated with both a wavy underline and bold letters (e.g., hinge).
  • TNFR2 agonism by tetravalent VHH-Fc fusion increases suppressive function and stabilizes effector diferentiation in vitro [0665] and activation. It was hypothesized that TNFR2 stimulation wil also increase Treg stability based on the phenotype of TNFR2 knockout mice in which Treg are unstable and convert into effector cels. To test this hypothesis, multivalent anti-TNFR2 VHH proteins with agonist activity on TNFR2 were assessed for their impact on Treg proliferation, activation, immune suppressive function, and stability compared to IL-2 muteins.
  • Treg treated with anti-TNFR2 VHH or IL-2 mutein were evaluated to detect effects on proliferation, activation, suppressive function, and stability in inflammatory conditions.
  • tetravalent-Fc agonists T-007_2xVHH-Fc and T-003_2xVHH-Fc were characterized in vitro for their ability to expand and activate Treg in the presence of anti-CD3 and IL-2 stimulation.
  • na ⁇ ve Treg CD4+CD25+CD45RA+
  • IL-21, IL-23, IL-1b +/- TGFb inflammatory cytokine chalenge
  • IL-17A or IFN ⁇ intracellular staining after PMA/ionomycin restimulation.
  • Suppressive function was measured by assessing Treg ability to inhibit the proliferation of na ⁇ ve CD4 responder cels.
  • TNFR2 agonist T-037on proinflammatory cytokine production was evaluated from human PBMC treated with 5 nM TNFR2 V- body or CD28 agonist for 5 days in the presence of anti-CD3.
  • Treg proliferation was measured by assessing percent of proliferating Treg (CD4+FOXP3+) by cel tracer dilution by flow cytometry and cytokine production was measured in the supernatant by homogeneous time resolved fluorescence (HTRF) assay ( Figures 44A and 44B).
  • HTRF time resolved fluorescence
  • Figures 31 and 33A-33B show that tetravalent TNFR2 VHH-Fc antibodies induced the expansion of naive human Treg and up-regulated biomarkers of enhanced immunosuppressive activity such as CCR8 and HLA-DR and stability marker EZH2.
  • activation of TNFR2 increased the ability of na ⁇ ve human Treg to suppress the proliferation of CD4 responder cels (Figure 35).
  • TNFR2 agonist expanded Treg (CD4+FOXP3+) without inducing proinflammatory cytokines compared to CD28 agonist.
  • Figure 44 Agonistic TNFR2 VHH induced the expansion of na ⁇ ve human Treg, increased the expression of activation markers and stimulated suppressive effectss against CD4+ T effector cels.
  • TNFR2 VHH constructs but not IL-2 muteins, increased human Treg stability in the presence of proinflammatory cytokines based on sustained presence of FOXP3 bright cels and prevention of conversion of Treg into IL-17A- or IFN ⁇ -secreting cels.
  • agonism of TNFR2 by a tetravalent VHH-Fc fusion antibody expands human Treg, increases their suppressive function and stabilize their phenotype under inflammatory conditions in vitro.
  • TNFR2 agonism by tetravalent VHH-Fc fusion and expands and activates Treg cel in vivo The effects of anti-TNFR2 VHH agonists on spleen lymphocyte population in human TNFR2 knock-in mice were assessed by flow cytometry 5 days after a single intravenous injection (2.5 mg/kg) of tetravalent VHH-Fc antibody T-007_2xVHH-Fc, or control VHH, or mAb into human TNFR2 knock-in mice.
  • Anti-TNFR2 VHH agonistic proteins are effete at expanding Tregs that have a more stable immunosuppressive capacity and phenotype (preventing pathogenic conversion to Tef) compared to IL-2 muteins and may provide a durable and disease modifying therapy for multiple autoimmune diseases.
  • Example 11 Evaluation of effect of VHH-Fc fusion on Treg function in vivo 258 310886415v1 Attorney Docket No: 260525.000071 [0672] Human TNFR2 knock-in mice were injected with the constructs as indicated in Figures 42A-42B at 3 mg/kg intravenously.
  • Treg (FOXP3+CD4+) among CD45+ cel as wel as FOXP3, ICAM-1, ICOS expression (MFI, mean fluorescent intensity) on Treg was measured by flow cytometry.
  • Data as depicted in Figures 42A and 42B show Treg expansion in the spleen as wel as increased expression of FOXP3, linked to Treg stability and function, and Treg activation shown by up- regulation of ICAM-1 and ICOS.
  • anti-TNFR2 VHH agonists administered to mice increased Treg by three-fold in blood and tissues without increasing conventional Teff or NK cels as it induced a higher level of FOXP3 and surface markers (FOXP3, ICAM-1, OX-40, ICOS, and CCR8).
  • FOXP3 and surface markers FOXP3, ICAM-1, OX-40, ICOS, and CCR8.
  • Treg cels were measured at day 6 and at day 7, arthritis score (total number of afected digits) and paw volume were measured. The same experiment was repeated with T-043 construct. Data as depicted in Figure 43B and 43C show reduction of arthritis, measured by paw volume and arthritis score, in a model of colagen-antibody induced arthritis upon treatment with TNFR2 agonist T-037and T-043.
  • Amino acid sequences of exemplary fusion protein constructs described in Examples 11 and 12 as wel as additional engineered constructs are provided below.
  • VHH sequences are indicated with a straight underline (e.g., VHH), Fc regions are indicated with bold letters (e.g., hIgG4- SPLE or hIgG1 LALAPA), N-terminal modification are indicated with both bold and a straight underline (e.g., N-term modification), C-terminal modification are indicated with both italic and a wavy underline (e.g., C-term modification), linker sequences are indicated with a wavy underline (e.g., Linker), and hinge regions are indicated with both a wavy underline and bold letters (e.g., hinge).
  • VHH sequences are indicated with a straight underline (e.g., VHH)
  • Fc regions are indicated with bold letters (e.g., hIgG4- SPLE or hIgG1 LALAPA)
  • N-terminal modification are indicated with both bold and a straight underline (e.g., N-term modification)
  • VHH sequences (T-009Hu1_SGR_N/C) are indicated with a straight underline (e.g., VHH), the Fc region is indicated with bold leters (e.g., hIgG1 LALAPA), N-terminal modification are indicated with both bold and a straight underline (e.g., N-term modification), C- terminal modification are indicated with both italic and a wavy underline (e.g., C-term modification), linker sequences are indicated with a wavy underline (e.g., Linker), and the hinge region is indicated with both a wavy underline and bold letters (e.g., hinge).
  • VHH sequences T-009Hu1_SGR_N/C
  • the Fc region is indicated with bold leters (e.g., hIgG1 LALAPA)
  • N-terminal modification are indicated with both bold and a straight underline
  • C- terminal modification are indicated with both italic and a wavy underline
  • Sequence identifiers for exemplary anti-TNFR2 VHH antibodies obtained by alanine scanning mutagenesis CDR1 CDR2 CDR3 Humanized VHH Antibody ID Group Amino acid Amino acid Amino acid Amino acid Nucleotide e 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 Humanized VHH Antibody ID Group Amino acid Amino acid Amino acid Nucleotide e Example 15.
  • Binding Ratio binding Ratio binding Ratio binding Ratio TNFR2 to Fc-tagged V-bodies [0678] Binding Ratio binding Ratio TNFR2 (extracellular domain) to selected Fc-tagged V- bodies listed in Table 8 was determined by surface plasmon resonance (SPR) using a Caterra LSA instrument. Purified TNFR2 was covalently crosslinked onto an LSA HC30M chip using EDC/Sulfo NHS.
  • VHH sequences are indicated with a straight underline (e.g., VHH), Fc regions are indicated with bold letters (e.g., hIgG1 LALAPA), N-terminal modification are indicated with both bold and a straight underline (e.g., N-term modification), C- terminal modification are indicated with both italic and a wavy underline (e.g., C-term modification), linker sequences are indicated with a wavy underline (e.g., Linker), and hinge regions are indicated with both a wavy underline and bold letters (e.g., hinge).
  • VHH sequences are indicated with a straight underline (e.g., VHH)
  • Fc regions are indicated with bold letters (e.g., hIgG1 LALAPA)
  • N-terminal modification are indicated with both bold and a straight underline (e.g., N-term modification)
  • C- terminal modification are indicated with both italic and a wavy underline (e.g.
  • the monomer V-bodies were modified to replace Glu (E) with Asp (D) at the first position of the amino-terminus and to introduce the amino acid sequence VPAG (SEQ ID NO: 4698) at the carboxy-terminus for preparing the respective fusion protein 282 310886415v1 Attorney Docket No: 260525.000071 constructs.
  • the amino acid sequences of monomer V-bodies present within the fusion protein constructs are provided as SEQ ID Nos: 4994-5001 in the section titled ‘List of Sequences’.

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Abstract

The present application provides antigen-binding proteins (e.g., antibodies such as single-domain antibodies) that specifically bind tumor necrosis factor receptor 2 (TNFR2). The application also provides fusion proteins and conjugates comprising the antigen-binding proteins, polynucleotides and recombinant vectors encoding the antigen-binding proteins, as well as host cells and methods for preparing the antigen-binding proteins. The application further provides pharmaceutical compositions comprising the antigen-binding proteins and methods for treating a disease or disorder using the antigen-binding proteins.

Description

Attorney Docket No: 260525.000071 ANTI-TNFR2 ANTIGEN-BINDING PROTEINS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application No.63/632,315, filed April 10, 2024, and U.S. Provisional Patent Application No.63/664,961, filed June 27, 2024, the disclosures of which are herein incorporated by reference in their entireties. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submited electronicaly in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on April 2, 2025, is named 260525_000071_SL.xml and is 4,926,319 bytes in size. FIELD OF THE INVENTION [0003] The present application relates to antigen-binding proteins (e.g., antibodies such as single- domain antibodies) that specificaly bind tumor necrosis factor receptor 2 (TNFR2), methods for their preparation, and uses thereof. BACKGROUND OF THE INVENTION [0004] Regulatory T cels (Tregs) are a subset of T cels that play a crucial role in peripheral self- tolerance and the prevention of autoimmunity. Due to their potent immunosuppressive function, Tregs can be targeted for the treatment of autoimmunity. Current strategies seeking to increase or modulate Tregs in autoimmune patients are based on the ex vivo expansion of Tregs prior to autologous transfer. However, a major limitation of the current strategies is their inability to stabilize Tregs phenotype to ensure long-lasting immunoregulation. [0005] Tumor necrosis factor receptor 2 (TNFR2) signaling has been shown to induce proliferation, sustained suppressive function and FOXP3 promoter demethylation in Tregs (Tseng et al., 2019). TNFR2 signaling also induces the expression of EZH2 (Urbano et al., 2018), a histone methyl transferase involved in the repression of the efector transcriptomic program and stabilization of the Treg phenotype (DuPage et al., 2015). Because of its role in Tregs biology and FOXP3 promoter demethylation, TNFR2 signaling can be leveraged to induce a stable immunosuppressive phenotype and enhance their function to the benefit of autoimmune diseases. Accordingly, there is a need in the art to develop therapeutic molecules that can efectively activate TNFR2 signaling. 1 310886415v1 Attorney Docket No: 260525.000071 SUMMARY OF THE INVENTION [0006] As mentioned in the background section above, there is an unmet need in the art to develop therapeutic molecules that can efectively activate TNFR2 signaling. This application provides compositions and methods to address this and other related needs. [0007] In one aspect, the present disclosure provides an antigen-binding protein that specificaly binds tumor necrosis factor receptor 2 (TNFR2), comprising a complementarity determining region 3 (CDR3) comprising the amino acid sequence AADSDL(S/R)TV(V/T)VGPHDY (SEQ ID NO: 61), A(A/G)(T/A/S)(P/L)(S/T)GKAY(T/S)Y (SEQ ID NO: 4787), or (T/A/V)A(S/A)PTGRAF(T/N/A)Y (SEQ ID NO: 66), wherein one or more non-alanine residues in the CDR3 sequence are optionaly replaced with an alanine, and/or one or more alanine residues in the CDR3 sequence are optionaly replaced with a glycine. [0008] In some embodiments, the CDR3 comprises the amino acid sequence (T/A/V)(A/G)(S/A)(A/P)(A/T)(A/G)(A/R)A(A/F)(T/N/A)(A/Y) or (A/G)(A/G)(T/A/S)(A/P/L)(A/S/T)(A/G)(A/K)(A/G)(A/Y)(A/T/S)(A/Y). [0009] In some embodiments, the CDR3 comprises an amino acid sequence selected from SEQ ID NOs: 10, 34, 4524, 4530, 4774, 18, 4727, 4810-4833, and 4835-4855. [0010] In some embodiments, the antigen-binding protein further comprises a CDR1 comprising the amino acid sequence GRTFSDYG (SEQ ID NO: 16), GRTF(G/R/S)(N/S)(Y/L)(T/F) (SEQ ID NO:73), or GFT(F/L)DD(I/Y)A (SEQ ID NO: 69). [0011] In some embodiments, the CDR1 comprises the amino acid sequence of SEQ ID NO: 16, 32 or 4061. [0012] In some embodiments, the antigen-binding protein further comprises a CDR2 comprising the amino acid sequence INWS(N/Q/E/S)(G/A)RT (SEQ ID NO: 4809), IR(W/R/Y)(T/P)G(G/L)(S/I)T (SEQ ID NO: 80), or I(Y/F)SY(S/G)(S/P)NT (SEQ ID NO: 76). [0013] In some embodiments, the CDR2 comprises an amino acid sequence selected from SEQ ID NOs: 4062, 4527, 4070, and 4788-4793. [0014] In some embodiments, the antigen-binding protein comprises i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4809, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4787; i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 69, a CDR2 comprising an amino acid sequence of SEQ ID NO: 76, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 61; 2 310886415v1 Attorney Docket No: 260525.000071 ii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4809, and a CDR3 comprising an amino acid sequence of (A/G)(A/G)(T/A/S)(A/P/L)(A/S/T)(A/G)(A/K)(A/G)(A/Y)(A/T/S)(A/Y); or iv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 73, a CDR2 comprising an amino acid sequence of SEQ ID NO: 80, and a CDR3 comprising an amino acid sequence of (T/A/V)(A/G)(S/A)(A/P)(A/T)(A/G)(A/R)A(A/F)(T/N/A)(A/Y). [0015] In some embodiments, the antigen-binding protein comprises i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10; ii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4524; iv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727; v) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727; vi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; vi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; vii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; ix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4791, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; x) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4792, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; xi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4793, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; xi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; 3 310886415v1 Attorney Docket No: 260525.000071 xii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4810; xvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4811; xvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4812; xvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4813; xix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4814; xx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4815; xxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4816; xxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4817; xxii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4818; xxiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4819; xxv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4820; 4 310886415v1 Attorney Docket No: 260525.000071 xxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4821; xxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4822; xxvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4823; xxix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4824; xxx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4825; xxxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4826; xxxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4827; xxxii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4828; xxxiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 34; xxxv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4829; 5 310886415v1 Attorney Docket No: 260525.000071 xxxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4830; xxxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4831; xxxvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4832; xxxix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4833; xl) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4835; xli) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4836; xli) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4837; xlii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4838; xliv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4839; xlv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4840; xlvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4841; 6 310886415v1 Attorney Docket No: 260525.000071 xlvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4842; xlvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4843; xlix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4844; l) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4845; li) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4846; li) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4847; lii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4848; liv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4849; lv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4850; lvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4851; lvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4852; lvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4853; lix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4854; or lx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4855. 7 310886415v1 Attorney Docket No: 260525.000071 [0016] In some embodiments, the antigen-binding protein is a single-domain antibody. [0017] In some embodiments, the single-domain antibody is a VHH, a VNAR, or a VH domain. [0018] In some embodiments, the VHH is a camelid VHH. [0019] In some embodiments, the VHH comprises the amino acid sequence of SEQ ID NO: 4781 or 4783, or a sequence having at least 75% identity thereto. [0020] In some embodiments, the VHH is a humanized VHH. [0021] In some embodiments, the humanized VHH comprises an amino acid sequence selected from any one of SEQ ID NOs: 4775, 4782, 4784, 4794-4808, 4857-4902, 4994-5001, or a sequence having at least 75% identity thereto. [0022] In some embodiments, the antigen-binding protein has an agonist efect upon binding to TNFR2. [0023] In some embodiments, the antigen-binding protein binds to human TNFR2. [0024] In some embodiments, the antigen-binding protein binds to human TNFR2 with a KD of about 1x10-8 M to about 2.7 x 10-6 M. [0025] In some embodiments, the antigen-binding protein binds to cyno TNFR2. [0026] In some embodiments, the antigen-binding protein binds to cyno TNFR2 with a K - D of about 3x10 8 M to about 2.4 x 10-6 M. [0027] In some embodiments, the antigen-binding protein increases expression of one or more proteins selected from a protein in the NF-kB pathway, FOXP3, HELIOS, EZH2, HLA-DR, ICAM-1, OX-40, ICOS, and CCR8. [0028] In some embodiments, the antigen-binding protein comprises one or more modifications that reduce binding of the antigen-binding protein by pre-existing antibodies found in human blood or serum. [0029] In some embodiments, the single-domain antibody comprises one or more modifications at the amino-terminus and/or the carboxy-terminus. [0030] In some embodiments, the single-domain antibody comprises the amino acid sequence VPAG (SEQ ID NO: 4698) or VAGG (SEQ ID NO: 4697) at the carboxy-terminus starting from position 111 according to Chothia. [0031] In some embodiments, the single-domain antibody comprises a substitution of amino acid residue Glu with Asp (E1D) at the first position of the amino-terminus. [0032] In another aspect, provided herein is an antigen-binding protein that specificaly binds tumor necrosis factor receptor 2 (TNFR2), comprising a means for binding an epitope within human TNFR2 8 310886415v1 Attorney Docket No: 260525.000071 bound by an antibody selected from T-004, T-004.VTV, T-007hu1 with CDR2 G/A, CDR3 T/S, T- 009Hu1_QGR, T-009Hu1_SGR, T-009Hu1_QGR_N/C, T-009Hu1_NAR_N/C, T-009Hu1_SGR_N/C, T- 007Hu1.S3.QGR, T-007Hu1.S3.EGR, T-007Hu1.S3.SGR, T-007Hu1.S3.NSR, T-007Hu1.S3.NTR, T- 007Hu1.S3.SAR, T-007Hu1.EQ.QGR, T-007Hu1.EQ.EGR, T-007Hu1.EQ.SGR, T-007Hu1.EQ.S3.NSR, T- 016hu1.A1, T-016hu1.G2, T-016hu1.A3, T-016hu1.A4, T-016hu1.A5, T-016hu1.A6, T-016hu1.A7, T- 016hu1.A9, T-016hu1.A10, T-016hu1.A11, T-016Hu1.A5.A7, T-016Hu1.A5.A1, T-016Hu1.A5.A3, T- 016Hu1.A5.A4, T-016Hu1.A5.A6, T-016Hu1.A7.A1, T-016Hu1.A7.A3, T-016Hu1.A7.A4, T-016Hu1.A7.A6, T-016Hu1.A1.A3, T-016Hu1.A1.A4, T-016Hu1.A1.A6, T-016Hu1.A3.A4, T-016Hu1.A3.A6, T-016Hu1.A4.A6, T-008Hu1.G1, T-008Hu1.G2, T-008Hu1.A4, T-008Hu1.A5, T-008Hu1.A6, T-008Hu1.A7, T-008Hu1.G8, T- 008Hu1.A9, T-008Hu1.A10, T-008Hu1.A11, T-009Hu1_SGR.G1, T-009Hu1_SGR.G2, T-009Hu1_SGR.A3, T- 009Hu1_SGR.A4, T-009Hu1_SGR.A5, T-009Hu1_SGR.A6, T-009Hu1_SGR.A7, T-009Hu1_SGR.G8, T- 009Hu1_SGR.A9, T-009Hu1_SGR.A10, and T-009Hu1_SGR.A11. [0033] In another aspect, the present disclosure provides a fusion protein that specificaly binds tumor necrosis factor receptor 2 (TNFR2), comprising one or more of the antigen-binding proteins described herein. [0034] In some embodiments, the fusion protein comprises two of the antigen-binding proteins. [0035] In some embodiments, the fusion protein comprises four of the antigen-binding proteins. [0036] In some embodiments, the one or more antigen-binding proteins bind to the same epitope on TNFR2. [0037] In some embodiments, the one or more antigen-binding proteins bind to diferent epitopes on TNFR2. [0038] In some embodiments, the one or more antigen-binding proteins are one or more single-domain antibodies. [0039] In some embodiments, the one or more single-domain antibodies are one or more VHHs. [0040] In some embodiments, the fusion protein further comprises an immunoglobulin Fc region. [0041] In some embodiments, the immunoglobulin Fc region is an Fc region of a human immunoglobulin. [0042] In some embodiments, the immunoglobulin Fc region is an Fc region of human IgG1, IgG2, IgG3 or IgG4, or a variant thereof. [0043] In some embodiments, the immunoglobulin Fc region is an Fc region of human IgG1, or a variant thereof. 9 310886415v1 Attorney Docket No: 260525.000071 [0044] In some embodiments, the Fc region of human IgG1 comprises one or more mutations selected from L234A, L235A, G237A, M252Y, S254T, T256E, D265A, N297A, and/or P329A according to EU numbering. [0045] In some embodiments, the Fc region of human IgG1 comprises a set of mutations selected from 1). L234A and L235A; 2). L234A, L235A, and P329A; 3). D265A, N297A and P329A; 4). L234A, L235A, and G237A; 5). M252Y, S254T, and T256E. [0046] In some embodiments, the Fc region of human IgG1 comprises L234A, L235A, and P329A. [0047] In some embodiments, the Fc region of human IgG1 comprises M252Y, S254T, and T256E. [0048] In some embodiments, the immunoglobulin Fc region is an Fc region of human IgG4, or a variant thereof. [0049] In some embodiments, the Fc region of human IgG4 comprises one or more mutations selected from S228P, L235E, L235A, and/or F234A according to EU numbering. [0050] In some embodiments, the Fc region of human IgG4 comprises a set of mutations selected from 1). S228P and L235E; 2). S228P and L235A; 3). S228P, F234A, and L235E; and 4). S228P, F234A, and L235A. [0051] In some embodiments, the Fc region of human IgG4 comprises S228P and L235E. [0052] In some embodiments, the fusion protein described herein further comprises a cytokine. [0053] In some embodiments, the cytokine is IL-2, or a variant thereof. [0054] In some embodiments, the cytokine is an IL-2 variant comprising a N88D mutation. [0055] In some embodiments, the fusion protein further comprises a moiety that binds to serum albumin. [0056] In some embodiments, the fusion protein comprises the amino acid sequence of any one of SEQ ID Nos: 4772, 4773, 4776-4779, 4903, 4979, 4981, 4983, 4985, 4987, 4989, 4991, and 4993, or a sequence having at least 75% identity thereto. [0057] In some embodiments, the fusion protein has an agonist efect upon binding to TNFR2. [0058] In some embodiments, the fusion protein binds to human TNFR2. 10 310886415v1 Attorney Docket No: 260525.000071 [0059] In some embodiments, the fusion protein binds to human TNFR2 with a K -12 D of about 3x10 M to about 1 x 10-7 M. [0060] In some embodiments, the fusion protein binds to cyno TNFR2. [0061] In some embodiments, the fusion protein binds to cyno TNFR2 with a K -12 D of about 1x10 M to about 5 x 10-8 M. [0062] In another aspect, the present disclosure provides a conjugate comprising an antigen-binding protein described herein or a fusion protein described herein, wherein the antigen-binding protein or fusion protein is conjugated to a second moiety. [0063] In some embodiments, the second moiety is selected from a detectable label, a drug, a toxin, a radionuclide, an enzyme, an immunomodulatory agent, a cytokine, a cytotoxic agent, a chemotherapeutic agent, and a diagnostic agent, or a combination thereof. [0064] In some embodiments, the second moiety is a cytokine. [0065] In some embodiments, the cytokine is IL-2, or a variant thereof. [0066] In some embodiments, the cytokine is IL-2 variant comprising a N88D mutation. [0067] In another aspect, the present disclosure provides a polynucleotide molecule encoding an antigen-binding protein described herein or a fusion protein described herein. [0068] In another aspect, the present disclosure provides a recombinant vector comprising a polynucleotide molecule described herein. [0069] In another aspect, the present disclosure provides a host cel comprising a polynucleotide molecule described herein, or a recombinant vector described herein. [0070] In another aspect, the present disclosure provides a kit comprising an antigen-binding protein described herein, a fusion protein described herein, a conjugate described herein, a polynucleotide molecule described herein, or a recombinant vector described herein, and optionaly, instructions and/or packaging for the same. [0071] In another aspect, the present disclosure provides a pharmaceutical composition comprising an antigen-binding protein described herein, a fusion protein described herein, a conjugate described herein, a polynucleotide molecule described herein, or a recombinant vector described herein, and a pharmaceuticaly acceptable carrier and/or excipient. [0072] In another aspect, the present disclosure provides a method for preparing an antigen-binding protein or a fusion protein that specificaly binds tumor necrosis factor receptor 2 (TNFR2), comprising the steps of: 11 310886415v1 Attorney Docket No: 260525.000071 (a) culturing a host cel described herein in a culture medium under conditions suitable for expression of an antigen-binding protein described herein or a fusion protein described herein; and (b) isolating the antigen-binding protein or the fusion protein from the host cel and/or the culture medium. [0073] In another aspect, the present disclosure provides a method for promoting proliferation, activating and/or enhancing suppressive function, and/or stabilizing immunosuppressive phenotype of a population of regulatory T cels (Treg) comprising contacting the population of Treg with an antigen- binding protein described herein, a fusion protein described herein, or a conjugate described herein. [0074] In some embodiments, the contacting occurs in vitro. [0075] In some embodiments, the contacting occurs in vivo. [0076] In some embodiments, the method further comprises administering the antigen-binding protein described herein, the fusion protein described herein, or the conjugate described herein into a subject in need thereof. [0077] In another aspect, the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject an antigen- binding protein described herein, a fusion protein described herein, or a conjugate described herein. [0078] In some embodiments, the disease or disorder is an immunological disease, inflammatory disease, cancer, cardiovascular disease, or an infertility and pregnancy-associated disease. [0079] In some embodiments, the immunological disease is selected from an autoimmune disease, a neurological condition, an alergy, asthma, macular degeneration, muscular atrophy, a disease related to miscarriage, atherosclerosis, bone loss, a musculoskeletal disease, obesity, a graft-versus-host disease, and an alograft rejection. [0080] In some embodiments, the autoimmune disease is selected from lupus, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, bulous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Goodpastures disease, Graves' disease, Guilain-Barré, Hashimoto's thyroiditis, hypothyroidism, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, juvenile arthritis, lichen planus, lichen sclerosis, IgG4-related disease, Meniere's disease, mixed connective tissue 12 310886415v1 Attorney Docket No: 260525.000071 disease, multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disease, pemphigus vulgaris or related blistering skin disease, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, premature ovarian failure, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, primary ovarian insuficiency, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, spondyloarthritis, stif-man syndrome, type I diabetes, Takayasu arteritis, temporal arteritis/giant cel arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener's granulomatosis (Granulomatosis with polyangitis) or other immune vasculitis. [0081] In some embodiments, the lupus is systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis, neonatal lupus, or drug-induced lupus. [0082] In some embodiments, the cutaneous lupus is acute cutaneous lupus, chronic cutaneous lupus erythematosus, discoid lupus erythematosus (DLE), or subacute cutaneous lupus erythematosus. [0083] In some embodiments, the neurological condition is selected from a brain tumor, a brain metastasis, a spinal cord injury, schizophrenia, epilepsy, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's disease, Parkinson's disease, and stroke. [0084] In some embodiments, the alergy is selected from food alergy, seasonal alergy, pet alergy, hives, hay fever, alergic conjunctivitis, poison ivy alergy oak alergy, mold alergy, drug alergy, dust alergy, cosmetic alergy, and chemical alergy. [0085] In some embodiments, the alograft rejection is selected from skin graft rejection, bone graft rejection, vascular tissue graft rejection, ligament graft rejection, and organ graft rejection. [0086] In some embodiments, the ligament graft rejection is selected from cricothyroid ligament graft rejection, caudal cruciate ligament graft rejection, periodontal ligament graft rejection, suspensory ligament of the lens graft rejection, palmar radiocarpal ligament graft rejection, dorsal radiocarpal ligament graft rejection, ulnar colateral ligament graft rejection, radial colateral ligament graft rejection, suspensory ligament of the breast graft rejection, anterior sacroiliac ligament graft rejection, posterior sacroiliac ligament graft rejection, sacrotuberous ligament graft rejection, sacrospinous ligament graft rejection, inferior pubic ligament graft rejection, superior pubic ligament graft rejection, anterior cruciate ligament graft rejection, lateral colateral ligament graft rejection, posterior cruciate ligament graft rejection, medial colateral ligament graft rejection, cranial cruciate ligament graft rejection, and patelar ligament graft rejection. 13 310886415v1 Attorney Docket No: 260525.000071 [0087] In some embodiments, the organ graft rejection is selected from heart graft rejection, lung graft rejection, kidney graft rejection, liver graft rejection, pancreas graft rejection, intestine graft rejection, and thymus graft rejection. [0088] In some embodiments, the graft-versus-host disease arises from a bone marrow transplant or one or more blood cels selected from B-cels, T-cels, basophils, common myeloid progenitor cels, common lymphoid progenitor cels, dendritic cels, eosinophils, hematopoietic stem cels, neutrophils, natural kiler cels, megakaryocytes, monocytes, or macrophages. [0089] In some embodiments, the inflammatory disease is acute or chronic inflammation. [0090] In some embodiments, the inflammatory disease is selected from osteoarthritis, atopic dermatitis, endometriosis, polycystic ovarian syndrome, inflammatory bowel disease, fibrotic lung disease, and cardiac inflammation. [0091] In some embodiments, the cancer is selected from adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith- Wiedemann syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer (sarcoma of bone), brain stem glioma, brain tumor, breast cancer, inflammatory breast cancer, metastatic breast cancer, male breast cancer, Carney complex, central nervous system tumors (brain and spinal cord), cervical cancer, childhood cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, desmoid tumor, desmoplastic infantile ganglioglioma, childhood tumor, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial pancreatic cancer, galbladder cancer, gastrointestinal stromal tumor (GIST), germ cel tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary difuse gastric cancer, hereditary leiomyomatosis and renal cel cancer, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papilary renal carcinoma, HIV/AIDS-related cancer, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumor, laryngeal and hypopharyngeal cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cel prolymphocytic leukemia and hairy cel leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cel lymphocytic leukemia, eosinophilic leukemia, Li-Fraumeni syndrome, liver cancer, lung cancer, non-smal cel lung cancer, smal cel lung cancer, hodgkin lymphoma, non-hodgkin lymphoma, lynch syndrome, mastocytosis, meduloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, 14 310886415v1 Attorney Docket No: 260525.000071 myelodysplastic syndromes (MDS), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumor of the gastrointestinal tract, neuroendocrine tumor of the lung, neuroendocrine tumor of the pancreas, neuroendocrine tumors, neurofibromatosis type 1, neurofibromatosis type 2, nevoid basal cel carcinoma syndrome, oral and oropharyngeal cancer, osteosarcoma, ovarian, falopian tube, and peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma and paraganglioma, pituitary gland tumor, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Kaposi sarcoma, soft tissue sarcomas, skin cancer (non-melanoma), smal bowel cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis complex, uterine cancer, vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Waldenstrom macroglobulinemia (lymphoplasmacytic lymphoma), Werner syndrome, Wilms tumor, or xeroderma pigmentosum. [0092] In some embodiments, the cardiovascular disease is selected from atherosclerosis, heart failure, left heart failure with reduced ejection fraction, left heart failure with preserved ejection fraction, right ventricular failure, congestive heart failure, restrictive cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, idiopathic cardiomyopathy, and hypertension. [0093] In some embodiments, the infertility and pregnancy-associated diseases is selected from recurrent pregnancy loss, pre-eclampsia, preterm labor, fetal growth restriction, and intrauterine growth restriction. [0094] In another aspect, the present disclosure provides a method of regenerating a tissue or an organ comprising one or more TNFR2+ cels, the method comprising contacting the tissue or the organ with an efective amount of an antigen-binding protein described herein, a fusion protein described herein, or a conjugate described herein. [0095] In some embodiments, the tissue or the organ is selected from pancreas, salivary gland, pituitary gland, kidney, heart, lung, hematopoietic system, cranial nerves, heart, aorta, olfactory gland, ear, nerve, eye, thymus, tongue, bone, liver, smal intestine, large intestine, gastrointestinal, lung, brain, skin, peripheral nervous system, central nervous system, spinal cord, breast, embryonic structures, embryo, and testes tissue. [0096] In some embodiments, the contacting occurs in vitro. [0097] In some embodiments, the contacting occurs in vivo. 15 310886415v1 Attorney Docket No: 260525.000071 [0098] In some embodiments, the method further comprises administering the antigen-binding protein described herein, the fusion protein described herein, or the conjugate described herein into a subject in need thereof. [0099] In another aspect, the present disclosure provides a method for inducing tolerance to a foreign agent and/or preventing or reducing immune response to a foreign agent in a subject in need thereof, the method comprising administering to the subject an antigen-binding protein described herein, a fusion protein described herein, or a conjugate described herein. [0100] In some embodiments, the foreign agent is a therapeutic protein or peptide, a viral vector, a bacterial vector, a fungal vector, a biochemical vector, a lipid, carbohydrate, a nucleic acid, a sperm, an oocyte, or an embryo. [0101] In some embodiments, the viral vector is a DNA or RNA vector. [0102] In some embodiments of any of the above-described methods, the subject is a mammal. [0103] In some embodiments, the mammal is human. BRIEF DESCRIPTION OF DRAWINGS [0104] Figure 1 depicts an exemplary general panning strategy for isolation of tumor necrosis factor (TNF) receptor type 2 (TNFR2)-specific variable domain of heavy chain (VHH) antibodies, also referred to herein as V-bodies (Vbs). Binders to human and rodent TNFR2 were enriched from VHH immune libraries by two rounds of phage display. BM, bone marrow. [0105] Figure 2 shows VHH immune library selection for next-generation sequencing (NGS) across the phage display process. Three initial libraries, 12 samples of the first panning round, and 36 samples of the second panning round, were sequenced with 20 milion, 2 milion, and 2 milion reads, respectively. Comparison of V-body enrichment from the initial library to the first and second round of panning enabled identification of potential V-body candidates. [0106] Figure 3 shows a schematic diagram of an exemplary NGS workflow. Folowing phage display, the VHH region of the phage eluate was amplified via polymerase chain reaction (PCR). Unique and sample-specific barcodes were then fused, and NGS was subsequently performed using the Ilumina NovaSeq platform (Genewiz). The raw data were de-multiplexed, and then processed by the NGS analysis pipeline. Forward and reverse sequence pairs were merged via overlapping regions and the VHHs, including complementarity determining regions (CDRs) were annotated. Based on CDR3 identity, V-body sequences were clustered, thereby alowing for detailed analysis of, e.g., V-body enrichment during phage display, sequence diversity, CDR3 length distribution, and cluster abundance. Based on 16 310886415v1 Attorney Docket No: 260525.000071 such analyses, more than 600 candidates were selected for DNA synthesis (Twist) and further characterization. [0107] Figures 4A-4B ilustrate human TNFR2 (hTNFR2) V-body binding validation at a fixed concentration of 1 µM V-body. The bar histogram (Figure 4A) and table (Figure 4B) show the percentage of Alexa488-positive cels for al VHHs tested. For the bar histogram, the black dotted line indicates background staining (~5%), and the gray dotted line indicates two times the background level. A V-body having a signal-to-noise ratio greater than 2 is considered as a “binder”. Gray shading within the table indicates binders to hTNFR2. [0108] Figures 5A-5B ilustrate human TNFR2 (hTNFR2) V-body binding validation at a fixed concentration of 100 nM V-body. The bar histogram (Figure 5A) and table (Figure 5B) show the percentage of Alexa488-positive cels for al VHHs tested. For the bar histogram, the black dotted line indicates background staining (~5%), and the gray doted line indicates two times the background level. A V-body having a signal-to-noise ratio greater than 2 is considered as a “binder”. Gray shading within the table indicates binders to hTNFR2. [0109] Figures 6A-6C depict cross-specificity of V-body binding to mouse TNFR2 (mTNFR2) (Figure 6A) and cynomolgus TNFR2 (cTNFR2) (Figure 6B) at a fixed concentration of 100 nM. The bar histograms (Figure 6A-6B) and table (Figure 6C) show the percentage of Alexa488-positive cels for al VHHs tested. For the bar histogram, the black dotted line indicates background staining, and the gray dotted line indicates two times the background level. [0110] Figure 7 shows testing of human TNFR2 V-body binding across a range of concentrations for V- bodies T-002, T-014, T-001, T-006, T-007, T-003, and V-bodies. V-bodies were tested at molar concentrations of 100 nM, 50 nM, 12.5 nM, 6.25 nM, 3.12 nM, and 1.55 nM. [0111] Figure 8 shows a schematic diagram of an exemplary experimental setup for determination of binding afinities of the V-bodies for their respective target via surface plasmon resonance (SPR) (left panel) and a corresponding table describing the V-body candidates analyzed (right panel). Figure discloses SEQ ID NO: 4717. [0112] Figures 9A-9F depict surface plasmon resonance (SPR) sensorograms of VHH binding to human, cynomolgus, and mouse TNFR2. Fitted binding curves and calculated dissociation constants (KD) are included. [0113] Figure 10 shows a summary of binding afinities of 16 selected anti-TNFR2 V-bodies to human, cynomolgus and mouse TNFR2. Cyno, cynomolgus. 17 310886415v1 Attorney Docket No: 260525.000071 [0114] Figure 11 demonstrates that some humanized anti-TNFR2 V-bodies targeted the epitope recognized by a MR2-1 bivalent agonist. T-013hu1 and T-018hu1 may recognize the same epitope as MR2-1. MR2-1 binding enhanced binding of T-015hu1, T-017hu1 and T-011hu1 to TNFR2. [0115] Figures 12A-12E show TNFR2 agonism by multivalent V-body fusion constructs. Agonism of bivalent (Figure 12A), tetravalent (Figures 12B-12C), and IL-2 N88D fusion (Figure 12D) anti-TNFR2 constructs were characterized on NF-κB reporter HEK293 cels stably expressing TNFR2. Dot plots show a dose-dependent response of anti-TNFR2 VHHs compared to a control VHH (Ctrl). Figure 12E shows that activity of T-007_2xVHH-Fc, and an IL-2 mutein, was demonstrated in reporter cel lines specific for each signaling pathway. RLU, relative luminescence unit. [0116] Figure 13 depicts HEK293 TNFR2 NF-κB (Luc) reporter gene assay controls. Anti-hTNFR2 agonist MR2-1 monoclonal antibodies were tested on NF-κB reporter (Luc) HEK293 reporter cel-line stably expressing TNFR2 (clone 25) versus parental cel line (PCL). RLU, relative luminescence unit. [0117] Figures 14A-14C shows HEK293 TNFR2 NF-κB (Luc) reporter gene assay samples and assay controls. A description of reporter gene assay samples and assay controls is shown in Figure 14A. A bar graph showing protein concentration (mg/mL) for the V-body constructs and respective controls is depicted in Figure 14B. A bar graph showing RLUs for V-body constructs and respective controls tested on a PCL control is depicted in Figure 14C. [0118] Figures 15A-15B depict concentration range curve data generated using MR2-1 (Figure 15A) and TNFα (Figure 15B) controls for four assay plates. [0119] Figures 16A-16C show exemplary dot plots of RLUs measured across increasing concentrations (mol/L) of control (control 12) and tetravalent V-body fusion constructs comprising four V-bodies mounted onto the fragment crystalizable (Fc) region of a IgG4 variant comprising S228P, L235E and P329G mutations. [0120] Figures 17A-17F show exemplary dot plots of RLUs measured across increasing concentrations (mol/L) of control (control 10) and an alternative design of tetravalent V-body fusion constructs comprising four V-bodies mounted onto the Fc region of a IgG4 variant comprising S228P, L235E and P329G mutations. [0121] Figures 18A-18C show exemplary dot plots of RLUs measured across increasing concentrations (mol/L) of control (control 2) and bivalent V-body fusion constructs. Limit of detection, LOD. [0122] Figures 19A-19C show exemplary dot plots of RLUs measured across increasing concentrations (mol/L) of control (control 13) and IL-2 N88D V-body fusion constructs. Limit of detection, LOD. 18 310886415v1 Attorney Docket No: 260525.000071 [0123] Figure 20 depicts a comparison of RLUs measured across increasing concentrations (mol/L) of monospecific construct 10 (tetravalent Fc) and construct 12 (Vb-Fc-Vb) tested on NF-κB reporter (Luc) HEK293 reporter cel-line stably expressing TNFR2 (clone 8). [0124] Figure 21 depicts an exemplary experimental timeline of TNFR2 stimulation by multivalent V- body fusion constructs (e.g., tetravalent Fc, Vb-Fc-Vb, rigid bivalent no Fc) on primary human peripheral blood mononuclear cels (PBMCs) and cluster of diferentiation 4 positive (CD4+) CD25+ CD127dim regulatory T cels (Tregs). [0125] Figure 22 shows a bar graph of an overview of in-assay concentrations (nM) of multivalent V- body fusion constructs first wave binders. Concentrations (nM) of the VHH constructs is also shown. [0126] Figure 23 ilustrates an exemplary gating strategy applied for Treg markers. Treg Donor 1 is shown as an example and an identical strategy was used for Treg Donor 1 and Donor 3. Live cel and CD4 gating were based on Fluorescence Minus One (FMO) FMO control determination of the cut-of point between background fluorescence and positive cel populations. Forkhead box P3 (FoxP3), Human Leukocyte Antigen, DR isotype (HLA-DR), chemokine motif (C-C motif) receptor 8 (CCR8), and OX-40 gating was based on the CD4 subset of IgG control-stained sample from the same donor. For FoxP3, the gate was set at approximately 0.2%. For OX-40, HLA-DR and CCR8, the gate was set at approximately 2%. [0127] Figures 24A-24B demonstrate multivalent anti-TNFR2 V-body fusion constructs increased expression of the Treg suppression marker HLA-DR and CCR8. Histograms displaying expression of Treg suppression marker HLA-DR for specific T-003 binders compared to control formats (Figure 24A). Density plots displaying expression of Treg suppression marker HLA-DR and CCR8 for specific T-003 binders compared to control formats (Figure 24B). Fluorescein isothiocyanate, FITC; Phycoerythrin, PE. [0128] Figures 25A-25B demonstrates tetravalent anti-TNFR2 V-body fusion constructs strongly increased expression of Treg suppression marker HLA-DR on FoxP3+ Tregs. The bar graphs show HLA-DR mean fluorescent intensity (MFI) measured for each of the tetravalent Fc, Vb-Fc-Vb, and rigid bivalent no Fc V-body fusion formats relative to control formats. [0129] Figure 26 shows dose-response curves based on HLA-DR MFI values of CD4+ FoxP3+ Tregs for construct T-003 and control 10 for Donor 2. [0130] Figure 27 shows dose-dependent induction of Treg suppression marker HLA-DR expression across various concentrations of tetravalent anti-TNFR2 V-body Fc fusion construct 10 for Donor 1 (top panel) and Donor 2 (botom panel). 19 310886415v1 Attorney Docket No: 260525.000071 [0131] Figure 28 shows dose-dependent induction of Treg suppression marker HLA-DR expression across various concentrations of rigid bivalent anti-TNFR2 V-body fusion construct 2 for Donor 1 (top panel) and Donor 2 (botom panel). [0132] Figure 29 shows dose-dependent induction of Treg suppression marker HLA-DR expression across various concentrations of tetravalent anti-TNFR2 V-body Vb-Fc-Vb fusion construct 12 for Donor 1 (top panel) and Donor 2 (bottom panel). [0133] Figure 30 shows exemplary design of multivalent anti-TNFR2 V-body fusion constructs. Anti- TNFR2 V-bodies are shown as ovals, linkers are shown with flexible (e.g., GS linkers) as curved lines, rigid linkers (e.g., proline linker) as straight lines, and Fc domains as dimeric bars. Figure discloses SEQ ID NO: 4718. [0134] Figure 31 shows assessment of tetravalent-Fc VHH activity on naïve CD4+CD25+CD45RA+ human Treg. HLA-DR and CCR8 expression on CD4+FOXP3+ and expansion after 5 day stimulation with anti-CD3/IL-2 plus VHH or MR2-1 are shown. [0135] Figure 32A shows the ability of TNFR2 VHH to stabilize Treg. Naive CD4+CD25+CD45RA+ human Treg from healthy donors were stimulated with IL-2 and anti-CD3 in the presence of TNFR2 agonist VHH or TNFR2 monoclonal agonist MR2-1 for 5 days. [0136] Figure 32B shows the efect of TNFR2 VHH on early markers of Treg stability. Naive CD4+CD25+CD45RA+ human Treg from healthy donors were stimulated with IL-2 and anti-CD3 in the presence of TNFR2 agonist VHH or IL-2 mutein for 5 days. [0137] Figures 33A-33B show additional results of in vitro treatment of human Treg (CD4+ FOXP3+) with VHH T-007_2xVHH-Fc or IL-2 mutein in the presence of anti-CD3 and IL-2. T-007_2xVHH-Fc induced and expanded a Treg population with high levels of FOXP3, EZH2 (a marker of stability), CCR8, and HLA- DR (biomarkers of tissue homing and Treg immunosuppressive functionality). T-test: * p < 0.05; ** p < 0.01; n = 3. [0138] Figures 34A-34C show the efect of TNFR2 VHH on Treg stability under inflammatory conditions. Human Treg were expanded with IL-2 mutein or TNFR2 VHH in the presence of anti-CD3 and IL-2 for 5 days and then cultured with proinflammatory cytokines (IL-1b, IL-21, and IL-23 +/- TGFb) for 11 to 12 days; IL-17A or IFN^ production after PMA/ionomycin stimulation was assessed together with FOXP3 by flow cytometry. The conversion of human Treg in vitro to cels that produce Th1/17 cytokines (IFNγ/IL- 17A) triggered by the inflammatory cytokines shown was prevented by co-stimulation with TNFR2 VHH 20 310886415v1 Attorney Docket No: 260525.000071 but not with IL-2 mutein. P-values indicate results of a paired T-test; * = p < 0.05; ** = p < 0.01; Fc = human IgG4 mutant Fc. [0139] Figure 35 shows assessment of Treg function upon TNFR2 agonism. Naive Treg were stimulated for 7 days with anti-CD3/IL-2 plus TNFR2 VHH (T-007_2xVHH-Fc), control VHH, MR2-1, control IgG, or IL- 2 mutein; after 7 days, stimuli were removed and cels were incubated with cel tracer-labeled autologous responder cels (naïve CD4+ T cels); bar graph shows efector CD4 cel proliferation measured as % dividing CD4+FOXP3- cels; FACS histograms show dilution of the cel tracer at diferent Treg:CD4 (responder) ratios of one of four donors. T-007_2xVHH-Fc induces Treg that are better able to restrain effector CD4 cel proliferation than IL-2 mutein. [0140] Figure 36 shows the efect of TNFR2 agonist VHH on Treg population size in mice. An exemplary design of the experimental procedure is shown. CD4+FOXP3+ Treg expansion in the spleen of mice 5 days after a single injection of 2.5 mg/kg control VHH or TNFR2-specific VHH T-007_2xVHH-Fc is shown. [0141] Figure 37 shows that TNFR2 agonist VHH activates Treg in vivo. CCR8 is a chemokine receptor expressed on highly suppressive Treg and involved in cel migration (Whiteside et al., Immunol 2021;163:512). ICAM-1 surface adhesion molecule is required for Treg function (Gottrand et al., Immunol 2015;146(4): 657). ICOS costimulatory molecule is upregulated upon Treg activation and maintains FOXP3 expression (Landuyt et al., J Immunol 2019;202(4):1039). Proportion of Treg (CD4+ CD25+ FOXP3+) in spleen expressing activation markers (CCR8, ICAM-1, or ICOS) 5 days after a single injection of control VHH or TNFR2-specific VHH T-007_2xVHH-Fc is shown.1-way ANOVA was performed for control VHH vs. T-007_2xVHH-Fc; only significant diferences are shown; **** = p < 0.0001. [0142] Figure 38 shows that TNFR2 agonist VHH selectively expands Treg in the spleen. Cel subsets as percentage of CD45+ cels in the spleen 5 days after single injection of TNFR2-specific VHH T- 007_2xVHH-Fc or control VHH are shown. [0143] Figure 39 shows that TNFR2 agonist VHH increases serum level of IL-10. IL-10 is a key anti- inflammatory cytokine (Saraiva et al., J Exp Med 2020;217(1):e20190418). Serum cytokine concentration 5 days after single injection of TNFR2-specific VHH T-007_2xVHH-Fc or control VHH is shown.1-way ANOVA performed for control VHH vs. T-007_2xVHH-Fc; only significant diferences are shown; **** = p < 0.0001. [0144] Figure 40A-40B show frequency of Treg (CD4+ FOXP3+) among total immune cels (CD45+) in the spleen, blood, colon, and lung in human TNFR2 knock-in mice 5 days after single injection of T-037. T-test: *** p < 0.001; **** p < 0.0001; n = 4. 21 310886415v1 Attorney Docket No: 260525.000071 [0145] Figures 41A-41E show T-037 selectively increases the Treg population in the spleen 5 days after a single administration compared to IL-2 N88D, a mutein that is active in mice. T-007_2xVHH-Fc is more selective for Treg and induces a higher level of FOXP3 and surface markers (FOXP3, ICAM-1, OX-40, ICOS, and CCR8), consistent with superior function and stability. One-way ANOVA test: **** p < 0.0001; n = 4. [0146] Figures 42A-42B show that Treg expansion in the spleen as wel as increased expression of FOXP3, linked to Treg stability and function, and Treg activation shown by up-regulation of ICAM-1 and ICOS. [0147] Figures 43A-43C show that reduction of arthritis, measured by paw volume and arthritis score, in a model of colagen-antibody induced arthritis upon treatment with TNFR2 agonists T-037 and T-043. [0148] Figures 44A-44B show Treg expansion by TNFR2 agonist without inducing proinflammatory cytokines when compared to CD28 agonist. [0149] Figures 45A-45F depict surface plasmon resonance (SPR) sensorograms of VHH binding to human and cynomolgus TNFR2. Fitted binding curves and calculated dissociation constants (KD) are included. [0150] Figures 46A-46J depict surface plasmon resonance (SPR) sensorograms of VHH (obtained by alanine scanning mutagenesis) binding to human and cynomolgus TNFR2. Fitted binding curves and calculated dissociation constants (KD) are included. [0151] Figures 47A-47B depict surface plasmon resonance (SPR) sensorgrams of Fc-tagged bivalent V- bodies binding to human or cynomolgus TNFR2. Fitted binding curves and calculated dissociation constants (KD) are included. [0152] Figures 48A-48B depict flow cytometry plots (Figure 48A) and luminescence plots (Figure 48B) upon incubation of TNFR2 HEK reporter cels with the Fc-tagged bivalent V-bodies. DETAILED DESCRIPTION OF THE INVENTION [0153] Regulatory T cels (Treg) are a population of lymphocytes with immunosuppressive function. Activation and expansion of Treg is an attractive therapeutic approach for autoimmune diseases currently being evaluated clinicaly. In addition to inducing Treg activation and expansion, an efective Treg-directed therapy needs to generate cels with a stable immunosuppressive phenotype that is resistant to conversion to T efector function under inflammatory conditions. Nevertheless, current clinical approaches to stimulate Treg to treat autoimmunity expand Treg by increasing homeostatic proliferation (e.g., via IL-2 muteins) without improving Treg stability. Clinical trials testing IL-2-based approaches to treat autoimmune disease by enhancing Treg function have demonstrated safety and the 22 310886415v1 Attorney Docket No: 260525.000071 ability to expand Treg across diseases; however, Treg specificity, Treg stability, and therapeutic efficacy are not optimal (PNAS 2010;107(45):19402; clinicaltrials.gov/study/NCT03943550; clinicaltrials.gov/study/NCT04433585). Optimal Treg therapy needs to (1) expand Treg population size with cels that (2) migrate to tissues where disease occurs and (3) exert immunosuppressive effects, while (4) resisting conversion to inflammatory Th1/17 cels. Therefore, improved therapeutic approaches to promote and stabilize Treg immunosuppressive activity are needed. [0154] TNFR2 agonism is an alternative approach to enhance Treg function that is projected to address al objectives required for an optimal therapy, including the generation of stable Treg cels that resist conversion to Th1/17 (Front Immunol 2022;13:888274; Sci Rep 2023;13(1):13762; PNAS 2019;116(43):21666; J Immunol 2013;190:1076; Arthritis Rheumatol 2020;72(4):576). In one aspect, the present invention provides as described herein, TNFR2 agonists to enhance Treg immunosuppressive activity using a single-domain antibody (e.g., VHH) platform. Definitions [0155] Unless defined otherwise, al technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skil in the art to which this disclosure belongs. For purposes of interpreting this specification, the folowing description of terms wil apply and whenever appropriate, terms used in the singular wil also include the plural and vice versa. Al patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that any description of terms set forth conflicts with any document incorporated herein by reference, the description of term set forth below shal control. [0156] 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 5%. For example, as used herein, the expression "about 100" includes 95 and 105 and al values in between (e.g., 96, 97, 98, 99, etc.). [0157] The term “antigen” encompasses any agent (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleotide, portions thereof, or combinations thereof) that may be specificaly bound by the products of specific humoral or celular immunity, such as an antibody molecule or T-cel receptor. In various embodiments of the present disclosure, the antigen described herein is TNFR2, including human, cynomolgus, and/or mouse TNFR2. 23 310886415v1 Attorney Docket No: 260525.000071 [0158] The term "epitope" can refer to an antigenic determinant on the surface of an antigen to which an antibody molecule binds. A single antigen may have more than one epitope. Thus, diferent antibodies may bind to diferent areas on an antigen and may have diferent biological efects (e.g., agnostic, or antagonistic efects). Epitopes may be either conformational or linear. A conformational epitope is formed by spatialy juxtaposed amino acids from diferent segments of the linear polypeptide chain. A linear epitope is formed by adjacent amino acid residues in a polypeptide chain. In some cases, an epitope may include non-peptidic moieties on the antigen, such as saccharides, phosphoryl groups, or sulfonyl groups. [0159] The term "antigen-binding protein" refers in its broadest sense to a protein that specificaly binds an antigen (e.g., TNFR2). In certain embodiments, an antigen-binding protein is an antibody or an antigen-binding fragment of an antibody, such as a human antibody, a humanized antibody; a camelid antibody; a chimeric antibody; a recombinant antibody; a heavy chain antibody; a single-domain antibody (e.g., VHH); a single chain antibody (e.g., single chain fragment variable (scFv); a diabody; a triabody; a tetrabody; a Fab fragment; a F(ab′) 2 fragment; an IgD antibody; an IgE antibody; an IgM antibody; an IgG1 antibody; an IgG2 antibody; an IgG3 antibody; or an IgG4 antibody, and fragments thereof. The term "antigen-binding protein" also encompasses, for example, an alternative protein scafold or artificial scafold with grafted CDRs or CDR derivatives. Such scafolds include, but are not limited to, antibody-derived scafolds comprising mutations introduced to, for example, stabilize the three-dimensional structure of the antigen-binding protein as wel as wholy synthetic scafolds comprising, for example, a biocompatible polymer. In addition, peptide antibody mimetics can be used, as wel as scafolds based on antibody mimetics utilizing fibronectin components (e.g., fibronectin type II domain (FN3) as a scafold. [0160] The term “antibody” and “immunoglobulin” or “Ig” are used interchangeably herein, and is used in the broadest sense and encompasses, for example, individual monoclonal antibodies (including agonist, antagonist, neutralizing antibodies, ful length or intact monoclonal antibodies), antibody compositions with polyepitopic or monoepitopic specificity, polyclonal antibodies, monovalent antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific antibodies), single-domain antibodies (e.g., VHH), single chain antibodies, intrabodies, anti-idiotypic (anti-Id) antibodies, and antigen-binding fragments of antibodies, as described below. An antibody can be human, humanized, camelized, recombinantly produced, chimeric, synthetic, afinity de-matured and/or afinity matured as wel as an antibody from other species, for example mouse, camel, lama, rabbit, etc. In specific 24 310886415v1 Attorney Docket No: 260525.000071 embodiments, the specific target antigen that can be bound by an antibody provided herein includes a TNFR2 polypeptide, TNFR2 fragment or TNFR2 epitope. An “antigen-binding fragment” generaly refers a portion of an antibody heavy and/or light chain polypeptide that retains some or al of the binding activity of the antibody from which the fragment was derived. Non-limiting examples of antigen-binding fragments include single-domain antibody (e.g., VHH), single-chain Fvs (scFv), Fab fragments, F(ab′) fragments, F(ab)2 fragments, F(ab′)2 fragments, disulfide-linked Fvs (sdFv), Fd fragments, Fv fragments, diabody, triabody, tetrabody and minibody, or a chemicaly modified derivative thereof. In particular, antibodies provided herein include immunoglobulin molecules and molecules that contain immunologicaly active portion(s) of an immunoglobulin molecule, for example, one or more complementarity determining regions (CDRs) of an antibody that binds to TNFR2. Such antibody fragments can be found described in, for example, Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York (1989); Myers (ed.), Molec. Biology and Biotechnology: A Comprehensive Desk Reference, New York: VCH Publisher, Inc.; Huston et al., Cel Biophysics, 22:189- 224 (1993); Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989) and in Day, E.D., Advanced Immunochemistry, Second Ed., Wiley-Liss, Inc., New York, N.Y. (1990). The antibodies provided herein can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or any subclass (e.g., IgG2a and IgG2b) of immunoglobulin molecule. [0161] The term “single-domain antibody” or “sdAb” as used herein, refers to an antibody or antibody fragment containing a single antibody variable domain that is able to bind to a specific antigen alone, without the requirement of another antibody variable domain. The complementarity determining regions (CDRs) of a single-domain antibody are part of a single antibody variable domain. Examples of single-domain antibodies include, but are not limited to, heavy chain antibodies, antibodies naturaly devoid of light chains, single domain antibodies derived from conventional four-chain antibodies, engineered antibodies, variable domains derived from the aforementioned antibodies, and single domain scafolds other than those derived from antibodies. Single domain antibodies may be derived from any species including, but not limited to mouse, human, camel, lama, shark, goat, rabbit, and/or bovine. In some embodiments, a single domain antibody as used herein is a naturaly occurring single domain antibody known as heavy chain antibody devoid of light chains. For clarity reasons, the variable domain derived from a heavy chain antibody naturaly devoid of light chain is known herein as a VHH to distinguish it from the conventional VH of four-chain immunoglobulins. Such a VHH molecule can be derived from antibodies raised in Camelidae species, e.g., camel, lama, dromedary, alpaca, and 25 310886415v1 Attorney Docket No: 260525.000071 guanaco. Other species besides Camelidae may produce heavy chain antibodies naturaly devoid of light chain, which are also within the scope of the invention. For example, cartilaginous fishes such as sharks can produce immunoglobulin-like structures known as VNAR. In some embodiments, a single-domain antibody may be obtained from a Camelidae VH domain. In some embodiments, a single-domain antibody may be obtained from human VH by camelization. See Saerens et al., Current Opinion in Pharmacology, 2008, 8:600-608, the disclosure of which being incorporated by reference, for review of single-domain antibodies. [0162] The term “specificaly binds” as used herein means that an antigen-binding protein forms a complex with a target antigen that is relatively stable under physiologic conditions. Specific binding can be characterized by a dissociation constant (K) of about -6 -6 D 1x10 M or less (e.g., less than 10 M, less than 5x10-7 M, less than 10-7 M, less than 5x10-8 M, less than 10-8 M, less than 5x10-9 M, less than 10-9 M, or less than 10-10 M). Methods for determining the binding afinity of an antigen-binding protein, e.g., an antibody or an antibody fragment, to a target antigen are wel known in the art and include, e.g., surface plasmon resonance (e.g., BIACORE® assays), bio-layer interferometry, ligand binding assays (e.g., enzyme-linked immunosorbent assay (ELISA), equilibrium dialysis, fluorescent-activated cel sorting (FACS), or flow cytometry-based binding assays and the like. Specific binding to a particular target antigen from a certain species does not exclude that the antigen-binding protein can also specificaly bind to the analogous target from a diferent species. For example, specific binding to human TNFR2 does not exclude that the antigen-binding protein can also specificaly bind to TNFR2 from cynomolgus monkeys (“cyno”) or mice. [0163] The term "isolated" when used in the context of antigen-binding proteins (e.g., antibodies, such as single-domain antibodies), polypeptides, polynucleotides, and vectors, means the antigen-binding proteins (e.g., antibodies, such as single-domain antibodies), polypeptides, polynucleotides and vectors are at least partialy free of other biological molecules from the cels or cel culture from which they are produced. Such biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other material such as celular debris and growth medium. An isolated antigen-binding protein may further be at least partialy free of expression system components such as biological molecules from a host cel or of the growth medium thereof. Generaly, the term "isolated" is not intended to refer to a complete absence of such biological molecules (e.g., minor, or insignificant amounts of impurity may remain) or to an absence of water, bufers, or salts or to 26 310886415v1 Attorney Docket No: 260525.000071 components of a pharmaceutical formulation that includes the antigen-binding proteins (e.g., antibodies, such as single-domain antibodies). [0164] 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. [0165] As used herein, the term “variant”, “derivative” or “derived from” in the context of proteins or polypeptides (e.g., antigen-binding proteins or domains thereof) refer to: (a) a polypeptide that has at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to the polypeptide it is a variant or derivative of; (b) a polypeptide encoded by a nucleotide sequence that has at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to a nucleotide sequence encoding the polypeptide it is a variant or derivative of; (c) a polypeptide that contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acid mutations (i.e., additions, deletions and/or substitutions) relative to the polypeptide it is a variant or derivative of; (d) a polypeptide encoded by nucleic acids can hybridize under high, moderate or typical stringency hybridization conditions to nucleic acids encoding the polypeptide it is a variant or derivative of; (e) a polypeptide encoded by a nucleotide sequence that can hybridize under high, moderate or typical stringency hybridization conditions to a nucleotide sequence encoding a fragment of the polypeptide, it is a variant or derivative of, of at least 20 contiguous amino acids, at least 30 contiguous amino acids, at least 40 contiguous amino acids, at least 50 contiguous amino acids, at least 75 contiguous amino acids, at least 100 contiguous amino acids, at least 125 contiguous amino acids, or at least 150 contiguous amino acids; or (f) a fragment of the polypeptide it is a variant or derivative of. The terms also encompass a fusion protein or polypeptide comprising the polypeptide it is a variant or derivative of. [0166] The term "substantial identity" or "substantialy identical," when referring to a nucleic acid or fragment thereof, indicates that, when optimaly aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 95%, and more preferably at least about 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any wel-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 substantialy similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule. 27 310886415v1 Attorney Docket No: 260525.000071 [0167] As applied to polypeptides, the term "substantial similarity" or "substantialy similar" means that two peptide sequences, when optimaly aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 95% sequence identity, even more preferably at least 98% or 99% sequence identity. Preferably, residue positions which are not identical difer 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 wil not substantialy change the functional properties of a protein. In cases where two or more amino acid sequences difer 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 wel-known to those of skil 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. [0168] Sequence similarity for polypeptides, which is also referred to as sequence identity, is typicaly 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 diferent 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 28 310886415v1 Attorney Docket No: 260525.000071 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 diferent organisms is the computer program BLAST, especialy BLASTP or TBLASTN, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res.25:3389-402, each herein incorporated by reference. [0169] The terms “enhance” or “promote,” or “increase,” or “expand,” or “improve” refer generaly to the ability of a composition contemplated herein to produce, elicit, or cause a greater physiological response (i.e., downstream efects) compared to the response caused by either vehicle or a control molecule/composition. A measurable physiological response may include an increase in immune cel expansion, activation, efector function, persistence, and/or an increase in tumor cel death kiling ability, among others apparent from the understanding in the art and the description herein. In certain embodiments, an “increased” or “enhanced” amount can be a “statisticaly significant” amount, and may include an increase that is 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 or more times (e.g., 500, 1000 times) (including al integers and decimal points in between and above 1, e.g., 1.5, 1.6, 1.7.1.8, etc.) the response produced by vehicle or a control composition. [0170] The terms “decrease” or “lower,” or “lessen,” or “reduce,” or “abate” refer generaly to the ability of composition contemplated herein to produce, elicit, or cause a lesser physiological response (i.e., downstream efects) compared to the response caused by either vehicle or a control molecule/composition. In certain embodiments, a “decrease” or “reduced” amount can be a “statisticaly significant” amount, and may include a decrease that is 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 or more times (e.g., 500, 1000 times) (including al integers and decimal points in between and above 1, e.g., 1.5, 1.6, 1.7.1.8, etc.) the response (reference response) produced by vehicle or a control composition. [0171] The terms “treat” or “treatment” of a state, disorder or condition include: (1) preventing, delaying, or reducing the incidence and/or likelihood of the appearance of at least one clinical or sub- clinical symptom of the state, disorder or condition developing in a subject that may be aflicted with or predisposed to the state, disorder or condition, but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, 29 310886415v1 Attorney Docket No: 260525.000071 disorder or condition or at least one of its clinical or sub-clinical symptoms. The benefit to a subject to be treated is either statisticaly significant or at least perceptible to the patient or to the physician. [0172] The terms “efective amount” or “therapeuticaly efective amount” refer to a quantity and/or concentration of a composition containing an active ingredient (e.g., anti-TNFR2 antigen-binding protein) that when administered into a patient either alone (i.e., as a monotherapy) or in combination with additional therapeutic agents, yields a significant decrease in disease progression as, for example, by ameliorating or eliminating symptoms and/or the cause of the disease. An efective amount may be an amount that relieves, lessens, or aleviates at least one symptom or biological response or efect associated with a disease or disorder, prevents progression of the disease or disorder, or improves physical functioning of the patient. A therapeuticaly efective amount of a composition containing an active agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the active agent to elicit a desired response in the individual. A therapeuticaly efective amount is also one in which any toxic or detrimental efects of the active agent are outweighed by the therapeuticaly beneficial efects. A therapeuticaly efective amount may be delivered in one or more administrations. A therapeuticaly efective amount refers to an amount efective, at dosages and for periods of time necessary, to achieve the desired therapeutic and/or prophylactic result. [0173] The terms “individual”, “subject” and “patient” are used interchangeably herein to refer to an animal, for example a mammal. The terms include human and veterinary subjects. In some embodiments, methods of treating mammals, including, but not limited to, humans, rodents, simians, felines, canines, equines, bovines, porcines, ovines, caprines, mammalian laboratory animals, mammalian farm animals, mammalian sport animals, and mammalian pets, are provided. The subject can be male or female and can be any suitable age, including infant, juvenile, adolescent, adult, and geriatric subjects. In some embodiments, a subject can be a subject in need of treatment for a disease or disorder. In particular embodiments, the subject is a human. Anti-TNFR2 Antigen-binding Proteins [0174] The present disclosure provides antigen-binding proteins (e.g., antibodies, such as single-domain antibodies) that bind to tumor necrosis factor receptor 2 (TNFR2). [0175] TNFR2 is a single pass type-1 membrane protein belonging to the TNFR superfamily. It consists of an extracelular domain with four cysteine rich domains (CRD) and an intracelular domain that is involved in signaling. The cysteine rich domains contain a total of 10 disulfide bonds stabilizing the 30 310886415v1 Attorney Docket No: 260525.000071 elongated structure of the protein. Unlike TNFR1 which is widely expressed, the expression of TNFR2 is restricted on immune cels including Tregs, myeloid cels, CD8 and NK cels but also glial cels, endothelial cels, and fibroblasts (Medler and Wajant, 2019). [0176] In some embodiments, the human TNFR2 protein is encoded by the human TNF receptor superfamily member 1B (TNFRSF1B) gene (NCBI Gene ID: 7133) and has the amino acid sequence of MAPVAVWAALAVGLELWAAAHALPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCD SCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRKCRPGFGVARPG TETSDVVCKPCAPGTFSNTTSSTDICRPHQICNVVAIPGNASMDAVCTSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPE PSTAPSTSFLLPMGPSPPAEGSTGDFALPVGLIVGVTALGLLIGVVNCVIMTQVKKKPLCLQREAKVPHLPADKARGTQ GPEQQHLLITAPSSSSSSLESSASALDRRAPTRNQPQAPGVEASGAGEARASTGSSDSSPGGHGTQVNVTCIVNVCSSS DHSSQCSSQASSTMGDTDSSPSESPKDEQVPFSKEECAFRSQLETPETLLGSTEEKPLPLGVPDAGMKPS (UniProtKB Accession No. P20333) (SEQ ID NO: 4028) [0177] In some embodiments, the cyno TNFR2 protein is encoded by the Cyno TNF receptor superfamily member 1B (TNFRSF1B) gene (Gene ID: 102144224) and has the amino acid sequence of MVTRRGGDDRRRLKGHRVLGVTLEVLARRCWGGRVGGPAEAGEGRGGGVSKAGWPRPAPPRCLASGPLQRGLSLS VAAGWRAQRSLGRRRCAARARGREGRGNRIPPAPMAPAAVWAALAVGLELWAAGHALPAQVAFTPYAPEPGGTCR LREYYDQTAQMCCSKCPPGQHAKVFCTKTSDTVCDSCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRIC TCRPGWYCALSKQEGCRLCAQLRKCRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDICRPHQICHVVAIPGNASM DAVCTSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPAPSTAPGTSFLLPVGPSPPAEGSTGDIVLPVGLIVGVTALGLLIG VVNCVIMTQVKKKPLCLQRETKVPHLPADKARGAQGPEQQHLLTTVPSSSSSSLESSASALDRRAPTRNQPQAPGAEK ASGAGEARASTGSSDSSPGGHGTQVNVTCIVNVCSSSDHSSQCSSQASSTMGDTDASPSGSPKDEQVPFSKEECAFRS QLETPETLLGSTEEKPLPLGVPDAGMKPS (UniProtKB Accession No. A0A2K5VET2) (SEQ ID NO: 4029) [0178] In some embodiments, the mouse TNFR2 protein is encoded by the mouse TNF receptor superfamily member 1B (Tnfrsf1b) gene (Gene ID: 21938) and has the amino acid sequence of MAPAALWVALVFELQLWATGHTVPAQVVLTPYKPEPGYECQISQEYYDRKAQMCCAKCPPGQYVKHFCNKTSDTVC ADCEASMYTQVWNQFRTCLSCSSSCTTDQVEIRACTKQQNRVCACEAGRYCALKTHSGSCRQCMRLSKCGPGFGVAS SRAPNGNVLCKACAPGTFSDTTSSTDVCRPHRICSILAIPGNASTDAVCAPESPTLSAIPRTLYVSQPEPTRSQPLDQEPG PSQTPSILTSLGSTPIEQSTKGGISLPIGLIVGVTSLGLLMLGLVNCILVQRKKKPSCLQRDAKVPHVPDEKSQDAVGLEQ QHLLTTAPSSSSSSLESSASAGDRRAPPGGHPQARVMAEAQGFQEARASSRISDSSHGSHGTHVNVTCIVNVCSSSDHS SQCSSQASATVGDPDAKPSASPKDEQVPFSQEECPSQSPCETTETLQSHEKPLPLGVPDMGMKPSQAGWFDQIAVKV A (UniProtKB Accession No. P25119) (SEQ ID NO: 4030) [0179] In various embodiments, antigen-binding proteins of the present disclosure have an agonist efect upon binding to TNFR2. While not wishing to be bound by theory, an agonistic TNFR2 binder can promote or increase activation of TNFR2 and/or potentiate one or more signal transduction pathways mediated by TNFR2. For example, agonistic TNFR2 binders may promote or increase the proliferation of a population of Treg cels. Agonistic TNFR2 binders may promote or increase TNFR2 activation by 31 310886415v1 Attorney Docket No: 260525.000071 binding TNFR2, e.g., to induce a conformational change that renders the receptor biologicaly active. For example, agonistic TNFR2 binders may nucleate the trimerization of TNFR2 in a manner similar to the interaction between TNFR2 and its cognate ligand, tumor necrosis factor (TNF), thus inducing TNFR2- mediated signaling. In some embodiments, agonistic TNFR2 binding proteins of the present disclosure may be capable of inducing the proliferation of Treg cels (e.g., CD4+, CD25+, FOXP3+ Treg cels). Agonistic TNFR2 binding proteins of the present disclosure may also be capable of suppressing the proliferation of cytotoxic T lymphocytes (e.g., CD8+ T-cels), e.g., through activation of immunomodulatory Treg cels or by directly binding TNFR2 on the surface of an autoreactive cytotoxic T- cel and inducing apoptosis. [0180] In some embodiments, antigen-binding proteins of the present disclosure upon binding to TNFR2 do not impair the binding of its cognate ligand, tumor necrosis factor (TNF), to TNFR2. In some embodiments, antigen-binding proteins of the present disclosure do not have overlapping epitopes with TNF. In some embodiments, antigen-binding proteins of the present disclosure have overlapping epitopes with TNF. In some embodiments, antigen-binding proteins of the present disclosure upon binding to TNFR2 promote or facilitate TNFR2 oligomerization (in the presence or absence of TNF, respectively). In some embodiments, antigen-binding proteins of the present disclosure upon binding to TNFR2 multimerize (e.g., dimerize) the TNFR2 trimers to induce intracelular signaling. [0181] In some embodiments, antigen-binding proteins of the present disclosure bind to human TNFR2. In some embodiments, antigen-binding proteins (e.g., antibodies such as single-domain antibodies) of the present disclosure may bind to human TNFR2 with a K −6 D of less than about 1×10 M, for example, less than about 5×10−7 M, less than about 3×10−7 M, less than about 1×10−7 M, less than about 8×10−8 M, less than about 5×10−8 M, less than about 3×10−8 M, less than about 1×10−8 M, less than about 8×10−9 M, less than about 5×10−9 M, less than about 3×10−9 M, or less than about 1×10−9 M, or about 1×10−10 to 1×10−9 M, 1×10−10 to 5×10−9 M, about 1×10−10 to 1×10−8 M, about 1×10−10 to 5×10−8 M, about 1×10−9 to 1×10−8 M, about 1×10−9 to 5×10−8 M, about 1×10−9 to 1×10−7 M, or about 1×10−8 to 1×10−7 M. In certain embodiments, antigen-binding proteins (e.g., antibodies such as single-domain antibodies) of the present disclosure may bind to human TNFR2 with a K -12 −6 D of about 1x10 M to about 1×10 M. In certain embodiments, antigen-binding proteins (e.g., antibodies such as single-domain antibodies) of the present disclosure may bind to human TNFR2 with a K −8 −6 D of about 1 ×10 M to about 2.7 ×10 M. [0182] In some embodiments, antigen-binding proteins of the present disclosure bind to cynomolgus monkey (“cyno”) TNFR2. In some embodiments, antigen-binding proteins (e.g., antibodies such as 32 310886415v1 Attorney Docket No: 260525.000071 single-domain antibodies) of the present disclosure may bind to cyno TNFR2 with a KD of less than about 1×10−6 M, for example, less than about 5×10−7 M, less than about 3×10−7 M, less than about 1×10−7 M, less than about 8×10−8 M, less than about 5×10−8 M, less than about 3×10−8 M, less than about 1×10−8 M, less than about 8×10−9 M, less than about 5×10−9 M, less than about 3×10−9 M, or less than about 1×10−9 M, or about 1×10−10 to 1×10−9 M, 1×10−10 to 5×10−9 M, about 1×10−10 to 1×10−8 M, about 1×10−10 to 5×10−8 M, about 1×10−9 to 1×10−8 M, about 1×10−9 to 5×10−8 M, about 1×10−9 to 1×10−7 M, about 1×10−9 to 2×10−7 M, about 1×10−9 to 5×10−7 M, about 1×10−8 to 1×10−7 M, about 1×10−8 to 2×10−7 M, about 1×10−8 to 5×10−7 M, or about 1×10−8 to 1×10−6 M. In certain embodiments, antigen-binding proteins (e.g., antibodies such as single-domain antibodies) of the present disclosure may bind to cyno TNFR2 with a K of -12 −6 D about 1x10 M to about 1×10 M. In certain embodiments, antigen-binding proteins (e.g., antibodies such as single-domain antibodies) of the present disclosure may bind to cyno TNFR2 with a KD of about 3x10-8 M to about 2.4 ×10−6 M. [0183] In some embodiments, antigen-binding proteins of the present disclosure bind to mouse TNFR2. In some embodiments, antigen-binding proteins of the present disclosure may bind to mouse TNFR2 with a K of less than about 1×10−6 M, fo −7 −7 D r example, less than about 5×10 M, less than about 3×10 M, less than about 1×10−7 M, less than about 8×10−8 M, less than about 5×10−8 M, less than about 3×10−8 M, less than about 1×10−8 M, less than about 8×10−9 M, less than about 5×10−9 M, less than about 3×10−9 M, or less than about 1×10−9 M, or about 1×10−10 to 1×10−9 M, 1×10−10 to 5×10−9 M, about 1×10−10 to 1×10−8 M, about 1×10−10 to 5×10−8 M, about 1×10−9 to 1×10−8 M, about 1×10−9 to 5×10−8 M, about 1×10−9 to 1×10−7 M, about 1×10−9 to 2×10−7 M, about 1×10−9 to 5×10−7 M, about 1×10−8 to 1×10−7 M, about 1×10−8 to 2×10−7 M, about 1×10−8 to 5×10−7 M, or about 1×10−8 to 1×10−6 M. In some embodiments, antigen- binding proteins of the present disclosure do not bind to mouse TNFR2. [0184] In some embodiments, anti-TNFR2 antigen-binding proteins of the present disclosure may specificaly bind TNFR2 without exhibiting specific binding for another receptor of the tumor necrosis factor receptor (TNFR) superfamily. [0185] Binding afinity of a molecular interaction between two molecules can be measured via various techniques, such as surface plasmon resonance (SPR), bio-layer interferometry (BLI), enzyme-linked immunosorbent assay (ELISA), equilibrium dialysis, fluorescent-activated cel sorting (FACS), or flow cytometry binding assays and the like. Surface plasmon resonance is a biosensor technique that alows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, where one molecule is immobilized on the biosensor chip and the other 33 310886415v1 Attorney Docket No: 260525.000071 molecule is passed over the immobilized molecule under flow conditions (see e.g., Ober et al.2001, Intern. Immunology 13: 1551-1559). SPR can for example be performed using the BIACORE® system or Carterra LSA system. Another biosensor technique that can be used to determine afinities of biomolecular interactions is bio-layer interferometry (BLI) (see e.g., Abdiche et al.2008, Anal. Biochem. 377: 209-217). Bio-layer Interferometry is a label-free optical technique that analyzes the interference pattern of light reflected from two surfaces: an internal reference layer (reference beam) and a layer of immobilized protein on the biosensor tip (signal beam). A change in the number of molecules bound to the tip of the biosensor causes a shift in the interference pattern, reported as a wavelength shift (nm), the magnitude of which is a direct measure of the number of molecules bound to the biosensor tip surface. Since the interactions can be measured in real-time, association and dissociation rates and afinities can be determined. BLI can for example be performed using the Octet® Systems. Alternatively, afinities can be measured in Kinetic Exclusion Assay (KinExA) (see e.g., Drake et al.2004, Anal. Biochem., 328: 35-43), which is a solution-based method to measure true equilibrium binding afinity and kinetics of unmodified molecules. Equilibrated solutions of an antibody/antigen complex are passed over a column with beads precoated with antigen (or antibody), alowing the free antibody (or antigen) to bind to the coated molecule. Detection of the antibody (or antigen) thus captured is accomplished with a fluorescently labeled protein binding the antibody (or antigen). [0186] Antigen-binding proteins of the present disclosure can include an antibody or an antigen-binding fragment of an antibody, such as a human antibody, a humanized antibody; a camelid antibody; a chimeric antibody; a recombinant antibody; a heavy chain antibody; a single-domain antibody (e.g., VHH); a single chain antibody (e.g., single chain fragment variable (scFv); a diabody; a triabody; a tetrabody; a Fab fragment; a F(ab′) 2 fragment; an IgD antibody; an IgE antibody; an IgM antibody; an IgG1 antibody; an IgG2 antibody; an IgG3 antibody; or an IgG4 antibody, and fragments thereof. [0187] In some embodiments, an antigen-binding protein that binds to TNFR2 is a single-domain antibody (also termed as “sdAb”). The single-domain antibodies of the present disclosure can be derived from numerous sources, including but not limited to VHHs, VNARs, or VH domains (naturaly occurring or engineered VH domains). VHHs can be generated from camelid heavy chain only antibodies and libraries thereof. VNARs can be generated from cartilaginous fish heavy chain only antibodies and libraries thereof. Various methods have been implemented to generate monomeric sdAbs from conventionaly heterodimeric VH and VL domains, including interface engineering and selection of 34 310886415v1 Attorney Docket No: 260525.000071 specific germline families. In some embodiments, the sdAb of the present invention are human or humanized. [0188] In some embodiments, a single-domain antibody described herein is a VHH fragment (also known as a nanobody). VHH fragments are also referred to as “V-bodies” in the present disclosure. In some embodiments, the VHH is a camelid VHH, a humanized VHH or a camelized VH. In some embodiments, a single-domain antibody described herein is a VH domain. In some embodiments, a single-domain antibody described herein is a naturaly occurring VH domain or engineered VH domain. [0189] The variable domain of an antigen-binding protein (e.g., antibody such as a single-domain antibody) of the present disclosure comprises at least three complementarity determining regions (CDRs) which determine its binding specificity. Preferably, in a variable domain, the CDRs are distributed between framework regions (FRs). The variable domain typicaly contains 4 framework regions interspaced by 3 CDR regions, resulting in the folowing typical antibody variable domain structure: FR1- CDR1-FR2-CDR2-FR3-CDR3-FR4. CDRs and/or FRs of the single domain antibody of the invention may be fragments or derivatives from a naturaly occurring antibody variable domain or may be synthetic. [0190] Sequence identifiers corresponding to exemplary anti-TNFR2 VHH antibodies provided herein are listed in Table 1-1. Table 1-1 sets forth the sequence identifiers of amino acid sequences of the complementarity determining regions (CDR1, CDR2 and CDR3), amino acid and DNA sequences of the ful-length camelid VHH antibodies, as wel as amino acid sequences of corresponding humanized VHH antibodies. In the present disclosure, the sufix "-Hu1" in an antibody ID indicates a humanized version of the referenced antibody. Amino acid sequences of additional exemplary anti-TNFR2 VHH antibodies and corresponding humanized VHH antibodies are provided in Table 1-2. Table 1-1. Sequence identifiers for exemplary anti-TNFR2 VHH antibodies CDR1 CDR2 CDR3 Non-humanized VHH Humanized VHH e 35 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 Non-humanized VHH Humanized VHH Antibody ID Group DNA A i id DNA e 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 Non-humanized VHH Humanized VHH Antibody ID Group DNA A i id DNA e 37 310886415v1 Attorney Docket No: 260525.000071 Table 1-2. Sequence identifiers for additional exemplary VHH antibodies and humanized VHH antibodies Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence 310886415v1 Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence [0191] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single- domain antibody) of the present disclosure comprises a complementarity determining region 1 (CDR1) comprising an amino acid sequence selected from (amino acids listed in a pair of brackets represent the possible amino acids at the particular position) a). GSI(V/F)(R/S)(T/A)(N/D)(S/G/A); b). GFT(F/L)DD(I/Y)A (SEQ ID NO: 69); c). GFTFS(S/R/G)YA (SEQ ID NO: 70); d). GRTFSDYG (SEQ ID NO: 16); e). G(L/F)TLDYYA (SEQ ID NO: 71); f). GF(T/N)FSMYS (SEQ ID NO: 72); g). GRTF(G/R/S)(N/S)(Y/L)(T/F) (SEQ ID NO: 73); 53 310886415v1 Attorney Docket No: 260525.000071 h). GASLSRNA (SEQ ID NO: 40); i). GS(I/T)FRFPP (SEQ ID NO: 74); j). GFTLDDYA (SEQ ID NO: 4061); and k). G(F/V)(S/T)LD(D/Y)(H/Y)T (SEQ ID NO: 4519). [0192] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single- domain antibody) of the present disclosure comprises a complementarity determining region 2 (CDR2) comprising an amino acid sequence selected from (amino acids listed in a pair of brackets represent the possible amino acids at the particular position) a). IRSDGF(T/I) (SEQ ID NO: 75); b). I(Y/F)SY(S/G)(S/P)NT (SEQ ID NO: 76); c). I(Y/S)(S/D)DGS(E/D)T (SEQ ID NO: 77); d). INWSN(G/A)RT (SEQ ID NO: 4699); e). I(S/N)(V/T)(S/G)DGST (SEQ ID NO: 78); f). IDT(R/G)GST (SEQ ID NO: 79); g). IR(W/R/Y)(T/P)G(G/L)(S/I)T (SEQ ID NO: 80); h). IYDDGET (SEQ ID NO: 41); i). LTSGGST (SEQ ID NO: 45); j). IFSYSSNT (SEQ ID NO: 4062); k). I(N/S)SNDG(S/T)(T/V) (SEQ ID NO: 4518); and l). INWS(N/Q/E/S)(G/A)RT (SEQ ID NO: 4809). [0193] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single- domain antibody) of the present disclosure comprises a complementarity determining region 3 (CDR3) comprising an amino acid sequence selected from (amino acids listed in a pair of brackets represent the possible amino acids at the particular position) a). (Y/F)YQ(S/A)LS(T/S)(P/A)N(Y/F)GQ(V/T)F (SEQ ID NO: 60); b). AADSDL(S/R)TV(V/T)VGPHDY (SEQ ID NO: 61); c). AKDAG(S/G)WG(T/R)GPFG(Y/F)(E/D)YDY (SEQ ID NO: 62); d). AA(T/A)PSGKAY(T/S)Y (SEQ ID NO: 63); e). ATPGPY(T/S/M)YCAPYGSSWSRGYDY (SEQ ID NO: 64); f). ARV(R/G)G(T/S/A)PY(E/D)Y(N/G)Y (SEQ ID NO: 65); g). (T/A/V)A(S/A)PTGRAF(T/N/A)Y (SEQ ID NO: 66); 54 310886415v1 Attorney Docket No: 260525.000071 h). AGSAFDF (SEQ ID NO: 42); i). S(V/M)(V/L)GRDM(M/V)TY (SEQ ID NO: 67); j). AVGDFEGELVLKGDY (SEQ ID NO: 4063); k). AAD(L/V)G(F/V/Y)LY(A/T/V)DYV(P/R)LH(M/T)HHFGS (SEQ ID NO: 4517); l). A(A/G)(T/A)(P/L)(S/T)GKAY(T/S)Y (SEQ ID NO: 4771); and m). A(A/G)(T/A/S)(P/L)(S/T)GKAY(T/S)Y (SEQ ID NO: 4787), wherein one or more non-alanine residues in the CDR3 sequence are optionaly replaced with an alanine, and/or one or more alanine residues in the CDR3 sequence are optionaly replaced with a glycine. [0194] In certain embodiments, the CDR3 sequence comprises the amino acid sequence: a). (T/A/V)(A/G)(S/A)(A/P)(A/T)(A/G)(A/R)A(A/F)(T/N/A)(A/Y); or b). (A/G)(A/G)(T/A/S)(A/P/L)(A/S/T)(A/G)(A/K)(A/G)(A/Y)(A/T/S)(A/Y). [0195] In certain embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single- domain antibody) of the present disclosure comprises i) a CDR1 comprising an amino acid sequence of GSI(V/F)(R/S)(T/A)(N/D)(S/G/A), a CDR2 comprising an amino acid sequence of SEQ ID NO: 75, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 60; i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 69, a CDR2 comprising an amino acid sequence of SEQ ID NO: 76, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 61; ii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 70, a CDR2 comprising an amino acid sequence of SEQ ID NO: 77, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 62; iv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4699, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 63; v) a CDR1 comprising an amino acid sequence of SEQ ID NO: 71, a CDR2 comprising an amino acid sequence of SEQ ID NO: 78, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 64; vi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 72, a CDR2 comprising an amino acid sequence of SEQ ID NO: 79, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 65; vi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 73, a CDR2 comprising an amino acid sequence of SEQ ID NO: 80, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 66; vii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 40, a CDR2 comprising an amino acid sequence of SEQ ID NO: 41, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 42; or 55 310886415v1 Attorney Docket No: 260525.000071 ix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 74, a CDR2 comprising an amino acid sequence of SEQ ID NO: 45, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 67; x) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4063; xi). a CDR1 comprising an amino acid sequence of SEQ ID NO: 4519, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4518, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4517; xi). a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4699, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4771; xii). a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4699, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4787; xiv). a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4809, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4787; xv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4809, and a CDR3 comprising an amino acid sequence of (A/G)(A/G)(T/A/S)(A/P/L)(A/S/T)(A/G)(A/K)(A/G)(A/Y)(A/T/S)(A/Y); or xvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 73, a CDR2 comprising an amino acid sequence of SEQ ID NO: 80, and a CDR3 comprising an amino acid sequence of (T/A/V)(A/G)(S/A)(A/P)(A/T)(A/G)(A/R)A(A/F)(T/N/A)(A/Y). [0196] In certain embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single- domain antibody) of the present disclosure comprises a) a CDR1 comprising an amino acid sequence of SEQ ID NO: 69, a CDR2 comprising an amino acid sequence of SEQ ID NO: 76, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 61; b) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4699, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 63; c) a CDR1 comprising an amino acid sequence of SEQ ID NO: 73, a CDR2 comprising an amino acid sequence of SEQ ID NO: 80, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 66; d) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4699, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4771; e) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4809, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4787; 56 310886415v1 Attorney Docket No: 260525.000071 f) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4809, and a CDR3 comprising an amino acid sequence of (A/G)(A/G)(T/A/S)(A/P/L)(A/S/T)(A/G)(A/K)(A/G)(A/Y)(A/T/S)(A/Y); or g) a CDR1 comprising an amino acid sequence of SEQ ID NO: 73, a CDR2 comprising an amino acid sequence of SEQ ID NO: 80, and a CDR3 comprising an amino acid sequence of (T/A/V)(A/G)(S/A)(A/P)(A/T)(A/G)(A/R)A(A/F)(T/N/A)(A/Y). [0197] In certain embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single- domain antibody) of the present disclosure comprises i) a CDR1 comprising an amino acid sequence of GSI(V/F)(R/S)(A/T)(N/D)(G/A), a CDR2 comprising an amino acid sequence of IRSDGFT (SEQ ID NO: 2), and a CDR3 comprising an amino acid sequence of YYQ(S/A)LSSPNYGQ(V/T)F (SEQ ID NO: 4701); i) a CDR1 comprising an amino acid sequence of GFTFDDIA (SEQ ID NO: 8), a CDR2 comprising an amino acid sequence of IYSYGPNT (SEQ ID NO: 9), and a CDR3 comprising an amino acid sequence of AADSDLSTVV(V/T)GPHDY (SEQ ID NO: 4702); ii) a CDR1 comprising an amino acid sequence of GFTFSRYA (SEQ ID NO: 12), a CDR2 comprising an amino acid sequence of ISDDGSDT (SEQ ID NO: 13), and a CDR3 comprising an amino acid sequence of AKDAGSWGTGPFGYEYDY (SEQ ID NO: 14); iv) a CDR1 comprising an amino acid sequence of GRTFSDYG (SEQ ID NO: 16), a CDR2 comprising an amino acid sequence of INWSN(G/A)RT (SEQ ID NO: 4699), and a CDR3 comprising an amino acid sequence of AA(T/A)PSGKAYSY (SEQ ID NO: 4703); v) a CDR1 comprising an amino acid sequence of GLTLDYYA (SEQ ID NO: 20), a CDR2 comprising an amino acid sequence of ISTSDGST (SEQ ID NO: 21), and a CDR3 comprising an amino acid sequence of ATPGPYTYCAPYGSSWSRGYDY (SEQ ID NO: 22); vi) a CDR1 comprising an amino acid sequence of GF(T/N)FSMYS (SEQ ID NO: 72), a CDR2 comprising an amino acid sequence of IDT(R/G)GST (SEQ ID NO: 79), and a CDR3 comprising an amino acid sequence of ARV(G/R)G(T/A)PYEY(N/G)Y (SEQ ID NO: 4704); vi) a CDR1 comprising an amino acid sequence of GRTF(G/S)S(Y/L)(T/F) (SEQ ID NO: 4705), a CDR2 comprising an amino acid sequence of IR(W/R/Y)(T/P)G(G/L)(S/I)T (SEQ ID NO: 80), and a CDR3 comprising an amino acid sequence of (A/V)A(A/S)PTGRAF(T/N)Y (SEQ ID NO: 4707); 57 310886415v1 Attorney Docket No: 260525.000071 vii) a CDR1 comprising an amino acid sequence of GASLSRNA (SEQ ID NO: 40), a CDR2 comprising an amino acid sequence of IYDDGET (SEQ ID NO: 41), and a CDR3 comprising an amino acid sequence of AGSAFDF (SEQ ID NO: 42); ix) a CDR1 comprising an amino acid sequence of GS(T/I)FRFPP (SEQ ID NO: 4708), a CDR2 comprising an amino acid sequence of LTSGGST (SEQ ID NO: 45), and a CDR3 comprising an amino acid sequence of SVLGRDM(M/V)TY (SEQ ID NO: 4706); x) a CDR1 comprising an amino acid sequence of GFTLDDYA (SEQ ID NO: 4061), a CDR2 comprising an amino acid sequence of IFSYSSNT (SEQ ID NO: 4062), and a CDR3 comprising an amino acid sequence of AVGDFEGELVLKGDY (SEQ ID NO: 4063); xi) a CDR1 comprising an amino acid sequence of GFTLDYYT (SEQ ID NO: 4065), a CDR2 comprising an amino acid sequence of ISSNDGSV (SEQ ID NO: 4066), and a CDR3 comprising an amino acid sequence of AADLGYLYVDYVRLHTHHFGS (SEQ ID NO: 4067); xi) . a CDR1 comprising an amino acid sequence of GRTFSDYG (SEQ ID NO: 4719), a CDR2 comprising an amino acid sequence of INWSNGRT (SEQ ID NO: 4723), and a CDR3 comprising an amino acid sequence of AATPTGKAYTY (SEQ ID NO: 4727); xii). a CDR1 comprising an amino acid sequence of GRTFSDYG (SEQ ID NO: 4720), a CDR2 comprising an amino acid sequence of INWSNART (SEQ ID NO: 4724), and a CDR3 comprising an amino acid sequence of AATPTGKAYTY (SEQ ID NO: 4728); xiv). a CDR1 comprising an amino acid sequence of GRTFSDYG (SEQ ID NO: 4721), a CDR2 comprising an amino acid sequence of INWSNGRT (SEQ ID NO: 4725), and a CDR3 comprising an amino acid sequence of AGTLSGKAYTY (SEQ ID NO: 4729); xv). a CDR1 comprising an amino acid sequence of GRTFSDYG (SEQ ID NO: 4722), a CDR2 comprising an amino acid sequence of INWSNART (SEQ ID NO: 4726), and a CDR3 comprising an amino acid sequence of AGTLSGKAYTY (SEQ ID NO: 4730); or xvi) a CDR1 comprising an amino acid sequence of GFT(F/L)DD(I/Y)A (SEQ ID NO: 69), a CDR2 comprising an amino acid sequence of I(Y/F)SY(S/G)(S/P)NT (SEQ ID NO: 76), and a CDR3 comprising an amino acid sequence of AADSDLSTVV(V/T)GPHDY (SEQ ID NO: 4702). [0198] In certain embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single- domain antibody) of the present disclosure comprises 58 310886415v1 Attorney Docket No: 260525.000071 a) a CDR1 comprising an amino acid sequence of GFTFDDIA (SEQ ID NO: 8), a CDR2 comprising an amino acid sequence of IYSYGPNT (SEQ ID NO: 9), and a CDR3 comprising an amino acid sequence of AADSDLSTVV(V/T)GPHDY (SEQ ID NO: 4702); b) a CDR1 comprising an amino acid sequence of GRTFSDYG (SEQ ID NO: 16), a CDR2 comprising an amino acid sequence of INWSN(G/A)RT (SEQ ID NO: 4699), and a CDR3 comprising an amino acid sequence of AA(T/A)PSGKAYSY (SEQ ID NO: 4703); c) a CDR1 comprising an amino acid sequence of GRTF(G/S)S(Y/L)(T/F) (SEQ ID NO: 4705), a CDR2 comprising an amino acid sequence of IR(W/R/Y)(T/P)G(G/L)(S/I)T (SEQ ID NO: 80), and a CDR3 comprising an amino acid sequence of (A/V)A(A/S)PTGRAF(T/N)Y (SEQ ID NO: 4707); or d) a CDR1 comprising an amino acid sequence of GRTFSDYG (SEQ ID NO: 16), a CDR2 comprising an amino acid sequence of INWSN(G/A)RT (SEQ ID NO: 4699), and a CDR3 comprising an amino acid sequence of A(A/G)(T/A)(P/L)(S/T)GKAY(T/S)Y (SEQ ID NO: 4771). [0199] Provided herein are anti-TNFR2 antigen-binding proteins (e.g., antibodies such as single-domain antibodies) comprising a CDR1 (CDR1) comprising an amino acid sequence selected from any of the CDR1 amino acid sequences listed in Table 1-1, Table 5, Table 7, or Table 8, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity. [0200] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence selected from SEQ ID Nos: 1, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 4061, 4065, 4069, 4520, 4719-4722, 1128-1686, 4173-4234, and 4533-4556, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity. [0201] Provided herein are anti-TNFR2 antigen-binding proteins (e.g., antibodies such as single-domain antibodies) comprising a CDR2 (CDR2) comprising an amino acid sequence selected from any of the CDR2 amino acid sequences listed in Table 1-1, Table 5, Table 7, or Table 8, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity. [0202] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 2, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 4062, 4066, 4070, 4527, 4723-4726, 1687- 2245, 4235-4296, 4557- 4580, and 4788-4793, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity. 59 310886415v1 Attorney Docket No: 260525.000071 [0203] Provided herein are anti-TNFR2 antigen-binding proteins (e.g., antibodies such as single-domain antibodies) comprising a CDR3 (CDR3) comprising an amino acid sequence selected from any of the CDR3 amino acid sequences listed in Table 1-1, Table 5, Table 7, or Table 8, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity. [0204] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR3 comprising an amino acid sequence selected from SEQ ID Nos: 3, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 4063, 4067, 4071, 4524, 4530, 4727-4730, 2246-2804, 4297-4358, 4581-4604, 4774, 4810-4833, and 4835-4855, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity. [0205] Provided herein are anti-TNFR2 antigen-binding proteins (e.g., antibodies such as single-domain antibodies) comprising a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within any of the exemplary anti-TNFR2 VHH antibodies listed in Tables 1-1, Table 1-2, Table 5, Table 7, or Table 8. In certain embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) of the present disclosure comprises i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 1, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 3; i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 5, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6; ii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 8, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10; iv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 12, a CDR2 comprising an amino acid sequence of SEQ ID NO: 13, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 14; v) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 17, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; vi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 20, a CDR2 comprising an amino acid sequence of SEQ ID NO: 21, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 22; 60 310886415v1 Attorney Docket No: 260525.000071 vi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 24, a CDR2 comprising an amino acid sequence of SEQ ID NO: 25, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 26; vii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 28, a CDR2 comprising an amino acid sequence of SEQ ID NO: 29, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 30; ix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 33, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 34; x) a CDR1 comprising an amino acid sequence of SEQ ID NO: 36, a CDR2 comprising an amino acid sequence of SEQ ID NO: 37, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 38; xi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 40, a CDR2 comprising an amino acid sequence of SEQ ID NO: 41, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 42; xi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 44, a CDR2 comprising an amino acid sequence of SEQ ID NO: 45, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 46; xii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4063; xiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4065, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4066, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4067; xv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4071; xvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4520, a CDR2 comprising an amino acid sequence of SEQ ID NO: 45, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 46; 61 310886415v1 Attorney Docket No: 260525.000071 xvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 8, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4524; xvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4530; xx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4723, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727; xxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727; xxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4723, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4729; xxii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4729; xxiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; xxv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10; xxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4524; 62 310886415v1 Attorney Docket No: 260525.000071 xxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727; xxvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727; xxix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; xxx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; xxxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; xxxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4791, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; xxxii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4792, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; xxxiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4793, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; xxxv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xxxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; 63 310886415v1 Attorney Docket No: 260525.000071 xxxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xxxvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4810; xxxix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4811; xl) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4812; xli) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4813; xli) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4814; xlii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4815; xliv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4816; xlv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4817; xlvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4818; 64 310886415v1 Attorney Docket No: 260525.000071 xlvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4819; xlvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4820; xlix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4821; l) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4822; li) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4823; li) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4824; lii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4825; liv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4826; lv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4827; lvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4828; 65 310886415v1 Attorney Docket No: 260525.000071 lvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 34; lvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4829; lix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4830; lx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4831; lxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4832; lxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4833; lxii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4835; lxiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4836; lxv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4530; lxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4837; 66 310886415v1 Attorney Docket No: 260525.000071 lxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4838; lxvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4839; lxix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4840; lxx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4841; lxxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4842; lxxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4843; lxxii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4844; lxxiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4845; lxxv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4846; lxxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4847; 67 310886415v1 Attorney Docket No: 260525.000071 lxxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4848; lxxvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4849; lxxix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4850; lxxx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4851; lxxxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4852; lxxxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4853; lxxxii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4854; or lxxxiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4855. [0206] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 17, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; 68 310886415v1 Attorney Docket No: 260525.000071 b) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; c) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4530; d) a CDR1 comprising an amino acid sequence of SEQ ID NO: 8, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10; e) a CDR1 comprising an amino acid sequence of SEQ ID NO: 8, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4524; f) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4071; g) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4723, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727; h) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727; i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4723, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4729; j) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4729; k) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; 69 310886415v1 Attorney Docket No: 260525.000071 l) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10; or m) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4524. [0207] In a related embodiment, provided herein are anti-TNFR2 antigen-binding proteins (e.g., antibodies such as single-domain antibodies) comprising a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within a VHH amino acid sequence as defined by any of the exemplary anti-TNFR2 VHH antibodies listed in Table 1-1, Table 1-2, Table 5, Table 7, or Table 8. For example, provided herein are antibodies, or antigen-binding fragments thereof, comprising the set of CDR1-CDR2-CDR3 amino acid sequences contained within a VHH amino acid sequence selected from SEQ ID Nos: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 4064, 4068, 4072, 4521, 4780, 4781, 4783, 4785, 4786, 81-92, 93-640, 4079-4125, 2805-3363, 4359-4420, 4605-4628, 4526, 4529, 4532, 4078, 4523, 4076, 4077, 4078, 4731-4734, 4775, 4782, 4784, 4794-4808, 4857-4902, and 4994-5001. [0208] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single- domain antibody) of the present disclosure can include a. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4; b. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7; c. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 11; d. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 15; e. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 19; f. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 23; g. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 27; 70 310886415v1 Attorney Docket No: 260525.000071 h. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 31; i. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 35; j. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 39; k. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 43; l. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 47; m. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4064; n. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4068; o. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4072; p. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4521; q. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4526; r. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4529; s. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4532; t. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4078; u. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4731; v. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4732; 71 310886415v1 Attorney Docket No: 260525.000071 w. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4733; x. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4734; y. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4775; z. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4782; aa. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4784; bb. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4780; cc. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4781; dd. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4783; ee. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4785; f. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4786; gg. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4794; hh. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4795; i. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4796; j. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4797; kk. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4798; 72 310886415v1 Attorney Docket No: 260525.000071 l. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4799; mm. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4800; nn. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4801; oo. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4802; pp. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4803; qq. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4804; rr. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4805; ss. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4806; tt. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4807; uu. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4808; vv. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4857; ww. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4858; xx. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4859; yy. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4860; zz. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4861; 73 310886415v1 Attorney Docket No: 260525.000071 aaa. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4862; bbb. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4863; ccc. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4864; ddd. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4865; eee. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4866; ff. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4867; ggg. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4868; hhh. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4869; ii. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4870; jj. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4871; kkk. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4872; ll. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4873; mmm. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4874; nnn. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4875; ooo. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4876; 74 310886415v1 Attorney Docket No: 260525.000071 ppp. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4877; qqq. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4878; rrr. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4879; sss. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4880; ttt. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4881; uuu. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4882; vvv. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4883; www. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4884; xxx. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4885; yyy. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4886; zzz. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4887; aaaa. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4888; bbbb. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4889; cccc. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4890; dddd. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4891; 75 310886415v1 Attorney Docket No: 260525.000071 eeee. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4892; ff. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4893; gggg. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4894; hhhh. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4895; ii. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4896; jj. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4897; kkkk. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4898; ll. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4899; mmmm. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4900; nnnn. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4901; oooo. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4902; pppp. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4994; qqqq. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4995; rrrr. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4996; ssss. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4997; 76 310886415v1 Attorney Docket No: 260525.000071 tttt. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4998; uuuu. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4999; vvvv. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 5000; or wwww. a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 5001. [0209] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single- domain antibody) of the present disclosure can include a). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 19; b). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4072; c). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4526; d). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4529; e). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4532; f). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4731; g). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4732; h). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4733; i). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4734; j). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4775; 77 310886415v1 Attorney Docket No: 260525.000071 k). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4782; l). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4784; m). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4780; n). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4781; o). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4783; p). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4785; q). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4786; r). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4794; s). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4795; t). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4796; u). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4797; v). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4798; w). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4799; x). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4800; y). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4801; 78 310886415v1 Attorney Docket No: 260525.000071 z). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4802; aa). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4803; bb). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4804; cc). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4805; dd). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4806; ee). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4807; f). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4808; gg). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4857; hh). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4858; i). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4859; j). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4860; kk). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4861; l). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4862; mm). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4863; nn). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4864; 79 310886415v1 Attorney Docket No: 260525.000071 oo). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4865; pp). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4866; qq). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4867; rr). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4868; ss). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4869; tt). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4870; uu). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4871; vv). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4872; ww). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4873; xx). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4874; yy). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4875; zz). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4876; aaa). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4877; bbb). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4878; ccc). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4879; 80 310886415v1 Attorney Docket No: 260525.000071 ddd). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4880; eee). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4881; ff). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4882; ggg). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4883; hhh). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4884; ii). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4885; jj). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4886; kkk). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4887; ll). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4888; mmm). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4889; nnn). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4890; ooo). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4891; ppp). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4892; qqq). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4893; rrr). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4894; 81 310886415v1 Attorney Docket No: 260525.000071 sss). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4895; ttt). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4896; uuu). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4897; vvv). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4898; www). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4899; xxx). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4900; yyy). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4901; zzz). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4902; aaaa). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4994; bbbb). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4995; cccc). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4996; dddd). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4997; eeee). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4998; ff). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 4999; gggg). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 5000; or 82 310886415v1 Attorney Docket No: 260525.000071 hhhh). a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 5001. [0210] In an embodiment provided herein, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) of the present disclosure can include a VHH amino acid sequence selected from SEQ ID Nos: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 4064, 4068, 4072, 4521, 93-640, 4079-4125, 2805-3363, 4359-4420, 4605-4628, 4653-4685, 4780, 4781, 4783, 4785, and 4786, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0211] In an embodiment provided herein, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) of the present disclosure can include a VHH amino acid sequence selected from SEQ ID Nos: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 4064, 4068, 4072, 4521, 4653-4685, 4732, 4780, 4781, 4783, 4785, and 4786, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0212] In an embodiment provided herein, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) of the present disclosure can include a humanized VHH amino acid sequence selected from SEQ ID Nos: 81-92, 4076-4078, 4523, 4526, 4529, 4532, 4731-4734, 641-1127, 4126-4172, 4775, 4782, 4784, 4794-4808, 4857-4902, and 4994-5001, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0213] In an embodiment provided herein, an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) of the present disclosure can include a VHH amino acid sequence selected from SEQ ID Nos: 19, 4072, 4078, 4526, 4529, 4532, 4653-4685, 4732, 4775, 4782, 4784, 4780, 4781, 4783, 4785, 4786, 4794-4808, 4857-4902 and 4994-5001, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0214] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) 83 310886415v1 Attorney Docket No: 260525.000071 comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4794. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4794, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0215] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4732. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4732, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0216] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some 84 310886415v1 Attorney Docket No: 260525.000071 embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4795. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4795, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0217] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4796. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4796, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. 85 310886415v1 Attorney Docket No: 260525.000071 [0218] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4797. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4797, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0219] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4798. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4798, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, 86 310886415v1 Attorney Docket No: 260525.000071 at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0220] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4799. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4799, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0221] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4800. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4800, 87 310886415v1 Attorney Docket No: 260525.000071 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0222] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4801. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4801, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0223] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4791. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4802. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4791, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen-binding protein 88 310886415v1 Attorney Docket No: 260525.000071 (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4802, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0224] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4792. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4803. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4792, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4803, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0225] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4793. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4804. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4793, and a CDR3 comprising an 89 310886415v1 Attorney Docket No: 260525.000071 amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4804, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0226] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 18. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4805. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4805, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0227] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 18. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4806. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ 90 310886415v1 Attorney Docket No: 260525.000071 ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4806, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0228] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 18. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4807. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4807, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0229] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4791. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4808. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., 91 310886415v1 Attorney Docket No: 260525.000071 antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4791, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4808, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0230] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4071. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4078, 4624, 4626, or 4994. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4071. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4078, 4624, 4626, or 4994, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0231] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4810. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino 92 310886415v1 Attorney Docket No: 260525.000071 acid sequence of SEQ ID NO: 4857. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4810. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4857, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0232] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4811. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4858. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4811. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4858, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0233] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4812. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of 93 310886415v1 Attorney Docket No: 260525.000071 three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4859. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4812. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4859, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0234] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4813. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4860. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4813. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4860, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0235] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4814. In some embodiments, an anti-TNFR2 antigen- 94 310886415v1 Attorney Docket No: 260525.000071 binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4861. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4814. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4861, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0236] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4815. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4862. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4815. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4862, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0237] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 95 310886415v1 Attorney Docket No: 260525.000071 comprising an amino acid sequence of SEQ ID NO: 4816. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4863. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4816. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4863, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0238] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4817. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4864. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4817. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4864, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0239] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an 96 310886415v1 Attorney Docket No: 260525.000071 anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4818. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4865. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4818. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4865, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0240] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4819. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4866. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4819. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4866, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0241] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) 97 310886415v1 Attorney Docket No: 260525.000071 comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4820. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4867 or 4995. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4820. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4867 or 4995, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0242] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4821. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4868 or 4996. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4821. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4868 or 4996, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0243] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some 98 310886415v1 Attorney Docket No: 260525.000071 embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4822. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4869 or 4997. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4822. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4869 or 4997, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0244] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4823. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4870 or 4998. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4823. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4870 or 4998, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. 99 310886415v1 Attorney Docket No: 260525.000071 [0245] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4824. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4871 or 4999. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4824. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4871 or 4999, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0246] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4825. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4872. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4825. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4872, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, 100 310886415v1 Attorney Docket No: 260525.000071 at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0247] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4826. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4873. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4826. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4873, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0248] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4827. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4874 or 5000. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4827. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of 101 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 4874 or 5000, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0249] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4828. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4875. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4828. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4875, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0250] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 34. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4876. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 34. In some embodiments, an anti-TNFR2 antigen-binding protein 102 310886415v1 Attorney Docket No: 260525.000071 (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4876, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0251] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4829. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4877 or 5001. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4829. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4877 or 5001, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0252] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4830. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4878. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an 103 310886415v1 Attorney Docket No: 260525.000071 amino acid sequence of SEQ ID NO: 4830. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4878, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0253] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4831. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4879. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4831. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4879, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0254] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4832. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4880. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ 104 310886415v1 Attorney Docket No: 260525.000071 ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4832. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4880, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0255] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4833. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4881. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4833. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4881, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0256] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4835. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4882. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., 105 310886415v1 Attorney Docket No: 260525.000071 antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4835. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4882, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0257] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4836. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4883. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4836. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4883, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0258] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4530. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino 106 310886415v1 Attorney Docket No: 260525.000071 acid sequence of SEQ ID NO: 4532. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4530. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4532, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0259] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4837. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4884. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4837. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4884, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0260] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4838. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of 107 310886415v1 Attorney Docket No: 260525.000071 three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4885. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4838. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4885, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0261] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4839. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4886. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4839. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4886, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0262] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4840. In some embodiments, an anti-TNFR2 antigen- 108 310886415v1 Attorney Docket No: 260525.000071 binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4887. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4840. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4887, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0263] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4841. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4888. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4841. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4888, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0264] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 109 310886415v1 Attorney Docket No: 260525.000071 comprising an amino acid sequence of SEQ ID NO: 4842. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4889. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4842. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4889, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0265] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4843. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4890. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4843. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4890, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0266] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an 110 310886415v1 Attorney Docket No: 260525.000071 anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4844. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4891. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4844. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4891, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0267] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4845. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4892. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4845. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4892, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0268] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) 111 310886415v1 Attorney Docket No: 260525.000071 comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4846. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4893. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4846. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4893, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0269] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4847. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4894. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4847. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4894, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0270] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some 112 310886415v1 Attorney Docket No: 260525.000071 embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4848. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4895. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4848. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4895, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0271] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4849. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4896. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4849. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4896, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. 113 310886415v1 Attorney Docket No: 260525.000071 [0272] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4850. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4897. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4850. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4897, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0273] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4851. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4898. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4851. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4898, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, 114 310886415v1 Attorney Docket No: 260525.000071 at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0274] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4852. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4899. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4852. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4899, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0275] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4853. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4900. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4853. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4900, 115 310886415v1 Attorney Docket No: 260525.000071 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0276] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4854. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4901. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4854. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4901, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0277] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4855. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4902. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4855. In some embodiments, an anti-TNFR2 antigen-binding protein 116 310886415v1 Attorney Docket No: 260525.000071 (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4902, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0278] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4775. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4775, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0279] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 8. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 9. In some embodiments, an anti- TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4524. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4526 or 4780. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 8, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9, and a CDR3 117 310886415v1 Attorney Docket No: 260525.000071 comprising an amino acid sequence of SEQ ID NO: 4524. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4526 or 4780, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0280] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4781 or 4782. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4781 or 4782, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0281] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4524. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4783 or 4784. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid 118 310886415v1 Attorney Docket No: 260525.000071 sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4524. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4783 or 4784, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0282] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 4719. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4723. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4731 or 4785. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 4719, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4723, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4731 or 4785, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0283] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 4721. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 4725. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 4729. In some embodiments, an anti-TNFR2 antigen- binding protein (e.g., antibody such as single-domain antibody) described herein comprises a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within an anti-TNFR2 VHH antibody comprising the amino acid sequence of SEQ ID NO: 4733 or 4786. In some embodiments, an anti-TNFR2 antigen-binding 119 310886415v1 Attorney Docket No: 260525.000071 protein (e.g., antibody such as single-domain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 4721, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4725, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4729. In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 4733 or 4786, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0284] In some embodiments, the present disclosure also provides an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) that competes for binding to TNFR2 with any one of the exemplary anti-TNFR2 VHH antibodies listed in Table 1-1, Table 1-2, Table 5, Table 7 , or Table 8. [0285] In some embodiments, the present disclosure also provides an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) that binds to the same epitope on TNFR2 as any one of the exemplary anti-TNFR2 VHH antibodies listed in Table 1-1, Table 1-2, Table 5, Table 7, or Table 8. [0286] In some embodiments, the present disclosure also provides an anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) that comprises a means for binding an epitope within human TNFR2 bound by any one of the exemplary anti-TNFR2 VHH antibodies listed in Table 1-1, Table 1-2, Table 5, Table 7, or Table 8. Single-domain antibodies [0287] A single-domain antibody (e.g., VHH) can be obtained by immunization of dromedaries, camels, lamas, alpacas, or sharks with the desired antigen and subsequent isolation of the mRNA coding for heavy-chain antibodies. Antigens can be purified from natural sources, or in the course of recombinant production. Immunization and/or screening for immunoglobulin sequences can be performed using peptide fragments of such antigens. By reverse transcription and polymerase chain reaction (PCR), a gene library of single-domain antibodies containing several milion clones can be produced. Screening techniques such as phage display, yeast display, and ribosome display help to identify the clones binding the antigen. Methods generation of heavy-chain antibody fragments are described in e.g., WO 94/04678; Hamers-Casterman et al.1993; Muyldermans et al.2001; and Arbabi Ghahroudi, M. et al. (1997). FEBS Leters 414 (3): 521-526, each of which is incorporated herein by reference in its entirety. 120 310886415v1 Attorney Docket No: 260525.000071 [0288] A diferent method may use gene libraries from animals that have not been previously immunized. Such naïve libraries usualy contain only antibodies with low afinity to the desired antigen, making it necessary to apply afinity maturation by random mutagenesis as an additional step. See e.g., Saerens, D.; et al. (2008). “Single-domain antibodies as building blocks for novel therapeutics”. Current Opinion in Pharmacology 8 (5): 600-608. [0289] Afinity maturation strategies can be categorized as either targeted/rational approaches or untargeted/random approaches. For targeted approaches information about the VHH of interest is needed, such as hot spots for afinity maturation or structural information on the VHH:antigen complex, whereas for untargeted approaches no prior information is needed. Targeted approaches that may be applied for afinity maturation of VHHs include site-directed in-vitro mutagenesis and in- silico/computational approaches. Common untargeted approaches used for afinity maturation of VHHs include random in-vitro mutagenesis, CDR swapping and autonomous hypermutation yeast surface display, with the latter two being novel, emerging and very time eficient techniques. Most of these strategies have in common, that after applying a certain randomization strategy to generate a mutational library, the resulting library can be screened by employing standard display techniques such as yeast, phage or ribosome display to select for the best binders. The choice of the display system is often guided by the library size to be displayed, with yeast display being able to handle library sizes of ~107 – 109, phage display ~108-1010 and ribosome display ~1012-1013 (Chan and Groves, 2021). Notably, during afinity maturation the number of highly interactive residues such as aromatic amino acids usualy increase in the CDR regions. The selected afinity matured clones may be further evaluated by a developability assessment to test for undesired properties, such as unspecific binding to of-targets or VHH instability. [0290] For targeted in vitro mutagenesis, a set of selected residues within the CDRs of a VHH may be mutated (Tiler et al., 2017; Yau et al., 2005). Pre-selection of these residues can be either performed using alanine scanning to identify hot spot residues for mutation or by using structural data of the antigen:VHH complex to identify positions to be mutated. These sites can then be either submitted to saturating mutagenesis to substitute a specific site with al possible amino acids or specific amino acid substitutions yielding several smaler libraries. After mutagenesis binders can be displayed to select the best matured candidate. Usualy, several rounds of targeted mutagenesis are performed with separate sub-libraries to obtain combinations of individual mutations that cooperatively result in increased binding afinity. 121 310886415v1 Attorney Docket No: 260525.000071 [0291] Computer-aided/in silico methods are often used to guide targeted in vitro mutagenesis. Using homology modeling of the target:VHH complex or docking, hotspots for mutations can be identified that are then submited to in vitro mutagenesis (Bert Schepens et al., 2021; Cheng et al., 2019; Inoue et al., 2013; Mahajan et al., 2018). Further, in silico methods can search al designed variants in a virtual library (1̃040 members) in a rather short amount of time to identify a feasible number of promising candidates to be tested experimentaly. These techniques can be especialy valuable if structural data on the drug- target interaction are available. [0292] Untargeted/random afinity maturation strategies that can be applied to afinity mature VHHs include random in vitro mutagenesis, CDR shufling/swapping and in vivo afinity maturation via yeast display. For random in vitro mutagenesis the sequence of either the entire VHH or only the CDRs are mutated randomly (Chen et al., 2021; Ye et al., 2021; Zupancic et al., 2021). The most commonly used technique is error prone PCR employing a DNA polymerase that lacks proof reading activity and PCR conditions that increase the polymerase error rate even further. This technique can be applied without further structural knowledge or information on the importance of residues that contribute to antigen:VHH interaction. The resulting mutational library can then be displayed to select the best matured candidate. This technique may also be combined with NGS sequencing of the display elutions to get an in-depth readout of al obtained candidates, enabling the identification of low abundant but stil promising clones (Chen et al., 2021). [0293] In some embodiments, CDR shufling or swapping is applied for VHH afinity maturation, such as described in Zupancic et al., 2021. For CDR swapping, enriched libraries can be used as input material for a PCR reaction to individualy amplify the CDR of the VHHs. The PCR products can then be mixed and reassembled using overlapping PCR to generate the entire plasmid for further rounds of display to select for the best matured binder. One limitation of this approach is that it can only be used for VHHs comprising the same framework as it is the case for synthetic libraries. [0294] In some embodiments, in vivo afinity maturation via yeast display is applied for VHH afinity maturation, such as described in Welner et al., 2021. The method is based on an autonomous hypermutation yeast surface display (AHEAD), which imitates somatic hypermutation during VHH selection using engineered yeast strains. The yeast’s error prone orthogonal DNA replication system can generate new variants during plasmid replication by randomly introducing mutations. The new variants can then be displayed and selected using yeast surface display to identify the best binders. This enables the production of high afinity clones in very litle time (about 2 weeks), which is significantly faster than 122 310886415v1 Attorney Docket No: 260525.000071 classical afinity maturation procedures. The method can be applied using synthetic or immune libraries using unenriched libraries enriched libraries or a subset of preselected clones. [0295] In case binders with medium afinity are required, as it is the case for the anti-TNFR2 V-bodies and the afinity of the identified candidates need to be decreased, very similar techniques can be applied. For example, mutations that are aiming at lowering the afinity can be introduced using the same targeted or untargeted approaches as described for the afinity maturation. The selection afterwards can be adapted accordingly. If larger libraries are generated that need to be screened via a display technique, the selection strategy can be adapted to enrich medium afinity binders while excluding high afinity candidates. This could, for example be a pre-panning in phage display with low antigen concentration to remove al higher afinity candidates, folowed by a selection with high antigen concentration to obtain medium afinity VHHs. For library sizes of up to 1000 candidates a kinetic of- rate characterization can be used to get immediate information about the kinetic behavior of the candidates. [0296] When the most potent clones have been identified, their DNA sequence can be optimized, for example to improve their stability towards enzymes. Another goal is humanization to prevent immunological reactions of the human organism against the antibody. Humanization can be achieved based on the homology between camelid VHH and human VH fragments, which is described in further detail below. Finaly, the optimized single-domain antibody can be translated and expressed in suitable organisms such as E. coli or Saccharomyces cerevisiae. [0297] Single-domain antibodies can also be derived from conventional antibodies. In some embodiments, single-domain antibodies can be made from conventional murine or human IgG with four chains. The process is similar, comprising gene libraries from immunized or naïve donors and display techniques for identification of the most specific antigens. However, the binding region of a conventional IgG consists of two domains (VH and VL), which tend to dimerize or aggregate because of their lipophilicity. Monomerization can be accomplished by replacing lipophilic by hydrophilic amino acids. (See e.g., Borrebaeck, C. A. K.; Ohlin, M. (2002). “Antibody evolution beyond Nature”. Nature Biotechnology 20 (12): 1189-90.) If afinity can be retained after monomerization, the single-domain antibodies can likewise be produced in E. coli, S. cerevisiae or other suitable organisms. [0298] A “humanized antibody” refers to a chimeric, geneticaly engineered, antibody in which the amino acid sequences (typicaly CDRs) from an antibody (donor antibody), e.g., a camelid antibody, are grafted onto a human antibody (acceptor antibody). Thus, a humanized antibody typicaly comprises 123 310886415v1 Attorney Docket No: 260525.000071 CDRs from a donor antibody and variable region framework and constant regions, when present, from a human antibody. Accordingly, a “humanized VHH” comprises CDRs that corresponds to the CDRs of a naturaly occurring VHH domain (e.g., a camelid VHH), but that has been “humanized”. Humanized VHH may be prepared by replacing one or more amino acid residues in the amino acid sequence of the naturaly occurring VHH sequence (particularly in the framework sequences) by one or more of the amino acid residues that occur at the corresponding position(s) in a VH domain from a conventional 4- chain human antibody. Such humanized VHHs can be obtained in any suitable manner known to a skiled person in the art and thus not strictly limited to methods described herein. [0299] Humanization of VHHs can achieved using resurfacing or CDR grafting. Resurfacing strategies have been described in e.g., Conrath et al., 2005 J Mol Biol; Kazemi-Lomedasht et al., 2018; Vincke et al., 2009 J Biol Chem, and CDR grafting strategies have been described in e.g., ben Abderrazek et al., 2011; van Faassen et al., 2020 FASEB; Li et al., 2018; Vaneycken et al., 2010; Vincke et al., 2009 J Biol Chem; and Yu et al., 2017, each of which is incorporated herein by reference in its entirety. [0300] To humanize a camelid VHH using a resurfacing approach, a human germline reference that is most similar to the camelid germline sequence of the selected VHH may be identified. Most of the isolated camelid VHHs in literature belong to the camelid IGHV3 subfamily 2 (Nguyen et al., 2000, EMBO J) with DP-47/VH3-23 from the IGHV3 family commonly used as human reference. The framework of the camelid VHH can then be compared to the human reference sequence. Surface exposed residues are substituted to their human counterpart as it is assumed that their contribution to protein stability is rather low. Buried residues however remain of camelid origin, as they likely contribute to the overal VHH stability. Humanization of framework regions 1, 3 and 4 usualy does not impact the physicochemical properties of the VHHs, whereas a general humanization of framework 2 would significantly increase local hydrophobicity. Residues H37, H44, H45 and H47 (Chothia numbering) in framework 2, the so caled tetrade or halmark residues, have a rather hydrophobic nature in human VHs (VGLW) as they are partialy buried and involved in VH/VL paring, while in camelid VHHs these residues are partialy charged (FERG), which significantly increases VHH solubility and inhibits paring of camelid VL (Soler et al., 2021, Biomolecules, Conrath et al., 2005 J Mol Biol). Further, residues H37 and H47 are known to interact with the CDR-H3 loop in many VHHs, stabilizing its conformation and thereby contributing to antigen binding afinity. In addition, a significant number of VHHs use framework 2 residues H44, H45 and H47 for antigen binding (Zavrtanik et al., 2018, J Mol Biol). A ful humanization of these residues hence frequently results in reduced solubility or aggregation of the VHHs and a reduced 124 310886415v1 Attorney Docket No: 260525.000071 or complete loss of binding afinity for the target antigen (van Faassen et al., 2020, Vincke et al., 2009). In consequence, al or at least some of these halmark residues in framework 2 remain of camelid origin when humanizing VHHs. [0301] Another approach that may be applied to humanize VHHs is CDR grafting. CDRs of the selected VHHs can be transplanted onto a universal VHH framework that has been partialy or fuly humanized (Saerens et al., 2009 J Biol Chem, Soler et al., 2021, Vincke et al., 2009 J Biol Chem). CDR grafting has been successfuly used in some cases but failed for several others, with VHHs frequently losing their potential to bind to the desired antigen and/or becoming structuraly instable with a high tendency to aggregate (van Faassen et al., 2020, FASEB). This is mostly atributed to interactions of CDR3 with specific residues in framework 2 that are important for CDR3 conformation, general VHH stability and overal hydrophobicity, which are impaired by this approach. Sometimes camelid backmutations are introduced into the framework to compensate for these efects (van Faassen et al., 2020, FASEB). [0302] An alternative strategy to mitigate the need of humanizing the selected VHH sequences is to use fuly or partialy humanized synthetic VHH libraries instead of camelid immune libraries for VHH discovery (Moutel et al.2016, eLife; McMahon, 2018, NSMB; Zimmermann et al., 2018, eLife). In many of these libraries the halmark residues are stil of camelid origin for reasons discussed above. [0303] Other suitable humanizing substitutions are described in WO 09/138519 and WO 08/020079, as wel as Tables A-3 to A-8 from WO 08/020079 (which are lists showing possible humanizing substitutions), each of which is incorporated herein by reference in its entirety. Non-limiting examples of such humanizing substitutions include Q108L and A14P. Such humanizing substitutions may also be suitably combined with one or more other mutations as described herein (such as with one or more mutations that reduce binding by pre-existing antibodies). [0304] In some embodiments, humanized VHH sequences stil retain the residues that are relevant for protein A binding. In some embodiments, the engineering activities during humanization may be applied to engineer protein A binding properties into a VHH that did previously not interact with protein A (Graile et al., 2000, PNAS). [0305] Like a “humanized antibody”, a “camelized antibody” refers to an antibody having amino acid sequences (typicaly CDRs) from a donor antibody, e.g., a human antibody, and variable region framework and constant regions, when present, from a camelid antibody. Accordingly, a “camelized VH” comprises an amino acid sequence that corresponds to the amino acid sequence of a naturaly occurring VH domain, but that has been “camelized”. Camelized VH may be prepared by replacing one or more 125 310886415v1 Attorney Docket No: 260525.000071 amino acid residues in the amino acid sequence of a naturaly occurring VH domain from a conventional 4-chain antibody by one or more of the amino acid residues that occur at the corresponding position(s) in a VHH domain of a heavy chain antibody. This can be performed in a manner, for example as described in WO 2008/020079. Such “camelizing” substitutions are usualy inserted at amino acid positions that form and/or are present at the VH—VL interface, and/or at the so-caled Camelidae halmark residues, e.g., F37, E44, R45 and F47 (see for example WO 94/04678 and Davies and Riechmann (1994 and 1996). In one embodiment, the VH sequence that is used as a starting material or starting point for generating or designing the camelized VH is a VH sequence from a mammal, or the VH sequence of a human antibody. However, such camelized VH can be obtained in any suitable manner known to a skiled person in the art and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturaly occurring VH domain as a starting material. [0306] The amino acid residues of a single-domain antibody can be numbered according to the general numbering for VH domains given by Kabat et al. (“Sequence of proteins of immunological interest”, US Public Health Services, NIH Bethesda, Md., Publication No.91), as applied to VHH domains from Camelids described in Riechmann and Muyldermans, 2000 (J. Immunol. Methods 240 (1-2): 185-195; see for example FIG.2 of this publication). The total number of amino acid residues in each of the CDRs may vary and may not correspond to the total number of amino acid residues indicated by the Kabat numbering. For example, one or more positions according to the Kabat numbering may not be occupied in the actual sequence, or the actual sequence may contain more amino acid residues than the number alowed for by the Kabat numbering. As a result, the numbering according to Kabat may or may not correspond to the actual numbering of the amino acid residues in the actual sequence. The total number of amino acid residues in a VH domain and a VHH domain is usualy in the range of from 110 to 120, often between 112 and 115. However, smaler, and longer sequences may also be suitable for the purposes described herein. [0307] Determination of CDR regions in a single-domain antibody may be accomplished using diferent methods, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (“Kabat” numbering scheme); Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme); MacCalum et al., J. Mol. Biol.262:732-745 (1996), “Antibody-antigen interactions: Contact analysis and binding site topography,” J. Mol. Biol.262, 732-745.” (“Contact” numbering scheme); Lefranc M P et al., “IMGT unique numbering for immunoglobulin and T cel receptor variable domains and Ig superfamily V-like 126 310886415v1 Attorney Docket No: 260525.000071 domains,” Dev Comp Immunol, 2003 January; 27(1):55-77 (“IMGT” numbering scheme); Honegger A and Plückthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol, 2001 Jun.8; 309(3):657-70, (“Aho” numbering scheme); and Martin et al., “Modeling antibody hypervariable loops: a combined algorithm,” PNAS, 1989, 86(23):9268-9272, (“AbM” numbering scheme), each reference cited herein is incorporated by reference in its entirety. [0308] The boundaries of a given CDR or framework (FR) may vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignments, while the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, with insertions accommodated by insertion letters, for example, “30a,” and deletions appearing in some antibodies. The two schemes place certain insertions and deletions (“indels”) at diferent positions, resulting in diferential numbering. The Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme. The AbM scheme is a compromise between Kabat and Chothia definitions based on that used by Oxford Molecular's AbM antibody modeling software. [0309] In some embodiments, CDRs can be defined in accordance with any of the Kabat numbering scheme, the Chothia numbering scheme, a combination of Kabat and Chothia, the AbM numbering scheme, and/or the Contact numbering scheme. A VHH typicaly comprises three CDRs, designated CDR1, CDR2, and CDR3. Table 1-3, below, lists exemplary position boundaries of CDR-H1, CDR-H2, CDR- H3 as identified by Kabat, Chothia, AbM, and Contact schemes, respectively. For CDR-H1, residue numbering is listed using both the Kabat and Chothia numbering schemes. FRs are located between CDRs, for example, with FR-H1 located before CDR-H1, FR-H2 located between CDR-H1 and CDR-H2, FR- H3 located between CDR-H2 and CDR-H3 and so forth. It is noted that because the shown Kabat numbering scheme places insertions at H35A and H35B, the end of the Chothia CDR-H1 loop when numbered using the shown Kabat numbering convention varies between H32 and H34, depending on the length of the loop. Table 1-3. CDRs definitions according to various numbering schemes CDR Kabat Chothia AbM Contact 127 310886415v1 Attorney Docket No: 260525.000071 CDR Kabat Chothia AbM Contact (Kabat individual specified CDRs (e.g., CDR-H1, CDR-H2, CDR-H3), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) CDR as defined by any of the above-mentioned schemes. For example, where it is stated that a particular CDR (e.g., a CDR-H3) contains the amino acid sequence of a corresponding CDR in a given VHH amino acid sequence, it is understood that such a CDR has a sequence of the corresponding CDR (e.g., CDR-H3) within the VHH, as defined by any of the above-mentioned schemes. In some embodiments, specific CDR sequences are specified. Exemplary CDR sequences of provided antibodies are described using various numbering schemes (see e.g., Table 1-3), although it is understood that a provided antibody can include CDRs as described according to any of the other above-mentioned numbering schemes or other numbering schemes known to a person of ordinary skil in the art. [0311] In a single-domain antibody sequence of the present disclosure, the framework sequences may be any suitable framework sequences. For example, the framework sequences may be framework sequences derived from a heavy chain variable domain (e.g., a VH sequence or VHH sequence). In some embodiments, the framework sequences are either framework sequences that have been derived from a VHH sequence (in which said framework sequences may optionaly have been partialy or fuly humanized) or are conventional VH sequences (in which said framework sequences may optionaly have been partialy or fuly camelized). [0312] Antigen-binding fragments (or combinations of fragments) of any of single-domain antibodies described herein, such as fragments that contain one or more CDR sequences, suitably flanked by 1 Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD 2 Al-Lazikani et al., (1997) JMB 273, 927-948 128 310886415v1 Attorney Docket No: 260525.000071 and/or linked via one or more framework sequences, are also encompassed within the present disclosure. [0313] It should be noted, however, that the present disclosure is not limited to the origin of the single- domain antibody (or of the nucleotide sequence used to express it), nor to the way that the single- domain antibody or nucleotide sequence is generated or obtained. Thus, an antigen-binding protein of the present disclosure may comprise naturaly occurring sequences (from a suitable species), recombinant sequences, or synthetic or semi-synthetic sequences. Similarly, nucleotide sequences encoding antigen-binding proteins of the present disclosure may comprise naturaly occurring nucleotide sequences, recombinant sequences, or synthetic or semi-synthetic sequences (for example, sequences that are prepared by PCR or isolated from a library). [0314] Anti-TNFR2 antigen-binding proteins (e.g., antibodies such single-domain antibodies) 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 chain variable domains as compared to the exemplary antibody sequences provided herein. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The antigen-binding molecules of the present disclosure may comprise antigen-binding domains which are derived from any of the exemplary amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein colectively as "germline mutations"). A person of ordinary skil in the art, starting with the heavy 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, al of the framework and/or CDR residues within the VHH domains are mutated back to the residues found in the original germline sequence from which the antigen-binding domain was originaly 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 129 310886415v1 Attorney Docket No: 260525.000071 residue(s) of a diferent germline sequence (i.e., a germline sequence that is diferent from the germline sequence from which the antigen-binding domain was originaly derived). [0315] Furthermore, the antigen-binding domains may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that difer from the original germline sequence are maintained or are mutated to the corresponding residue of a diferent 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 afinity, improved, or enhanced biological properties (e.g., agonistic efect), reduced immunogenicity, etc. Antigen-binding proteins comprising one or more antigen-binding domains obtained in this general manner are encompassed within the present disclosure. [0316] Provided herein are anti-TNFR2 antigen-binding proteins comprising variants of any of the VHH and/or CDR amino acid sequences disclosed herein having one or more amino acid substitutions. For example, the present disclosure includes anti-TNFR2 antigen-binding proteins having VHH 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 amino acid substitutions relative to any of the VHH and/or CDR amino acid sequences set forth in Tables 1-1, 1-2, 5 and 7 herein. Amino acid substitutions may be introduced into an antigen-binding protein of interest and the resultant variants can screened for a desired activity, for example, retained/improved antigen binding, decreased immunogenicity, or reduced ADCC or CDC. [0317] Amino acids may be grouped according to common side-chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; (6) aromatic: Trp, Tyr, Phe. In some embodiments, an amino acid substitution is a conservative substitution, meaning exchanging an amino acid with another amino acid of the same class. In some embodiments, amino acid substitutions may also include a non-conservative substitution, meaning exchanging an amino acid with an amino acid of a diferent class. Other exemplary amino acid substitutions are shown in Table 1-4. Table 1-4. Exemplary amino acid substitutions Original Residue Exemplary Substitutions Ala (A) Val; Leu; Ile 130 310886415v1 Attorney Docket No: 260525.000071 Original Residue Exemplary Substitutions Asp (D) Glu; Asn [0318] In som , g .g., p sclosure may comprise one or more mutations to reduce oxidation levels of oxidation-labile residues such as Met (M). In certain embodiments, it may be desirable to address Met (M) oxidation liability by mutation of a Met (M) residue. In some embodiments, the single-domain antibodies (e.g., VHH) of the present disclosure may comprise one or more mutations (e.g., substitution mutations) of a Met residue to reduce oxidation. As a non-limiting example, a Met residue may be substituted in any of the single-domain antibodies described herein with e.g., Ile (I), Ala (A), or Leu (L), to reduce oxidation. [0319] In some embodiments, single-domain antibodies (e.g., VHH) of the present disclosure comprise one or more modifications that reduce binding of the single-domain antibodies (e.g., VHH) by pre- existing antibodies found in human blood or serum. In some embodiments, single-domain antibodies (e.g., VHHs) of the present disclosure are modified by mutation of amino acid position 11, for example Leu11Glu (L11E), Leu11Lys (L11K), or Leu11Val (L11V). In one embodiment, a single-domain antibody (e.g., VHH) of the present disclosure may comprise a valine (V) at amino acid position 11 and a leucine (L) at amino acid position 89 (according to Kabat numbering). As another example, a single-domain antibody (e.g., VHH) of the present disclosure may comprise an extension of 1 to 5 (naturaly occurring) amino acids, such as a single alanine (A) extension, at the C-terminus of the single-domain antibody (e.g., VHH). The C-terminus of a VHH is normaly VTVSS (SEQ ID NO: 4031). In one embodiment, a single- 131 310886415v1 Attorney Docket No: 260525.000071 domain antibody (e.g., VHH) of the present disclosure comprises a lysine (K) or glutamine (Q) at position 110 (according to Kabat numbering). In another embodiment, a single-domain antibody (e.g., VHH) of the present disclosure comprises a lysine (K) or glutamine (Q) at position 112 (according to Kabat numbering). Accordingly, the C-terminus of a single-domain antibody (e.g., VHH) can be any one of VKVSS (SEQ ID NO: 4032), VQVSS (SEQ ID NO: 4033), VTVKS (SEQ ID NO: 4034), VTVQS (SEQ ID NO: 4035), VKVKS (SEQ ID NO: 4036), VKVQS (SEQ ID NO: 4037), VQVKS (SEQ ID NO: 4038), or VQVQS (SEQ ID NO: 4039). In another embodiment, a single-domain antibody (e.g., VHH) of the present disclosure comprises a valine (V) at amino acid position 11 and a leucine (L) at amino acid position 89 (according to Kabat numbering), optionaly a lysine (K) or glutamine (Q) at position 110 (according to Kabat numbering) and an extension of 1 to 5 (naturaly occurring) amino acids, such as a single alanine (A) extension at the C-terminus of the single-domain antibody (e.g., VHH) (such that the C-terminus of the single-domain antibody (e.g., VHH) for example has the sequence VTVSSA (SEQ ID NO: 4040), VKVSSA (SEQ ID NO: 4041) or VQVSSA (SEQ ID NO: 4042). In further embodiments, single-domain antibodies (e.g., VHH) of the present disclosure are modified by changes in carboxy-terminal region, for example to a terminal sequence having the sequence GQGTLVTVKPGG (SEQ ID NO: 4043) or GQGTLVTVEPGG (SEQ ID NO: 4044) or modification thereof. Additional modification to reduce binding by pre-existing antibodies in human serum can be found in e.g., WO2012/175741, WO2015/173325, WO2016/150845, WO2011/003622, WO2013/024059; US 11,426,468, US 10,526,397, which are incorporated herein by reference in their entities. [0320] In one embodiment, a single-domain antibody (e.g., VHH) of the present disclosure comprises at the carboxy-terminus starting from position 111 according to Chothia the amino acid sequence VAGG (SEQ ID NO: 4697) or VPAG (SEQ ID NO: 4698). In one embodiment, a single-domain antibody (e.g., VHH) of the present disclosure comprises at the carboxy-terminus starting from position 111 according to Chothia the amino acid sequence VAGG (SEQ ID NO: 4697). In one embodiment, a single-domain antibody (e.g., VHH) of the present disclosure comprises at the carboxy-terminus starting from position 111 according to Chothia the amino acid sequence VPAG (SEQ ID NO: 4698). [0321] Additional carboxy-terminus modifications to introduce to a single-domain antibody (e.g., VHH) of the present disclosure include those described in in e.g., WO2024/238790, which is incorporated herein by reference in its entirety. [0322] In some embodiments, a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 132 310886415v1 Attorney Docket No: 260525.000071 4064, 4068, 4072, 4521, 93-640, 4079-41252805-3363, 4359-4420, 4605-4628, 4780, 4781, 4783, 4785, and 4786, or a sequence having at least 75% identity thereto, wherein the amino acid sequence at the carboxy-terminus starting from position 111 according to Chothia comprises VAGG (SEQ ID NO: 4697) or VPAG (SEQ ID NO: 4698). [0323] In some embodiments, a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 4064, 4068, 4072, 4521, 4780, 4781, 4783, 4785, and 4786, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, wherein the amino acid sequence at the carboxy-terminus starting from position 111 according to Chothia comprises VAGG (SEQ ID NO: 4697) or VPAG (SEQ ID NO: 4698). [0324] In some embodiments, a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 81-92, 4076-4078, 4523, 4526, 4529, 4532, 4731-4734, 641-1127, 4126-4172, 4775, 4782, 4784, 4794-4808, 4857-4902, and 4994-5001, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, wherein the amino acid sequence at the carboxy-terminus starting from position 111 according to Chothia comprises VAGG (SEQ ID NO: 4697) or VPAG (SEQ ID NO: 4698). [0325] In some embodiments, a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 81-92, 4076-4078, 4523, 4526, 4529, 4731-4734, 4532, 4775, 4782, 4784, 4794-4808, and 4857-4902, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, wherein the amino acid sequence at the carboxy-terminus starting from position 111 according to Chothia comprises VAGG (SEQ ID NO: 4697) or VPAG (SEQ ID NO: 4698). [0326] In some embodiments, a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 4994-5001, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, wherein the amino acid sequence at the carboxy-terminus starting from position 111 according to Chothia comprises VAGG (SEQ ID NO: 4697) or VPAG (SEQ ID NO: 4698). 133 310886415v1 Attorney Docket No: 260525.000071 [0327] In some embodiments, single-domain antibodies (e.g., VHH) of the present disclosure are modified to enhance binding to staphylococcal protein A (SpA) or streptococcal protein G (SpG). Binding of SpA and SpG to antibodies or antibody fragments can be useful in the manufacturing process of the antibodies or antibody fragments. The high-afinity interaction of the IgG Fc region with SpA and SpG has been extensively exploited and became the gold standard for monoclonal antibody purification (Björck and Kronval, 1984). Other non-Fc containing antibody fragments, such as VHHs and Fabs do not have the capacity to bind to SpA or SpG via their Fc regions. However, sequence-dependent interaction with SpA has been demonstrated for these non-Fc containing antibody fragments(Graile et al., 2000; Henry et al., 2016). This characteristic circumvents potential use of afinity tags fused to the drug candidate for afinity chromatography that have the disadvantage as being regarded as a sequence liability, as it may impact protein immunogenicity as wel as protein structure and stability and could compromise functionality. The interaction of the single-domain antibodies (e.g., VHH) to SpA relies on an alternative binding mode, with a 1-5 µM afinity, which is comparable to the 0.2 -3 µM measured for VH-SpA interactions (To et al., JBC, 2005; Henry et al., Plos One, 2016). [0328] In some embodiments, single-domain antibodies (e.g., VHH) of the present disclosure have, or are modified to have a SpA-binding motif. For example, The VHH-SpA interface has been mapped to thirteen residues, which cluster within the framework at the back side of the V-body, distant to the CDRs (Graile et al., 2000, Henry et al., 2016). In the absence of a VHH-SpA co-structure, superposition of a SpA-Fab crystal structure and a VHH alows for visualizing the binding mode. Based on a structural and functional analysis, the thirteen residues of the VHH-SpA interface have been characterized to be intolerant to substitutions (residues Gly15, Arg19, Tyr59, Gly65, and Arg66), tolerant to specific substitutions (residues Thr/Lys/Arg57, Thr68, Gln81, Asn82a, and Ser82b) or generaly tolerant to a variety of substitutions (residues Ser17, Lys64, and Ser70) (al residue positions refer to Kabat numbering) (Henry et al., Plos One, 2016). Thus, a SpA-binding motif included in a single-domain antibody (e.g., VHH) of the present disclosure may include one or more, or al of the thirteen residues. [0329] In some embodiments, single-domain antibodies (e.g., VHH) of the present disclosure comprise one or more modifications at N-terminus to prevent formation of a pyroglutamate and product heterogeneity. In one embodiment, the amino acid residue Glu at the first position of the single-domain antibodies (e.g., VHH) is replaced with Asp (E1D). [0330] In some embodiments, a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 134 310886415v1 Attorney Docket No: 260525.000071 4064, 4068, 4072, 4521, 93-640, 4079-41252805-3363, 4359-4420, 4605-4628, 4780, 4781, 4783, 4785, and 4786, or a sequence having at least 75% identity thereto, wherein the amino acid residue Glu at the first position of the single-domain antibody (e.g., VHH) is replaced with Asp (E1D). [0331] In some embodiments, a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 4064, 4068, 4072, 4521, 4780, 4781, 4783, 4785, and 4786, or a sequence having at least 75% identity thereto, wherein the amino acid residue Glu at the first position of the single-domain antibody (e.g., VHH) is replaced with Asp (E1D). [0332] In some embodiments, a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 81-92, 4076-4078, 4523, 4526, 4529, 4532, 4731-4734, 641-1127, 4126-4172, 4775, 4782, 4784, 4794-4808, 4857-4902, and 4994-5001, or a sequence having at least 75% identity thereto, wherein the amino acid residue Glu at the first position of the single-domain antibody (e.g., VHH) is replaced with Asp. [0333] In some embodiments, a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 81-92, 4076-4078, 4523, 4526, 4529, 4731-4734, 4532, 4775, 4782, 4784, 4794-4808, and 4857-4902, or a sequence having at least 75% identity thereto, wherein the amino acid residue Glu at the first position of the single-domain antibody (e.g., VHH) is replaced with Asp (E1D). [0334] In some embodiments, a single-domain antibody (e.g., VHH) of the present disclosure comprises an amino acid sequence selected from any one of SEQ ID NOs: 4994-5001, or a sequence having at least 75% identity thereto, wherein the amino acid residue Glu at the first position of the single-domain antibody (e.g., VHH) is replaced with Asp (E1D). Alternative protein scafolds [0335] In some embodiments, anti-TNFR2 antigen-binding proteins of the present disclosure can adopt an alternative protein scafold. Such alternative protein scafold may be a single chain polypeptidic framework, optionaly with a reduced size (e.g., less than about 200 amino acids), that contains a highly structured core associated with variable domains of high conformational tolerance alowing insertions, deletions, or other substitutions. Such antigen-binding proteins may be generated by grafting CDRs or variable regions described herein onto a suitable protein scafold. The structure of alternative scafolds may vary, but preferably are of human origin for those developed as therapeutics. 135 310886415v1 Attorney Docket No: 260525.000071 [0336] Alternative protein scafolds of the present disclosure can be based either on a conventional immunoglobulin (Ig) backbone, or are derived from a completely unrelated protein. These variable domains can be modified to create novel binding interfaces toward any targeted antigen. In some embodiments, an alternative protein scafold of the present disclosure can be derived from Protein A, e.g., the Z-domain thereof (afibodies), ImmE7 (immunity proteins), BPTI/APPI (Kunitz domains), Ras- binding protein AF-6 (PDZ-domains), charybdotoxin (Scorpion toxin), CTLA-4, Min-23 (knottins), lipocalins (anticalins), neokarzinostatin, a fibronectin domain (used in “adnectin”), an ankyrin repeat (AR) domain (used in “DARPins”), avidity multimers (also known as “avimers”), or thioredoxin (Skerra, A., Curr. Opin. Biotechnol.18 :295-304 (2005) ; Hosse et al., Protein Sci.15 :14-27 (2006) ; Nicaise et al., Protein Sci.13 :1882-1891 (2004) ; Nygren and Uhlen, Curr. Opin. Struc. Biol.7:463-469 (1997), al of which are hereby incorporated by reference in their entirety). [0337] Anticalins are a suitable type of non-Ig based alternative scafolds for use in the antigen-binding molecules of the present disclosure. Anticalins are a class of engineered ligand-binding proteins that are based on the lipocalin scafold. Lipocalins are a family of proteins that transport smal hydrophobic molecules such as steroids, bilins, retinoids, and lipids. Lipocalins have limited sequence homology, but share a common tertiary structure architecture based on eight antiparalel β-barrels. Lipocalins contain four exposed loops built on the rigid β-barrel structure. Exemplary anticalin proteins that are commonly used are about a size of about 180 amino acids and a mass of about 20 kDa. [0338] DARPins are another suitable non-Ig based alternative scafold that can be used in the antigen- binding molecules of the present disclosure. DARPins are geneticaly engineered antibody mimetic proteins typicaly exhibiting highly specific and high-afinity target protein binding. They are derived from natural ankyrin repeat (AR) proteins, which usualy contain a 33 amino acid protein motif consisting of two α-helices separated by loops, which repeats mediate protein—protein interactions. DARPins can be generated using combinatorial AR libraries constructed based on the 33 amino acid AR motif with seven randomized positions. DARPin libraries can be screened using ribosome display, and library members typicaly are wel produced in Escherichia coli, do not aggregate, and display high thermodynamic stability. Preferably, DARPins contain two to four of these motifs flanked by N- and C- terminal capping motifs to shield hydrophobic regions and alow increased solubility. [0339] The avimer structure can also be used as a protein backbone to generate a suitable non-Ig based alternative scafold. Avimers typicaly consist of two or more peptide sequences of 30 to 35 amino acids each, connected by peptide linker. The individual sequences are derived from A-domains of various 136 310886415v1 Attorney Docket No: 260525.000071 membrane receptors and have a rigid structure, stabilized by disulfide bridges and calcium. Each A- domain can bind to a certain epitope of the target protein. The combination of domains binding to diferent epitopes of the same protein increases afinity to this protein, an efect known as avidity. [0340] Proteins derived from fibronectin II (FN3) domains can also be used to generate a suitable non- Ig based alternative scafold (also known as “monobody”). For example, the tenth fibronectin type II domain (FN10) of human fibronectin corresponds to a β-sandwich with seven β-strands and three connecting loops showing structural homologies to Ig domains without disulfide bridges. In some cases, the connecting loops of FN10, each about 15 to 21 amino acids in length, can be randomized and the domains displayed on both phage and yeast to select for a scafold with the desirable properties. Adnectins™ is an exemplary scafold generated using 10th FN3 domains randomized and displayed in this way. Another exemplary scafold comprising FN3 domains is a Centyrin™. Centryrins™ contain the consensus sequence of FN3 domains of human Tenascin C (TNC), which is found in the extracelular matrix of various tissues. Centyrin™ scafolds have loops that have structural homology to antibody variable domains (i.e., CDR1, CDR2 and CDR3), and are smal (about 10 kDa), simple, and highly stable single domain proteins that do not contain cysteine, disulfides, or glycosylated residues. Centyrin™ possess excelent biophysical properties such as stability to heat, pH, denaturant and organic solvents, reversible unfolding and monodispersity. Another recent exemplary FN3-based scafold that can be used in the present disclosure is fluctuation-regulated afinity proteins (FLAPs), as described in See et al., 2020. Biotechnology Journal 15(12):e2000078, which is incorporated herein by reference in its entirety. Fusion Proteins and Conjugates [0341] In one aspect, provided herein are fusion proteins and conjugates comprising at least one anti- TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) linked, directly or indirectly, to one or more additional domains or moieties. The at least one anti-TNFR2 antigen-binding protein can specificaly bind TNFR2. In some embodiments, the fusion protein or conjugate of the present disclosure comprises a single polypeptide. In other embodiments, the fusion protein or conjugate of the present disclosure comprises more than one polypeptide. In some embodiments, the fusion protein or conjugate of the present disclosure comprises two polypeptides. [0342] In some embodiments, the fusion protein or conjugate of the present disclosure comprises at least one anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) described herein. In some embodiments, the fusion protein or conjugate is multivalent. For example, the fusion 137 310886415v1 Attorney Docket No: 260525.000071 protein or conjugate of the present disclosure may be at least bivalent, but can also be e.g., trivalent, tetravalent, pentavalent, hexavalent, etc. The terms “bivalent”, “trivalent”, “tetravalent”, “pentavalent”, or “hexavalent” al fal under the term “multivalent” and indicate the presence of two, three, four, five or six binding units (e.g., VHHs), respectively. [0343] In certain embodiments, the fusion protein or conjugate is multispecific. For example, in some cases, the one or more additional domain or moieties may be one or more additional binding domain that binds to one or more further antigen or protein. The fusion protein or conjugate of the present disclosure may be, for example, bispecific, trispecific, tetraspecific, pentaspecific, etc. The terms “bispecific”, “trispecific”, “tetraspecific”, “pentaspecific”, etc., al fal under the term “multispecific” and refer to binding to two, three, four, five, etc., diferent target molecules, respectively. [0344] When two or more anti-TNFR2 antigen-binding proteins are included in a fusion protein or conjugate, the two or more anti-TNFR2 antigen-binding proteins may comprise the same sequence or may comprise diferent sequences. In such embodiments, the two or more anti-TNFR2 antigen-binding proteins may bind to the same epitope on TNFR2 or diferent epitopes on TNFR2. For example, a fusion protein or conjugate of the present disclosure may be biparatopic, e.g., if two VHHs bind two diferent epitopes on TNFR2. [0345] In various embodiments, multivalent anti-TNFR2 fusion constructs can comprise two or more anti-TNFR2 antigen-binding proteins each comprising an amino acid sequence selected from any of the CDR1, CDR2, and/or CDR3 amino acid sequences listed in Table 1-1, Table 5, Table 7, or Table 8, or any combination thereof, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity, or any combination thereof. In various related embodiments, multivalent anti-TNFR2 fusion constructs can comprise two or more anti-TNFR2 antigen-binding proteins each comprising a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within any of the exemplary anti- TNFR2 VHH antibodies listed in Table 1-1, Table 1-2, Table 5, Table 7, or Table 8. In some embodiments, the two or more anti-TNFR2 antigen-binding proteins can comprise the same set of three CDRs. In some embodiments, the two or more anti-TNFR2 antigen-binding proteins can comprise diferent sets of three CDRs. [0346] Exemplary designs of multivalent anti-TNFR2 fusion constructs comprising two or more anti- TNFR2 binding units (e.g., VHHs) are shown in Figure 30. [0347] In some embodiments, fusion proteins of the present disclosure bind to human TNFR2. In some embodiments, fusion proteins (e.g., fusion proteins such as fusion proteins conjugated to Fc regions) of 138 310886415v1 Attorney Docket No: 260525.000071 the present disclosure may bind to human TNFR2 with a K of l −6 D ess than about 1×10 M, for example, less than about 5×10−7 M, less than about 3×10−7 M, less than about 1×10−7 M, less than about 8×10−8 M, less than about 5×10−8 M, less than about 3×10−8 M, less than about 1×10−8 M, less than about 8×10−9 M, less than about 5×10−9 M, less than about 3×10−9 M, less than about 1×10−9 M, less than about 8×10−10 M, less than about 5×10−10 M, less than about 3×10−10 M, less than about 1×10−10 M, less than about 8×10−11 M, less than about 5×10−11 M, less than about 3×10−11 M, less than about 1×10−11 M, less than about 8×10−12 M, less than about 5×10−12 M, less than about 3×10−12 M, or less than about 1×10−12 M, or about 1×10−10 to 1×10−9 M, 1×10−10 to 5×10−9 M, about 1×10−10 to 1×10−8 M, about 1×10−10 to 5×10−8 M, about 1×10−9 to 1×10−8 M, about 1×10−9 to 5×10−8 M, about 1×10−9 to 1×10−7 M, or about 1×10−8 to 1×10−7 M. In certain embodiments, fusion proteins (e.g., fusion proteins such as fusion proteins conjugated to Fc regions) of the present disclosure may bind to human TNFR2 with a K -12 D of about 1x10 M to about 1×10−6 M. In certain embodiments, fusion proteins (e.g., fusion proteins such as fusion proteins conjugated to Fc regions) of the present disclosure may bind to human TNFR2 with a KD of about 1 ×10−8 M to about 2.7 ×10−6 M. In certain embodiments, fusion proteins (e.g., fusion proteins such as fusion proteins conjugated to Fc regions) of the present disclosure may bind to human TNFR2 with a K of ab −12 −7 D out 3 ×10 M to about 1 ×10 M. [0348] In some embodiments, fusion proteins of the present disclosure bind to cynomolgus monkey (“cyno”) TNFR2. In some embodiments, fusion proteins (e.g., fusion proteins such as fusion proteins conjugated to Fc regions) of the present disclosure may bind to cyno TNFR2 with a KD of less than about 1×10−6 M, for example, less than about 5×10−7 M, less than about 3×10−7 M, less than about 1×10−7 M, less than about 8×10−8 M, less than about 5×10−8 M, less than about 3×10−8 M, less than about 1×10−8 M, less than about 8×10−9 M, less than about 5×10−9 M, less than about 3×10−9 M, or less than about 1×10−9 M, less than about 8×10−10 M, less than about 5×10−10 M, less than about 3×10−10 M, less than about 1×10−10 M, less than about 8×10−11 M, less than about 5×10−11 M, less than about 3×10−11 M, less than about 1×10−11 M, less than about 8×10−12 M, less than about 5×10−12 M, less than about 3×10−12 M, or less than about 1×10−12 M, or about 1×10−10 to 1×10−9 M, 1×10−10 to 5×10−9 M, about 1×10−10 to 1×10−8 M, about 1×10−10 to 5×10−8 M, about 1×10−9 to 1×10−8 M, about 1×10−9 to 5×10−8 M, about 1×10−9 to 1×10−7 M, about 1×10−9 to 2×10−7 M, about 1×10−9 to 5×10−7 M, about 1×10−8 to 1×10−7 M, about 1×10−8 to 2×10−7 M, about 1×10−8 to 5×10−7 M, or about 1×10−8 to 1×10−6 M. In certain embodiments, fusion proteins (e.g., fusion proteins such as fusion proteins conjugated to Fc regions) of the present disclosure may bind to cyno TNFR2 with a K -12 −6 D of about 1x10 M to about 1×10 M. In certain embodiments, fusion 139 310886415v1 Attorney Docket No: 260525.000071 proteins (e.g., fusion proteins such as fusion proteins conjugated to Fc regions) of the present disclosure may bind to cyno TNFR2 with a K -8 −6 D of about 3x10 M to about 2.4 ×10 M. In certain embodiments, fusion proteins (e.g., fusion proteins such as fusion proteins conjugated to Fc regions) of the present disclosure may bind to cyno TNFR2 with a K o -12 −8 D f about 3x10 M to about 5 ×10 M. Fusion or Conjugation to Fc regions [0349] In some embodiments, a fusion protein or conjugate of the present disclosure comprises at least one anti-TNFR2 antigen-binding protein (e.g., antibody such as a single-domain antibody) provided herein operably linked to a dimerization domain such as an immunoglobulin Fc region. An immunoglobulin Fc region may be linked indirectly or directly to the at least one anti-TNFR2 antigen- binding protein (e.g., antibody such as a single-domain antibody). In some embodiments, a fusion protein or conjugate of the present disclosure comprises one, two, three, four, five, six or more anti- TNFR2 antigen-binding proteins provided herein operably linked to an Fc region. [0350] In some embodiments, the present disclosure provides a fusion protein or conjugate that comprises (1) a means for binding an epitope within human TNFR2 bound by any one of the exemplary anti-TNFR2 VHH antibodies listed in Table 1-1, Table 1-2, Table 5, Table 7, or Table 8; and (2) an Fc region. [0351] In some embodiments, the present disclosure provides a fusion protein or conjugate that comprises (1) a means for binding an epitope within human TNFR2 bound by an antibody selected from T-004, T-004.VTV, T-007hu1 with CDR2 G/A, CDR3 T/S, T-009Hu1_QGR, T-009Hu1_SGR, T- 009Hu1_QGR_N/C, T-009Hu1_NAR_N/C, T-009Hu1_SGR_N/C, T-007Hu1.S3.QGR, T-007Hu1.S3.EGR, T- 007Hu1.S3.SGR, T-007Hu1.S3.NSR, T-007Hu1.S3.NTR, T-007Hu1.S3.SAR, T-007Hu1.EQ.QGR, T- 007Hu1.EQ.EGR, T-007Hu1.EQ.SGR, T-007Hu1.EQ.S3.NSR, T-016hu1.A1, T-016hu1.G2, T-016hu1.A3, T- 016hu1.A4, T-016hu1.A5, T-016hu1.A6, T-016hu1.A7, T-016hu1.A9, T-016hu1.A10, T-016hu1.A11, T- 016Hu1.A5.A7, T-016Hu1.A5.A1, T-016Hu1.A5.A3, T-016Hu1.A5.A4, T-016Hu1.A5.A6, T-016Hu1.A7.A1, T-016Hu1.A7.A3, T-016Hu1.A7.A4, T-016Hu1.A7.A6, T-016Hu1.A1.A3, T-016Hu1.A1.A4, T-016Hu1.A1.A6, T-016Hu1.A3.A4, T-016Hu1.A3.A6, T-016Hu1.A4.A6, T-008Hu1.G1, T-008Hu1.G2, T-008Hu1.A4, T- 008Hu1.A5, T-008Hu1.A6, T-008Hu1.A7, T-008Hu1.G8, T-008Hu1.A9, T-008Hu1.A10, T-008Hu1.A11, T- 009Hu1_SGR.G1, T-009Hu1_SGR.G2, T-009Hu1_SGR.A3, T-009Hu1_SGR.A4, T-009Hu1_SGR.A5, T- 009Hu1_SGR.A6, T-009Hu1_SGR.A7, T-009Hu1_SGR.G8, T-009Hu1_SGR.A9, T-009Hu1_SGR.A10, and T- 009Hu1_SGR.A11; and (2) an Fc region. 140 310886415v1 Attorney Docket No: 260525.000071 [0352] A “Fc region” as used herein refers to a portion of a heavy chain constant region comprising CH2 and CH3. In some embodiments, an Fc region comprises a hinge, CH2, and CH3. In various embodiments, when an Fc region comprises a hinge, the hinge can mediate dimerization between two Fc-containing polypeptides. An Fc region included in a fusion protein or conjugate may be an Fc region from any species, or derived from any species, including, but not limited to, human, mouse, rat, monkey (e.g., cyno), camel, lama, shark, goat, rabbit, and/or bovine. In various embodiments, an Fc region included in a fusion protein or conjugate of the present disclosure is a human immunoglobulin Fc region, or is derived from a human immunoglobulin Fc region. In some embodiments, the immunoglobulin Fc region is of IgG, IgE, IgM, IgD, IgA or IgY isotype. In some embodiments, the immunoglobulin Fc region is an IgG isotype, such as IgG1, IgG2, IgG3, or IgG4 subclass. The immunoglobulin Fc region may comprise a variant or fragment of a native IgG Fc region. [0353] In some embodiments, an Fc region included in a fusion protein or conjugate described herein may be a murine (e.g., a mouse or a rat) immunoglobulin Fc region, or derived from a murine immunoglobulin Fc region. In some embodiments, an Fc region included in a fusion protein or conjugate described herein may be a cyno immunoglobulin Fc region, or derived from a cyno immunoglobulin Fc region. [0354] A native Fc region typicaly possesses an efector function, including but not limited to, Fc receptor binding; Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cel-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cel surface receptors (for example B-cel receptor); and B-cel activation, etc. Such efector functions generaly require the Fc region to be combined with a binding domain (for example, an antibody variable domain) and can be assessed using various assays. [0355] In some embodiments, a fusion protein or conjugate of the present disclosure can comprise a dimer of Fc regions. In some embodiments, an Fc region mediates dimerization of the TNFR2-binding units at physiological conditions, such as when expressed from a cel, such that a dimer is formed that doubles the number of TNFR2 binding units. For example, a fusion polypeptide comprising one VHH domain that binds TNFR2 and an Fc region is monovalent as a monomer, but the Fc region can mediate dimerization; as a result, the fusion protein is bivalent (i.e., having two anti-TNFR2 VHH domains per molecule). Similarly, in some embodiments, two anti-TNFR2 VHH domains (2x) are fused to an IgG Fc region and as a result of dimerization, the fusion protein is tetravalent (i.e., having four anti-TNFR2 VHH domains per molecule). In some embodiments, three anti-TNFR2 VHH domain (3×) are fused to an IgG 141 310886415v1 Attorney Docket No: 260525.000071 Fc region and as a result of dimerization, the fusion protein is hexavalent (i.e., having six anti-TNFR2 VHH domains per molecule). [0356] In some embodiments, a fusion protein or conjugate of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)n- Linker-Fc, wherein n can be any integral number (e.g., 1, 2, 3, 4, 5, etc). When n≥2, each anti-TNFR2 VHH may be optionaly operably linked to another anti-TNFR2 VHH via a linker. [0357] In some embodiments, a fusion protein or conjugate of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)n- Linker-Fc-(anti-TNFR2 VHH)m, wherein n and m can independently be any integral number (e.g., 1, 2, 3, 4, 5, etc). When n≥2 or m≥2, each anti-TNFR2 VHH may be optionaly operably linked to another anti- TNFR2 VHH via a linker. [0358] In some embodiments, a fusion protein or conjugate of the present disclosure is bivalent. In some embodiments, the bivalent fusion protein or conjugate of the disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker-Fc. [0359] In some embodiments, a fusion protein or conjugate of the present disclosure is tetravalent. In some embodiments, the tetravalent fusion protein or conjugate of the disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker- (anti-TNFR2 VHH)-Linker-Fc. In some embodiments, the tetravalent fusion protein or conjugate of the disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker-Fc-Linker-(anti-TNFR2 VHH). The multiple linkers used in the fusion protein are not necessarily the same. [0360] In some embodiments, a fusion protein or conjugate of the disclosure is hexavalent. In some embodiments, the hexavalent fusion protein or conjugate of the disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker-(anti-TNFR2 VHH)-Linker-(anti-TNFR2 VHH)-Linker-Fc. In some embodiments, the hexavalent fusion protein or conjugate of the disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker-(anti-TNFR2 VHH)-Linker-Fc-linker-(anti-TNFR2 VHH). In some embodiments, the hexavalent fusion protein or conjugate of the disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker-Fc- Linker-(anti-TNFR2 VHH)-Linker-(anti-TNFR2 VHH). The multiple linkers used in the fusion protein are not necessarily the same. 142 310886415v1 Attorney Docket No: 260525.000071 [0361] In some embodiments, the CH3 domain of the Fc region can be used as homodimerization domain, such that the resulting fusion protein may be formed from two identical polypeptides. In other cases, the CH3 dimer interface region of the Fc region can be mutated to enable heterodimerization. For example, a heterodimerization domain can be incorporated into the fusion protein such that the construct is a heterodimeric fusion protein. [0362] When a dimer of Fc regions is used in a fusion protein or conjugate of the present disclosure, the first and second Fc regions may be of the same IgG isotype such as, e.g., IgG1/IgG1, IgG2/IgG2, IgG4/IgG4. Alternatively, the first and second Fc regions may be of diferent IgG isotypes such as, e.g., IgG1/IgG2, IgG1/IgG4, IgG2/IgG4, etc. [0363] In some embodiments, the Fc region included in a fusion protein or conjugate of the present disclosure can be mutated or modified. In some embodiments, the mutations include one or more amino acid substitutions to reduce an efector function of the Fc region. Various examples of mutations to Fc regions to alter, such as reduce, efector function are known, including any as described below. In general, the numbering of the residues in an immunoglobulin heavy chain or portion thereof, such as an Fc region, is according to the EU index as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991). [0364] In some embodiments, the human IgG Fc region is modified to alter antibody-dependent celular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC). Non-limiting examples of amino acid modifications that can alter ADCC and/or CDC are described in Alegre et al, 1992 J Immunol, 148: 3461-3468; Idusogie et al., 2001 J Immunol, 166(4): 2571-5; Shields et al., 2001 JBC, 276(9): 6591-6604; Lazar et al., 2006 PNAS, 103(11): 4005-4010; Stavenhagen et al., 2007 Cancer Res, 67(18): 8882-8890; Natsume et al., 2008 Cancer Res, 68(10): 3863-72; Stavenhagen et al., 2008 Advan. Enzyme Regul., 48: 152-164; Moore et al., 2010 mAbs, 2(2): 181-189; and Kaneko and Niwa, 2011 Biodrugs, 25(1):1-11, each of which is incorporated herein by reference in its entirety. [0365] In some embodiments, an Fc region included in a fusion protein or conjugate of the present disclosure exhibits reduced efector functions (such as CDC and ADCC). Various in vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the fusion protein construct and/or cleaved components thereof lack FcγR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cels for mediating ADCC are NK cels which express FcγRII only, whereas monocytes express FcγRI, FcγRI and FcγRII. Non-limiting examples of in vitro assays to assess 143 310886415v1 Attorney Docket No: 260525.000071 ADCC activity of a molecule of interest are described in e.g., US 5,500,362; US 5,821,337; Helstrom. et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986); and Helstrom et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); Bruggemann. et al., J. Exp. Med.166:1351-1361 (1987). Alternatively, non- radioactive assay methods may be employed, such as ACTI™ non-radioactive cytotoxicity assay for flow cytometry or CytoTox96™ non-radioactive cytotoxicity assay. Useful efector cels for such assays include peripheral blood mononuclear cels (PBMC) and Natural Kiler (NK) cels. Alternatively, or additionaly, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). C1q binding assays may also be carried out to confirm that the fusion protein construct or cleaved components thereof is unable to bind C1q and hence lacks CDC activity (see, e.g., C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402). To assess complement activation, a CDC assay may be performed (see, e.g., Gazzano- Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, M. S. et al., Blood 101:1045-1052 (2003); and Cragg, M. S. and M. J. Glennie, Blood 103:2738-2743 (2004). FcRn binding and in vivo clearance/half-life determinations can also be performed using methods known in the art (see, e.g., Petkova, S. B. et al., Int'l. Immunol.18(12):1759-1769 (2006). [0366] Examples of mutations that enhance ADCC include modification at Ser239 and Ile332, for example Ser239Asp and Ile332Glu (S239D, 1332E). Examples of mutations that enhance CDC include modifications at Lys326 and Glu333. In some embodiments, the Fc region is modified at one or both of these positions, for example Lys326Ala and/or Glu333Ala (K326A and E333A) using the Kabat numbering system. [0367] In some embodiments, the Fc region of the fusion protein is altered at one or more of the folowing positions to reduce Fc receptor binding: Leu 234 (L234), Leu235 (L235), Asp265 (D265), Asp270 (D270), Ser298 (S298), Asn297 (N297), Asn325 (N325) orAla327 (A327) or Pro329 (P329). For example, Leu 234Ala (L234A), Leu235Ala (L235A), Leu235Glu (L235E), Asp265Asn (D265N), Asp265Ala (D265A), Asp270Asn (D270N), Ser298Asn (S298N), Asn297Ala (N297A), Pro329Ala (P329A) or Pro239Gly (P329G), Asn325Glu (N325E) orAla327Ser (A327S). In some embodiments, modifications within the Fc region reduce binding to Fc-receptor-gamma receptors (FcγRs) while have minimal impact on binding to the neonatal Fc receptor (FcRn). [0368] In some embodiments, the human IgG1 Fc region is modified at amino acid Asn297 (Kabat Numbering) to prevent glycosylation of the fusion protein, e.g., Asn297Ala (N297A) or Asn297Asp (N297D). In some embodiments, the Fc region of the fusion protein is modified at amino acid Leu235 144 310886415v1 Attorney Docket No: 260525.000071 (Kabat Numbering) to alter Fc receptor interactions, e.g., Leu235Glu (L235E) or Leu235Ala (L235A). In some embodiments, the Fc region of the fusion protein is modified at amino acid Leu234 (Kabat Numbering) to alter Fc receptor interactions, e.g., Leu234Ala (L234A). In some embodiments, the Fc region of the fusion protein is modified at amino acid Leu234 (Kabat Numbering) to alter Fc receptor interactions, e.g., Leu235Glu (L235E). In some embodiments, the Fc region of the fusion protein is altered at both amino acids 234 and 235, e.g., Leu234Ala and Leu235Ala (L234A/L235A) or Leu234Val and Leu235Ala (L234V/L235A). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 234, 235, and 297, e.g., Leu234Ala, Leu235Ala, Asn297Ala (L234A/L235A/N297A). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 234, 235, and 329, e.g., Leu234Ala, Leu235Ala, Pro239Ala (L234A/L235A/P329A). In some embodiments, the Fc region of the fusion protein is modified at amino acid Asp265 (Kabat Numbering) to alter Fc receptor interactions, e.g Asp265Ala (D265A). In some embodiments, the Fc region of the fusion protein is modified at amino acid Pro329 (Kabat Numbering) to alter Fc receptor interactions, e.g., Pro329Ala (P329A) or Pro329Gly (P329G). In some embodiments, the Fc region of the fusion protein is altered at both amino acids 265 and 329, e.g., Asp265Ala and Pro329Ala (D265A/P329A) or Asp265Ala and Pro329Gly (D265A/P329G). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 234, 235, and 265, e.g., Leu234Ala, Leu235Ala, Asp265Ala (L234A/L235A/D265A). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 234, 235, and 329, e.g., Leu234Ala, Leu235Ala, Pro329Gly (L234A/L235A/P329G). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 234, 235, 265 and 329, e.g., Leu234Ala, Leu235Ala, Asp265Ala, Pro329Gly (L234A/L235A/D265A/P329G). In some embodiments, the Fc region of the fusion protein is altered at Gly235 to reduce Fc receptor binding. For example, wherein Gly235 is deleted from the fusion protein. In some embodiments, the human IgG1 Fc region is modified at amino acid Gly236 to enhance the interaction with CD32A, e.g., Gly236Ala (G236A). In some embodiments, the human IgG1 Fc region lacks Lys447 (EU index of Kabat et al 1991 Sequences of Proteins of Immunological Interest). [0369] In some embodiments, the Fc region of the fusion protein is altered at amino acids at 234, 235, and 236, e.g., Leu234Gly, Leu235Ser, Gly236Arg (L234G/L235S/G236R). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 234, 235, and 236, e.g., Leu234Ser, Leu235Thr, Gly236Arg (L234S/L235T/G236R). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 234, 235, and 236, e.g., Leu234Ser, Leu235Val, Gly236Arg (L234S/L235V/G236R). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 234, 235, and 236, e.g., 145 310886415v1 Attorney Docket No: 260525.000071 Leu234Thr, Leu235Gln, Gly236Arg (L234T/L235Q/G236R). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 234, 235, and 236, e.g., Leu234Thr, Leu235Thr, Gly236Arg (L234T/L235T/G236R). In some embodiments, the Fc region of the fusion protein fusion protein is altered at amino acids at 234, 235, and 329, e.g., Leu234Thr, Leu235Thr, Pro329Gly (L234A/L235A/P329G). In some embodiments, the Fc region of the fusion protein is altered at amino acids at 252, 254, and 256, e.g., Met252Tyr, Ser254Thr, Thr256Glu (M252Y/S254T/T256E). [0370] In some embodiments, the Fc region of the fusion protein is lacking an amino acid at one or more of the folowing positions to reduce Fc receptor binding: Glu233 (E233), Leu234 (L234), or Leu235 (L235). In some embodiments, the Fc region of the fusion protein is lacking an amino acid at one or more of the folowing positions Glu233 (E233), Leu234 (L234), or Leu235 (L235) and is modified at one or more of the Asp265 (D265), Asn297 (N297), or Pro329 (P329) to reduce Fc receptor binding. For example, an Fc region included in a TNFR2 binding polypeptide is derived from a human Fc domain, and comprises a three amino acid deletion in the lower hinge corresponding to IgG1 E233, L234, and L235. In some embodiments, such Fc polypeptides do not engage FcγRs and thus are referred to as “efector silent” or “efector nul.” For example, Fc deletion of these three amino acids reduces the complement protein C1q binding. In some embodiments, a polypeptide with an Fc region with Fc deletion of these three amino acids retains binding to FcRn and therefore has extended half-life and transcytosis associated with FcRn mediated recycling. [0371] In one embodiment, the immunoglobulin Fc region of the fusion protein is a variant of human IgG1 Fc region, having an amino acid sequence: IgG1 L234A, L235A (also known as “LALA” variant) (mutations bolded in the sequence below) DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 4045) [0372] In one embodiment, the immunoglobulin Fc region of the fusion protein is a variant of human IgG1 Fc region, having an amino acid sequence: IgG1 L234A, L235A, and P329A (also known as “LALAPA” variant) (mutations bolded in the sequence below) DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 4046) 146 310886415v1 Attorney Docket No: 260525.000071 [0373] In one embodiment, the variant of human IgG1 Fc region having the amino acid sequence of SEQ ID NO: 4045 or 4046 further comprises a lysine residue at the C-terminus. [0374] In one embodiment, the immunoglobulin Fc region of the fusion protein is a variant of human IgG1 Fc region, having an amino acid sequence: IgG1 D265A, N297A and P329A (also known as “DANAPA” variant) (mutations bolded in the sequence below) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYAST YRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 4047) [0375] In one embodiment, the immunoglobulin Fc region of the fusion protein is a variant of human IgG1 Fc region, having an amino acid sequence: IgG1 L234A, L235A, and G237A (also known as “LALAGA” variant) (mutations bolded in the sequence below) DKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 4048) [0376] In one embodiment, the immunoglobulin Fc region of the multispecific antigen-binding protein is a variant of human IgG1 Fc region, having an amino acid sequence: IgG1 L234G/L235S/G236R (mutations bolded in the sequence below) DKTHTCPPCPAPEGSRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 4054) [0377] In one embodiment, the immunoglobulin Fc region of the multispecific antigen-binding protein is a variant of human IgG1 Fc region, having an amino acid sequence: IgG1 L234S/L235T/G236R (mutations bolded in the sequence below) DKTHTCPPCPAPESTRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 4055) 147 310886415v1 Attorney Docket No: 260525.000071 [0378] In one embodiment, the immunoglobulin Fc region of the multispecific antigen-binding protein is a variant of human IgG1 Fc region, having an amino acid sequence: IgG1 L234S/L235V/G236R (mutations bolded in the sequence below) DKTHTCPPCPAPESVRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 4056) [0379] In one embodiment, the immunoglobulin Fc region of the multispecific antigen-binding protein is a variant of human IgG1 Fc region, having an amino acid sequence: IgG1 L234T/L235Q/G236R (mutations bolded in the sequence below) DKTHTCPPCPAPETQRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 4057) [0380] In one embodiment, the immunoglobulin Fc region of the multispecific antigen-binding protein is a variant of human IgG1 Fc region, having an amino acid sequence: IgG1 L234T/L235T/G236R (mutations bolded in the sequence below) DKTHTCPPCPAPETTRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 4058) [0381] In one embodiment, the immunoglobulin Fc region of the multispecific antigen-binding protein is a variant of human IgG1 Fc region, having an amino acid sequence: IgG1 L234A/L235A/P329G (mutations bolded in the sequence below) DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 4059) [0382] In one embodiment, the immunoglobulin Fc region of the multispecific antigen-binding protein is a variant of human IgG1 Fc region, having an amino acid sequence: IgG1 M252Y/S254T/T256E (mutations bolded in the sequence below) 148 310886415v1 Attorney Docket No: 260525.000071 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 4060) [0383] In some embodiments, the human IgG Fc region is modified to enhance FcRn binding. Examples of Fc mutations that enhance binding to FcRn are Met252Tyr, Ser254Thr, Thr256Glu (M252Y, S254T, T256E, respectively) (Kabat numbering, Dal'Acqua et al 2006, J. Biol Chem Vol.281(33) 23514-23524), Met428Leu and Asn434Ser (M428L, N434S) (Zalevsky et al 2010 Nature Biotech, Vol.28(2) 157-159), Met252Ile, Thr256Asp, Met428Leu (M252I, T256D, M428L, respectively) (EU index of Kabat et al 1991 Sequences of Proteins of Immunological Interest), Asn434Ala (N434A), Asn434Trp (N434W), Thr256Asp, Thr307Gln (T256D/T307Q), Thr256Asp, Thr307Trp (T256D/T307W), Met252Tyr, Thr256Asp (M252Y/T256D), Thr307Gln, Gln311Val, Ala378Val (T307Q/Q311V/A378V), Thr256Asp, His286Asp, Thr307Arg, Gln311Val, Ala378Val (T256D/H286D/T307R/Q311V/A378V), or Leu309Asp, Gln311His, Asn434Ser (L309D/Q311H/N434S) (see, Ko et al., BioDrugs (2021) 35:147–157). [0384] In some embodiments, the Fc region lacks or has reduced fucose attached to the N-linked glycan-chain at N297. There are numerous ways to prevent fucosylation, including but not limited to production in a FUT8 deficient cel line; addition inhibitors to the mammalian cel culture media, for example Castanospermine; and metabolic engineering of the production cel line. [0385] In some embodiments, the Fc domain included in a fusion protein or conjugate of the present disclosure is derived from a human Fc domain and comprises mutations M252Y and M428V. In some embodiments, the mutated or modified Fc polypeptide includes the folowing mutations: M252Y and M428L using the Kabat numbering system. In some embodiments, such mutations enhance binding to FcRn at the acidic pH of the endosome (near 6.5), while losing detectable binding at neutral pH (about 7.2), alowing for enhanced FcRn mediated recycling and extended half-life. [0386] In some embodiments, the Fc domain included in a fusion protein or conjugate is derived from a human Fc domain and comprises mutations to induce heterodimerization. In some embodiments, such mutations include those referred to as “knob” and “hole” mutations. For example, having an amino acid modification within the CH3 domain at Thr366, which when replaced with a bulkier amino acid, e.g., Try (T366W), is able to preferentialy pair with a second CH3 domain having amino acid modifications to less bulky amino acids at positions Thr366, Leu368, and Tyr407, e.g., Ser, Ala, and Val, respectively (T366S/L368A/Y407V). In some embodiments, the “knob” Fc domain comprises the mutation T366W. In 149 310886415v1 Attorney Docket No: 260525.000071 some embodiments, the “hole” Fc domain comprises mutations T366S, L368A, and Y407V. Heterodimerization via CH3 modifications can be further stabilized by the introduction of a disulfide bond, for example by changing Ser354 to Cys (S354C) and Y349 to Cys (Y349C) on opposite CH3 domains (Reviewed in Carter, 2001 Journal of Immunological Methods, 248: 7-15). In some embodiments, Fc domains used for heterodimerization comprise additional mutations, such as the mutation S354C on a first member of a heterodimeric Fc pair that forms an asymmetric disulfide with a corresponding mutation Y349C on the second member of a heterodimeric Fc pair. In some embodiments, one member of a heterodimeric Fc pair comprises the modification H435R or H435K to prevent protein A binding while maintaining FcRn binding. In some embodiments, one member of a heterodimeric Fc pair comprises the modification H435R or H435K, while the second member of the heterodimeric Fc pair is not modified at H435. In various embodiments, the hole Fc domain comprises the modification H435R or H435K (referred to as “hole-R” in some instances when the modification is H435R), while the knob Fc domain does not. In some instances, the hole-R mutation improves purification of the heterodimer over homodimeric hole Fc domains that may be present. [0387] In some embodiments, the human IgG Fc region is modified to prevent dimerization. In these embodiments, the fusion proteins of the present disclosure are monomeric. For example, modification at residue Thr366 to a charged residue, e.g. Thr366Lys, Thr366Arg, Thr366Asp, or Thr366Glu (T366K, T366R, T366D, or T366E, respectively), prevents CH3-CH3 dimerization. [0388] In some embodiments, the immunoglobulin Fc region of the fusion protein is of human IgG3 isotype, or a variant thereof. In one embodiment, the IgG3 Fc region is modified at amino acid Asn297 (Kabat Numbering) to prevent to glycosylation of the antibody, e.g., Asn297Ala (N297A) or Asn297Asp (N297D). In some embodiments, the human IgG3 Fc region is modified at amino acid 435 to extend the half-life, e.g., Arg435His (R435H). In some embodiments, the human IgG3 Fc region lacks Lys447 (EU index of Kabat et al 1991). [0389] In some embodiments, the immunoglobulin Fc region of the fusion protein is of human IgG4 isotype, or a variant thereof. [0390] As a non-limiting example, an immunoglobulin Fc region of human IgG4 isotype may have an amino acid sequence: ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 5005) 150 310886415v1 Attorney Docket No: 260525.000071 [0391] In some embodiments, the immunoglobulin Fc region of human IgG4 isotype may comprise the amino acid sequence set forth in SEQ ID NO: 5505, or a similar sequence thereof having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0392] In some embodiments, the human IgG4 Fc region comprises one or more mutations selected from, e.g., Ser228Pro (S228P), Leu235Glu (L235E), Leu235Ala (L235A), Phe234Ala (F234A), and/or Pro329Gly (P329G) according to EU numbering. [0393] In one embodiment, the human IgG4 Fc region is modified at amino acid 235 to alter Fc receptor interactions, e.g., Leu235Glu (L235E). In some embodiments, the human IgG4 Fc region is modified at amino acid Asn297 (Kabat Numbering) to prevent to glycosylation of the antibody, e.g., Asn297Ala (N297A) or Asn297Asp (N297D). In some embodiments, the human IgG4 Fc region is lacks Lys447 (EU index of Kabat et al 1991). [0394] In some embodiments, the IgG4 Fc region of the fusion protein is altered at amino acids at 228 and 235, e.g., Ser228Pro, Leu235Glu or Leu235Ala (S228P/L235E or S228P/L235A). In some embodiments, the IgG4 Fc region of the fusion protein is altered at amino acids at 228, 234 and 235, e.g., Ser228Pro, Phe234Ala, Leu235Glu or Leu235Ala (S228P/F234A/L235E or S228P/F234A/L235A). In some embodiments, the IgG4 Fc region of the fusion protein is altered at amino acids at 228, 235, and 329, e.g., Ser228Pro, Leu235Glu and P329G (S228P/L235E/P329G). [0395] In one embodiment, the immunoglobulin Fc region of the fusion protein is a variant of human IgG4 Fc region, having an amino acid sequence: IgG4 S228P, L235E (mutations bolded in the sequence below) ESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4049) [0396] In one embodiment, the immunoglobulin Fc region of the fusion protein is a variant of human IgG4 Fc region, having an amino acid sequence: IgG4 S228P, L235A (mutations bolded in the sequence below) ESKYGPPCPPCPAPEFAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4050) 151 310886415v1 Attorney Docket No: 260525.000071 [0397] In one embodiment, the immunoglobulin Fc region of the fusion protein is a variant of human IgG4 Fc region, having an amino acid sequence: IgG4 S228P, F234A, L235E (mutations bolded in the sequence below) ESKYGPPCPPCPAPEAEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4051) [0398] In one embodiment, the immunoglobulin Fc region of the fusion protein is a variant of human IgG4 Fc region, having an amino acid sequence: IgG4 S228P, F234A, L235A (mutations bolded in the sequence below) ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4052) [0399] In one embodiment, the immunoglobulin Fc region of the fusion protein is a variant of human IgG4 Fc region, having an amino acid sequence: IgG4 P329G, S228P, L235E (mutations bolded in the sequence below) ESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLGSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4053) [0400] Additional IgG4 heavy chain modifications suitable for use in the fusion proteins or conjugates of the present disclosure include those described in Tables 1 and 2 of Dumet et al., mAbs, 11:8, 1341-1350, which is incorporated herein by reference in its entirety. [0401] In some embodiments, the fusion protein or conjugate contains an immunoglobulin hinge region. In some embodiments, the hinge region serves as a linker to connect one or more TNFR2 binding units (e.g., VHHs) to the Fc region. In other embodiments, the fusion protein can comprise a linker in addition to the hinge region to connect the one or more TNFR2 binding units (e.g., VHHs) to the Fc region. The hinge region can be selected from any of the human IgG subclasses. For example, the fusion protein may contain a modified IgG1 hinge having the sequence of EPKSSDKTHTCPPC (SEQ ID NO: 3923), wherein the Cys220 that typicaly forms a disulfide bond with the C-terminal cysteine of the light chain is mutated to serine, e.g., Cys220Ser (C220S). In other embodiments, the fusion protein contains a truncated hinge having a sequence DKTHTCPPC (SEQ ID NO: 3924). In other embodiments, the fusion protein contains a truncated hinge having a sequence DKTHTCPPCP (SEQ ID NO: 5008). 152 310886415v1 Attorney Docket No: 260525.000071 [0402] In some embodiments, the fusion protein or conjugate has a modified hinge from IgG4, which is modified to prevent or reduce strand exchange, e.g., Ser228Pro (S228P), having the sequence ESKYGPPCPPC (SEQ ID NO: 3925). [0403] In alternative embodiments, a fusion protein or conjugate of the present disclosure may comprise sequences other than an Fc region to achieve multimerization (e.g., dimerization). For example, an amino acid sequence containing at least one cysteine residue may be included to facilitate dimerization of two polypeptides by formation of a disulfide bond between the two polypeptides. In some embodiments, such multimerizing domain may comprise one or more cysteine residues, 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. [0404] Fc mutations suitable for use in the fusion proteins disclosed herein are also discussed in, e.g., Wilkinson et al., Fc-engineered antibodies with immune efector functions completely abolished. PLoS One.2021; WO2021234402A2; US 8,969,526; EP3692065B1; and US 7,083,784, each of which is incorporated herein by reference. Fusion or Conjugation to Half-Life Extension Moieties [0405] In some embodiments, a fusion protein or conjugate of the present disclosure may comprise one or more other moieties which provide the fusion protein or conjugate with increased (in vivo) half- life. In vivo half-life extension means, that the fusion protein or conjugate has an increased half-life in a mammal, such as a human subject, after administration. [0406] Non-limiting examples of half-life extension moieties suitable for use in the present disclosure include polyethylene glycol (PEG) molecules, serum proteins or fragments thereof, binding units that can bind to serum proteins, an Fc portion, and smal proteins or peptides that can bind to serum proteins. [0407] In some embodiments, a fusion protein or conjugate of the present disclosure may comprise a binding moiety that can bind to serum albumin, such as human serum albumin, or a serum immunoglobulin, such as IgG. In one embodiment, a fusion protein or conjugate of the present disclosure may comprise a binding moiety that can bind to human serum albumin. In one embodiment, the binding moiety is a single-domain antibody (e.g., VHH). [0408] For example and without limitation, albumin binders that are described in, e.g., WO 04/041865, WO 06/122787, WO2012/175400, WO 2012/175741, WO2015/173325, WO2017/080850, WO2017/085172, WO2018/104444, WO2018/134235, WO2018/134234, each of which is incorporated 153 310886415v1 Attorney Docket No: 260525.000071 herein by reference is its entirety, can be used in the fusion protein or conjugate of the present disclosure. Fusion or Conjugation to Cytokines [0409] In some embodiments, a fusion protein or conjugate of the present disclosure may comprise one or more cytokine molecules. Non-limiting exemplary cytokine molecules that may be conjugated with include interleukin-2 (IL-2), transforming growth factor beta (TGF-β), thymic stromal lymphopoietin (TSLP), or a variant or combination thereof. [0410] The cytokine IL-2 plays a major role in the activation and function of Tregs. Incorporating IL-2 into the anti-TNFR2 fusion protein or conjugate of the present disclosure may enhance the ability of the anti-TNFR2 antigen-binding protein to promote Tregs expansion and stabilization. [0411] In some embodiments, a fusion protein or conjugate of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)n- Linker-Fc-(IL-2)m, where n and m is independently any integral number (e.g., 1, 2, 3, 4, 5, etc). When n≥2, each anti-TNFR2 VHH may be optionaly operably linked to another anti-TNFR2 VHH via a linker. When m≥2, each IL-2 may be optionaly operably linked to another IL-2 via a linker. [0412] In one embodiment, a fusion protein or conjugate of the present disclosure comprises two polypeptide chains, each polypeptide chain having the folowing structure: (anti-TNFR2 VHH)-Linker-Fc- (IL-2). [0413] IL-2 fusion proteins may be prepared as described in e.g., US 10,174,091, WO2014/023752, WO2019/246404, each of which is incorporated by reference in its entirety. [0414] In one embodiment, the IL-2 molecule used in the fusion proteins or conjugates of the present disclosure is a wild-type IL-2 having the amino acid sequence: APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR PRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSISTLT (SEQ ID NO: 3926) [0415] In some embodiments, the IL-2 molecule used in the fusion proteins or conjugates of the present disclosure is a variant of IL-2 having an amino acid sequence that is at least 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 3926. [0416] In one embodiment, the IL-2 molecule used in the fusion proteins or conjugates of the present disclosure is a variant of IL-2 with a N88D mutation (bolded in the sequence below), having the amino acid sequence: 154 310886415v1 Attorney Docket No: 260525.000071 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR PRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSISTLT (SEQ ID NO: 3927) [0417] Other suitable IL-2 variants that can be used in the fusion proteins or conjugates of the present disclosure include those described in US 10,174,091, US 10,174,092, US 11,091,526, US 11,091,527, WO2016/164937, US 9,580,486, US 7,105,653, US 9,616,105, US 9,428,567, US2017/0051029, US2014/0286898A1, WO2014/153111, WO2010/085495, WO2016/014428, WO2016/025385, and US2006/0269515, each of which are incorporated by reference in its entirety. Fusion or Conjugation to Other Moieties [0418] Anti-TNFR2 antigen-binding proteins (e.g., antibodies such as single-domain antibodies) provided herein may be operably linked, directly or indirectly, to a second moiety, such as but not limited to, a detectable label, a drug, a toxin, a radionuclide, an enzyme, an immunomodulatory agent, a cytokine, a cytotoxic agent, a smal molecule drug, a chemotherapeutic agent, a therapeutic agent, a diagnostic agent, or a combination thereof. [0419] In some embodiments, a conjugate of the present disclosure comprises a label, which can generate a detectable signal. Such conjugates can be used for research or diagnostic purposes, such as for the in vivo detection of cancer. Preferably, the label is capable of producing, either directly or indirectly, a detectable signal. For example, the label may be radio-opaque or a radioisotope (such as 3H, 14C, 32P, 35S, 123I, 125I, 131I); a fluorescent (fluorophore) or chemiluminescent (chromophore) compound (such as fluorescein isothiocyanate, rhodamine or luciferin); an enzyme (such as β- galactosidase, alkaline phosphatase, or horseradish peroxidase); an imaging agent; or a metal ion. In some embodiments, the label is a radioactive atom for scintigraphic studies, for example 99Tc or 123I, or a spin label for nuclear magnetic resonance (NMR) imaging, such as zirconium-89, iodine-123, iodine- 131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron. Zirconium-89 may also be complexed to various metal chelating agents and conjugated to antibodies, e.g., for PET imaging (WO 2011/056983). [0420] Anti-TNFR2 antigen-binding proteins (e.g., antibodies such as single-domain antibodies) of the present disclosure may be conjugated to another moiety, such as an epitope tag, e.g., for the purpose of purification or detection. Examples of such molecules that are useful in protein purification include those that present structural epitopes capable of being recognized by a second molecule. This is commonly employed in protein purification by afinity chromatography, in which a molecule is immobilized on a solid support and exposed to a heterogeneous mixture containing a target protein 155 310886415v1 Attorney Docket No: 260525.000071 conjugated to a molecule capable of binding the immobilized compound. Non-limiting examples of epitope tag molecules that can be conjugated to anti-TNFR2 antigen-binding proteins (e.g., antibodies such as single-domain antibodies) of the present disclosure, e.g., for the purposes of molecular recognition include a poly-histidine tag (His-tag), a myc-tag, human influenza hemagglutinin (HA) tag, a FLAG-tag, maltose-binding protein, glutathione-S-transferase, biotin, and streptavidin. Conjugates containing the epitopes presented by these molecules are capable of being recognized by complementary molecules such as maltose, glutathione, a nickel-containing complex, an anti-FLAG antibody, an anti-myc antibody, an anti-HA antibody, streptavidin, or biotin, respectively. For example, one can purify an anti-TNFR2 antigen-binding protein of the present disclosure that has been conjugated to an epitope tag from a complex mixture of other proteins and biomolecules (e.g., DNA, RNA, carbohydrates, phospholipids, etc) by treating the mixture with a solid phase resin containing a complementary molecule that can selectively recognize and bind the epitope tag of the TNFR2 antibody or fragment thereof. Examples of solid phase resins include agarose beads, which are compatible with purifications in aqueous solution. [0421] In some embodiments, a conjugate of the present disclosure may comprise one or more anti- TNFR2 VHH domains described herein conjugated to a therapeutic agent, which can be cytotoxic, cytostatic, or otherwise provides some therapeutic benefit. In some embodiments, the cytotoxic agent is a drug, a chemotherapeutic agent, a growth inhibitory agent, a toxin (e.g., an enzymaticaly active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (e.g., a radioconjugate). Such conjugates may be applicable to, e.g., the treatment or prevention of a disease associated with autoreactive cytotoxic T-cel activity. In some embodiments, antibody drug conjugates described herein may alow targeted delivery of a drug moiety to a target tissue (e.g., tumors). [0422] In some embodiments, a conjugate of the present disclosure comprises a toxin. In some embodiments, the toxin includes, for example, bacterial toxins such as diphtheria toxin, plant toxins such as ricin, smal molecule toxins such as geldanamycin (Mandler et al., J. Nat. Cancer Inst. 92(19):1573-1581 (2000); Mandler et al., Bioorganic & Med. Chem. Letters 10:1025-1028 (2000); Mandler et al., Bioconjugate Chem.13:786-791 (2002), maytansinoids (EP 1391213; Liu et al., Proc. Natl. Acad. Sci. USA 93:8618-8623 (1996), and calicheamicin (Lode et al., Cancer Res.58:2928 (1998); Hinman et al., Cancer Res.53:3336-3342 (1993). The toxins may exert their cytotoxic and cytostatic efects by mechanisms including tubulin binding, DNA binding, or topoisomerase inhibition. Examples of 156 310886415v1 Attorney Docket No: 260525.000071 other therapeutic agents that can be conjugated to an anti-TNFR2 antigen-binding protein of the present disclosure are described herein (see “Treatment Methods and Other Uses” section). [0423] In some embodiments, anti-TNFR2 antigen-binding proteins (e.g., antibodies such as single- domain antibodies) of the present disclosure may be fused or conjugated to one or more moieties that facilitate delivery to the central nervous system (CNS)/brain. The moiety that can facilitate delivery of an anti-TNFR2 antigen-binding protein to the central nervous system (CNS)/brain can be for example, a peptide, a polypeptide, smal molecule, a lipid, or a synthetic polymer. Various approaches to deliver single-domain antibodies into the brain are described in Pothin et al., Pharmaceutics 2020, 12(10), 937, which is incorporated herein by reference in its entirety. [0424] As a non-limiting example, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) of the present disclosure may be fused or conjugated to a moiety (e.g., an antibody) that binds to the transferrin receptor (TfR) or insulin receptor. The transferrin receptor (TfR) is highly expressed by brain capilary endothelial cels (BCECs) forming the blood-brain barrier (BBB) and has been utilized as a target for brain drug delivery. Monoclonal antibodies binding to the TfR, such as clone Ri7, have been shown to internalize into BCECs in vivo. As another example, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) of the present disclosure may be conjugated to hydrophobic fatty acid moieties, such as C18 faty acid (stearic acid), C16 faty acid (palmitic acid) or C8 fatty acid (octanoic acid) moieties; or amphiphilic block copolymer moieties, such as poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (pluronics or poloxamers) or poly(2-oxasolines). Various faty acid moieties and block copolymer moieties that can be utilized for brain delivery of proteins are described in, e.g., Yi and Kabanov, J Drug Target.2013; 21(10): 940–955, which is incorporated herein by reference in its entirety. [0425] Example methods for ataching a moiety, such as a label, to a binding protein include those described in Hunter, et al., Nature 144:945 (1962); David, et al., Biochemistry 13:1014 (1974); Pain, et al., J. Immunol. Meth.40:219 (1981); Nygren, J. Histochem. and Cytochem.30:407 (1982); Wensel and Meares, Elsevier, N.Y. (1983); and Colcher et al., Meth. Enzymol., 121 :802-16 (1986). Additional suitable methods for preparing the conjugates of the present disclosure include those described in, e.g., WO 2009/067800, WO 2011/133886, and US2014322129, incorporated by reference herein in their entirety. [0426] In some embodiments, the attachment between an anti-TNFR2 antigen-binding protein and a second moiety can be covalent or non-covalent, e.g., via a biotin-streptavidin non-covalent interaction. In some embodiments, a second moiety can be atached to an anti-TNFR2 antigen-binding protein using 157 310886415v1 Attorney Docket No: 260525.000071 any of various molecular biological or chemical conjugation and linkage methods known in the art and described below. In some embodiments, linkers such as peptide linkers, cleavable linkers, non-cleavable linkers, or linkers that aid in the conjugation reaction, can be used to link, or conjugate a second moiety to an anti-TNFR2 antigen-binding protein described herein. [0427] In some embodiments, an anti-TNFR2 antigen-binding protein (e.g., antibody such as single- domain antibody) is conjugated to one or more second moieties, e.g., about 1 to about 20 moieties per molecule, optionaly via a linker. In some embodiments, the one or more second moieties can be the same or diferent. The linker may be composed of one or more linker components. For covalent attachment of an antibody and the second moiety, the linker typicaly has two reactive functional groups, i.e., bivalency in a reactive sense. Bivalent linker reagents which are useful to attach two or more functional or biologicaly active moieties, such as peptides, nucleic acids, drugs, toxins, antibodies, haptens, and reporter groups have been described in, e.g., Hermanson, G. T. (1996) Bioconjugate Techniques; Academic Press: New York, p 234-242. [0428] In some embodiments, a linker used in a conjugate of the present disclosure may include 6- maleimidocaproyl (“MC”), maleimidopropanoyl (“MP”), valine-citruline (“val-cit”), a alanine- phenylalanine (“ala-phe”), p-aminobenzyloxycarbonyl (“PAB”), N-Succinimidyl 4-(2- pyridylthio)pentanoate (“SPP”), N-Succinimidyl 4-(N-maleimidomethyl)cyclohexane-I carboxylate (“SMCC”), or N-Succinimidyl(4-iodo-acetyl)aminobenzoate (“STAB”), or a combination thereof. [0429] In some embodiments, a linker used in a conjugate of the present disclosure may comprise amino acid residues. Exemplary amino acid linker components include a dipeptide, a tripeptide, a tetrapeptide or a pentapeptide. Exemplary dipeptides include valine-citruline (vc or val-cit), alanine- phenylalanine (af or ala-phe). Exemplary tripeptides include glycine-valine-citruline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly). Amino acid residues used in an amino acid linker component may include naturaly occurring amino acids, as wel as minor amino acids and non-naturaly occurring amino acid analogs, such as citruline. Amino acid linker components can be designed and optimized in their selectivity for enzymatic cleavage by particular enzymes, for example, a tumor-associated protease, cathepsin B, C and D, or a plasmin protease. [0430] Conjugates of an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody) and second moiety (e.g., cytotoxic agent) can be made using a variety of bifunctional protein- coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as 158 310886415v1 Attorney Docket No: 260525.000071 disuccinimidyl substrate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p- azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)- ethylenediamine), disocyanates (such as toluene 2,6-disocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). [0431] Conjugates of the present disclosure can be prepared by a variety of methods. For example, the conjugation method may include: (1) reaction of a nucleophilic group of a VHH domain with a bivalent linker reagent, to form VHH-Linker, via a covalent bond, folowed by reaction with a drug moiety; or (2) reaction of a nucleophilic group of a drug moiety with a bivalent linker reagent, to form drug-linker, via a covalent bond, folowed by reaction with the nucleophilic group of a VHH domain. [0432] Nucleophilic groups on proteins including antibodies (e.g., VHH domains), include, but are not limited to: (i) N-terminal amine groups, (i) side chain amine groups (e.g., lysine), (ii) side chain thiol groups (e.g., cysteine), and (iv) sugar hydroxyl or amino groups where the antibody is glycosylated. Amine, thiol, and hydroxyl groups are nucleophilic and capable of reacting to form covalent bonds with electrophilic groups on linker moieties and linker reagents including: (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides; (i) alkyl and benzyl halides such as haloacetamides; (ii) aldehydes, ketones, carboxyl, and maleimide groups. Additional nucleophilic groups can be introduced into proteins (e.g., antibodies such as VHH domains) through the reaction of lysines with 2- iminothiolane (Traut's reagent) resulting in conversion of an amine into a thiol. Reactive thiol groups may be introduced into a protein (e.g., antibody such as a VHH domain) by introducing one, two, three, four, or more cysteine residues. [0433] Conjugates, such as antibody drug conjugates, may also be produced by modification of an antibody, such as a VHH domain, to introduce electrophilic moieties, which can react with nucleophilic substituents on the linker reagent or drug. The sugars of glycosylated antibodies may be oxidized, e.g., with periodate oxidizing reagents, to form aldehyde or ketone groups which may lead with the amine group of linker reagents or drug moieties. The resulting imine Schif base groups may form a stable linkage, or may be reduced, e.g., by borohydride reagents to form stable amine linkages. In one embodiment, reaction of the carbohydrate portion of a glycosylated antibody with either galactose oxidase or sodium meta-periodate may yield carbonyl (aldehyde and ketone) groups in the protein that can react with appropriate groups on the drug (Hermanson, Bioconjugate Techniques). In another embodiment, proteins containing N-terminal serine or threonine residues can react with sodium meta- 159 310886415v1 Attorney Docket No: 260525.000071 periodate, resulting in production of an aldehyde in place of the first amino acid. Such aldehyde can be reacted with a drug moiety or linker nucleophile. [0434] Likewise, nucleophilic groups on a drug moiety include, but are not limited to: amine, thiol, hydroxyl, hydrazide, oxime, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide groups capable of reacting to form covalent bonds with electrophilic groups on linker moieties and linker reagents including: (i) active esters such as NHS esters, HOBi esters, haloformates, and acid halides; (i) alkyl and benzyl halides such as haloacetamides; (ii) aldehydes, ketones, carboxyl, and maleimide groups. [0435] Alternatively, a fusion protein containing a VHH domain and cytotoxic agent may be made, e.g., by recombinant DNA techniques or peptide synthesis. A DNA sequence may be engineered to comprise respective regions encoding the two portions of the fusion protein either adjacent to one another or separated by a region encoding a linker peptide which does not impair the desired properties of the fusion protein. The DNA sequence can be then transfected into a host cel that expresses the fusion protein. The fusion protein can be recovered from the cel culture and purified using techniques known in the art. Linkers [0436] In some embodiments, the one or more polypeptides of the fusion proteins of the present disclosure are operably linked via peptide linkers. 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. [0437] In some embodiments, a peptide linker, e.g., a peptide linker separating two VHH domains or an VHH 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 optionaly is up to 30 amino acids, up to 40 amino acids, up to 50 amino acids or up to 60 amino acids in length. [0438] In some embodiments, 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 160 310886415v1 Attorney Docket No: 260525.000071 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. [0439] In some embodiments, charged (e.g., charged hydrophilic linkers) and/or flexible linkers are used. Examples of flexible linkers that can be used in the fusion proteins of the disclosure include those disclosed by Chen et ai, 2013, Adv Drug Deliv Rev.65(10): 1357-1369 and Klein et a/., 2014, Protein Engineering, Design & Selection 27(10): 325-330. Particularly useful flexible linkers are or comprise repeats of glycines and serines (termed “GS-linker” herein), e.g., a monomer or multimer of GnS (SEQ ID NO: 4013) or SGn (SEQ ID NO: 4014), where n is an integer from 1 to 10, e.g., 12, 3, 4, 5, 6, or 7, 8, 9 or 10. In one embodiment, the linker is or comprises a monomer or multimer of repeat of G4S (SEQ ID NO: 3969), e.g., (GGGGS)n (SEQ ID NO: 4015). In one embodiment, the linker is or comprises a monomer or multimer of repeat of G3S (SEQ ID NO: 5002), e.g., (GGGS)n (SEQ ID NO: 5003). [0440] Polyglycine linkers can suitably be used in the fusion proteins of the disclosure. In some embodiments, a peptide linker used herein comprises two consecutive glycines (2Gly), three consecutive glycines (3Gly), four consecutive glycines (4Gly) (SEQ ID NO: 4016), five consecutive glycines (5Gly) (SEQ ID NO: 4017), six consecutive glycines (6Gly) (SEQ ID NO: 4018), seven consecutive glycines (7Gly) (SEQ ID NO: 4019), eight consecutive glycines (8Gly) (SEQ ID NO: 4020), or nine consecutive glycines (9Gly) (SEQ ID NO: 4021). [0441] In some embodiments, a GS-linker used herein comprises an amino acid sequence selected from GGSGGS (SEQ ID NO: 4022), i.e., (GGS)2 (SEQ ID NO: 4022); GGSGGSGGS (SEQ ID NO: 4023), i.e., (GGS)3 (SEQ ID NO: 4023); GGSGGSGGSGGS (SEQ ID NO: 4024), i.e., (GGS)4 (SEQ ID NO: 4024); GGSGGSGGSGGSGGS, i.e., (GGS)5 (SEQ ID NO: 4025) and GGGS (SEQ ID NO: 5004). In some embodiments, the fusion proteins can include a combination of a GS-linker and a glycine linker. [0442] In one embodiment, two or more VHHs are linked via a GGGGSGGGGSGGGGS (SEQ ID NO: 3970) linker. In one embodiment, two or more VHHs are linked via a GGGGSGGGGS (SEQ ID NO: 4026) linker. In one embodiment, a VHH and an Fc region are linked via a GGGGSESKYGPPCPSCP (SEQ ID NO: 4008) linker. In one embodiment, a VHH and an Fc region are linked via a GGGGS (SEQ ID NO: 3969) linker. [0443] In some embodiments, the one or more polypeptides of the fusion proteins of the present disclosure are operably linked via a “rigid” peptide linker. Such peptidic linker may comprise a proline- rich peptide. In one embodiment, a rigid peptide linker comprises PAPAPAPAPAPAPAPAP (SEQ ID NO: 4009). In one embodiment, a rigid peptide linker comprises GGGGSPAPAPAPAPAPAPAPAP (SEQ ID NO: 4010). In one embodiment, a rigid peptide linker comprises PAPAPAPAPAPAPAPAPGGGGS (SEQ ID NO: 161 310886415v1 Attorney Docket No: 260525.000071 4011). In one embodiment, a rigid peptide linker comprises GGGGSPAPAPAPAPAPAPAPAPGGGGS (SEQ ID NO: 4012). In one embodiment, a rigid peptide linker comprises GGGGSPAPAPAPAPAPAPAPAPGGGS (SEQ ID NO: 5007).In one embodiment, a rigid peptide linker comprises A(EAAAK)nA (SEQ ID NO: 4027), where n is any integer, e.g., 12, 3, 4, 5, 6, or 7, 8, 9 or 10. [0444] Other exemplary peptide linkers that can be used in the fusion proteins described herein are shown in Table 2. Table 2. Exemplary Peptide Linker Sequences Linker Amino acid sequence SEQ ID NO G4S GGGGS 3969 310886415v1 Attorney Docket No: 260525.000071 Linker Amino acid sequence SEQ ID NO (GGGGS)6 linker GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS 4001 [0445] Non-limiting examples of fusion proteins (e.g., bivalent, or tetravalent constructs with/without Fc regions, IL-2 fusion constructs) are disclosed in the “Examples” and “List of Sequences” sections below. [0446] In various embodiments, a fusion protein of the present disclosure comprises any one of SEQ ID NOs: 3933-3964, 4483-4513, 4686-4696, 4709-4716, 4735- 4770, 4772-4773, 4776-4779, 4903, 4979, 4981, 4983, 4985, 4987, 4989, 4991, and 4993, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0447] In some embodiments, a fusion protein of the present disclosure comprises any one of SEQ ID NOs: 4483-4513, 4686-4696, 4709-4716, 4735-4770, 4772-4773, 4776-4779, 4903, 4979, 4981, 4983, 4985, 4987, 4989, 4991, and 4993, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0448] In some embodiments, a fusion protein of the present disclosure comprises SEQ ID NO: 4979 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. 163 310886415v1 Attorney Docket No: 260525.000071 [0449] In some embodiments, a fusion protein of the present disclosure comprises SEQ ID NO: 4981 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0450] In some embodiments, a fusion protein of the present disclosure comprises SEQ ID NO: 4983 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0451] In some embodiments, a fusion protein of the present disclosure comprises SEQ ID NO: 4985 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0452] In some embodiments, a fusion protein of the present disclosure comprises SEQ ID NO: 4987 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0453] In some embodiments, a fusion protein of the present disclosure comprises SEQ ID NO: 4989 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0454] In some embodiments, a fusion protein of the present disclosure comprises SEQ ID NO: 4991 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0455] In some embodiments, a fusion protein of the present disclosure comprises SEQ ID NO: 4993 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0456] In some embodiments, a fusion protein of the present disclosure comprises SEQ ID NO: 4903 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at 164 310886415v1 Attorney Docket No: 260525.000071 least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0457] In some embodiments, a fusion protein of the present disclosure comprises SEQ ID NO: 4483 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0458] In some embodiments, a fusion protein of the present disclosure comprises SEQ ID NO: 4489 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0459] In some embodiments, a fusion protein of the present disclosure comprises any one of SEQ ID NO: 4709-4716 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0460] In some embodiments, a fusion protein of the present disclosure comprises any one of SEQ ID NO: 4735-4770 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0461] In some embodiments, a fusion protein of the present disclosure comprises any one of SEQ ID NO: 4772-4773 or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0462] In some embodiments, a fusion protein of the present disclosure comprises any one of SEQ ID NO: 4776-4779, 4903, 4979, 4981, 4983, 4985, 4987, 4989, 4991, and 4993, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0463] In some embodiments, provided herein is a fusion protein that specificaly binds TNFR2, comprising two polypeptides, wherein each polypeptide comprises two anti-TNFR2 antigen-binding proteins as described herein which are operably linked to each other, wherein one of the antigen- binding proteins is further operably linked to a dimerization domain (e.g., an immunoglobulin Fc region). 165 310886415v1 Attorney Docket No: 260525.000071 The two polypeptides dimerize in the presence of the dimerization domain to form a tetravalent molecule (i.e., having four anti-TNFR2 antigen-binding proteins per molecule). [0464] In some embodiments, the two antigen-binding proteins are operably linked to each other via a peptide linker. In one embodiment, the peptide linker is a (G4S)n (SEQ ID NO: 4015) linker. In one embodiment, the peptide linker is a GGGGSGGGGSGGGGS linker (SEQ ID NO: 3970). In one embodiment, the peptide linker is a G3S (SEQ ID NO: 5002), e.g., (GGGS)n (SEQ ID NO: 5003) linker. In one embodiment, the peptide linker is GGGS (SEQ ID NO: 5004). [0465] In some embodiments, one of the two antigen-binding proteins is further operably linked to an immunoglobulin Fc region via a peptide linker. In one embodiment, the peptide linker is a (G4S)n (SEQ ID NO: 4015) linker. In one embodiment, the peptide linker is a GGGGS linker (SEQ ID NO: 3969). [0466] In some embodiments, the fusion protein described herein further comprises an immunoglobulin Fc region. In some embodiments, the immunoglobulin Fc region is an Fc region of a human immunoglobulin. In some embodiments, the immunoglobulin Fc region is an Fc region of human IgG1, IgG2, IgG3 or IgG4, or a variant thereof. [0467] In some embodiments, the immunoglobulin Fc region is an Fc region of human IgG1, or a variant thereof. In some embodiments, the Fc region of human IgG1 comprises one or more mutations selected from L234A, L235A, G237A, D265A, N297A, and/or P329A according to EU numbering. In some embodiments, the Fc region of human IgG1 comprises a set of mutations selected from 1). L234A and L235A; 2). L234A, L235A, and P329A; 3). D265A, N297A and P329A; and 4). L234A, L235A, and G237A. [0468] In some embodiments, the immunoglobulin Fc region is an Fc region of human IgG1 comprising L234A, L235A, and P329A. [0469] In some embodiments, the immunoglobulin Fc region is an Fc region of human IgG4, or a variant thereof. In some embodiments, the Fc region of human IgG4 comprises one or more mutations selected from S228P, L235E, L235A, and/or F234A according to EU numbering. In some embodiments, the Fc region of human IgG4 comprises a set of mutations selected from 1). S228P and L235E; 2). S228P and L235A; 3). S228P, F234A, and L235E; and 166 310886415v1 Attorney Docket No: 260525.000071 4). S228P, F234A, and L235A. [0470] In some embodiments, the immunoglobulin Fc region is an Fc region of human IgG4 comprising S228P and L235E. [0471] It is to be understood that although the exemplary fusion proteins described herein contain non-humanized VHH amino acid sequences, such non-humanized VHH amino acid sequences can be replaced with any of the humanized VHH amino acid sequences described herein (e.g., in Tables 1-1, 1- 2, 7, and 8). [0472] In some embodiments, the fusion protein described herein may further comprise a signal sequence at its N-terminus. Signal sequences may be present in the precursor molecule of the fusion protein and may be removed after the protein is secreted from the host cel during production. In some embodiments, the signal sequence is MAVMAPRTLVLLLSGALALTQTWA (SEQ ID NO: 3928) or a fragment or variant thereof. In some embodiments, the signal sequence is MYRMQLLSCIALSLALVTNS (SEQ ID NO: 3929), or a fragment or variant thereof. Polynucleotide Molecules [0473] In another aspect, provided herein are polynucleotide molecules encoding the anti-TNFR2 antigen-binding proteins (e.g., antibodies including single-domain antibodies) or fusion proteins described herein. Polynucleotide molecules encoding polypeptide portion(s) of a conjugate of the present disclosure are also encompassed within the present disclosure. [0474] In some embodiments, a polynucleotide molecule of the present disclosure encodes an anti- TNFR2 VHH amino acid sequence selected from SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 4064, 4068, 4072, 4521, 93-640, 4079-41252805-3363, 4359-4420, 4605-4628, 4780, 4781, 4783, 4785, and 4786, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0475] In some embodiments, a polynucleotide molecule of the present disclosure encoding an anti- TNFR2 VHH comprises the nucleotide sequence of any one of SEQ ID NOs: 48-59, 4073-4075, 4522, 4525, 4528, 4531, 3364-3922, 4421-4482, 4629-4652, 4904-4977, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. 167 310886415v1 Attorney Docket No: 260525.000071 [0476] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence selected from SEQ ID NOs: 81-92, 4076, 4078, 4523, 4526, 4529, 4532, 4731-4734, 641-1127, 4126-4172, 4775, 4782, 4784, 4794-4808, 4857-4902, and 4994-5001, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0477] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4526, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. In an embodiment provided herein, the polynucleotide molecule encoding a humanized VHH amino acid sequence of SEQ ID NO: 4526 comprises the nucleotide sequence of SEQ ID NO: 4525, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0478] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4529, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. In an embodiment provided herein, the polynucleotide molecule encoding a humanized VHH amino acid sequence of SEQ ID NO: 4529 comprises the nucleotide sequence of SEQ ID NO: 4528, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0479] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4532, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. In an embodiment provided herein, the polynucleotide molecule encoding a humanized VHH amino acid sequence of SEQ ID NO: 4532 comprises the nucleotide sequence of SEQ ID NO: 4531, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at 168 310886415v1 Attorney Docket No: 260525.000071 least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0480] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4775, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0481] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4782, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0482] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4784, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0483] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4780, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0484] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4781, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0485] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4783, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 169 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0486] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4785, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0487] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4786, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0488] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4794, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0489] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4732, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0490] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4795, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0491] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4796, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 170 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0492] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4797, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0493] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4798, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0494] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4799, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0495] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4800, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0496] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4801, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0497] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4802, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 171 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0498] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4803, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0499] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4804, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0500] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4805, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0501] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4806, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0502] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4807, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0503] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4808, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 172 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0504] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4857, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0505] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4858, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0506] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4859, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0507] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4860, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0508] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4861, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0509] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4862, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 173 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0510] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4863, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0511] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4864, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0512] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4865, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0513] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4866, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0514] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4867, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0515] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4868, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 174 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0516] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4869, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0517] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4870, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0518] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4871, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0519] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4872, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0520] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4873, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0521] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4874, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 175 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0522] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4875, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0523] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4876, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0524] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4877, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0525] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4878, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0526] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4879, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0527] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4880, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 176 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0528] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4881, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0529] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4882, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0530] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4883, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0531] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4532, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0532] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4884, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0533] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4885, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 177 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0534] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4886, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0535] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4887, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0536] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4888, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0537] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4889, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0538] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4890, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0539] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4891, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 178 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0540] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4892, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0541] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4893, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0542] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4894, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0543] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4895, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0544] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4896, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0545] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4897, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 179 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0546] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4898, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0547] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4899, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0548] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4900, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0549] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4901, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0550] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4902, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0551] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4994, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 180 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0552] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4995, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0553] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4996, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0554] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4997, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0555] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4998, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0556] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 4999, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0557] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 5000, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 181 310886415v1 Attorney Docket No: 260525.000071 least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0558] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a humanized VHH amino acid sequence of SEQ ID NO: 5001, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0559] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encodes a fusion protein comprising an amino acid sequence selected from SEQ ID NOs: 3933-3964, and 4483-4513, 4686-4696, 4709-4716, 4735- 4770, 4772, 4773, 4776-4779, 4903, 4979, 4981, 4983, 4985, 4987, 4989, 4991, and 4993, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0560] In an embodiment provided herein, a polynucleotide molecule of the present disclosure encoding a fusion protein comprises the nucleotide sequence of any one of SEQ ID NOs: 4978, 4980, 4982, 4984, 4986, 4988, 4990, and 4992, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity. [0561] A polynucleotide molecule may be used to transform/transfect a host cel or host organism, e.g., for expression and/or production of a polypeptide. Suitable hosts or host cels for production of an anti- TNFR2 polypeptides described herein include any suitable fungal, prokaryotic, or eukaryotic cel or cel line or any suitable fungal, prokaryotic, or eukaryotic organism. A host or host cel comprising a polynucleotide molecule encoding an anti-TNFR2 antigen-binding protein polypeptide or fusion protein described herein is also encompassed by the present disclosure. [0562] A polynucleotide molecule may be for example DNA, RNA, or a hybrid thereof, and may also comprise (e.g., chemicaly) modified nucleotides, like locked nucleic acids (LNA) or peptide nucleic acids (PNA). In some embodiments, the polynucleotide is single-stranded. In some embodiments, the polynucleotide is double-stranded. In one embodiment, the polynucleotide is in the form of double- stranded DNA (e.g., plasmid). In some embodiments, the polynucleotide is in the form of a single- stranded RNA (e.g., mRNA). 182 310886415v1 Attorney Docket No: 260525.000071 [0563] Techniques for generating polynucleotides may include, for example but not limited to, automated DNA synthesis; site-directed mutagenesis; combining two or more naturaly occurring and/or synthetic sequences (or two or more parts thereof), introduction of mutations that lead to the expression of a truncated expression product; introduction of one or more restriction sites (e.g. to create cassettes and/or regions that may easily be digested and/or ligated using suitable restriction enzymes), and/or the introduction of mutations by means of a PCR reaction using one or more “mismatched” primers. Alternatively, polynucleotides of the present disclosure may be isolated from a suitable natural source. Polynucleotide sequences encoding naturaly occurring (poly)peptides can for example be subjected to site-directed mutagenesis, to generate a polynucleotide molecule encoding polypeptide with sequence variation. Vectors [0564] Also provided herein are vectors comprising the polynucleotide molecules encoding the anti- TNFR2 antigen-binding proteins (e.g., antibodies including single-domain antibodies), fusion proteins, or other relevant polypeptides of the present disclosure. A “vector” as used herein is a vehicle suitable for carrying genetic material into a host cel. A vector can include a nucleic acid vector, such as a plasmid or mRNA, or nucleic acids embedded into a bigger structure, such as a liposome or viral vector. [0565] A vector can include one or more of the folowing elements: an origin of replication, one or more regulatory sequences (e.g., promoters, enhancers, terminators) that regulate the expression of a polypeptide of interest, and/or one or more selectable marker genes (such as, for example, antibiotic resistance genes and genes that can be used in colorimetric assays, for example, β-galactosidase). For DNA-based vectors, this usualy includes the presence of elements for transcription (e.g., a promoter and a polyA signal) and translation (e.g., Kozak sequence). In some embodiments, the vector is an expression vector, i.e. a vector suitable for expressing an encoded polypeptide or construct under suitable conditions in a host cel. [0566] To express an anti-TNFR2 antigen-binding protein or fusion protein (or fragments thereof) of the present disclosure, polynucleotides encoding partial or ful-length polypeptide chains, e.g., obtained as described above (e.g., VHH, VHH-Fc), can be inserted into expression vectors such that the genes are operatively linked to one or more transcriptional and translational control sequences. The expression vector and expression control sequences are chosen to be compatible with the expression host cel used. Polynucleotides encoding the two or more polypeptide chains (when present and difer from one 183 310886415v1 Attorney Docket No: 260525.000071 another) of an anti-TNFR2 antigen-binding protein or fusion protein of the present disclosure can be inserted into separate vectors, or, optionaly, incorporated into the same expression vector. [0567] In addition to polynucleotides encoding the polypeptide chain(s) of an anti-TNFR2 antigen- binding protein or fusion protein, the recombinant expression vectors of the invention may include regulatory sequences that control the expression of genes encoding the polypeptide chain(s) in a host cel. The design of the expression vector, including the selection of regulatory sequences, may depend on the choice of the host cel to be transformed and/or the desired level of protein expression. For example, suitable regulatory sequences for mammalian host cel expression include viral elements that direct high levels of protein expression in mammalian cels, such as promoters and/or enhancers derived from cytomegalovirus (CMV), Simian Virus 40 (SV40), adenovirus, (e.g., the adenovirus major late promoter (AdMLP) and polyoma. Additional examples of viral regulatory elements, and sequences thereof, include those described in, e.g., U.S. Pat. Nos.5, 168,062; 4,510,245; and 4,968,615; the disclosures of each of which are incorporated herein by reference. [0568] Recombinant expression vectors of the present disclosure may carry additional sequences, such as sequences that regulate replication of the vector in host cels (e.g., origins of replication) and selectable marker genes. A selectable marker gene facilitates selection of host cels into which the vector has been introduced (see e.g., US4,399,216; US 4,634,665; and US 5,179,017; the disclosure of each of which is incorporated herein by reference in its entirety). For example, typicaly the selectable marker gene confers resistance to antibiotics, such as ampicilin, chloramphenicol, kanamycin, or nourseothricin, or cytotoxic drugs, such as G418, puromycin, blasticidin, hygromycin or methotrexate, to a host cel into which the vector has been introduced. Suitable selectable marker genes can include the dihydrofolate reductase (DHFR) gene (for use in DHFR deficient host cels with methotrexate selection/amplification) and the neo gene (for G418 selection). [0569] Vectors of the present disclosure may further include sequence elements that enhance the rate of translation of these genes or improve the stability or nuclear export of the mRNA that results from gene transcription. These sequence elements include, e.g., 5′ and 3′ untranslated regions, an internal ribosomal entry site (IRES), and polyadenylation signal site in order to direct eficient transcription of the gene carried on the expression vector. [0570] Viral vectors can be used for the eficient delivery of exogenous genes into the genome of a cel (e.g., a eukaryotic or prokaryotic cel). Viral vectors are particularly useful for gene delivery because the polynucleotides contained within such genomes are typicaly incorporated into the genome of a target 184 310886415v1 Attorney Docket No: 260525.000071 cel by generalized or specialized transduction. These processes occur as part of the natural viral replication cycle, and do not require added proteins or reagents to induce gene integration. Examples of suitable viral vectors include a retrovirus, adenovirus (e.g., Ad5, Ad26, Ad34, Ad35, and Ad48), parvovirus (e.g., adeno-associated viruses (AAV) such as AAV2, AAV8, AAV9), negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e.g., rabies and vesicular stomatitis virus), paramyxovirus (e.g. measles and Sendai), positive strand RNA viruses, such as picornavirus and alphavirus, and double-stranded DNA viruses including adenovirus, herpes virus (e.g., Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus), baculovirus, coronavirus, and poxvirus (e.g., vaccinia, modified vaccinia Ankara (MVA), fowlpox and canarypox). Other viruses useful for delivering polynucleotides encoding polypeptides of the present disclosure include, for example Norwalk virus, togavirus, flavivirus, reoviruses, papovavirus, hepadnavirus, and hepatitis virus. Examples of retroviruses include, but are not limited to, avian leukosis-sarcoma, mammalian C-type, B-type viruses, D-type viruses, HTLV-BLV group, lentivirus, spumavirus (Cofin, J. M.1996. Fundamental Virology, DMKDN Fields, PM Howley, ed. (Philadelphia, Lippincot-Raven Publishers): 763-843., the disclosure of which is incorporated herein by reference). Other examples of viral genomes useful in the compositions and methods of the present disclosure include murine leukemia viruses, murine sarcoma viruses, mouse mammary tumor virus, bovine leukemia virus, feline sarcoma virus, feline leukemia virus, avian leukemia virus, human T-cel leukemia virus, baboon endogenous virus, Gibbon ape leukemia virus, Mason Pfizer monkey virus, simian immunodeficiency virus, simian sarcoma virus, Rous sarcoma virus, and lentiviruses. Host Cels [0571] In one aspect, the present disclosure also provides host cels or host organisms that comprise the polynucleotides or vectors encoding the anti-TNFR2 antigen-binding proteins (e.g., antibodies including single-domain antibodies), fusion proteins, or other relevant polypeptides described herein. Suitable host cels or host organisms can be any suitable fungal, prokaryotic, or eukaryotic cel or cel line or any suitable fungal, prokaryotic, or eukaryotic organism. Host cels include progeny of a single host cel, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cel due to natural, accidental, or deliberate mutation. Host cels can also include cels transfected in vivo with a polynucleotide(s) or vector provided herein. 185 310886415v1 Attorney Docket No: 260525.000071 [0572] Exemplary eukaryotic cels include mammalian cels, such as primate or non-primate animal cels; fungal cels, such as yeast (e.g., Saccharomyces cerevisiae or Pichia pastoris); plant cels; and insect cels. Non-limiting exemplary mammalian cels include, but are not limited to, NSO cels, PER.C6® cels (Crucel), COS cels, SP2/0 cels, and 293 and CHO cels, and their derivatives, such as 293-6E, CHO-DG44, CHO-K1, CHO-S, and CHO-DS cels. Exemplary prokaryotic cels include bacterial cels such as Escherichia coli. Preparation Methods [0573] The present disclosure also provides methods of producing the anti-TNFR2 antigen-binding proteins (e.g., antibodies including single-domain antibodies), fusion proteins, or conjugates described herein. [0574] In some embodiments, a method may comprise transforming/transfecting a host cel or host organism with a polynucleotide encoding an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody), fusion protein, or other relevant polypeptide(s) described herein, expressing the anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody), fusion protein, or other relevant polypeptide(s) in the host, optionaly folowed by one or more isolation and/or purification steps. [0575] When recombinant expression vectors encoding one or more polypeptide(s) of an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody), fusion protein, or conjugate of the present disclosure are introduced into mammalian host cels, the host cels are cultured for a period of time suficient to alow for expression of the protein(s) or polypeptide(s) in the host cels or secretion of the protein(s) or polypeptide(s) into the culture medium in which the host cels are grown. Protein(s) or polypeptide(s) can be recovered from the culture medium using standard protein purification methods. Host cels can also be used to produce portions of intact antibodies, such as VHH domains. [0576] Once a protein or polypeptide of the present disclosure has been produced by recombinant expression, it can be purified by any method known in the art for purification of a protein or polypeptide, for example, by chromatography (e.g., ion exchange, afinity, particularly by afinity for TNFR2 after Protein A or Protein G selection, and sizing column chromatography), centrifugation, diferential solubility, or by any other standard technique for the purification of proteins. Further, the proteins or polypeptides of the present disclosure can be fused to heterologous polypeptide sequences described herein (e.g., His-tag) or otherwise known in the art to facilitate purification or to produce 186 310886415v1 Attorney Docket No: 260525.000071 therapeutic conjugates below). Once isolated, a protein or polypeptide of the present disclosure can, if desired, be further purified, e.g., by high performance liquid chromatography, or by gel filtration chromatography, such as on a Superdex™ column. Pharmaceutical Compositions and Formulations [0577] The present disclosure also provides a composition comprising anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody), fusion protein, or conjugate of the present technology, at least one polynucleotide molecule encoding the same, at least one vector comprising such a polynucleotide molecule, or at least one host cel comprising the polynucleotide molecule or vector. The composition may be a pharmaceutical composition. The composition may further comprise at least one pharmaceuticaly acceptable carrier, diluent, or excipient and/or adjuvant, and optionaly comprise one or more further pharmaceuticaly active polypeptides and/or compounds. [0578] As used herein, the term “pharmaceuticaly acceptable carrier” is intended to include any and al solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, which is incorporated herein by reference. Suitable examples of such carriers or diluents include, but are not limited to, water, saline, ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. Supplementary active compounds can also be incorporated into the compositions. [0579] Examples of suitable formulations include, but are not limited to, solutions, suspensions, powders, pastes, ointments, jelies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN™, Life Technologies, Carlsbad, CA), DNA conjugates, anhydrous absorption pastes, oil-in- water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powel et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Phdomain Sci Technol 52:238- 311. [0580] A pharmaceutical composition of the present disclosure may be formulated according to its intended route of administration. Examples of suitable routes of administration include, e.g., intravenous, subcutaneous, intratumoral, oral (e.g., buccal, sublingual), intranasal, inhalation, intraocular, intramuscular, intradermal, transdermal (i.e., topical), intraperitoneal, transmucosal, 187 310886415v1 Attorney Docket No: 260525.000071 vaginal, and rectal administration, or injection to the CNS/brain (e.g., intraspinal, intracerebral, or intrathecal administration). Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the folowing components: a sterile diluent such as water for injection, saline solution, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; fixed oils; chelating agents such as ethylenediaminetetraacetic acid (EDTA); bufers such as phosphates, acetates, or citrates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of plastic or glass. [0581] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include, for example, physiological saline, bacteriostatic water, Cremophor EL®, or phosphate bufered saline (PBS). The composition is preferably sterile and has a proper fluidity. In most embodiments, the composition is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, e.g., water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the contamination by microorganisms can be achieved by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. [0582] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients described above, as required, folowed by filtered sterilization. Generaly, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile 188 310886415v1 Attorney Docket No: 260525.000071 injectable solutions, methods of preparation include vacuum drying and/or freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. [0583] Oral compositions may include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, capsules, or liquid forms. Formulation in tablet and liquid forms may be used for protease insensitive VHHs. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied oraly and swished and expectorated or swalowed. Pharmaceuticaly compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pils, capsules, troches and the like can contain any of the folowing ingredients, or compounds of a similar nature: a binder such as microcrystaline celulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as coloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. [0584] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propelant, e.g., a gas such as carbon dioxide, or a nebulizer. [0585] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generaly known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generaly known in the art. [0586] The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery. [0587] For brain delivery, compounds of the present disclosure may be formulated to facilitate crossing of the blood-brain barrier. For example, anti-TNFR2 antigen-binding proteins (e.g., antibody such as single-domain antibody), fusion proteins, or conjugates of the present disclosure may be encapsulated into brain targeted liposomes, lipid nanoparticles, lipid microparticles, or lipid microcapsules for brain 189 310886415v1 Attorney Docket No: 260525.000071 delivery. Example liposomes delivery systems are described in Pothin et al., Pharmaceutics 2020, 12(10), 937, which is incorporated herein by reference in its entirety. [0588] In some embodiments, the active compounds are prepared with carriers that can protect the compound against rapid elimination from the body, such as a controled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, colagen, polyorthoesters, and polylactic acid. Liposomal suspensions can also be used as pharmaceuticaly acceptable carriers. These can be prepared according to methods known to those skiled in the art, for example, as described in US 4,522,811, which is incorporated herein by reference in its entirety. [0589] It is especialy advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physicaly discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic efect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure is dependent on the unique characteristics of the active compound and the particular therapeutic efect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. [0590] The pharmaceutical compositions (or components thereof) can be included in a kit, container, pack, or dispenser together with instructions for administration. These pharmaceutical compositions can be included in diagnostic kits with instructions for use. [0591] Pharmaceutical compositions are administered in an amount efective for treatment or prophylaxis of the specific indication. The therapeuticaly efective amount is typicaly dependent on the weight of the subject being treated, the physical or health condition of the subject, the extensiveness of the condition to be treated, or the age of the subject being treated. In some embodiments, the pharmaceutical composition may be administered in an amount in the range of about 50 μg/kg body weight to about 50 mg/kg body weight per dose. In some embodiments, the pharmaceutical composition may be administered in an amount in the range of about 100 μg/kg body weight to about 50 mg/kg body weight per dose. In some embodiments, the pharmaceutical composition may be administered in an amount in the range of about 100 μg/kg body weight to about 20 mg/kg body weight per dose. In some embodiments, the pharmaceutical composition may be administered in an amount in the range of about 0.5 mg/kg body weight to about 20 mg/kg body weight per dose. Depending on the 190 310886415v1 Attorney Docket No: 260525.000071 severity of the condition, the frequency and the duration of the treatment can be adjusted. Efective dosages and schedules for administering a pharmaceutical composition of the present disclosure may be determined empiricaly; for example, patient progress can be monitored by periodic assessment, and the dose adjusted accordingly. Moreover, interspecies scaling of dosages can be performed using wel- known methods in the art (e.g., Mordenti et al., 1991, Phdomainaceut. Res.8:1351). [0592] In some embodiments, the pharmaceutical composition may be administered in an amount in the range of about 10 mg to about 1,000 mg per dose. In some embodiments, the pharmaceutical composition may be administered in an amount in the range of about 20 mg to about 500 mg per dose. In some embodiments, the pharmaceutical composition may be administered in an amount in the range of about 20 mg to about 300 mg per dose. In some embodiments, the pharmaceutical composition may be administered in an amount in the range of about 20 mg to about 200 mg per dose. [0593] In some embodiments wherein the antigen-binding proteins of the present disclosure are administered as a viral vector (e.g., an AAV), dose ranges and frequency of administration of the viral vector described herein can vary depending on the nature of the viral vector, and the medical condition, as wel 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. [0594] 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 cels 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, intraocular, epidural, intraspinal, intracerebral, intrathecal, and oral routes. The composition may be administered by any 191 310886415v1 Attorney Docket No: 260525.000071 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 biologicaly active agents. Administration can be systemic or local. [0595] 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 generaly utilizes a replaceable cartridge that contains a pharmaceutical composition. Once al 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 prefiled 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. [0596] In certain situations, the pharmaceutical composition can be delivered in a controled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng.14:201). In another embodiment, polymeric materials can be used; see, Medical Applications of Controled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, a controled 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 Controled Release, supra, vol.2, pp.115-138). Other controled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533. [0597] The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous, intramuscular, intratumoral, intraperitoneal, intraspinal, intracerebral, and intrathecal injections, drip infusions, etc. In one embodiment, 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 conventionaly 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 192 310886415v1 Attorney Docket No: 260525.000071 medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filed in an appropriate ampoule. [0001] 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, pils, capsules, injections (ampoules), suppositories, etc. The amount of the antigen-binding proteins described herein may be about 5 to about 500 mg per dosage form in a unit dose; especialy in the form of injection, the antigen-binding proteins described herein may be contained in about 5 to about 100 mg and in about 10 to about 250 mg for the other dosage forms. [0598] The pharmaceutical composition may be administered as needed to a subject. In some embodiments, an efective dose of the pharmaceutical composition is administered to a subject one or more times. In various embodiments, an efective dose of the pharmaceutical composition is administered to the subject once a month, less than once a month, such as, for example, every two months, every three months, or every six months. In other embodiments, an efective dose of the pharmaceutical composition is administered more than once a month, such as, for example, every two weeks, every week, twice per week, three times per week, daily, or multiple times per day. An efective dose of the pharmaceutical composition is administered to the subject at least once. In some embodiments, the efective dose of the pharmaceutical composition may be administered multiple times, including for periods of at least a month, at least six months, or at least a year. In some embodiments, the pharmaceutical composition is administered to a subject as needed to aleviate one or more symptoms of a condition. [0599] In some embodiments, a pharmaceutical composition of the present disclosure may be administered to a subject at levels lower than that required to achieve the desired therapeutic efect and the dosage may be gradualy increased until the desired efect is achieved. Alternatively, a pharmaceutical composition of the present disclosure may be administered at a high dose and subsequently administered progressively lower doses until a therapeutic efect is achieved. In general, a suitable daily dose of an antigen-binding protein of the invention is an amount of the antibody which is the lowest dose efective to produce a therapeutic efect. [0600] Pharmaceutical compositions of the present disclosure may optionaly include more than one active agent. For example, compositions of the present disclosure may contain an anti-TNFR2 antigen- 193 310886415v1 Attorney Docket No: 260525.000071 binding protein conjugated to, admixed with, or administered separately from another pharmaceuticaly active molecule, e.g., Treg cel, or an additional agent that is useful for induction of Treg cel expansion. For instance, an anti-TNFR2 antigen-binding protein may be admixed with one or more additional active agents, such as IL-2 or TNFα, to treat an immunological disease, e.g., a disorder described herein. Alternatively, pharmaceutical compositions of the present disclosure may be formulated for co- administration or sequential administration with one or more additional active agents that can be used to attenuate CD8+ T-cel growth. Examples of additional active agents that can be used to atenuate cytotoxic T-cel proliferation and that can be conjugated to, admixed with, or administered separately from an anti-TNFR2 antigen-binding protein of the present disclosure include cytotoxic agents, e.g., those described herein. Treatment Methods and Other Uses [0601] In one aspect, provided herein is a method of using anti-TNFR2 antigen-binding proteins, fusion proteins, or conjugates of the present disclosure to stimulate the proliferation of a population of regulatory T (Treg) cels (e.g., CD4+, CD25+, FOXP3+ Treg cels). This response may also have the efect of reducing populations of cytotoxic T-lymphocytes (e.g., CD8+ T-cels) that are often associated with mounting an inappropriate immune response that can cause an immunological disorder. In addition, anti-TNFR2 antigen-binding proteins, fusion proteins or conjugates of the present disclosure may synergize with existing Treg proliferating agents, such as IL-2 and TNFα. [0602] Also provided herein is a method of using anti-TNFR2 antigen-binding proteins, fusion proteins, or conjugates of the present disclosure to activate and/or enhance suppressive function (e.g. inhibition of efector T/B cel function or proliferation or antigen presenting cel function) of a population of Treg cels. [0603] Further provided herein is a method of using anti-TNFR2 antigen-binding proteins, fusion proteins, or conjugates of the present disclosure to stabilize immunosuppressive phenotype (including stable expression of e.g., FOXP3, HELIOS, CTLA-4) of a population of Treg cels. [0604] In various embodiments of the above methods, the methods may comprise contacting the population of regulatory T cels with an anti-TNFR2 antigen-binding protein, fusion protein or conjugate described herein. The methods may be carried out in vitro or in vivo. When such methods are carried out in vivo, the methods further comprise administering the anti-TNFR2 antigen-binding protein, fusion protein or conjugate described herein into a subject. 194 310886415v1 Attorney Docket No: 260525.000071 [0605] Tregs are a subset of T cels that play a crucial role in peripheral self-tolerance and the prevention of autoimmunity. Historicaly, Tregs have been identified as a CD4 subset that specificaly express CD25, the high afinity IL-2 receptor alpha chain (Sakaguchi et al., 1995). Subsequently, FOXP3 transcription factor was identified as CD4 Treg’s master regulator (Hori et al., 2003). In fact, FOXP3 deficiency leads to systemic autoimmunity in both mouse and human in which it causes the Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome due to Tregs deficiency and unregulated efector T cel function (Bennett et al., 2001). CD4 Tregs can diferentiate during T cel development (thymic “tTregs”) or in the periphery (peripheral “pTregs”) under non- inflammatory T cel receptor stimulation (Wing et al., 2019). Numerous subsets have been described including naïve and memory Tregs (Sakaguchi et al., 2020), Th-like Tregs (Halim et al., 2017) as wel as CD8 Tregs (Mishra et al., 2021; Niederlova et al., 2021). CD4 Tregs regulate immune response through various mechanisms including the secretion of regulatory cytokines (e.g., IL-10, IL-35, TGF-β), IL-2 scavenging, adenosine production, direct cytotoxicity, and dendritic cel regulation (Vignali et al., 2008). The terms “regulatory T cels” or “Treg” as used herein are meant to encompass al the above-described subsets of regulatory T cels. [0606] Tregs have enhanced afinity for MHC I-presented self-antigen peptide and have a TCR repertoire that is non-overlapping with efector CD4 T cels (Fazileau et al., 2007; Hsieh et al., 2006; Pacholczyk et al., 2006). Therefore, self-antigen recognition in the periphery can induce tTregs activation (Moran et al., 2011). Importantly however, once activated, Tregs can suppress efector cels that have diferent antigen specificity through bystander suppression (Thornton and Shevach, 2000; Yeh et al., 2017; Yu et al., 2005) by regulating antigen presenting cels or soluble factors. [0607] It has been shown that over time, Tregs retain some plasticity and can lose FOXP3 expression. These so caled “ex-Tregs” have increased level of FOXP3 promoter methylation and lower FOXP3 expression compared to Tregs and can acquire efector function (Zhou et al., 2009). In Tregs, the demethylation of FOXP3 promoter, particularly in the “Treg-specific demethylated region” (TSDR) (Huehn et al., 2009), stabilizes gene expression. Likewise, human Tregs exposed to IL-2 + inflammatory cytokines have been shown to lose FOXP3 expression while upregulating RORg and IL-17, a feature associated with TH17 cels. Instability of the Treg phenotype in the presence of inflammatory cytokines can be referred to as “Treg fragility” and is of crucial relevance for therapeutic purpose in autoimmune diseases. Indeed, to induce a long-lasting therapeutic benefit, it is important to stabilize the phenotype 195 310886415v1 Attorney Docket No: 260525.000071 and function of Tregs and prevent their conversion to pathogenic cels that further contribute to disease. [0608] In some embodiments, anti-TNFR2 antigen-binding proteins, fusion proteins or conjugates of the present disclosure may be capable of stimulating the proliferation of a population of Treg cels by between 1% and 100% relative to untreated cels (e.g., about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%), as measured, e.g., by fluorescence activated cel sorting (FACS) analysis. In certain embodiments, anti-TNFR2 antigen-binding proteins, fusion proteins or conjugates of the present disclosure may be capable of reducing the growth of a population of CD8+ T-cels, e.g., by about 10% to about 200% relative to untreated cels (e.g., 10%, 20%, 30%, 40%, 50%, 75%, 100%, 125%, 150%, 175%, or 200%). [0609] In some embodiments, anti-TNFR2 antigen-binding proteins of the present disclosure can be used to promote the proliferation of a population of Treg cels and thus enhance the immunomodulatory activity of these cels. Anti-TNFR2 antigen-binding proteins of the present disclosure can therefore be used to atenuate an aberrant cel-mediated or humoral immune response associated with a variety of human diseases, such as autoimmune disorders, asthma, alergic reactions, and diseases associated with alograft tolerance. For example, anti-TNFR2 antigen-binding proteins of the present disclosure may be administered to suppress cytotoxic T-cel and B-cel activity, thereby attenuating the response of a subject to a self or benign antigen. Anti-TNFR2 antigen-binding proteins of the present disclosure can be administered to a mammalian subject, such as a human, to attenuate an aberrant immune response, such as a response against a self or non-threatening antigen. Alternatively, anti-TNFR2 antigen-binding proteins of the present disclosure can be used to expand a population of Treg cels ex vivo that have been extracted, e.g., from a patient or an MHC-matched donor. After inducing proliferation of these Treg cels in culture by contacting with an anti-TNFR2 antigen-binding protein of the present disclosure, these cels can subsequently be administered to a subject, e.g., using adoptive cel transfer techniques known in the art or described herein. In this way, anti-TNFR2 antigen- binding proteins of the present disclosure may synergize with existing techniques to suppress humoral and cel-mediated immune responses as a treatment modality for patients sufering from a variety of immunological disorders. [0610] In some embodiments, anti-TNFR2 antigen-binding proteins of the present disclosure are capable of interacting with and promoting signal transduction events mediated by TNFR2. Anti-TNFR2 antigen-binding proteins of the present disclosure may be able to induce conformational changes within 196 310886415v1 Attorney Docket No: 260525.000071 TNFR2 that lead to receptor trimerization. This spatial configuration has been shown to render TNFR2 active for MAPK/TRAF 2/3 signal transduction, which subsequently leads to activation of NF-ĸB- mediated transcription of genes involved in Treg cel growth and escape from apoptosis (Faustman, et al., Nat Rev Drug Discov.9:482-493 (2010), the disclosure of which is incorporated herein by reference). [0611] In some embodiments, anti-TNFR2 antigen-binding proteins of the present disclosure may be capable of increasing the transcription and/or expression of various genes. For example, anti-TNFR2 antigen-binding proteins of the present disclosure may induce the expression of one or more of Akt, cIAP2, Etk, TRAF2, VEGFR2, P13K, genes encoding proteins involved in the angiogenic pathway, IKK complexes, RIP, NIK, MAP3K, genes encoding proteins involved in the NF-ĸB pathway, NIK, JNK, AP-1, a MEK (e.g., MEK1, MEK7), MKK3, NEMO, IL2R, Foxp3, IL2, TNF, and lymphotoxin (e.g., lymphotoxin a and lymphotoxin β). The increase in expression of these genes can be detected using established molecular biology techniques known in the art, e.g., by detecting an increase in mRNA levels by Northern blot analysis or reverse-transcription PCT (RT-PCR) methods, or by detecting an increase in protein levels by immunoblot analysis or ELISA-based techniques. In some embodiments, anti-TNFR2 antigen-binding proteins of the present disclosure may be capable of promoting the activity of one or more proteins associated with the TNFR2 signaling pathway (or related signaling pathways that are activated as a result of TNFR2 signaling). For instance, anti-TNFR2 antigen-binding proteins of the present disclosure may be capable of promoting an increase in the phosphorylation of one or more proteins, such as Akt, clAP2, Etk, TRAF2, VEGFR2, P13K, proteins involved in the angiogenic pathway, IKK complexes, RIP, NIK, MAP3K, proteins involved in the NF-ĸB pathway, NIK, JNK, AP-1, a MEK (e.g., MEK1, MEK7), MKK3, NEMO, IL2R, Foxp3, IL2, TNF, and lymphotoxin (e.g., lymphotoxin α and lymphotoxin β). An increase in the phosphorylation of one or more proteins that occurs, e.g., as a result of treatment of a subject or of a sample of cels isolated from a subject can be detected using standard molecular biology techniques known in the art, such as by immunoblot analysis or ELISA-based techniques. [0612] In some embodiments, antigen-binding proteins of the present disclosure increases expression of one or more proteins selected from a protein in the NF-kB pathway, FOXP3, HELIOS, EZH2, HLA-DR, ICAM-1, OX-40, ICOS, and CCR8. [0613] In another aspect, provided herein is a method of inhibiting an immune response mediated by a B cel or a CD8+ T cel in a subject, the methods including the step of administering to the subject an anti-TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody), a fusion protein, a conjugate, a polynucleotide molecule, a vector, or a host cel described herein. 197 310886415v1 Attorney Docket No: 260525.000071 [0614] In another aspect, anti-TNFR2 antigen-binding proteins (e.g., antibody such as single-domain antibody), fusion proteins, conjugates, polynucleotide molecules, vectors, and/or host cels described herein, or pharmaceutical compositions thereof, are useful for the (prophylactic or therapeutic) treatment of a wide array of diseases or disorders. Accordingly, the present technology provides an anti- TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody), a fusion protein, a conjugate, a polynucleotide molecule, a vector, or a host cel for use as a medicament. Also provided is a (prophylactic and/or therapeutic) method of treating a disease or disorder, wherein said method comprises administering, to a subject in need thereof, a pharmaceuticaly active amount of an anti- TNFR2 antigen-binding protein (e.g., antibody such as single-domain antibody), a fusion protein, a conjugate, a polynucleotide molecule, a vector, or a host cel described herein. [0615] The diseases or disorder that can be treated with the compositions and methods described herein include, but are not limited to, immunological diseases (e.g., autoimmune diseases), inflammatory diseases, cancers, cardiovascular diseases (e.g., atherosclerosis, heart failure, left heart failure with reduced ejection fraction, left heart failure with preserved ejection fraction, right ventricular failure, congestive heart failure, restrictive cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, idiopathic cardiomyopathy, hypertension), and infertility and pregnancy-associated diseases (e.g., recurrent pregnancy loss, pre-eclampsia, preterm labor, fetal growth restriction, intrauterine growth restriction). [0616] Examples of immunological diseases that can be treated with the compositions and methods described herein include, but are not limited to, autoimmune diseases, alergies, asthma, neurological diseases, metabolic diseases (e.g., diabetes), macular diseases (e.g., macular degeneration), muscular atrophy, diseases related to miscarriage, vascular diseases (e.g., atherosclerosis), diseases related to bone loss (e.g., bone loss as a result of menopause or osteoporosis), blood disorders (e.g., hemophilia), musculoskeletal disorders, diseases related to growth receptor expression or activity, obesity, graft- versus-host disease (GVHD), or alograft rejections. [0617] In some embodiments, the compositions and methods described herein are used to treat an autoimmune disease. In some embodiments, the autoimmune disease is selected from lupus, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, bulous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold 198 310886415v1 Attorney Docket No: 260525.000071 agglutinin disease, Crohn's disease, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Goodpastures disease, Graves' disease, Guilain-Barré, Hashimoto's thyroiditis, hypothyroidism, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, juvenile arthritis, lichen planus, lichen sclerosis, IgG4-related disease, Meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disease, pemphigus vulgaris or related blistering skin disease, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, premature ovarian failure, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, primary ovarian insuficiency, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, spondyloarthritis, stif-man syndrome, type I diabetes, Takayasu arteritis, temporal arteritis/giant cel arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener's granulomatosis (Granulomatosis with polyangitis) or other immune vasculitis. [0618] In some embodiments, the compositions and methods described herein are used to treat lupus. In some embodiments, the lupus is systemic lupus erythematosus (SLE), cutaneous lupus (including acute cutaneous lupus, chronic cutaneous lupus erythematosus, or discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus), lupus nephritis, neonatal lupus, or drug-induced lupus. [0619] In some embodiments, the compositions and methods described herein are used to treat alergy. In some embodiments, the alergy is an alergic conjunctivitis, chemical alergy, cosmetic alergy, drug alergy, dust alergy, food alergy, hay fever, hives, mold alergy, pet alergy, poison ivy alergy oak alergy, or seasonal alergy. [0620] In some embodiments, the compositions and methods described herein are used to treat a neurological condition. In some embodiments, the neurological condition is a brain tumor, a brain metastasis, a spinal cord injury, schizophrenia, epilepsy, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's disease, Parkinson's disease, or stroke. [0621] In some embodiments, the compositions and methods described herein are used to treat a graft rejection. Without wishing to be bound by theory, anti-TNFR2 antigen-binding proteins of the present disclosure may treat graft rejections, e.g., by binding TNFR2 receptors on the surface of autoreactive CD8+ T-cels that bind antigens presented on the surface of the graft and inducing apoptosis in these CD8+ T-cels, or by inducing the expansion of Treg cels that may subsequently eliminate autoreactive CD8+ T-cels. Examples of graft rejections that can be treated with the compositions and methods described herein include, without limitation, skin graft rejection, bone graft rejection, vascular tissue 199 310886415v1 Attorney Docket No: 260525.000071 graft rejection, ligament graft rejection (e.g., anterior cruciate ligament graft rejection, anterior sacroiliac ligament graft rejection, caudal cruciate ligament graft rejection, cranial cruciate ligament graft rejection, cricothyroid ligament graft rejection, dorsal radiocarpal ligament graft rejection, inferior pubic ligament graft rejection, lateral colateral ligament graft rejection, medial colateral ligament graft rejection, palmar radiocarpal ligament graft rejection, patelar ligament graft rejection, periodontal ligament graft rejection, posterior cruciate ligament graft rejection, posterior sacroiliac ligament graft rejection, radial colateral ligament graft rejection, sacrospinous ligament graft rejection, sacrotuberous ligament graft rejection, superior pubic ligament graft rejection, suspensory ligament of the breast graft rejection, suspensory ligament of the lens graft rejection, ulnar colateral ligament graft rejection) and organ graft rejection (e.g., heart, lung, kidney, liver, pancreas, intestine, and thymus graft rejection). [0622] In some embodiments, the compositions and methods described herein are used to treat a graft-versus-host disease. In some embodiments, the graft-versus-host disease arises from a bone marrow transplant or one or more blood cels such as B-cels, T-cels, basophils, common myeloid progenitor cels, common lymphoid progenitor cels, dendritic cels, eosinophils, hematopoietic stem cels, neutrophils, natural kiler cels, megakaryocytes, monocytes, or macrophages. [0623] In some embodiments, the compositions and methods described herein are used to treat an inflammatory disease. The inflammatory disease may be acute or chronic inflammation. In some embodiments, the inflammatory disease is selected from osteoarthritis, atopic dermatitis, endometriosis, polycystic ovarian syndrome, inflammatory bowel disease, fibrotic lung disease, and cardiac inflammation. [0624] In some embodiments, the compositions and methods described herein are used to treat a cancer. In some embodiments, the cancer is an adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer (sarcoma of bone), brain stem glioma, brain tumor, breast cancer, inflammatory breast cancer, metastatic breast cancer, male breast cancer, Carney complex, central nervous system tumors (brain and spinal cord), cervical cancer, childhood cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, desmoid tumor, desmoplastic infantile ganglioglioma, childhood tumor, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial pancreatic cancer, galbladder cancer, gastrointestinal stromal tumor (GIST), germ cel tumor (including childhood germ cel tumor), gestational 200 310886415v1 Attorney Docket No: 260525.000071 trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary difuse gastric cancer, hereditary leiomyomatosis and renal cel cancer, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papilary renal carcinoma, HIV/AIDS-related cancer, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumor, laryngeal and hypopharyngeal cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cel prolymphocytic leukemia and hairy cel leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cel lymphocytic leukemia, eosinophilic leukemia, Li-Fraumeni syndrome, liver cancer, lung cancer (e.g., non- smal cel lung cancer, smal cel lung cancer), hodgkin lymphoma, non-hodgkin lymphoma, lynch syndrome, mastocytosis, meduloblastoma (including childhood meduloblastoma), melanoma, meningioma, mesothelioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndromes (MDS), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma (including childhood neuroblastoma), neuroendocrine tumor of the gastrointestinal tract, neuroendocrine tumor of the lung, neuroendocrine tumor of the pancreas, neuroendocrine tumors, neurofibromatosis type 1, neurofibromatosis type 2, nevoid basal cel carcinoma syndrome, oral and oropharyngeal cancer, osteosarcoma, ovarian, falopian tube, and peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma and paraganglioma, pituitary gland tumor, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Kaposi sarcoma, soft tissue sarcomas, skin cancer (non-melanoma), smal bowel cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis complex, uterine cancer, vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Waldenstrom macroglobulinemia (lymphoplasmacytic lymphoma), Werner syndrome, Wilms tumor, or xeroderma pigmentosum. [0625] In some embodiments, anti-TNFR2 antigen-binding proteins of the present disclosure can also be used to treat a patient in need of organ repair or regeneration, e.g., by inducing the proliferation of cels within a damaged tissue or organ. While not wishing to be bound by any theory, it is contemplated that agonistic TNFR2 antibodies may stimulate organ repair or regeneration, e.g., by binding TNFR2 on the surface of cels within damaged tissue to induce TRAF2/3- and/or NF-ĸB-mediated cel proliferation. Examples of tissues and organs that may be induced to regenerate by the use of anti-TNFR2 antigen- binding proteins of the present disclosure include the blood vessels including the aorta, bone, cranial nerves, ear, eye, embryonic structures, heart, heart, hematopoietic system, kidney, smal intestine, large 201 310886415v1 Attorney Docket No: 260525.000071 intestine, liver, lung, nerves, olfactory gland, pancreas, pituitary gland, peripheral nervous system, central nervous system, spinal cord, salivary gland, structures of the head, testes, thymus, and tongue. [0626] Additional diseases that can be treated with the compositions and methods of the present disclosure include genetic diseases with an immunological phenotype. Exemplary genetic diseases with an immunological phenotype are described in, e.g., Table S2 of Tangye et al., Journal of Clinical Immunology volume 42, pages1473–1507 (2022), which is incorporated herein by reference in its entirety. [0627] In some embodiments, patients receiving an anti-TNFR2 treatment of the present disclosure can be monitored for their responsiveness to the treatment. For example, a physician may monitor the response of a mammalian subject (e.g., a human) to treatment with anti-TNFR2 antigen-binding proteins of the present disclosure by analyzing the quantity of IFNγ secreted by CD8+ T-cels within a particular patient. For example, a composition of the present disclosure may be capable of reducing IFNɣ secretion by between 1% and 100% (e.g., 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%). Alternatively, a physician may monitor the responsiveness of a subject (e.g., a human) to treatment with a composition of the present disclosure by analyzing the Treg cel population in the lymph of a particular subject. For example, a physician may withdraw a sample of blood from a mammalian subject (e.g., a human) and determine the quantity or density of a population of Treg cels (e.g., CD4+ CD25+ FOXP3+ Treg cels or CD17+ Treg cels) using established procedures, such as FACS analysis. In such embodiments, high counts of Treg cels can be indicative of eficacious therapy, while lower Treg cel counts may indicate that the patient is to be prescribed or administered higher dosages of the anti-TNFR2 antigen-binding protein of the present disclosure until, e.g., an ideal Treg cel count is achieved. In addition, a physician of skil in the art may monitor the efect of treatment by administration of a composition of the present disclosure to a subject sufering from an immunological disorder, such as an autoimmune disease described herein, by analyzing the quantity of autoreactive CD8+ T-cels within a lymph sample isolated from the patient. Anti-TNFR2 antigen-binding proteins of the invention may atenuate the proliferation of autoreactive T-cels, e.g., by binding TNFR2 at the surface of an autoreactive T-cel and inducing apoptosis, and/or by stimulating the expansion of Treg cels that subsequently eliminate autoreactive T lymphocytes. Treatment with anti-TNFR2 antigen- binding proteins may lead to reduced quantities of autoreactive T-cels within the lymph isolated from a patient receiving treatment, and a rapid decline in the population of autoreactive T-cels in a lymph sample isolated from such a patient may indicate efective treatment. In cases where a lymph sample 202 310886415v1 Attorney Docket No: 260525.000071 isolated from a patient exhibits an autoreactive T-cel count that has not declined in response to agonistic TNFR2 antibody therapy, a physician may prescribe the patient higher doses of the antibody or an antigen-binding fragment thereof or may administer the anti-TNFR2 antigen-binding proteins with higher frequency, e.g., multiple times per day, week, or month. [0628] Anti-TNFR2 antigen-binding proteins described herein may be administered as a monotherapy or in combination with one or more additional therapeutic agents. [0629] In some embodiments, anti-TNFR2 antigen-binding proteins of the present disclosure may also be admixed, conjugated, or administered with, or administered separately from, another agent that promotes Treg cel proliferation. Additional agents that can be used to promote Treg cel expansion include, e.g., IL-2 and TNFα, the cognate ligand for TNFR2. [0630] In some embodiments, pharmaceutical compositions of the invention may be formulated for co- administration or sequential administration with one or more additional active agents that can be used to inhibit CD8+ T-cel growth. Examples of additional active agents that can be used to inhibit cytotoxic T-cel proliferation and that can be conjugated to, admixed with, or administered separately from an anti-TNFR2 antigen-binding protein of the present disclosure include cytotoxic agents, e.g., those described herein. [0631] Exemplary cytotoxic agents that can be conjugated to, admixed with, or administered separately from anti-TNFR2 antigen-binding protein of the present disclosure include, but not limited to, 13-cis retinoic acid, 14-hydroxy-retro-retinol, 2-chloro-2′-deoxyadenosine, 2-Chloro-2'-arabino-fluoro-2'- deoxyadenosine, 2-chlorodeoxyadenosine, 2-chlorodeoxyadenosine (2-Cda), 2'-deoxycoformycin, 3- methyl TTNEB, 6-mercaptopurine, 6-thioguanine, 9-aminocamptothecin, 9-cis retinoic acid, aclarubicin, acodazole hydrochloride, acronine, adozelesin, adozelesin, adriamycin, aldesleukin, al-trans retinoic acid, al-trans retinol, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, amsacrine, anastrozole, anisomycin, anthramycin, acivicin, asparaginase, asperlin, azacitidine, azacitidine, azetepa, azotomycin, AZQ, batimastat, benzodepa, bicalutamide, Bis (platinum), bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, busulfan, cactinomycin, calusterone, camptothecin, caracemide, carbetimer, carboplatin, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, CEP-751, chlorambucil, chlorambucil, cirolemycin, cisplatin, cisplatin, cladribine, combretestatin a-4, C1-973, CPT-11, crisnatol mesylate, cyclophosphamide, cyclophosphamide, cytarabine, cytarabine, daca (n-[2-(dimethyl-amino) ethyl] acridine-4-carboxamide), dacarbazine, dactinomycin, Dactinomycin (Actinomycin D), darubicin, 203 310886415v1 Attorney Docket No: 260525.000071 daunomycin, Daunomycin, daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diacarbazine (DTIC), diaziquone, docetaxel, dolasatins, doxorubicin, Doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, DWA 2114R, edatrexate, eflornithine hydrochloride, elipticine, elsamitrucin, enloplatin, enpromate, epipropidine, Epirubicin, epirubicin hydrochloride, erbulozole, esorubicin hydrochloride, estramustine, estramustine phosphate sodium, etanidazole, ethiodized oil i 131, etoposide, etoposide phosphate, etoprine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine (2-F-ara-AMP), fludarabine phosphate, fluorodeoxyuridylate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium, gemcitabine, gemcitabine, gemcitabine hydrochloride, gold 198AU , homocamptothecin, hPRL-G129R, hydroxyurea, hypoxanthine, idarubicin hydrochloride, ifosfamide, ifosfamide, ilmofosine, interferon ɣ- 1b, interferon α-2b, interferon α-n1, interferon α-n3, interferon α-2a, interferon β-1a, iproplatin, irinotecan hydrochloride, JM216, JM335, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, linomide, lometrexol sodium, lomustine, losoxantrone, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocarcin, mitocromin, mitogilin, mitomalcin, mitomycin, mitomycin C, mitosper, mitotane, mitoxantrone, mitoxantrone hydrochloride, mitozolomide, mycophenolic acid, N-(2- chloroethyl)-N′ cyclohexyl-N-nitrosourea (CCNU), N-(2-chloroethyl)-N′-(diethyl) ethylphosphonate-N- nitrosourea (fotemustine), N-(2-chloroethyl)-N′-(trans-4-methylcyclohexyl-N-nitrosourea (MeCCNU), N- (4-hydroxyphenyl) retinamide, N,N′-Bis (2-chloroethyl)-N-nitrosourea (BCNU), nitrogen mustard (mechlor ethamine), N-methyl-Nnitrosourea (MNU), nocodazole, nogalamycin;ormaplatin, N-propargyl- 5,8-dideazafolic acid, ormaplatin, oxaliplatin, oxisuran, paclitaxel, pegaspargase, peliomycin, pentamustine, peploycinsulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, pyrazoloacridine, raltitrexed, rhizoxin, rhizoxin d, riboprine, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, streptozotocin, strontium chloride Sr 89, sulfur mustard, sulofenur, talisomycin, taxane, taxoid, tecogalan sodium, tegafur, teloxantrone hydrochloride, temoporfin, temozolomide, teniposide, teniposide 9-amino camptothecin, teroxirone, testolactone, thiamiprine, thioguanine, thiotepa, thiotepa, thymitaq, tiazofurin, tirapazamine, tomudex, tomudex, TOP-53, topotecan, topotecan 204 310886415v1 Attorney Docket No: 260525.000071 hydrochloride, toremifene citrate, trestolone acetate, trichostatin A, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tubulozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine, vinblastine sulfate, vincristine, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglycinate sulfate, vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, or zorubicin hydrochloride, . [0632] Other therapeutic agents that can be conjugated to, admixed with, or administered separately from anti-TNFR2 antigen-binding protein of the present disclosure include, but are not limited to, 2′ deoxycoformycin (DCF), 1,25 dihydroxyvitamin D3, 5-ethynyluracil, 9-dioxamycin, abiraterone, acylfulvene, adecypenol, ALL-TK antagonists, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, anagrelide, andrographolide, angiogenesis inhibitors, antagonist D, antagonist G, antarelix, antiandrogen, prostatic carcinoma, anti-dorsalizing morphogenetic protein-1, antiestrogen, antineoplaston, antisense oligonucleotides, aphidicolin glycinate, apoptosis gene modulators, apoptosis regulators, apurinic acid, ara-CDP-DL-PTBA, argininedeaminase, asulacrine, atamestane, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azatyrosine, baccatin II derivatives, balanol, BCR/ABL antagonists, benzochlorins, benzoylstaurosporine, beta lactam derivatives, beta- alethine, betaclamycin B, betulinic acid, bFGF inhibitor, bisantrene, bisaziridinylspermine, bisnafide, bistratene A, bleomycin A2, bleomycin B2, breflate, budotitane, buthionine sulfoximine, calcipotriol, calphostin C, camptothecin derivatives (e.g., 10-hydroxy-camptothecin), canarypox IL-2, capecitabine, carboxamide-amino-triazole, carboxyamidotriazole, CaRest M3, CARN 700, cartilage derived inhibitor, casein kinase inhibitors (ICOS), castanospermine, cecropin B, cetrorelix, chlorins, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin, clomifene analogues, clotrimazole, colismycin A , colismycin B, combretastatin A4, combretastatin analogue, conagenin, crambescidin 816, crisnatol, cryptophycin 8, cryptophycin A derivatives, curacin A, cyclopentanthraquinones, cycloplatam, cypemycin, cytarabine ocfosfate, cytolytic factor, cytostatin, dacliximab, dehydrodidemnin B, deslorelin, dexifosfamide, dexrazoxane, dexverapamil, didemnin B, didox, diethylnorspermine, dihydro-5-azacytidine, dihydrotaxol, , diphenyl spiromustine, discodermolide, docosanol, dolasetron, doxifluridine, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine, edrecolomab, eflornithine, elemene, emitefur, epithilones, epothilones (A, R=H; B, R=Me), epristeride, erythrocyte gene therapy, estramustine analogue, estrogen agonists, estrogen antagonists, etoposide 4′-phosphate (etopofos), exemestane, fadrozole, filgrastim, finasteride, flavopiridol, flezelastine, fluasterone, fludarabine, fluorodaunorunicin hydrochloride, forfenimex, formestane, fostriecin, fotemustine, gadolinium texaphyrin, galium nitrate, 205 310886415v1 Attorney Docket No: 260525.000071 galocitabine, ganirelix, gelatinase inhibitors, glutathione inhibitors, hepsulfam, heregulin, hexamethylene bisacetamide, homoharringtonine (HHT), hypericin, ibandronic acid, idarubicin, idoxifene, idramantone, ifepristone, ilomastat, imidazoacridones, imiquimod, immunostimulant peptides, insulin-like growth factor-1 receptor inhibitor, interferon agonists, interferons, interleukins, iobenguane, iododoxorubicin, ipomeanol, irinotecan, iroplact, irsogladine, isobengazole, isohomohalicondrin B, itasetron, jasplakinolide, kahalalide F, lamelarin-N triacetate, lanreotide, leinamycin, lenograstim, lentinan sulfate, leptolstatin, leukemia inhibiting factor, leukocyte alpha interferon, leuprolide+estrogen+progesterone, leuprorelin, levamisole, liarozole, linear polyamine analogue, lipophilic disaccharide peptide, lipophilic platinum compounds, lissoclinamide 7, lobaplatin, lombricine, lometrexol, lonidamine, lovastatin, loxoribine, lurtotecan, lutetium texaphyrin, lysofyline, lytic peptides, mannostatin A, marimastat, maspin, matrilysin inhibitors, matrix metaloproteinase inhibitors, meterelin, methioninase, metoclopramide, MIF inhibitor, miltefosine, mirimostim, mismatched double stranded RNA, mithracin, mitoguazone, mitolactol, mitomycin analogues, mitonafide, mitotoxin fibroblast growth factor-saporin, mofarotene, molgramostim, monoclonal antibody, human chorionic gonadotrophin, monophosphoryl lipid A+myobacterium cel wal sk, mopidamol, multiple drug resistance gene inhibitor, multiple tumor suppressor 1-based therapy, mustard anticancer agent, mycaperoxide B, mycobacterial cel wal extract, myriaporone, N- acetyldinaline, nafarelin, nagrestip, naloxone+pentazocine, napavin, naphterpin, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulators, nitroxide antioxidant, nitrulyn, N-substituted benzamides, O6-benzylguanine, octreotide, okicenone, oligonucleotides, onapristone, ondansetron, oracin, oral cytokine inducer, osaterone, oxaliplatin, oxaunomycin, paclitaxel analogues, paclitaxel derivatives, palauamine, palmitoylrhizoxin, pamidronic acid, panaxytriol, panomifene, parabactin, pazeliptine, peldesine, pentosan polysulfate sodium, pentostatin, pentrozole, perflubron, perilyl alcohol, phenazinomycin, phenylacetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piritrexim, placetin A, placetin B, plasminogen activator inhibitor, platinum complex, platinum compounds, platinum-triamine complex, podophylotoxin, propyl bis-acridone, prostaglandin J2, proteasome inhibitors, protein A-based immune modulator, protein kinase C inhibitor, protein kinase C inhibitors, microalgal, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurins, pyridoxylated hemoglobin polyoxyethylene conjugate, raf antagonists, ramosetron, ras farnesyl protein transferase inhibitors, ras inhibitors, ras-GAP inhibitor, reteliptine demethylated, rhenium Re 186 etidronate, 206 310886415v1 Attorney Docket No: 260525.000071 ribozymes, RI retinamide, rnerbarone, rohitukine, romurtide, roquinimex, rubiginone B 1, ruboxyl, saintopin, SarCNU, sarcophytol A, sargramostim, Sdi 1 mimetics, senescence derived inhibitor 1, sense oligonucleotides, signal transduction inhibitors, signal transduction modulators, single chain antigen- binding protein, sizofiran, sobuzoxane, sodium borocaptate, sodium phenylacetate, solverol, somatomedin binding protein, sonermin, sparfosic acid, spicamycin D, splenopentin, spongistatin 1, squalamine, stem cel inhibitor, stem-cel division inhibitors, stipiamide, stromelysin inhibitors, sulfinosine, superactive vasoactive intestinal peptide antagonist, suradista, suramin, swainsonine, synthetic glycosaminoglycans, talimustine, tamoxifen methiodide, tauromustine, tazarotene, telurapyrylium, telomerase inhibitors, tetrachlorodecaoxide, tetrazomine, thaliblastine, thalidomide, thiocoraline, thrombopoietin, thrombopoietin mimetic, thymalfasin, thymopoietin receptor agonist, thymotrinan, thyroid stimulating hormone, tin ethyl etiopurpurin, titanocene dichloride, topsentin, toremifene, totipotent stem cel factor, translation inhibitors, tretinoin, triacetyluridine, triciribine, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, variolin B, velaresol, veramine, verdins, vinorelbine, vinxaltine, vitaxin, zanoterone, zilascorb, or zinostatin stimalamer. [0633] In some embodiments, anti-TNFR2 antigen-binding proteins of the present disclosure may be admixed, conjugated, or administered with, or administered separately from, an anti-inflammatory agent. Exemplary anti-inflammatory agents useful in conjunction with the compositions and methods of the invention include steroids, colchicine, hydroxychloroquine, sulfasalazine, dapsone, methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, sirolimus, everolimus, azathioprine, leflunomide, mycophenolate, inhibitors of IL-1/IL-2/IL-4/IL5/IL-6/IL-13/IL-17/IL- 23/TNF/complement/BAFF/interferon/JAK/CD28/IgE/Integrins/T cel costimulation pathway or B-cel depleting agents. [0634] In some embodiments, anti-TNFR2 antigen-binding proteins of the present disclosure may be admixed, conjugated, or administered with, or administered separately from, an immunotherapy agent. Exemplary immunotherapy agents useful in conjunction with the compositions and methods of the invention include an anti-CTLA-4 agent, an anti-PD-1 agent, an anti-PD-L1 agent, an anti-PD-L2 agent, a TNFα cross-linking agent, a TRAIL cross-linking agent, an anti-CD27 agent, an anti-CD30 agent, an anti- CD40 agent, an anti-4-1BB agent, an anti-GITR agent, an anti-OX40 agent, an anti-TRAILR1 agent, an anti-TRAILR2 agent, an anti-TWEAKR agent, an anti-TL1A agent, an anti-LIGHT agent, an anti-BTLA agent, an anti-LAG3 agent, an anti-Siglecs agent, an anti-ICOS ligand agent, an anti-B7-H3 antibody; an anti-B7- 207 310886415v1 Attorney Docket No: 260525.000071 H4 agent; an anti-VISTA agent; an anti-TMIGD2 agent; an anti-BTNL2 agent; an anti-CD48 agent; an anti- KIR agent; an anti-LIR agent; an anti-ILT agent; an anti-NKG2D agent; an anti-NKG2A agent; an anti-MICA agent; an anti-MICB agent; an anti-CD244 agent; an anti-CSF1 R agent; an anti-IDO agent; an anti-TGFβ agent; an anti-CD39 agent; an anti-CD73 agent; an anti-CXCR4 agent; an anti-CXCL12 agent; an anti- SIRPA agent; an anti-CD47 agent; an anti-VEGF agent; and an anti-neuropilin agent and, e.g., agents directed toward the immunological targets described in Table 1 of Mahoney et al., Cancer Immunotherapy, 14:561-584 (2015), the disclosure of which is incorporated herein by reference. The immunotherapy agent described herein may be, for example, an antibody, a smal molecule, or a chimeric antigen receptor. [0635] In some embodiments, anti-TNFR2 antigen-binding protein of the present disclosure can also be admixed with, co-administered with, or administered separately from Bacilus Calmete-Guérin (BCG), a bacterial strain that has been used to treat a variety of immunological disorders, such as type I diabetes, multiple sclerosis, scleroderma, Sjogren's disease, systemic lupus erythematosus, Grave's disease, hypothyroidism, Crohn's disease, colititis, an autoimmune skin disease, and rheumatoid arthritis, among others. For instance, anti-TNFR2 antigen-binding protein of the present disclosure may be included in a therapeutic regimen in combination with BCG for the treatment of an immunological disorder (e.g., one of those described above, such as type I diabetes or rheumatoid arthritis). The anti-TNFR2 antigen- binding protein may be co-administered with BCG, e.g., by an injection route described herein. Alternatively, the anti-TNFR2 antigen-binding protein may be administered separately from a BCG- containing composition. The use of BCG to treat immunological disorders has been described, e.g., in US 6,660,487; and US 6,599,710; the disclosures of each of which are incorporated herein by reference in its entirety. EXAMPLES [0636] The folowing examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to ilustrate, not to limit, the disclosed embodiments. Example 1. Camelid immunization [0637] Three alpacas were immunized by four subcutaneous injections with recombinant human TNFR2 (10417-H08H, Sino Biologicals) and complete/incomplete Freund’s or Gerbu FAMA adjuvant using standard protocols to elicit a humoral immune response that included the generation of antigen-specific conventional and heavy-chain only (VHH) antibodies. 208 310886415v1 Attorney Docket No: 260525.000071 [0638] Before the first and after the third injection, serum was prepared from blood samples. Antibody induction was monitored by comparing antigen-specific antibody titers in the sera before and after immunization by enzyme-linked immunosorbent assay (ELISA). Briefly, 96-wel Maxisorp plates were coated with human TNFR2 (10417-H08H, Sino Biologicals), blocked, and incubated with diluted serum samples. TNFR2-specific antibodies were bound by alkaline phosphatase-conjugated goat anti-alpaca IgG (H+L) (Jackson ImmunoResearch, Cat. No.128-055-160) and detected using p-Nitrophenyl Phosphate. Example 2. Phage library construction [0639] Four to ten days after the fourth injection in accordance with procedures described in Example 1, blood samples were colected, and four to six days after the fourth injection a bone marrow sample was aspirated. Peripheral blood mononuclear cels (PBMCs) were isolated from heparinized blood or bone marrow folowing density gradient purification with Ficol-PaqueTM Plus. Total RNA was extracted from freshly isolated PBMCs. [0640] To generate VHH immune libraries, total RNA was reverse transcribed to cDNA using random hexamer primers. Conventional and heavy chain IgH cDNA fragments were amplified by polymerase chain reaction (PCR) using primers annealing to the IgH leader sequence region and the CH2 region. The resulting amplicons represented the VHH and VH cDNAs, respectively. The VHH fragment was isolated and used as template for a nested PCR to introduce appropriate endonuclease recognition sites for cloning into the pQ81 phagemid in frame with gene II. Libraries were transformed into electrocompetent E. coli TG1 cels. In total, six libraries were built, with 95.5% to 100% VHH insert frequency and maximum library sizes between 4.2x108 and 2.4x109. Phage for phage display was prepared folowing standard protocols. [0641] Binders to human and mouse TNFR2 were enriched from VHH immune libraries by two rounds of phage display. The general panning strategy is ilustrated in Figure 1 using the panning substrates listed Table 3. For the Table below: Hu, Human; Ms, mouse; PBS, phosphate bufered saline; Cat., catalog; MW, molecular weight; Calc., Calculated; Seq., Sequence; N-term., N-terminal; aa, amino acid. Table 3. Panning substrates Species Modification Bufer Cat. # Lot # Vendor MW N-term. Source S 3 310886415v1 Attorney Docket No: 260525.000071 Species Modification Bufer Cat. # Lot # Vendor MW N-term. Source Seq., aa Seq. 3 he first harvested bone marrow sample of the same animal were pooled in equal parts (at the phage level), resulting in three pooled input libraries per antigen. Each library was panned under four conditions (two antigen concentrations and two ways of antigen immobilization) with human TNFR2, resulting in 12 panning reactions. For the second rounds of panning, six output samples (enriched libraries) from the first round were chosen and served as input libraries for the second round. Preferentialy, the enriched libraries from the higher panning substrate concentration were chosen to preserve maximum diversity. Pannings of the second round were performed with three antigen concentrations of human and mouse antigen to result 24 conditions. Three antigen concentrations for TNFR2 were further chosen to recover binders with lower afinity. This panning regimen was implemented to identify binders that cross- reacted with human and mouse TNFR2. [0643] In some cases, binders with medium afinity were preferred since higher valency may drive avidity. Thus, the antigen concentrations in the second panning round were the same, one tenth and one hundredth of the first round. [0644] Phages were produced according to QVQ Holding B.V. (QVQ) standard operating procedures (SOPs) and phage titers were determined to ensure at least 10-fold excess over the maximum diversity of the libraries. Panning substrates were commercialy purchased (see Table 1). The panning substrates were immobilized either by direct coating on enzyme-linked immunoassay (ELISA) plates or by binding of biotinylated antigen on neutravidin-coated ELISA plate. Glycerol stocks were prepared from al outputs and are stored at -80°C. [0645] Panning outputs were analyzed by random clone picking/periplasmic extract (PE)-ELISA/Sanger sequencing (QVQ) and next-generation sequencing (NGS; Genewiz/PipeBio). [0646] For random colony picking, rescued outputs of the first and second panning rounds were plated out and 920 random single clones (equal numbers of colonies from each condition) were selected to create masterplates (96-wel format). From the masterplates, expression cultures in deep-wel plates were inoculated to produce periplasmic extracts containing monoclonal VHH. Periplasmic extracts were 210 310886415v1 Attorney Docket No: 260525.000071 used to determine binding of individual VHHs to human, mouse and cynomolgus antigen by ELISA. For conditions where the panning substrate was biotinylated and captured by neutravidin, background binders were identified by ELISA with neutravidin. Al masterplates were sequenced by the Sanger method. [0647] For NGS analysis, minipreps from input libraries and outputs after the first and second rounds of panning were prepared, amplified by PCR, and sequenced by NGS. Example 3. Next-generation sequencing [0648] Folowing two rounds of panning, phages were eluted and corresponding phagemid DNA was extracted. Identification of initial V-body candidates was performed in a paralelized fashion, employing a random colony picking, as wel as a next-generation sequencing (NGS) approach, as orthogonal techniques to yield a particularly diverse set of initial candidates. Prior to NGS techniques, random colony picking was the prevalent method for initial hit identification, which involved transformation of a phagemid pool (from a panning elution) and selection of individual bacterial colonies to isolate single clones. Folowing this approach, 920 single colonies were randomly picked from the 36 samples of the second panning round (Figure 2). Then, individual clones were expressed and subject to ELISA screening against the target antigen to select for antigen binding V-bodies, which were further functionaly characterized. [0649] Al panning eluates were sequenced using NGS. In brief, the entire VHH region was PCR- amplified from isolated phagemid pools by primers annealing to universal phagemid sequences 5’ and 3’ of the VHH-encoding region. In a second step, the generated amplicons were fused to sequencing- compatible and sample-specific barcodes. By fusing unique barcodes, it was possible to multiplex hundreds of diferent samples. Folowing the preparation of 51 samples, an Ilumina NovaSeq 6000 with an SP flowcel was employed for sequencing, yielding 250 base pair (bp) reads from each direction and a total of ~600 milion reads. To account for diferences in the number of expected unique sequences in the library, and both panning rounds, each library was sequenced with a total of 20 milion reads, compared to the first and second round of panning with 2 milion reads each. This strategy alowed for covering suficient sequence space in the libraries, as wel as in the panning eluates. A spike-in of 30% of a standard PhiX reference genome control into the sequencing reaction helped to provide a technical quality control for assessing sequencing accuracy. The NGS raw data contained multiplexed sequencing reads, which were de-multiplexed based on the sample-specific barcodes. The de-multiplexed data containing unmerged sequencing reads were then processed by employing an NGS analysis platform. In 211 310886415v1 Attorney Docket No: 260525.000071 brief, forward and reverse sequence pairs were merged by their overlapping sequence, thereby generating a ful VHH sequence from two half sequences (Figure 3). The framework regions, CDRs, and sequence-specific liabilities were then annotated for the merged V-body sequences. [0650] Based on CDR3 identity, V-body sequences were clustered, alowing for a detailed analysis of V- body enrichment during phage display, sequence diversity, CDR3 length distribution and cluster abundance. Identified V-bodies can be classified into eleven distinct clusters, as folows: Group A, Group B, Group C, Group D, Group G, Group J, Group K, Group L, Group M, Group N, and Group O. The folowing Table 4-1 to Table 4-33 display the amino acid frequency distribution at each amino acid (AA) position (IMGT) for CDR1, CDR2 and CDR3 for the eleven clusters. Table 5 provides the sequence identifiers of amino acid sequences of the complementarity determining regions (CDR1, CDR2 and CDR3), amino acid and DNA sequences of the ful-length VHH domain for the identified V-bodies. 212 310886415v1 Attorney Docket No: 260525.000071 Table 4-1 CDR1 amino acid frequency distribution for Group A Position AA 27 28 29 30 35 36 37 38 A 0 0 0 0 0 53 0 36 Position AA 56 57 58 59 63 64 65 213 310886415v1 Attorney Docket No: 260525.000071 Table 4-3 CDR3 amino acid frequency distribution for Group A Position AA 105 106 107 108 109 110 111 112.1 112 113 114 115 116 117 A 0 0 0 239 0 0 2 206 0 0 03 0 17 0 Position AA 27 28 29 30 35 36 37 38 A 214 310886415v1 Attorney Docket No: 260525.000071 roup B 0 ro AA 105 1 A 90 1 0 0 0 0 C 0 0 0 0 0 0 D 0 0 0 0 100 0 E 0 0 0 0 0 0 F 0 0 0 0 0 0 G 0 0 0 0 0 0 H 0 0 0 100 0 0 I 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 K 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 L 0 0 0 0 0 100 0 0 0 0 0 0 0 0 0 0 M 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 N 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 P 0 0 0 0 0 0 0 0 0 0 0 0 100 0 0 0 Q 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 R 0 0 0 0 0 0 40 0 0 0 0 0 0 0 0 0 S 0 0 0 100 0 0 60 0 0 0 0 0 0 0 0 10 T 0 0 0 0 0 0 0 100 0 0 0 0 0 0 0 0 V 10 0 0 0 0 0 0 0 90 90 90 0 0 0 0 0 W 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Y 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 90 215 310886415v1 Attorney Docket No: 260525.000071 Table 4-7 CDR1 amino acid frequency distribution for Group C Position AA 27 28 29 30 35 36 37 38 A 0 0 0 0 0 0 0 100 T roup C Position AA 56 57 58 59 62 63 64 65 0 216 310886415v1 Attorney Docket No: 260525.000071 Table 4-9 CDR3 amino acid frequency distribution for Group C Position A 10 10 10 10 10 11 11 111 111 112 112 112 11 11 11 11 11 11 A 5 6 7 8 9 0 1 1 2 3 2 1 2 3 4 5 6 7 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 10 0 217 310886415v1 Attorney Docket No: 260525.000071 Table 4-10 CDR1 amino acid frequency distribution for Group D Position AA 27 28 29 30 35 36 37 38 A 0 0 0 0 0 C 0 0 0 0 0 Ta roup D Position AA 56 57 58 59 62 63 64 65 0 218 310886415v1 Attorney Docket No: 260525.000071 Table 4-12 CDR3 amino acid frequency distribution for Group D Position AA 105 106 107 108 109 110 113 114 115 116 117 A C 3 8 3 .7 Position AA 27 28 29 30 35 36 37 38 A 0 0 0 0 219 310886415v1 Attorney Docket No: 260525.000071 Table 4-14 CDR2 amino acid frequency distribution for Group G Position AA 56 57 58 59 62 63 64 65 A 0 0 0 0 0 0 0 0 0 220 310886415v1 AttorneyDocketNo:260525.000071 170000.5250 7 6 1 0 1 000 00 0 0 0 00 0 0 0 00 0 0 000 2 1 :o 6 N 1 0 1 0001 000 0 0 00 0 0 0 00 0 0 000 tek 5 c 11 000 o D 4 y 1 e 1 00 0 nr 3 o 1 t 1 00 0 t A 21 G 1 00 0 p 1 u . o 2 r 11 000 Gr 2.211 000 3.2 u 1 bi 1 00 0 rt 4 s . i 2 d 11 000 yc 5 n n . e o 2 i 1 u ti 1 000 q s e o 4 r P . f 11 d 1 00 0 i c 3 a .1 0 o 1 n 1 01 0000 0 0 0 00 0 0 0 00 0 0 00 0 i 2 m . a 11 0 3 1 001 000 0 0 0 00 0 0 0 00 0 0 00 0 R 1 D . C 11 0 1 00 0 00 0 0 0 00 0 5 0 0 0 00 0 0 001 1- 1 3 33 4 1 . 1 00 0 00 0 0 3 .3.3 e 0 00 3 0 0 00 33 000 lb 0 a 1 0 T 1 00 0 00 0 0 0 00 0 00 00 0 0 0001 90 0 1 00 0 000 0 0 00 0 001 000 0 00 0 80 0 1 00 0 0001 00 00 0 00 00 0 0 00 0 70 0 1 00 0 00 0 0 0 00 0 001 0000 00 0 60 0 1 00 0 00 0 0 0 00 0 0 0 00 001 000 500 1 01 0000 0 0 0 00 0 0 0 00 0 0 00 0 A A A C D E F G H I K L M N P Q R S T V W Y 1v514688013 Attorney Docket No: 260525.000071 Table 4-16 CDR1 amino acid frequency distribution for Group J Position AA 27 28 29 30 35 36 37 38 A 0 0 0 0 0 0 0 2 C 0 0 0 0 0 0 0 0 Ta roup J Position AA 56 57 58 59 62 63 64 65 A 0 0 0 0 0 0 0 0 0 222 310886415v1 Attorney Docket No: 260525.000071 Table 4-18 CDR3 amino acid frequency distribution for Group J Position AA 105 106 107 108 109 110 112 113 114 115 116 117 A 100 0 0 0 0 18 0 0 2 0 2 0 C 0 0 0 0 0 0 0 0 0 0 0 0 0 Position AA 27 28 29 30 35 36 37 38 A 0 0 0 0 223 310886415v1 Attorney Docket No: 260525.000071 Table 4-20 CDR2 amino acid frequency distribution for Group K Position AA 56 57 58 59 62 63 64 65 A 0 0 0 20 0 0 0 0 0 Ta roup K Position AA 105 106 107 108 109 110 113 114 115 116 117 A 21.6 100 88.2 0 9.8 0 0 96.1 0 23.5 0 0 0 .1 224 310886415v1 Attorney Docket No: 260525.000071 Table 4-22 CDR1 amino acid frequency distribution for Group L Position AA 27 28 29 30 35 36 37 38 A 0 100 0 0 0 0 0 100 C 0 0 0 0 0 0 0 0 Ta roup L Position AA 56 57 58 59 63 64 65 0 225 310886415v1 Attorney Docket No: 260525.000071 Table 4-24 CDR3 amino acid frequency distribution for Group L Position AA 105 106 107 108 115 116 117 A 100 0 0 100 0 0 0 0 Table r Group M Position AA 27 28 29 30 35 36 37 38 A 0 0 0 0 226 310886415v1 Attorney Docket No: 260525.000071 Table 4-26 CDR2 amino acid frequency distribution for Group M Position AA 56 57 58 59 63 64 65 A 0 0 0 0 0 0 13 Table r Group M Position AA 105 106 107 108 109 113 114 115 116 117 A 1 3 3 227 310886415v1 Attorney Docket No: 260525.000071 Table 4-28 CDR1 amino acid frequency distribution for Group N Position AA 27 28 29 30 35 36 37 38 A 0 0 0 0 0 0 0 100 Ta roup N Position AA 56 57 58 59 62 63 64 65 228 310886415v1 Attorney Docket No: 260525.000071 Table 4-30 CDR3 amino acid frequency distribution for Group N Position AA 105106107108109110111111.1112.1112113114115116117 A 1000 0 0 0 0 0 0 0 0 0 0 0 0 0 00 O Position AA 27 28 29 30 35 36 37 38 3 310886415v1 Attorney Docket No: 260525.000071 Table 4-32 CDR2 amino acid frequency distribution for Group O Position AA 56 57 58 59 62 63 64 65 A 0 0 0 0 0 0 0 0 5 8 p O Position AA 105106107108109110111111.1111.2111.3111.4112.4112.3112.2112.1112113114115116117 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 100 0 0 0 0 230 310886415v1 Attorney Docket No: 260525.000071 Table 5. Sequence Identifiers of V-bodies identified from panning CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 231 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 VHH VHH Group Amino Acid Amino Acid Amino Acid Amino Acid DNA Sequence Seuence Seuence Seuence Seuence Example 4. Flow cytometry binding [0651] To measure the to cel-displayed TNFR2 from human, cynomolgus or mouse, HEK293 cels were encoding for respective antigens. After 48 to 72 hours, binding was measured by incubation of His-tagged V-bodies with cels at various fixed concentrations, folowed by washing and detection with Alexa488 fluorophore-labeled anti-His antibodies. To detect the binding of V-bodies to specific cysteine- rich domains (CRDs) of TNFR2, binding to HEK293 transfected with constructs where a single CRD was exchanged for camel CRD was measured. Lack of binding to a particular construct indicated binding to the domain which was exchanged. [0652] For generation of data depicted in Figures 4A-4B, HEK293T cels were transiently transfected with a plasmid encoding human TNFR2 (hTNFR2; hTNFR2_pcDNA3.4.dna). After 48 hours, HEK293T cels were harvested and incubated with 1 µM purified His-tagged (myc-his tag) VHHs, including a control 247 310886415v1 Attorney Docket No: 260525.000071 VHH against an irrelevant antigen. VHH binding was then detected using an Alexa488-labeled anti-His tag antibody and measured by flow cytometry (iQue). [0653] For generation of data depicted in Figures 5A-5B HEK293T cels were transiently transfected with a plasmid encoding human TNFR2 (hTNFR2; hTNFR2_pcDNA3.4.dna). After 48 hours, HEK293T cels were harvested and incubated with 100 nM purified His-tagged (myc-his tag) VHHs, including a control VHH against an irrelevant antigen. VHH binding was then detected using an Alexa488-labeled anti-His tag antibody and measured by flow cytometry (iQue). [0654] For generation of data depicted in Figures 6A-6B, HEK293T cels were transiently transfected with a plasmid encoding cynomolgus TNFR2 (cTNFR2; cTNFR2_pcDNA3.4.dna) or mouse TNFR2 (mTNFR2; mTNFR2_pcDNA3.4.dna). After 48 hours, HEK293T cels were harvested and incubated with 100 nM purified His-tagged (myc-his tag) VHHs, including a control VHH against an irrelevant antigen. VHHs binding was then detected using a Alexa488-labeled anti-His tag antibody and measured by flow cytometry (iQue). [0655] Figure 7 shows testing of human TNFR2 V-body binding across a range of concentrations for T- 002, T-014, T-001, T-006, T-007, and T-003. V-bodies were tested at the folowing molar concentrations: 100 nM, 50 nM, 12.5 nM, 6.25 nM, 3.12 nM, and 1.55 nM. For generation of data depicted in Figure 7, HEK293T cels were transiently transfected with a plasmid encoding human TNFR2 (hTNFR2; hTNFR2_pcDNA3.4.dna). After 48 hours, HEK293T cels were harvested and incubated with increasing molar concentrations of purified His-tagged (myc-his tag) VHHs, including a control VHH against an irrelevant antigen. VHH binding was then detected using an Alexa488-labeled anti-His tag antibody and measured by flow cytometry (iQue). The bar histogram (Figure 7) shows the percentage of Alexa488 positive cels for T-002, T-014, T-001, T-006, T-007, and T-003. Example 5. Surface plasmon resonance binding afinities [0656] Binding afinities of the V-bodies to their respective target was determined by surface plasmon resonance (SPR) using a Caterra LSA instrument. A schematic diagram depicting the experimental setup of the present Example is shown in Figure 8. Afinity purified V-bodies were covalently crosslinked onto an LSA HC200M chip using EDC/Sulfo NHS. The interaction with human, cynomolgus, and mouse TNFR2 (extracelular domain) (V-body coupling concentration: human, 1 µM; cynomolgus/mouse, 4 µM) was measured under physiological conditions (Running Bufer: HBST- 50 mM HEPES pH 7.4, 150 mM NaCl, 0.1 % (w/v) BSA, 0.05% (v/v) Tween20, 25°C) using eight diferent antigen concentrations (3-fold serial dilutions, start at 200 nM). Resulting sensorgrams (Figures 9A-9F) were analyzed and equilibrium- binding afinities (KDs) were calculated using Carterra’s data analysis software. Figure 10 shows a 248 310886415v1 Attorney Docket No: 260525.000071 summary of binding afinities of 16 anti-TNFR2 V-bodies including T-002, T-006, T-001, T-007, T-014, and T-003. Seven of the 16 V-body candidates tested (including T-002, T-006, T-001, T-007, T-014, and T- 003) were shown to bind human TNFR2 with 1–2-digit nM afinity. Nine and zero V-bodies demonstrated cross-reactivity to cynomolgus TNFR2 (96% identical to hTNFR2 sequence) and mouse TNFR2 (63% identical to hTNFR2 sequence), respectively. Example 6. MR2-1 competition [0657] To whether humanized TNFR2 V-bodies targeted the epitope recognized by a MR2-1 bivalent expressing HEK cels (clone 25) were incubated with or without MR2-1 (5 or 10 µg/mL) prior to (pre-) and/or during (co-) incubation with His-tagged TNFR2-specific V-bodies. After washing, V-body binding was detected by labeled anti-His antibody. Binding inhibition in the presence of MR2-1 indicated binding of TNFR2 V-bodies and MR2-1 bivalent agonist to an overlapping epitope. Specificaly, T-013hu1 and T-018hu1 may recognize the same epitope as MR2-1. MR2-1 binding enhanced binding of T-015hu1, T-017hu1 and T-011hu1 to TNFR2 (Figure 11). Example 7. TNFR2 reporter assay [0658] HEK293 nuclear factor kappa B (NF-κB) reporter (Luc) cels stably expressing TNFR2 were established by transfection and antibiotic selection. Several clones were derived from the cel pool. In these cels, TNFR2 signaling was measured by NF-κB-induced expression of firefly luciferase (Luc). Data showing agonism of multivalent constructs characterized on NF-kB reporter HEK293 cels stably expressing TNFR2 are displayed in Figures 12A-12D. Typicaly, luciferase activity was measured 16- to 24-hours after incubation with the V-bodies. For assay control experiments, commercialy available human TNFR2 agonist MR2-1 monoclonal antibodies were tested on NF-κB reporter (Luc) HEK293 reporter cel-line stably expressing TNFR2 (clone 25) versus parental cel line (PCL) (Figure 13). For the sample analysis (n = 1), 2 µL of purified sample (43 mM Citrate 148 mM HEPES, pH 6) was diluted using 10-fold serial dilutions (1:10) in assay medium. A bar graph showing protein concentration (mg/mL) for the V-body constructs and respective controls (see Figure 14A, for sample details) is shown in Figure 14B. A bar graph showing relative luciferase units (RLUs) for V-body constructs and respective controls (see Figure 14A, for sample details) tested on a PCL control is shown in Figure 14C. Concentration range curve data generated using MR2-1 (Hycult) and TNFα controls revealed increasing RLU measured with increasing concentrations of MR2-1 (mol/L) and TNFα (ng/mL) (Figures 15A-15B, respectively). Figures 16A-16C show dot plots of RLU measured across increasing concentrations (mol/L) of control (control 12) and tetravalent V-body fusion constructs comprising four V-bodies mounted onto an Fc of a IgG4 variant comprising S228P and L235E mutations. Figures 17A-17F show dot plots of RLU measured across 249 310886415v1 Attorney Docket No: 260525.000071 increasing concentrations (mol/L) of control (control 10) and tetravalent V-body fusion constructs comprising four V-bodies mounted onto an Fc of a IgG4 variant comprising S228P and L235E mutations. Figures 18A-18C show dot plots of RLU measured across increasing concentrations (mol/L) of control (control 10) and tetravalent V-body fusion constructs comprising four V-bodies mounted onto an Fc of a IgG4 variant comprising S228P and L235E mutations. Figures 19A-19C show exemplary dot plots of RLUs measured across increasing concentrations (mol/L) of control (control 13) and IL-2N88D V-body fusion constructs. Limit of detection is denoted as “LOD”. A comparison of RLU measured across increasing concentrations (mol/L) of monospecific constructs 10 and 12 tested on NF-κB reporter (Luc) HEK293 reporter cel-line stably expressing TNFR2 (clone 8) is shown in Figure 20. Example 8. Testing of TNFR2 agonism by multivalent constructs [0659] The ability to agonize TNFR2 on human regulatory T cels (Tregs) was demonstrated by Leukocyte Antigen, DR isotype (HLA-DR) and chemokine motif (C-C motif) receptor 8 (CCR8) upon activation of TNFR2. HLA-DR and CCR8 are markers expressed on highly suppressive Tregs, which have been shown to be upregulated by TNFR2 agonist MR2-1. A description of established Treg markers (e.g., forkhead box P3 (FoxP3), HLA-DR, CCR8, and OX-40) useful in, e.g., screening of multivalent constructs in first wave binders on primary cels, is described in Table 6. Table 6. Treg Markers for Screening Multivalent Constructs Marker Exemplary biological function(s) FoxP3 ^ Treg marker - g g, g y sing magnetic beads, and subsequently stimulated with anti-CD3 and anti-CD28 coated stimulation beads with IL-2, in the presence or absence of fixed or increasing concentrations of a control VHH or TNFR2- specific V-bodies. [0661] An exemplary experimental timeline of TNFR2 stimulation by multivalent constructs on primary human peripheral blood mononuclear cels (PBMCs) and CD4+ CD25+ CD127dim Tregs is shown in Figure 21. Briefly, on Day 0, PBMCs were isolated and selected from three donors (Donors 1-3). Tregs were positively selected for CD4+ CD25+ CD127dim (Mitlenyi Cat. No.130-094-775). Fluorescence-activated 250 310886415v1 Attorney Docket No: 260525.000071 cel sorting (FACS) analysis was used in cel quality control (QC) experiments to confirm cel populations based on CD4, CD25, CD127, FoxP3, and TNFR2 markers. For the assay set-up, a 96-wel plate was seeded with 2x104 cels/wel CD4+ C25+ CD127dim Tregs or PBMCs (200 µl total culture volume). Cels were activated with anti-CD3/anti-CD28 coated stimulation beads (using a ratio of 1:2 for beads:cels) and IL-2 (5 IU/mL). Multivalent constructs and controls were added to each wel at a 1:100 dilution. Controls were multivalent control V-body fusion constructs, IL-2 N88D fusion constructs, and TNFR2 agonist MR2-1. On Day 6, FACS analysis was performed for live/dead quantification of cels and assessment of cel populations based on expression levels and density of CD4, FoxP3, HLA-DR, and/or CCR8 markers. A bar graph of an overview of in-assay concentrations (nM) of multivalent (e.g., tetravalent Fc, Vb-Fc-Vb, rigid bivalent no Fc) binders is shown in Figure 22. An exemplary gating strategy for Treg markers useful in the practice of the present Example is shown in Figure 23. Briefly, Treg Donor 1 is shown as an example and an identical strategy was used for Treg Donor 2 and Donor 3. Live cel and CD4 gating were based on Fluorescence Minus One (FMO) control determination of the cut- of point between background fluorescence and positive cel populations. FOXP3, HLA-DR, CCR8, and OX-40 gating was based on the CD4 subset of IgG control-stained sample from the same donor. For FoxP3, the gate was set at approximately 0.2%. For OX-40, HLA-DR and CCR8, the gate was set at approximately 2%. [0662] Findings from the present Example showed that multivalent anti-TNFR2 constructs increased expression of the Treg suppression marker HLA-DR (Figures 24A-B) and CCR8 (Figure 24B). In particular, each of the multivalent formats tested herein resulted in increased HLA-DR and CCR8 expression for specific T-003 binder compared to control with formats, with 4 binders showing the strongest increase. IL-2 N88D fusion constructs increased HLA-DR expression however a tetravalent anti-TNFR2 V-body formal was required for an additional increase in HLA-DR expression compared to control. Further, tetravalent anti-TNFR2 V-bodies strongly increased expression of Treg suppression marker HLA-DR on Fox P3+ Tregs (Figures 25A-25B). [0663] Results additionaly revealed anti-TNFR2 V-body fusion construct dose-dependent induction of Treg-suppression marker HLA-DR in FoxP3+ CD4+ Tregs (see, e.g., Figures 26-29). Dose-dependent induction of Treg suppression marker HLA-DR expression across various concentrations of tetravalent anti-TNFR2 V-body Fc fusion construct 10 for Donor 1 (top panel) and Donor 2 (bottom panel) are shown in Figure 27. Tetravalent Fc constructs, irrespective of binder, showed dose-dependent induction of Treg suppression marker HLA-DR expression. Maximal induction of HLA-DR expression was binder dependent. Construct T-003_10 reached a higher plateau compared to monoclonal TNFR2 agonist MR2- 251 310886415v1 Attorney Docket No: 260525.000071 1. Dose-dependent induction of Treg suppression marker HLA-DR expression across various concentrations of rigid bivalent anti-TNFR2 V-body fusion construct 2 for Donor 1 (top panel) and Donor 2 (bottom panel) is shown in Figure 28. Rigid bivalent constructs at higher concentrations showed modest induction of Treg suppression marker HLA-DR expression with donor dependent diferences in maximal expression compared to MR2-1. Dose-dependent induction of Treg suppression marker HLA-DR expression across various concentrations of tetravalent anti-TNFR2 V-body (Vb-Fc-Vb) fusion construct 12 for Donor 1 (top panel) and Donor 2 (bottom panel) is shown in Figure 29. Vb-Fc-Vb constructs demonstrated dose-dependent induction of Treg suppression marker HLA-DR expression. Maximal induction and potency was dose dependent. [0664] Amino acid sequences of exemplary fusion protein constructs described in Examples 7 and 8 are provided below. In the sequences, VHH sequences are indicated with a straight underline (e.g., VHH), Fc regions are indicated with bold letters (e.g., hIgG4-P329G SPLE or hIgG1 LALAGA), IL-2 N88D sequence is indicated with italic letters (e.g., IL2N88D), linker sequences are indicated with a wavy underline (e.g., Linker), and hinge regions are indicated with both a wavy underline and bold letters (e.g., hinge). T-002_2xVHH-Fc EVQLVESGGGLVQAGGSLRLSCAASGSIVSTNGMGWHRQVPGKGRELVAGIRSDGFTNYADSVKGRFTISSDNVKNT VYLQMNSLKAEDSGVYFCYYQALSSPNYGQTFWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLVESGGGLVQAGGS LRLSCAASGSIVSTNGMGWHRQVPGKGRELVAGIRSDGFTNYADSVKGRFTISSDNVKNTVYLQMNSLKAEDSGVYFC YYQALSSPNYGQTFWGQGTQVTVSSGGGGSESKYGPPCPSCPESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGL GSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 3933) T-002_VHH-Fc-VHH EVQLVESGGGLVQAGGSLRLSCAASGSIVSTNGMGWHRQVPGKGRELVAGIRSDGFTNYADSVKGRFTISSDNVKNT VYLQMNSLKAEDSGVYFCYYQALSSPNYGQTFWGQGTQVTVSSGGGGSESKYGPPCPSCPESKYGPPCPPCPAPEFE GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKGLGSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKGGGGSGGGGSEVQLVES GGGLVQAGGSLRLSCAASGSIVSTNGMGWHRQVPGKGRELVAGIRSDGFTNYADSVKGRFTISSDNVKNTVYLQMNS LKAEDSGVYFCYYQALSSPNYGQTFWGQGTQVTVSS (SEQ ID NO: 3935) T-002_IL2N88D-Fc-VHH 252 310886415v1 Attorney Docket No: 260525.000071 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR PRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSISTLTGGGGSGGGGSGGGGSGGGGSDKTHTCPPC PAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEV QLVESGGGLVQAGGSLRLSCAASGSIVSTNGMGWHRQVPGKGRELVAGIRSDGFTNYADSVKGRFTISSDNVKNTVYL QMNSLKAEDSGVYFCYYQALSSPNYGQTFWGQGTQVTVSS (SEQ ID NO: 3937) T-002_VHH-rigid_linker-VHH EVQLVESGGGLVQAGGSLRLSCAASGSIVSTNGMGWHRQVPGKGRELVAGIRSDGFTNYADSVKGRFTISSDNVKNT VYLQMNSLKAEDSGVYFCYYQALSSPNYGQTFWGQGTQVTVSSGGGGSPAPAPAPAPAPAPAPAPGGGGSEVQLVE SGGGLVQAGGSLRLSCAASGSIVSTNGMGWHRQVPGKGRELVAGIRSDGFTNYADSVKGRFTISSDNVKNTVYLQMN SLKAEDSGVYFCYYQALSSPNYGQTFWGQGTQVTVSS (SEQ ID NO: 3938) T-006_2xVHH-Fc EVQLVESGGGLAQPGGSLRLSCAASGFTFSRYAMSWARQAPGKGLEWVSGISDDGSDTYYADSVKGRFTISRDNAKN TVYLQMNSLKPEDTALYYCAKDAGSWGTGPFGYEYDYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLVESGGGLA QPGGSLRLSCAASGFTFSRYAMSWARQAPGKGLEWVSGISDDGSDTYYADSVKGRFTISRDNAKNTVYLQMNSLKPE DTALYYCAKDAGSWGTGPFGYEYDYWGQGTQVTVSSGGGGSESKYGPPCPSCPESKYGPPCPPCPAPEFEGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKGLGSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 3939) T-006_VHH-Fc-VHH EVQLVESGGGLAQPGGSLRLSCAASGFTFSRYAMSWARQAPGKGLEWVSGISDDGSDTYYADSVKGRFTISRDNAKN TVYLQMNSLKPEDTALYYCAKDAGSWGTGPFGYEYDYWGQGTQVTVSSGGGGSESKYGPPCPSCPESKYGPPCPPC PAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKGLGSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKGGGGSGGGGSE VQLVESGGGLAQPGGSLRLSCAASGFTFSRYAMSWARQAPGKGLEWVSGISDDGSDTYYADSVKGRFTISRDNAKNT VYLQMNSLKPEDTALYYCAKDAGSWGTGPFGYEYDYWGQGTQVTVSS (SEQ ID NO: 3941) T-006_IL2N88D-Fc-VHH APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR PRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSISTLTGGGGSGGGGSGGGGSGGGGSDKTHTCPPC PAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEV Attorney Docket No: 260525.000071 QLVESGGGLAQPGGSLRLSCAASGFTFSRYAMSWARQAPGKGLEWVSGISDDGSDTYYADSVKGRFTISRDNAKNTV YLQMNSLKPEDTALYYCAKDAGSWGTGPFGYEYDYWGQGTQVTVSS (SEQ ID NO: 3943) T-006_ VHH-rigid_linker-VHH EVQLVESGGGLAQPGGSLRLSCAASGFTFSRYAMSWARQAPGKGLEWVSGISDDGSDTYYADSVKGRFTISRDNAKN TVYLQMNSLKPEDTALYYCAKDAGSWGTGPFGYEYDYWGQGTQVTVSSGGGGSPAPAPAPAPAPAPAPAPGGGGS EVQLVESGGGLAQPGGSLRLSCAASGFTFSRYAMSWARQAPGKGLEWVSGISDDGSDTYYADSVKGRFTISRDNAKN TVYLQMNSLKPEDTALYYCAKDAGSWGTGPFGYEYDYWGQGTQVTVSS (SEQ ID NO: 3944) T-001_2xVHH-Fc EVQLVESGGGLVQAGGSLRVSCAASGSIFRADAMGWHRQVPGKPREFVAGIRSDGFTNYAEAVKGRFTISWDTVKNT VYLQMNSLKPEDTAVYTCYYQSLSSPNYGQVFWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLVESGGGLVQAGGS LRVSCAASGSIFRADAMGWHRQVPGKPREFVAGIRSDGFTNYAEAVKGRFTISWDTVKNTVYLQMNSLKPEDTAVYT CYYQSLSSPNYGQVFWGQGTQVTVSSGGGGSESKYGPPCPSCPESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGL GSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 3945) T-001_VHH-Fc-VHH EVQLVESGGGLVQAGGSLRVSCAASGSIFRADAMGWHRQVPGKPREFVAGIRSDGFTNYAEAVKGRFTISWDTVKNT VYLQMNSLKPEDTAVYTCYYQSLSSPNYGQVFWGQGTQVTVSSGGGGSESKYGPPCPSCPESKYGPPCPPCPAPEFE GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKGLGSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKGGGGSGGGGSEVQLVES T-001_IL2N88D-Fc-VHH APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR PRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSISTLTGGGGSGGGGSGGGGSGGGGSDKTHTCPPC PAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEV QLVESGGGLVQAGGSLRVSCAASGSIFRADAMGWHRQVPGKPREFVAGIRSDGFTNYAEAVKGRFTISWDTVKNTVY LQMNSLKPEDTAVYTCYYQSLSSPNYGQVFWGQGTQVTVSS (SEQ ID NO: 3949) T-001_ VHH-rigid_linker-VHH 254 310886415v1 Attorney Docket No: 260525.000071 EVQLVESGGGLVQAGGSLRVSCAASGSIFRADAMGWHRQVPGKPREFVAGIRSDGFTNYAEAVKGRFTISWDTVKNT VYLQMNSLKPEDTAVYTCYYQSLSSPNYGQVFWGQGTQVTVSSGGGGSPAPAPAPAPAPAPAPAPGGGGSEVQLVE SGGGLVQAGGSLRVSCAASGSIFRADAMGWHRQVPGKPREFVAGIRSDGFTNYAEAVKGRFTISWDTVKNTVYLQM NSLKPEDTAVYTCYYQSLSSPNYGQVFWGQGTQVTVSS (SEQ ID NO: 3950) T-007_2xVHH-Fc EVQLVESGGGLVQAGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAK NTGYLEMNSLKVEDTAVYYCAATPSGKAYSYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLVESGGGLVQAGGSL RLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAKNTGYLEMNSLKVEDTAVYY CAATPSGKAYSYWGQGTQVTVSSGGGGSESKYGPPCPSCPESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLGSS IEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSR LTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 3951) T-007_VHH-Fc-VHH EVQLVESGGGLVQAGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAK NTGYLEMNSLKVEDTAVYYCAATPSGKAYSYWGQGTQVTVSSGGGGSESKYGPPCPSCPESKYGPPCPPCPAPEFEG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKGLGSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKGGGGSGGGGSEVQLVESG GGLVQAGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAKNTGYLEMN SLKVEDTAVYYCAATPSGKAYSYWGQGTQVTVSS (SEQ ID NO: 3953) T-007_IL2N88D-Fc-VHH APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR PRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSISTLTGGGGSGGGGSGGGGSGGGGSDKTHTCPPC PAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEV QLVESGGGLVQAGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAKNT GYLEMNSLKVEDTAVYYCAATPSGKAYSYWGQGTQVTVSS (SEQ ID NO: 3955) T-007_ VHH-rigid_linker-VHH EVQLVESGGGLVQAGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAK NTGYLEMNSLKVEDTAVYYCAATPSGKAYSYWGQGTQVTVSSGGGGSPAPAPAPAPAPAPAPAPGGGGSEVQLVES Attorney Docket No: 260525.000071 T-014_VHH-Fc-VHH EVQLVESGGGLVEAGGSLRLSCAASGRTFGSYTMGWFRQAPGREQEFLASIRRTGGSTSYADSVKGRFTISRDNAKKAV YLQMNSLKPEDTAVYYCAAAPTGRAFTYWGQGTQVTVSSGGGGSESKYGPPCPSCPESKYGPPCPPCPAPEFEGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKGLGSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKGGGGSGGGGSEVQLVESGGG LVEAGGSLRLSCAASGRTFGSYTMGWFRQAPGREQEFLASIRRTGGSTSYADSVKGRFTISRDNAKKAVYLQMNSLKPE DTAVYYCAAAPTGRAFTYWGQGTQVTVSS (SEQ ID NO: 3957) T-003_2xVHH-Fc EVQLVESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLKPEDTAVYYCAADSDLSTVVVGPHDYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGG SLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTLYLQMNSLKPEDTAVYY CAADSDLSTVVVGPHDYWGQGTQVTVSSGGGGSESKYGPPCPSCPESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KGLGSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 3959) T-003_VHH-Fc-VHH EVQLVESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLKPEDTAVYYCAADSDLSTVVVGPHDYWGQGTQVTVSSGGGGSESKYGPPCPSCPESKYGPPCPPCPAPEF EGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLGSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKGGGGSGGGGSEVQLVE SGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTLYLQMN SLKPEDTAVYYCAADSDLSTVVVGPHDYWGQGTQVTVSS (SEQ ID NO: 3961) T-003_IL2N88D-Fc-VHH APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR PRDLISDINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSISTLTGGGGSGGGGSGGGGSGGGGSDKTHTCPPC PAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEV QLVESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTLYL QMNSLKPEDTAVYYCAADSDLSTVVVGPHDYWGQGTQVTVSS (SEQ ID NO: 3963) 256 310886415v1 Attorney Docket No: 260525.000071 T-003_ VHH-rigid_linker-VHH EVQLVESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLKPEDTAVYYCAADSDLSTVVVGPHDYWGQGTQVTVSSGGGGSPAPAPAPAPAPAPAPAPGGGGSEVQLV ESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTLYLQM NSLKPEDTAVYYCAADSDLSTVVVGPHDYWGQGTQVTVSS (SEQ ID NO: 3964) Example 9. TNFR2 agonism by tetravalent VHH-Fc fusion increases suppressive function and stabilizes efector diferentiation in vitro [0665] and activation. It was hypothesized that TNFR2 stimulation wil also increase Treg stability based on the phenotype of TNFR2 knockout mice in which Treg are unstable and convert into efector cels. To test this hypothesis, multivalent anti-TNFR2 VHH proteins with agonist activity on TNFR2 were assessed for their impact on Treg proliferation, activation, immune suppressive function, and stability compared to IL-2 muteins. [0666] Human naïve Treg treated with anti-TNFR2 VHH or IL-2 mutein were evaluated to detect efects on proliferation, activation, suppressive function, and stability in inflammatory conditions. Specificaly, tetravalent-Fc agonists (T-007_2xVHH-Fc and T-003_2xVHH-Fc) were characterized in vitro for their ability to expand and activate Treg in the presence of anti-CD3 and IL-2 stimulation. The stability of human naïve Treg (CD4+CD25+CD45RA+) sorted from healthy donor PBMC by magnetic beads was investigated upon stimulation with tetravalent VHH for 5 days folowed by 11 to 12 days of inflammatory cytokine chalenge (IL-21, IL-23, IL-1b +/- TGFb) and IL-17A or IFN^ intracelular staining after PMA/ionomycin restimulation. Suppressive function was measured by assessing Treg ability to inhibit the proliferation of naïve CD4 responder cels. Similarly, the efect of TNFR2 agonist T-037on proinflammatory cytokine production was evaluated from human PBMC treated with 5 nM TNFR2 V- body or CD28 agonist for 5 days in the presence of anti-CD3. Treg proliferation was measured by assessing percent of proliferating Treg (CD4+FOXP3+) by cel tracer dilution by flow cytometry and cytokine production was measured in the supernatant by homogeneous time resolved fluorescence (HTRF) assay (Figures 44A and 44B). [0667] Figures 31 and 33A-33B show that tetravalent TNFR2 VHH-Fc antibodies induced the expansion of naive human Treg and up-regulated biomarkers of enhanced immunosuppressive activity such as CCR8 and HLA-DR and stability marker EZH2. In line with these results, activation of TNFR2 increased the ability of naïve human Treg to suppress the proliferation of CD4 responder cels (Figure 35). Furthermore, stimulation of naïve human Treg with VHH-Fc prevented the loss of FOXP3 and their 257 310886415v1 Attorney Docket No: 260525.000071 diferentiation into IL-17A- or IFN^-secreting cels when cultivated in the presence of inflammatory cytokines (Figures 32A, 32B and 34A-34C). TNFR2 agonist expanded Treg (CD4+FOXP3+) without inducing proinflammatory cytokines compared to CD28 agonist. (Figure 44). [0668] Agonistic TNFR2 VHH induced the expansion of naïve human Treg, increased the expression of activation markers and stimulated suppressive efects against CD4+ T efector cels. TNFR2 VHH constructs, but not IL-2 muteins, increased human Treg stability in the presence of proinflammatory cytokines based on sustained presence of FOXP3 bright cels and prevention of conversion of Treg into IL-17A- or IFN^-secreting cels. These data demonstrate that agonism of TNFR2 by a tetravalent VHH-Fc fusion antibody expands human Treg, increases their suppressive function and stabilize their phenotype under inflammatory conditions in vitro. Example 10. TNFR2 agonism by tetravalent VHH-Fc fusion and expands and activates Treg cel in vivo [0669] The efects of anti-TNFR2 VHH agonists on spleen lymphocyte population in human TNFR2 knock-in mice were assessed by flow cytometry 5 days after a single intravenous injection (2.5 mg/kg) of tetravalent VHH-Fc antibody T-007_2xVHH-Fc, or control VHH, or mAb into human TNFR2 knock-in mice. [0670] Upon injection in human TNFR2 knock-in mice, tetravalent VHH-Fc antibody T-007_2xVHH-Fc led to a 3-fold increase in the percentage of FOXP3+ cel among CD4+ cels in the spleen, while no increase of CD4+FOXP3- and CD8+FOXP3- conventional T cels and only a minor impact on overal splenic immune cel composition was observed (Figures 36 and 38). Treatment led to Treg activation as shown by the upregulation of ICOS and ICAM-1 (Figure 37). Importantly, injection was wel tolerated and did not induce weight loss or changes in systemic levels of inflammatory cytokines (TNF, IL-6, IFN^, IL-5) but increased serum level of IL-10, a cytokine with demonstrated immune-regulatory functions (Figure 39). TNFR2 agonists, but not IL-2 muteins, increased human Treg stability in the presence of proinflammatory cytokines based on sustained high expression of FOXP3 and prevention of conversion of Treg into IL-17A or IFNγ-secreting cels (Figures 34A-34C). [0671] These data demonstrated that in vivo, a single injection is safe in mice and leads to Treg expansion and activation. Anti-TNFR2 VHH agonistic proteins are efective at expanding Tregs that have a more stable immunosuppressive capacity and phenotype (preventing pathogenic conversion to Tef) compared to IL-2 muteins and may provide a durable and disease modifying therapy for multiple autoimmune diseases. Example 11. Evaluation of efect of VHH-Fc fusion on Treg function in vivo 258 310886415v1 Attorney Docket No: 260525.000071 [0672] Human TNFR2 knock-in mice were injected with the constructs as indicated in Figures 42A-42B at 3 mg/kg intravenously. After 5 days, percentage of Treg (FOXP3+CD4+) among CD45+ cel as wel as FOXP3, ICAM-1, ICOS expression (MFI, mean fluorescent intensity) on Treg was measured by flow cytometry. Data as depicted in Figures 42A and 42B show Treg expansion in the spleen as wel as increased expression of FOXP3, linked to Treg stability and function, and Treg activation shown by up- regulation of ICAM-1 and ICOS. Administration of anti-TNFR2 VHH agonists to mice increased Treg by three-fold in blood and tissues without increasing conventional Teff or NK cels as it induced a higher level of FOXP3 and surface markers (FOXP3, ICAM-1, OX-40, ICOS, and CCR8). The efects of anti-TNFR2 VHH agonists on spleen lymphocyte population or on blood cels (eosinophils) in human TNFR2 knock-in mice were assessed after a single intravenous injection (3 mg/kg) of tetravalent VHH-Fc antibody T-037, or control VHH, or IL-2 N88D into human TNFR2 knock-in mice. Similarly, the efect of anti-TNFR2 VHH agonist was assessed on serum cytokines 1 day after the single injection of tetravalent VHH-Fc antibody T-037, control VHH or IL-2 N88D (Figures 41A-41E). Further, anti-TNFR2 VHH agonists expand Treg across tissues (Figures 40A-40B). Example 12. Evaluation of the efect of VHH-Fc fusion on arthritis in vivo [0673] At day 0, human TNFR2 knock-in mice were injected with anti-colagen antibodies as wel construct T-037at 3 mg/kg intravenously or control VHH. At day 3, mice were chalenged with lipopolysaccharide (LPS). Treg cels were measured at day 6 and at day 7, arthritis score (total number of afected digits) and paw volume were measured. The same experiment was repeated with T-043 construct. Data as depicted in Figure 43B and 43C show reduction of arthritis, measured by paw volume and arthritis score, in a model of colagen-antibody induced arthritis upon treatment with TNFR2 agonist T-037and T-043. [0674] Amino acid sequences of exemplary fusion protein constructs described in Examples 11 and 12 as wel as additional engineered constructs are provided below. In the sequences, VHH sequences are indicated with a straight underline (e.g., VHH), Fc regions are indicated with bold letters (e.g., hIgG4- SPLE or hIgG1 LALAPA), N-terminal modification are indicated with both bold and a straight underline (e.g., N-term modification), C-terminal modification are indicated with both italic and a wavy underline (e.g., C-term modification), linker sequences are indicated with a wavy underline (e.g., Linker), and hinge regions are indicated with both a wavy underline and bold letters (e.g., hinge). T-037 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL 259 310886415v1 Attorney Docket No: 260525.000071 SCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPSGKAYSYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4483) T-038 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPSGKAYSYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:4484) T-039 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCATTPSGKAYSYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC ATTPSGKAYSYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:4485) T-040 EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLS CAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKTVYLQMNSLRPEDTAVYYCVAS PTGRAFTYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4486) T-041 EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLS CAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKTVYLQMNSLRPEDTAVYYCVAS PTGRAFTYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4487) T-042 260 310886415v1 Attorney Docket No: 260525.000071 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGKTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGKTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPSGKAYSYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4488) T-043 EVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGG SLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVYY CAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4489) T-044 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPSGKAYSYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4490) T-045 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAATPSGKAYSYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4491) T-046 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAATPSGKAYSYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4492) 261 310886415v1 Attorney Docket No: 260525.000071 T-047 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLRL SCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKTVYLQMNSLRPEDTAVYYCVA SPTGRAFTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4493) T-048 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLRL SCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKTVYLQMNSLRPEDTAVYYCVA SPTGRAFTYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4494) T-049 DVQLVESGGGLVQPGGSLRLSCAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNT WYLQMNSLRPEDTAVYYCSVLGRDLVTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLVESGGGLVQPGGSLRLS CAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNTWYLQMNSLRPEDTAVYYCSVL GRDLVTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4686) T-050 DVQLVESGGGLVQPGGSLRLSCAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNT WYLQMNSLRPEDTAVYYCSVLGRDRVTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLVESGGGLVQPGGSLRL SCAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNTWYLQMNSLRPEDTAVYYCSV LGRDRVTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4687) T-051 DVQLVESGGGLVQPGGSLRLSCAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNT WYLQMNSLRPEDTAVYYCSVLGRDIVTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLVESGGGLVQPGGSLRLS CAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNTWYLQMNSLRPEDTAVYYCSVL GRDIVTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVY 262 310886415v1 Attorney Docket No: 260525.000071 TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4688) T-052 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAAAPSGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAAAPSGKAYSYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4689) T-053 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATASGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAATASGKAYSYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4690) T-054 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPAGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAATPAGKAYSYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4691) T-055 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSAKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAATPSAKAYSYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4692) T-056 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGAAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAATPSGAAYSYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH Attorney Docket No: 260525.000071 EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4693) T-057 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAASYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAATPSGKAASYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4694) T-058 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYAYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAATPSGKAYAYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4695) T-059 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSAWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAATPSGKAYSAWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4696) T-060 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAK NTGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSL RLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVY YCAATPSGKAYSYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4495) T-061 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAK NTGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSL RLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVY 264 310886415v1 Attorney Docket No: 260525.000071 YCAATPSGKAYSYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4496) T-062 EVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGG SLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVYY CAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4497) T-063 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPSGKAYSYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4498) T-064 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLRLS CAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKTVYLQMNSLRPEDTAVYYCVAS PTGRAFTYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4499) T-065 DVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGG SLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVYY CAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4500) T-066 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAK NTGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSL 265 310886415v1 Attorney Docket No: 260525.000071 RLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVY YCAATPSGKAYSYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4501) T-067 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLRLS CAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKTVYLQMNSLRPEDTAVYYCVAS PTGRAFTYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4502) T-068 DVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGG SLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVYY CAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4503) T-069 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAK NTGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSL RLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVY YCAATPSGKAYSYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4504) T-070 EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLS CAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKTVYLQMNSLRPEDTAVYYCVAS PTGRAFTYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4505) T-071 266 310886415v1 Attorney Docket No: 260525.000071 EVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGG SLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVYY CAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4506) T-072 EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLS CAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKTVYLQMNSLRPEDTAVYYCVAS PTGRAFTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4507) T-073 EVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGG SLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVYY CAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4508) T-074 DVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPG GSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVY YCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4509) T-075 DVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPG GSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVY YCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISK AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4510) 267 310886415v1 Attorney Docket No: 260525.000071 T-076 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTYWGQGTQVTVAGGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLRL SCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKTVYLQMNSLRPEDTAVYYCVA SPTGRAFTYWGQGTQVTVAGGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4511) T-077 DVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVAGGGGGSGGGGSGGGGSDVQLLESGGGLVQPG GSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVY YCAADSDLSTVTVGPHDYWGQGTQVTVAGGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4512) T-078 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAK NTGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVAGGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSL RLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVY YCAATPSGKAYSYWGQGTQVTVAGGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4513) T-079 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAAAPSGKAYSYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AAAPSGKAYSYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4709) T-080 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAAAPSGKAYSYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AAAPSGKAYSYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPRE 268 310886415v1 Attorney Docket No: 260525.000071 PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4710) T-081 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAK NTGYLQMNSLRVEDTAVYYCAAAPSGKAYSYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSL RLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVY YCAAAPSGKAYSYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4711) T-082 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAK NTGYLQMNSLRVEDTAVYYCAAAPSGKAYSYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSL RLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVY YCAAAPSGKAYSYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4712) T-083 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAAAPSGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAAAPSGKAYSYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4713) T-084 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAAAPSGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAAAPSGKAYSYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4714) T-085 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAK NTGYLQMNSLRVEDTAVYYCAAAPSGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSL RLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVY YCAAAPSGKAYSYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV Attorney Docket No: 260525.000071 SQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4715) T-086 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAK NTGYLQMNSLRVEDTAVYYCAAAPSGKAYSYWGQGTQVTVAGGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGS LRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVY YCAAAPSGKAYSYWGQGTQVTVAGGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4716) T-087 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA ATPTGKAYTYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4735) T-088 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA ATPTGKAYTYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4736) T-089 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4737) T-090 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC 270 310886415v1 Attorney Docket No: 260525.000071 AATPTGKAYTYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4738) T-091 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4739) T-092 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4740) T-093 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4741) T-094 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4742) T-095 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVAGGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR 271 310886415v1 Attorney Docket No: 260525.000071 LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVAGGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA ATPTGKAYTYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4744) T-097 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA ATPTGKAYTYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4745) T-098 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4746) T-099 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4747) T-100 272 310886415v1 Attorney Docket No: 260525.000071 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4749) T-102 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4750) T-103 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4751) T-104 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVAGGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVAGGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4752) 273 310886415v1 Attorney Docket No: 260525.000071 T-105 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA GTLSGKAYTYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4753) T-106 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA GTLSGKAYTYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4754) T-107 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA GTLSGKAYTYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4755) T-108 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA GTLSGKAYTYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4756) T-109 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA GTLSGKAYTYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE 274 310886415v1 Attorney Docket No: 260525.000071 PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4757) T-110 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA GTLSGKAYTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4758) T-111 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AGTLSGKAYTYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4759) T-112 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AGTLSGKAYTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4760) T-113 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVAGGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AGTLSGKAYTYWGQGTQVTVAGGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4761) T-114 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA GTLSGKAYTYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE Attorney Docket No: 260525.000071 DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4762) T-115 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA GTLSGKAYTYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4763) T-116 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA GTLSGKAYTYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4764) T-117 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA GTLSGKAYTYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4765) T-118 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA GTLSGKAYTYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4766) T-119 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRL SCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYCA 276 310886415v1 Attorney Docket No: 260525.000071 GTLSGKAYTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4767) T-120 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AGTLSGKAYTYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4768) T-121 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AGTLSGKAYTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:4769) T-122 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVAGGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AGTLSGKAYTYWGQGTQVTVAGGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:4770) T-030 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAK NTGYLQMNSLRVEDTAVYYCAASPSGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSL RLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVY YCAASPSGKAYSYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4772) T-031 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAK NTGYLQMNSLRVEDTAVYYCAASPSGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSL 277 310886415v1 Attorney Docket No: 260525.000071 RLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVY YCAASPSGKAYSYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4773) T-032 DVQLLESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGG SLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVYY CAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4776) T-033 DVQLLESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGG SLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVYY CAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4777) T-034 DVQLLESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPG GSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVY YCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS KAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4778) T-035 DVQLLESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPG GSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVY YCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISK AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4779) 278 310886415v1 Attorney Docket No: 260525.000071 Example 13. Surface plasmon resonance binding afinities of additional V-bodies of cluster D [0675] Binding afinities of the V-bodies to human or cynomolgus TNFR2 was determined by surface plasmon resonance (SPR) using a Caterra LSA instrument. A schematic diagram depicting the experimental setup of the present Example is shown in Figure 8. Afinity purified V-bodies were covalently crosslinked onto an LSA HC30M or HC200M chip using EDC/Sulfo NHS. The interaction with human and cynomolgus TNFR2 (extracelular domain) (V-body coupling concentration: human, 1 µM; cynomolgus, 3-4 µM) was measured under physiological conditions (Running Bufer: HBST- 50 mM HEPES pH 7.4, 150 mM NaCl, 0.1 % (w/v) BSA, 0.05% (v/v) Tween20, 25°C) using twelve diferent antigen concentrations (2-fold serial dilutions, start at 1000 nM). Resulting sensorgrams (Figures 45A-45F) were analyzed and equilibrium-binding afinities (KDs) were calculated using Carterra’s data analysis software. [0676] Amino acid sequence of an exemplary fusion protein construct from cluster D is provided below. In the sequence, VHH sequences (T-009Hu1_SGR_N/C) are indicated with a straight underline (e.g., VHH), the Fc region is indicated with bold leters (e.g., hIgG1 LALAPA), N-terminal modification are indicated with both bold and a straight underline (e.g., N-term modification), C- terminal modification are indicated with both italic and a wavy underline (e.g., C-term modification), linker sequences are indicated with a wavy underline (e.g., Linker), and the hinge region is indicated with both a wavy underline and bold letters (e.g., hinge). T-036 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4903) Example 14. Surface plasmon resonance binding afinities of additional V-bodies of clusters D and K obtained by alanine scanning mutagenesis [0677] Binding afinities of the V-bodies listed in Table 7 to human or cynomolgus TNFR2 was determined by surface plasmon resonance (SPR) using a Caterra LSA instrument. A schematic diagram depicting the experimental setup of the present Example is shown in Figure 8. Afinity purified V-bodies were covalently crosslinked onto an LSA HC30M or HC200M chip using EDC/Sulfo NHS. The interaction with human and cynomolgus TNFR2 (extracelular domain) (V-body coupling concentration: human, 1 µM; cynomolgus, 3-4 µM) was measured under physiological conditions (Running Bufer: HBST- 50 mM 279 310886415v1 Attorney Docket No: 260525.000071 HEPES pH 7.4, 150 mM NaCl, 0.1 % (w/v) BSA, 0.05% (v/v) Tween20, 25°C) using twelve diferent antigen concentrations (2-fold serial dilutions, start at 1000 nM). Resulting sensorgrams (Figures 46A-46J) were analyzed and equilibrium-binding afinities (KDs) were calculated using Carterra’s data analysis software. For data processing, high or low antigen concentration curves were excluded based on afinity or curve fit. Table 7. Sequence identifiers for exemplary anti-TNFR2 VHH antibodies obtained by alanine scanning mutagenesis CDR1 CDR2 CDR3 Humanized VHH Antibody ID Group Amino acid Amino acid Amino acid Amino acid Nucleotide e 310886415v1 Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 Humanized VHH Antibody ID Group Amino acid Amino acid Amino acid Amino acid Nucleotide e Example 15. Surface plasmon resonance binding afinities of human or cynomolgus TNFR2 to Fc-tagged V-bodies [0678] Binding afinities of human or cynomolgus TNFR2 (extracelular domain) to selected Fc-tagged V- bodies listed in Table 8 was determined by surface plasmon resonance (SPR) using a Caterra LSA instrument. Purified TNFR2 was covalently crosslinked onto an LSA HC30M chip using EDC/Sulfo NHS. The interaction with the Fc-tagged V-bodies (TNFR2 coupling concentration: 75nM) was measured under physiological conditions (Running Bufer: HBST- 50 mM HEPES pH 7.4, 150 mM NaCl, 0.1 % (w/v) BSA, 0.05% (v/v) Tween20, 25°C) using twelve diferent antigen concentrations of TNFR2 (2-fold serial dilutions, starting from 1000 nM). Resulting sensorgrams (Figures 47A-47B) were analyzed and equilibrium-binding afinities (KDs) were calculated using Carterra’s data analysis software. For data processing, high or low antigen concentration curves were excluded based on afinity or curve fit. 281 310886415v1 Attorney Docket No: 260525.000071 Example 16. Binding and agonistic activity of bivalent V-bodies on TNFR2 HEK NF-kB reporter cels [0679] incubation of increasing concentrations of the V-bodies listed in Table 8 on TNFR2 HEK reporter cels, folowed by washing and detection by an anti-human IgG secondary antibody. On-cel binding was measured by flow cytometry (Figure 48A). [0680] Agonistic activity was characterized by measuring reporter activity via luminescence after overnight incubation of TNFR2 HEK NF-kB-luciferase reporter cels with the tested V-bodies (Figure 48B). Data demonstrate that decreased TNFR2 agonism can be engineered by introducing specific mutations in the CDR regions. Table 8. Sequence identifiers for exemplary anti-TNFR2 Fc-tagged bivalent V-bodies Fc-tagged Amino N ltid M nmr CDR1 CDR2 CDR3 id e [0681] The Fc-tagged bivalent V-bodies listed in Table 8 contain two copies of the respective monomer V-bodies as indicated. Amino acid sequences of exemplary Fc-tagged bivalent B-body constructs described in Table 8 are provided below. In the sequences, VHH sequences are indicated with a straight underline (e.g., VHH), Fc regions are indicated with bold letters (e.g., hIgG1 LALAPA), N-terminal modification are indicated with both bold and a straight underline (e.g., N-term modification), C- terminal modification are indicated with both italic and a wavy underline (e.g., C-term modification), linker sequences are indicated with a wavy underline (e.g., Linker), and hinge regions are indicated with both a wavy underline and bold letters (e.g., hinge). The monomer V-bodies were modified to replace Glu (E) with Asp (D) at the first position of the amino-terminus and to introduce the amino acid sequence VPAG (SEQ ID NO: 4698) at the carboxy-terminus for preparing the respective fusion protein 282 310886415v1 Attorney Docket No: 260525.000071 constructs. The amino acid sequences of monomer V-bodies present within the fusion protein constructs are provided as SEQ ID Nos: 4994-5001 in the section titled ‘List of Sequences’. T-022 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4979) T-023 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPAGAAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4981) T-024 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCAASPAGRAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4983) T-025 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVAAPAGRAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4985) T-026 283 310886415v1 Attorney Docket No: 260525.000071 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASAAGRAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4987) T-027 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPAARAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4989) T-028 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASATGAAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4991) T-029 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCAASATGRAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA LAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4993) * * * [0682] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein wil become apparent to those skiled in the art from the foregoing description. Such modifications are intended to fal within the scope of the appended claims. 284 310886415v1 Attorney Docket No: 260525.000071 [0683] Al patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physicaly present in this specification. 285 310886415v1 Attorney Docket No: 260525.000071 List of Sequences SEQ ID NO: 1 T-001_CDR1 GSIFRADA SEQ ID NO: 2 T-001/T-002_CDR2 IRSDGFT SEQ ID NO: 3 T-001_CDR3 YYQSLSSPNYGQVF SEQ ID NO: 4 T-001_ful-length VHH (amino acid sequence) EVQLVESGGGLVQAGGSLRVSCAASGSIFRADAMGWHRQVPGKPREFVAGIRSDGFTNYAEAVKGRFTISWDTVKNT VYLQMNSLKPEDTAVYTCYYQSLSSPNYGQVFWGQGTQVTVSS SEQ ID NO: 5 T-002_CDR1 GSIVSTNG SEQ ID NO: 6 T-002_CDR3 YYQALSSPNYGQTF SEQ ID NO: 7 T-002_ful-length VHH (amino acid sequence) EVQLVESGGGLVQAGGSLRLSCAASGSIVSTNGMGWHRQVPGKGRELVAGIRSDGFTNYADSVKGRFTISSDNVKNT VYLQMNSLKAEDSGVYFCYYQALSSPNYGQTFWGQGTQVTVSS SEQ ID NO: 8 T-003_T-005hu1_CDR1 GFTFDDIA SEQ ID NO: 9 T-003_T-005hu1_CDR2 IYSYGPNT SEQ ID NO: 10 T-003_CDR3; T-004_CDR3 AADSDLSTVVVGPHDY SEQ ID NO: 11 T-003_ful-length VHH (amino acid sequence) EVQLVESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLKPEDTAVYYCAADSDLSTVVVGPHDYWGQGTQVTVSS SEQ ID NO: 12 T-006_CDR1 GFTFSRYA SEQ ID NO: 13 T-006_CDR2 ISDDGSDT 286 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 14 T-006_CDR3 AKDAGSWGTGPFGYEYDY SEQ ID NO: 15 T-006_ful-length VHH (amino acid sequence) EVQLVESGGGLAQPGGSLRLSCAASGFTFSRYAMSWARQAPGKGLEWVSGISDDGSDTYYADSVKGRFTISRDNAKN TVYLQMNSLKPEDTALYYCAKDAGSWGTGPFGYEYDYWGQGTQVTVSS SEQ ID NO: 16 T-007_T-008hu1_T-008hu1.A3 CDR1 GRTFSDYG SEQ ID NO: 17 T-007_CDR2 INWSNGRT SEQ ID NO: 18 T-007_T-008hu1_CDR3 AATPSGKAYSY SEQ ID NO: 19 T-007_ful-length VHH (amino acid sequence) EVQLVESGGGLVQAGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAK NTGYLEMNSLKVEDTAVYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO: 20 T-011_CDR1 GLTLDYYA SEQ ID NO: 21 T-011_CDR2 ISTSDGST SEQ ID NO: 22 T-011_CDR3 ATPGPYTYCAPYGSSWSRGYDY SEQ ID NO: 23 T-011_ful-length VHH (amino acid sequence) EVQLVESGGGLVQPGGSLRLSCAASGLTLDYYAIGWFRQAPGKEREGVSCISTSDGSTYYTDSVKGRFTISRDNAKNTVY LQMNSLKPEDTAVYYCATPGPYTYCAPYGSSWSRGYDYWGQGTQVTVSS SEQ ID NO: 24 T-012_CDR1 GFTFSMYS SEQ ID NO: 25 T-012_CDR2 IDTRGST SEQ ID NO: 26 T-012_CDR3 ARVGGAPYEYNY SEQ ID NO: 27 T-012_ful-length VHH (amino acid sequence) 287 310886415v1 Attorney Docket No: 260525.000071 EVQLVESGGGLVQPGGSLRLSCAASGFTFSMYSMSWVRQAPGKGPEWVSAIDTRGSTRYADSVKGRFTISRDNAKNT LYLQMDSLKPEDTALYYCARVGGAPYEYNYRGQGTQVTVSS SEQ ID NO: 28 T-013_CDR1 GFNFSMYS SEQ ID NO: 29 T-013_CDR2 IDTGGST SEQ ID NO: 30 T-013_CDR3 ARVRGTPYEYGY SEQ ID NO: 31 T-013_ful-length VHH (amino acid sequence) EVQLVESGGGLVQPGGSLRLSCAASGFNFSMYSMSWVRQAPGKGPEWVSAIDTGGSTRYADSVKGRFTISRDNAKNT LYLQMDSLKPEDTALYYCARVRGTPYEYGYRGQGTQVTVSS SEQ ID NO: 32 T-014_CDR1 GRTFGSYT SEQ ID NO: 33 T-014_CDR2 IRRTGGST SEQ ID NO: 34 T-014_CDR3 AAAPTGRAFTY SEQ ID NO: 35 T-014_ful-length VHH (amino acid sequence) EVQLVESGGGLVEAGGSLRLSCAASGRTFGSYTMGWFRQAPGREQEFLASIRRTGGSTSYADSVKGRFTISRDNAKKAV YLQMNSLKPEDTAVYYCAAAPTGRAFTYWGQGTQVTVSS SEQ ID NO: 36 T-015_CDR1 GRTFSSLF SEQ ID NO: 37 T-015_CDR2 IRYPGLIT SEQ ID NO: 38 T-015_CDR3 AAAPTGRAFNY SEQ ID NO: 39 T-015_ful-length VHH (amino acid sequence) EVQLVESGGGLVQAGGSLRLSCLASGRTFSSLFMGWFRQAPGKEREFVASIRYPGLITNYADSAKGRFISRDSAKNTVY LQMDSLKPEDTGLYSCAAAPTGRAFNYWGLGTQVTVSS SEQ ID NO: 40 T-017_CDR1 GASLSRNA 288 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 41 T-017_CDR2 IYDDGET SEQ ID NO: 42 T-017_CDR3 AGSAFDF SEQ ID NO: 43 T-017_ful-length VHH (amino acid sequence) EVQLVESGGGSVQPGGSLRLLCAVSGASLSRNAIWVRQTPEKGLEWVSTIYDDGETYYRDSVKGRFTISRDLAENTVHL QMGNLQAEDTAVYYCAGSAFDFWGRGTQVTVSS SEQ ID NO: 44 T-018_CDR1 GSTFRFPP SEQ ID NO: 45 T-018_T-019_CDR2 LTSGGST SEQ ID NO: 46 T-018_T-019_CDR3 SVLGRDMMTY SEQ ID NO: 47 T-018_ful-length VHH (amino acid sequence) EVQLVESGGGLVQAGGSLRLSCAASGSTFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNT WYLQMSSLRPEDTAVYYCSVLGRDMMTYWGQGTQVTVSS SEQ ID NO: 48 T-001_ful-length VHH (DNA sequence) GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTGCAGGCTGGGGGGTCTCTGAGAGTCTCCTGTGCAGCCTC TGGAAGCATCTTCAGGGCCGATGCCATGGGCTGGCACCGCCAGGTTCCAGGGAAGCCGCGCGAGTTTGTCGCGG GTATTCGTAGTGATGGATTTACCAACTATGCGGAGGCCGTGAAGGGCCGATTCACCATCTCCTGGGATACCGTCAA GAACACGGTGTATCTGCAGATGAACAGCCTGAAACCTGAGGACACAGCCGTCTATACTTGTTATTATCAATCCCTC AGTAGTCCTAATTACGGTCAAGTCTTCTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 49 T-002_ful-length VHH (DNA sequence) GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTGCAGGCTGGGGGGTCTCTGAGACTCTCCTGTGCAGCCTC TGGAAGCATCGTCAGTACGAATGGCATGGGATGGCACCGCCAGGTTCCAGGGAAGGGCCGCGAGTTGGTCGCAG GTATTCGTAGTGATGGATTTACAAACTATGCGGACTCCGTGAAGGGCCGATTCACCATCTCCAGCGATAACGTCAA GAACACGGTGTATCTGCAGATGAACAGCCTGAAAGCTGAGGACTCAGGCGTCTATTTTTGTTATTATCAAGCCCTC AGTTCTCCTAATTACGGCCAAACCTTCTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 50 T-003_ful-length VHH (DNA sequence) GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTGCAGCCTGGGGGTTCTCTGAGACTCTCCTGTGCAGCCTCT GGATTCACTTTTGATGATATTGCCATGACCTGGGTCCGACAGGCTCCAGGGAAGGGGCTGGAGTGGGTGTCCAGT ATTTATAGTTACGGGCCAAACACATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCACAGACAGCGCCA AGAACACACTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACGGCCGTGTATTACTGTGCAGCAGATTCAG ACCTAAGTACAGTAGTAGTTGGTCCCCATGACTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA 289 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 51 T-006_ful-length VHH (DNA sequence) GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGCGCAGCCTGGGGGGTCTCTGAGACTCTCCTGTGCAGCCTC TGGATTCACCTTCAGTCGCTATGCCATGAGCTGGGCCCGCCAGGCTCCAGGAAAGGGGCTCGAATGGGTGTCCGG TATTTCTGATGATGGCAGTGACACATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCC AAGAACACGGTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACGGCACTGTATTACTGTGCAAAAGACGCG GGGAGTTGGGGTACGGGTCCCTTTGGCTATGAGTATGACTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 52 T-007_ful-length VHH (DNA sequence) GAGGTGCAGCTGGTGGAGTCTGGGGGAGGATTGGTGCAGGCTGGGGGCTCTCTGAGACTCTCCTGTGCAGCCTC TGGACGCACCTTTAGTGACTATGGCATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGATAGTGAGTTTGTAGCGGC GATTAACTGGAGTAATGGTCGCACAAACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAACGC CAAGAACACGGGGTATCTGGAAATGAACAGCCTGAAAGTTGAGGACACGGCCGTTTATTACTGTGCAGCAACCCC CTCCGGAAAGGCGTATAGCTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA SEQ ID NO: 53 T-011_ful-length VHH (DNA sequence) GAAGTCCAATTAGTAGAGTCTGGTGGCGGTCTGGTCCAGCCTGGCGGTTCTTTGCGCCTCAGCTGCGCCGCATCC GGTTTAACCCTGGATTATTATGCAATAGGATGGTTTCGTCAAGCTCCGGGCAAAGAGCGGGAAGGCGTATCATGT ATTTCAACATCCGATGGGTCTACTTACTACACCGACAGCGTTAAGGGACGCTTCACAATCTCGCGTGATAACGCTA AAAATACAGTTTATCTTCAGATGAATAGTCTGAAACCCGAAGACACTGCGGTGTACTATTGCGCGACGCCTGGCCC ATATACTTACTGTGCCCCGTATGGAAGCTCATGGAGTAGAGGTTATGATTATTGGGGGCAGGGGACGCAGGTGAC CGTTTCGAGT SEQ ID NO: 54 T-012_ful-length VHH (DNA sequence) GAAGTTCAGTTGGTCGAGTCGGGTGGGGGATTAGTACAGCCAGGGGGCTCTCTCCGCCTGTCATGTGCAGCATCG GGCTTTACTTTTAGCATGTATAGTATGAGCTGGGTCCGACAGGCCCCCGGTAAAGGCCCGGAGTGGGTGTCTGCC ATTGATACACGTGGATCCACTCGGTATGCTGACAGTGTGAAAGGCCGTTTCACCATCTCCAGAGACAATGCAAAAA ACACGTTATACCTTCAGATGGATAGCCTGAAGCCTGAAGATACCGCGCTGTACTATTGCGCTCGTGTTGGTGGAGC GCCGTATGAATACAATTATCGCGGTCAAGGTACACAAGTAACCGTTTCATCT SEQ ID NO: 55 T-013_ful-length VHH (DNA sequence) GAAGTCCAACTGGTAGAGAGCGGTGGCGGACTGGTGCAACCGGGTGGTAGTTTACGCTTGTCTTGCGCAGCTTCC GGATTCAATTTTTCTATGTATTCAATGTCATGGGTGCGGCAGGCGCCAGGCAAAGGGCCTGAATGGGTTTCGGCC ATTGATACTGGCGGGTCTACACGTTATGCGGACAGTGTCAAAGGTCGTTTTACCATCAGCAGAGACAACGCTAAG AATACACTCTATCTTCAGATGGATAGCTTAAAACCCGAGGATACCGCACTGTACTATTGTGCCCGTGTTCGAGGCA CGCCGTACGAATATGGATACCGCGGTCAGGGCACTCAGGTTACCGTATCCTCG SEQ ID NO: 56 T-014_ful-length VHH (DNA sequence) GAGGTGCAGCTGGTGGAGTCTGGGGGAGGATTGGTGGAGGCTGGGGGTTCTCTGAGACTCTCCTGTGCAGCCTC TGGACGCACCTTCGGGAGCTATACCATGGGCTGGTTCCGCCAGGCTCCAGGAAGGGAGCAAGAGTTTTTAGCGA GTATTAGGCGGACTGGTGGTAGCACAAGTTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAACG CCAAGAAGGCGGTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACGGCCGTTTATTACTGTGCAGCAGCCC CCACCGGGAGAGCGTTTACCTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA 290 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 57 T-015_ful-length VHH (DNA sequence) GAGGTCCAATTGGTTGAATCTGGCGGTGGTTTAGTACAGGCAGGTGGATCCCTGAGACTCTCGTGTTTGGCCAGC GGCCGGACTTTTAGTTCCCTGTTCATGGGGTGGTTTCGCCAGGCCCCCGGGAAGGAACGAGAGTTTGTCGCGAGT ATACGTTATCCTGGTCTGATTACAAATTACGCCGATAGCGCGAAAGGCCGTTTTATCATTTCACGTGATTCTGCAAA AAATACGGTGTATCTTCAGATGGACTCGCTTAAACCGGAAGATACTGGTCTGTACTCTTGCGCAGCGGCTCCAACC GGCCGCGCTTTCAACTATTGGGGATTAGGAACCCAAGTTACAGTGTCAAGC SEQ ID NO: 58 T-017_ful-length VHH (DNA sequence) GAAGTGCAGCTGGTTGAGAGCGGTGGTGGATCGGTGCAGCCTGGCGGCTCTTTACGATTACTCTGCGCCGTTTCC GGAGCGAGCTTGTCTCGCAATGCAATCATTTGGGTGAGACAGACACCGGAAAAGGGTCTGGAGTGGGTCAGTAC GATCTATGATGACGGCGAGACATATTATCGCGATTCAGTTAAAGGGCGTTTTACCATTTCCCGTGATCTTGCAGAA AATACGGTTCATCTGCAAATGGGGAACCTGCAGGCGGAAGACACTGCCGTATACTACTGTGCTGGTAGTGCTTTC GATTTTTGGGGACGGGGCACCCAAGTCACTGTATCAAGC SEQ ID NO: 59 T-018_ful-length VHH (DNA sequence) GAAGTTCAACTGGTGGAAAGTGGCGGTGGCTTGGTTCAGGCTGGGGGAAGTCTGCGTTTATCGTGTGCCGCTTCT GGATCCACGTTTCGTTTTCCGCCTATGGGTTGGTATCGACAGGCACCCGGGAAGCAGAGAGAACAAGTCGCGCAG CTCACGTCAGGTGGTAGCACCAACTATGCCGACTCTGTGAAAGGCCGGTTCACTATTTCCCGTGATAATGCGAAAA ATACATGGTATCTTCAAATGTCTTCATTACGCCCAGAGGATACTGCAGTGTACTATTGCAGCGTCCTGGGCCGCGA TATGATGACATACTGGGGGCAGGGTACCCAGGTTACCGTATCGAGC SEQ ID NO: 60 CDR3 consensus (Y/F)YQ(S/A)LS(T/S)(P/A)N(Y/F)GQ(V/T)F SEQ ID NO: 61 CDR3 consensus AADSDL(S/R)TV(V/T)VGPHDY SEQ ID NO: 62 CDR3 consensus AKDAG(S/G)WG(T/R)GPFG(Y/F)(E/D)YDY SEQ ID NO: 63 CDR3 consensus AA(T/A)PSGKAY(T/S)Y SEQ ID NO: 64 CDR3 consensus ATPGPY(T/S/M)YCAPYGSSWSRGYDY SEQ ID NO: 65 CDR3 consensus ARV(R/G)G(T/S/A)PY(E/D)Y(N/G)Y SEQ ID NO: 66 CDR3 consensus (T/A/V)A(S/A)PTGRAF(T/N/A)Y SEQ ID NO: 67 CDR3 consensus S(V/M)(V/L)GRDM(M/V)TY 291 310886415v1 Attorney Docket No: 260525.000071 CDR1 consensus GSI(V/F)(R/S)(T/A)(N/D)(S/G/A) SEQ ID NO: 69 CDR1 consensus GFT(F/L)DD(I/Y)A SEQ ID NO: 70 CDR1 consensus GFTFS(S/R/G)YA SEQ ID NO: 71 CDR1 consensus G(L/F)TLDYYA SEQ ID NO: 72 CDR1 consensus GF(T/N)FSMYS SEQ ID NO: 73 CDR1 consensus GRTF(G/R/S)(N/S)(Y/L)(T/F) SEQ ID NO: 74 CDR1 consensus GS(I/T)FRFPP SEQ ID NO: 75 CDR2 consensus IRSDGF(T/I) SEQ ID NO: 76 CDR2 consensus I(Y/F)SY(S/G)(S/P)NT SEQ ID NO: 77 CDR2 consensus I(Y/S)(S/D)DGS(E/D)T SEQ ID NO: 78 CDR2 consensus I(S/N)(V/T)(S/G)DGST SEQ ID NO: 79 CDR2 consensus IDT(R/G)GST SEQ ID NO: 80 CDR2 consensus IR(W/R/Y)(T/P)G(G/L)(S/I)T SEQ ID NO: 81 T-001_Humanized VHH EVQLVESGGGLVQPGGSLRVSCAASGSIFRADAMGWHRQAPGKPREFVAGIRSDGFTNYADSVKGRFTISWDTVKNT VYLQMNSLRPEDTAVYYCYYQSLSSPNYGQVFWGQGTQVTVSS 292 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 82 T-002_Humanized VHH EVQLVESGGGLVQPGGSLRLSCAASGSIVSTNGMGWHRQAPGKGRELVAGIRSDGFTNYADSVKGRFTISSDNVKNT VYLQMNSLRAEDTGVYYCYYQALSSPNYGQTFWGQGTQVTVSS SEQ ID NO: 83 T-003_Humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVVVGPHDYWGQGTQVTVSS SEQ ID NO: 84 T-006_Humanized VHH EVQLLESGGGLAQPGGSLRLSCAASGFTFSRYAMSWARQAPGKGLEWVSGISDDGSDTYYADSVKGRFTISRDNAKNT VYLQMNSLRPEDTAVYYCAKDAGSWGTGPFGYEYDYWGQGTQVTVSS SEQ ID NO: 85 T-007_Humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO: 86 T-011_Humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGLTLDYYAIGWFRQAPGKEREGVSCISTSDGSTYYADSVKGRFTISRDNAKNTVY LQMNSLRPEDTAVYYCATPGPYTYCAPYGSSWSRGYDYWGQGTQVTVSS SEQ ID NO: 87 T-012_Humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGFTFSMYSMSWVRQAPGKGPEWVSAIDTRGSTRYADSVKGRFTISRDNAKNTL YLQMNSLRPEDTAVYYCARVGGAPYEYNYRGQGTQVTVSS SEQ ID NO: 88 T-013_Humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGFNFSMYSMSWVRQAPGKGPEWVSAIDTGGSTRYADSVKGRFTISRDNAKNT LYLQMNSLRPEDTAVYYCARVRGTPYEYGYRGQGTQVTVSS SEQ ID NO: 89 T-014_Humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEQEFLASIRRTGGSTSYADSVKGRFTISRDNAKKTV YLQMNSLRPEDTAVYYCAAAPTGRAFTYWGQGTQVTVSS SEQ ID NO: 90 T-015_Humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGRTFSSLFMGWFRQAPGKEREFVASIRYPGLITNYADSAKGRFTISRDSAKNTVY LQMNSLRPEDTGVYYCAAAPTGRAFNYWGQGTQVTVSS SEQ ID NO: 91 T-017_Humanized VHH EVQLVESGGGLVQPGGSLRLSCAVSGASLSRNAIWVRQAPGKGLEWVSTIYDDGETYYADSVKGRFTISRDLAKNTVYL QMNSLRAEDTAVYYCAGSAFDFWGQGTQVTVSS SEQ ID NO: 92 T-018_Humanized VHH EVQLVESGGGLVQPGGSLRLSCAASGSTFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNT WYLQMNSLRPEDTAVYYCSVLGRDMMTYWGQGTQVTVSS 293 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 4054 IgG1 L234G/L235S/G236R DKTHTCPPCPAPEGSRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 4055 IgG1 L234S/L235T/G236R DKTHTCPPCPAPESTRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 4056 IgG1 L234S/L235V/G236R DKTHTCPPCPAPESVRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 4057 IgG1 L234T/L235Q/G236R DKTHTCPPCPAPETQRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 4058 IgG1 L234T/L235T/G236R DKTHTCPPCPAPETTRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 4059 IgG1 L234A/L235A/P329G DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 4060 IgG1 M252Y/S254T/T256E DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO:4061 T-020_CDR1; T-004_CDR1; T-004.VTV_CDR1 GFTLDDYA SEQ ID NO:4062 T-020_CDR2; T-004_CDR2; T-004.VTV_CDR2 IFSYSSNT SEQ ID NO:4063 T-020_CDR3 AVGDFEGELVLKGDY 294 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO:4064 T-020_ful-length VHH (amino acid sequence) EVQLVESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDNAKNT LYLQMNSLKPEDTAVYYCAVGDFEGELVLKGDYWGQGTQVTVSS SEQ ID NO:4065 T-021_CDR1 GFTLDYYT SEQ ID NO:4066 T-021_CDR2 ISSNDGSV SEQ ID NO:4067 T-021_CDR3 AADLGYLYVDYVRLHTHHFGS SEQ ID NO:4068 T-021_ful-length VHH (amino acid sequence) EVQLVESGGGLVQSGGSLRLSCAASGFTLDYYTIGWFRQAPGKEREGVSYISSNDGSVYYADSVKGRFTIEKDSAKNTVY LQMNSLKPEDTAVYYCAADLGYLYVDYVRLHTHHFGSWGQGTQVTVSS SEQ ID NO:4069 T-016_CDR1 GRTFGSYT SEQ ID NO:4070 T-016_CDR2 IRWTGGST SEQ ID NO:4071 T-016_CDR3 VASPTGRAFTY SEQ ID NO:4072 T-016_ful-length VHH (amino acid sequence) EVQLVESGGGLVEAGGSLRLSCAASGRTFGSYTMGWFRQAPGREREFLASIRWTGGSTSYADSVKGRFTISRDDAKKA VYLQMNSLKPEDTAVYYCVASPTGRAFTYWGQGTQVTVSS SEQ ID NO:4073 T-020_ful-length VHH (DNA sequence) GAGGTGCAGCTTGTAGAGAGTGGCGGTGGACTGGTCCAGCCGGGTGGATCGTTGCGTCTCTCATGTGCTGCGTCT GGTTTTACGCTGGATGATTATGCCATGTCATGGGTGCGCCAAGCTCCTGGTAAAGGCTTGGAATGGGTGAGCACT ATTTTTAGCTATTCCAGTAATACCTATTACGCGGACTCTGTTAAGGGGCGGTTTACAATCTCCACTGATAACGCCAA AAATACCTTATACCTGCAGATGAACTCGCTTAAACCAGAAGATACCGCAGTTTACTATTGCGCAGTTGGGGACTTC GAAGGTGAACTGGTCTTAAAAGGCGATTATTGGGGACAGGGCACACAAGTAACGGTTAGTAGC SEQ ID NO:4074 T-021_ful-length VHH (DNA sequence) GAGGTGCAGCTGGTGGAGTCTGGGGGAGGTTTGGTGCAGTCTGGGGGGTCTCTGAGACTCTCCTGTGCAGCCTC TGGATTCACTTTGGATTATTATACCATAGGCTGGTTCCGCCAGGCCCCAGGGAAGGAGCGTGAGGGGGTCTCATA TATTAGTAGTAACGATGGTAGTGTGTACTATGCAGACTCCGTGAAGGGCCGATTCACCATCGAGAAAGACAGTGC CAAGAACACGGTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACAGCCGTCTATTACTGTGCAGCAGATCT CGGTTATCTGTACGTCGACTATGTCCGTCTTCACACGCATCACTTTGGTTCCTGGGGCCAGGGGACCCAGGTCACC GTCTCCTCA 295 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO:4075 T-016_ful-length VHH (DNA sequence) GAGGTACAGCTGGTGGAGAGTGGGGGCGGCTTAGTTGAAGCGGGCGGTAGTCTGCGACTCTCTTGCGCCGCATC CGGGCGGACTTTTGGTAGCTATACGATGGGCTGGTTCCGCCAAGCCCCTGGACGTGAACGGGAATTTTTGGCATC GATTCGCTGGACAGGTGGTAGCACATCTTACGCTGACTCAGTCAAAGGAAGATTCACAATCTCACGTGATGATGC GAAAAAGGCTGTATATCTTCAGATGAATAGCCTGAAACCAGAAGATACTGCAGTCTACTATTGTGTTGCGTCGCCG ACGGGGCGTGCCTTTACCTATTGGGGCCAAGGTACCCAGGTGACCGTTTCCTCT SEQ ID NO:4076 T-020_Humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDNAKNTL YLQMNSLRPEDTAVYYCAVGDFEGELVLKGDYWGQGTQVTVSS SEQ ID NO:4077 T-021_Humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGFTLDYYTIGWFRQAPGKEREGVSYISSNDGSVYYADSVKGRFTISKDSAKNTVY LQMNSLRPEDTAVYYCAADLGYLYVDYVRLHTHHFGSWGQGTQVTVSS SEQ ID NO:4078 T-016_Humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTYWGQGTQVTVSS SEQ ID NO:4517 CDR3 consensus AAD(L/V)G(F/V/Y)LY(A/T/V)DYV(P/R)LH(M/T)HHFGS SEQ ID NO:4518 CDR2 consensus I(N/S)SNDG(S/T)(T/V) SEQ ID NO:4519 CDR1 consensus G(F/V)(S/T)LD(D/Y)(H/Y)T SEQ ID NO:4520 T-019_CDR1 GSIFRFPP SEQ ID NO:4521 T-019_ful-length VHH (amino acid sequence) EVQLVESGGGLVQAGGSLRLSCAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNT WYLQMSSLRPEDTAVYYCSVLGRDMVTYWGQGTQVTVSS SEQ ID NO:4522 T-019_ful-length VHH (DNA sequence) GAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGCGGCAGCCTGAGACTGAGCTGCGCCGCCA GCGGCAGCATCTTCAGATTCCCCCCCATGGGCTGGTACAGACAGGCCCCCGGCAAGCAGAGAGAGCAGGTGGCC CAGCTGACCAGCGGCGGCAGCACCAACTACGCCGACAGCGTGAAGGGCAGATTCACCATCAGCAGAGACAACGC CAAGAACACCTGGTACCTGCAGATGAACAGCCTGAGACCCGAGGACACCGCCGTGTACTACTGCAGCGTGCTGGG CAGAGACATGGTGACCTACTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGCTGA SEQ ID NO:4523 T-019_Humanized VHH 296 310886415v1 Attorney Docket No: 260525.000071 EVQLVESGGGLVQPGGSLRLSCAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNT WYLQMNSLRPEDTAVYYCSVLGRDMVTYWGQGTQVTVSS SEQ ID NO:4524 T-005hu1_CDR3; T-004.VTV_CDR3; T-004Hu1.VTV_CDR3 AADSDLSTVTVGPHDY SEQ ID NO:4525 T-005hu1_ful-length VHH (DNA sequence) GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGCGGCAGCCTGAGACTGAGCTGCGCCGCCA GCGGCTTCACCTTCGACGACATCGCCATGACCTGGGTGAGACAGGCCCCCGGCAAGGGCCTGGAGTGGGTGAGC AGCATCTACAGCTACGGCCCCAACACCTACTACGCCGACAGCGTGAAGGGCAGATTCACCATCAGCACCGACAGC GCCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGACCCGAGGACACCGCCGTGTACTACTGCGCCGCCGAC AGCGACCTGAGCACCGTGACCGTGGGCCCCCACGACTACTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGCTG A SEQ ID NO:4526 T-005hu1_Humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVSS SEQ ID NO:4527 T-008hu1/T-008hu1.A3_CDR2 INWSNART SEQ ID NO:4528 T-008hu1_ful-length VHH (DNA sequence) GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGCGGCAGCCTGAGACTGAGCTGCGCCGCCA GCGGCAGAACCTTCAGCGACTACGGCATGGGCTGGTTCAGACAGGCCCCCGGCAAGGACAGCGAGTTCGTGGCC GCCATCAACTGGAGCAACGCCAGAACCAACTACGCCGACAGCGTGAAGGGCAGATTCACCATCAGCAGAGACAA CGCCAAGAACACCGGCTACCTGCAGATGAACAGCCTGAGAGTGGAGGACACCGCCGTGTACTACTGCGCCGCCAC CCCCAGCGGCAAGGCCTACAGCTACTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGCTGA SEQ ID NO:4529 T-008hu1_Humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO:4530 T-008hu1.A3_CDR3 AAAPSGKAYSY SEQ ID NO:4531 T-008hu1.A3_ful-length VHH (DNA sequence) GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGCGGCAGCCTGAGACTGAGCTGCGCCGCCA GCGGCAGAACCTTCAGCGACTACGGCATGGGCTGGTTCAGACAGGCCCCCGGCAAGGACAGCGAGTTCGTGGCC GCCATCAACTGGAGCAACGCCAGAACCAACTACGCCGACAGCGTGAAGGGCAGATTCACCATCAGCAGAGACAA CGCCAAGAACACCGGCTACCTGCAGATGAACAGCCTGAGAGTGGAGGACACCGCCGTGTACTACTGCGCCGCCGC CCCCAGCGGCAAGGCCTACAGCTACTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGCTGA SEQ ID NO:4532 T-008hu1.A3_Humanized VHH 297 310886415v1 Attorney Docket No: 260525.000071 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAAAPSGKAYSYWGQGTQVTVSS SEQ ID NO:4653 T-003 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLKPEDTAVYYCAADSDLSTVVVGPHDYWGQGTQVTVSS SEQ ID NO:4654 T-003Hu1 EVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVVVGPHDYWGQGTQVTVSS SEQ ID NO:4655 T-003Hu1 VTV (T-005Hu1) EVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVSS SEQ ID NO:4656 DVQ-T-005hu1.VPAG DVQLLESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVPAG SEQ ID NO:4657 T-007 EVQLVESGGGLVQAGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAK NTGYLEMNSLKVEDTAVYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO:4658 T-007Hu1 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNGRTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO:4659 T-007Hu1 NAR (T-008Hu1) EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO:4660 T-008Hu1-VPAG EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVPAG SEQ ID NO:4661 DVQ-T-008Hu1-VPAG DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVPAG SEQ ID NO:4662 DVQ-T-008hu1.A3.VPAG DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAAAPSGKAYSYWGQGTQVTVPAG SEQ ID NO:4663 DVQ-T-008hu1.A4.VPAG 298 310886415v1 Attorney Docket No: 260525.000071 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATASGKAYSYWGQGTQVTVPAG SEQ ID NO:4664 DVQ-T-008hu1.A5.VPAG DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPAGKAYSYWGQGTQVTVPAG SEQ ID NO:4665 DVQ-T-008hu1.A6.VPAG DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSAKAYSYWGQGTQVTVPAG SEQ ID NO:4666 DVQ-T-008hu1.A7.VPAG DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGAAYSYWGQGTQVTVPAG SEQ ID NO:4667 DVQ-T-008hu1.A9.VPAG DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAASYWGQGTQVTVPAG SEQ ID NO:4668 DVQ-T-008hu1.A10.VPAG DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYAYWGQGTQVTVPAG SEQ ID NO:4669 DVQ-T-008hu1.A11.VPAG DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSAWGQGTQVTVPAG SEQ ID NO:4670 T-007Mu-2*01 EVQLVESGGGLVQPGESLKLSCEASGRTFSDYGMGWFRKTPEKDSEFVAAINWSNGRTNYPDTVERRFISRDNAKNT GYLQMSSLRVEDTALYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO:4671 T-007Mu-4*01 EVQLVESGGGLVKPGGSLKLSCAASGRTFSDYGMGWFRQTPEKDSEFVAAINWSNGRTNYPDNVKGRFTISRDNAKN NGYLQMSHLKVEDTAMYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO:4672 T-007Mu-6*01 EVQLVESGGDLVKPGGSLKLSCAASGRTFSDYGMGWFRQTPEKDSEFVAAINWSNGRTNYPDSVKGRFTISRDNAKN TGYLQMSSLKVEDTAMYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO:4673 T-007Mu-9*01 EVMLVESGGGLVKPGGSLKLSCAASGRTFSDYGMGWFRQTPEKDSEFVAAINWSNGRTNYPDSVKGRFTISRDNAKN TGYLQMSSLRVEDTALYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO:4674 T-007Mu-12*01 299 310886415v1 Attorney Docket No: 260525.000071 EVKLVESGGGLVQPGGSLKLSCAASGRTFSDYGMGWFRQTPEKDSEFVAAINWSNGRTNYPDTVKGRFTISRDNAKN TGYLQMSRLKVEDTAMYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO:4675 T-007Mu-15*01 EVKLVESGGGLVQPGGSLKLSCAASGRTFSDYGMGWFRQAPRKDSEFVAAINWSNGRTNYADTVTGRFTISRDNAKN TGYLEMSSLRVEDTAMYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO:4676 T-007Mu-16*01 EVKLVESEGGLVQPGSSLKLSCTASGRTFSDYGMGWFRQVPEKDSEFVAAINWSNGRTNYLDSVKSRFISRDNAKNIG YLQMSSLKVEDTATYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO:4677 T-007Mu-17*01 EVQLVESGGGLVKPGGSLKLSCAASGRTFSDYGMGWFRQAPEKDSEFVAAINWSNGRTNYADTVKGRFTISRDNAKN TGFLQMTSLRVEDTAMYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO:4678 T-007Mu-Consensus EVQLVESGGGLVQPGGSLKLSCAASGRTFSDYGMGWFRQTPEKDSEFVAAINWSNGRTNYPDTVKGRFTISRDNAKN TGYLQMSSLRVEDTAMYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO:4679 T-007Mu-Graft-IGHV5-9*01 EVMLVESGGGLVKPGGSLKLSCAASGRTFSDYGMSWVRQTPEKRLEWVATINWSNGRTYYPDSVKGRFTISRDNAKN TLYLQMSSLRSEDTALYYCAATPSGKAYSYWGQGTSVTVSS SEQ ID NO:4680 T-019 EVQLVESGGGLVQAGGSLRLSCAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNT WYLQMSSLRPEDTAVYYCSVLGRDMVTYWGQGTQVTVSS SEQ ID NO:4681 T-019Hu1 EVQLVESGGGLVQPGGSLRLSCAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNT WYLQMNSLRPEDTAVYYCSVLGRDMVTYWGQGTQVTVSS SEQ ID NO:4682 DVQ-T-019hu1.VPAG DVQLVESGGGLVQPGGSLRLSCAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNT WYLQMNSLRPEDTAVYYCSVLGRDMVTYWGQGTQVTVPAG SEQ ID NO:4683 DVQ-T-019hu1.LV.VPAG DVQLVESGGGLVQPGGSLRLSCAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNT WYLQMNSLRPEDTAVYYCSVLGRDLVTYWGQGTQVTVPAG SEQ ID NO:4684 DVQ-T-019hu1.RV.VPAG DVQLVESGGGLVQPGGSLRLSCAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNT WYLQMNSLRPEDTAVYYCSVLGRDRVTYWGQGTQVTVPAG SEQ ID NO:4685 DVQ-T-019hu1.IV.VPAG 300 310886415v1 Attorney Docket No: 260525.000071 DVQLVESGGGLVQPGGSLRLSCAASGSIFRFPPMGWYRQAPGKQREQVAQLTSGGSTNYADSVKGRFTISRDNAKNT WYLQMNSLRPEDTAVYYCSVLGRDIVTYWGQGTQVTVPAG SEQ ID NO: 4699 cluster D_CDR2 consensus INWSN(G/A)RT SEQ ID NO:4701 YYQ(S/A)LSSPNYGQ(V/T)F SEQ ID NO:4702 AADSDLSTVV(V/T)GPHDY SEQ ID NO:4703 AA(T/A)PSGKAYSY SEQ ID NO:4704 ARV(G/R)G(T/A)PYEY(N/G)Y SEQ ID NO:4705 GRTF(G/S)S(Y/L)(T/F) SEQ ID NO:4706 SVLGRDM(M/V)TY SEQ ID NO:4707 (A/V)A(A/S)PTGRAF(T/N)Y SEQ ID NO:4708 GS(T/I)FRFPP SEQ ID NO:4719 T-009Hu1_CDR1 GRTFSDYG SEQ ID NO:4720 T-009Hu1.NAR_CDR1 GRTFSDYG SEQ ID NO:4721 T-010Hu1_CDR1 GRTFSDYG SEQ ID NO:4722 T-010Hu1.NAR_CDR1 GRTFSDYG SEQ ID NO:4723 T-009Hu1_CDR2 INWSNGRT 301 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO:4724 T-009Hu1.NAR_CDR2 INWSNART SEQ ID NO:4725 T-010Hu1_CDR2 INWSNGRT INWSNART SEQ ID NO:4727 T-009Hu1_CDR3 AATPTGKAYTY SEQ ID NO:4728 T-009Hu1.NAR_CDR3 AATPTGKAYTY SEQ ID NO:4729 T-010Hu1_CDR3 AGTLSGKAYTY SEQ ID NO:4730 T-010Hu1.NAR_CDR3 AGTLSGKAYTY SEQ ID NO:4731 T-009Hu1_humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVSS SEQ ID NO:4732 T-009Hu1.NAR_humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVSS SEQ ID NO:4733 T-010Hu1_humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVSS SEQ ID NO:4734 T-010Hu1.NAR_humanized VHH EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNARTSYADSAKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTLSGKAYTYWGQGTQVTVSS SEQ ID NO: 4771 consensus sequence_CDR3 A(A/G)(T/A)(P/L)(S/T)GKAY(T/S)Y SEQ ID NO: 4772 T-030 (tetravalent IgG4 SPLE [N/C term modifications, CDR2 G/A integrin binding site mutation, CDR3 T/S ALK-2 mutation]; T-007hu1 CDR3 T/S) 302 310886415v1 Attorney Docket No: 260525.000071 DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAASPSGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAASPSGKAYSYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQ EDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 4773 T-031 (tetravalent IgG1 LALAPA [N/C term modifications, CDR2 G/A integrin binding site mutation, CDR3 T/S ALK-2 mutation]; T-007hu1 CDR3 T/S) DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAASPSGKAYSYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYY CAASPSGKAYSYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK SEQ ID NO: 4774 T-007hu1 CDR3 T/S, CDR3 sequence AASPSGKAYSY SEQ ID NO: 4775 T-007hu1 with CDR2 G/A, CDR3 T/S, Ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAASPSGKAYSYWGQGTQVTVSS SEQ ID NO: 4776 T-032, multivalent construct DVQLLESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGG SLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVYY CAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKG QPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 4777 T-033, multivalent construct DVQLLESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSGGGGSGGGGSDVQLLESGGGLVQPGG SLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVYY CAADSDLSTVTVGPHDYWGQGTQVTVSSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 4778 T-034, multivalent construct 303 310886415v1 Attorney Docket No: 260525.000071 DVQLLESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPG GSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVY YCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 4779 T-035, multivalent construct DVQLLESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPG GSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTLYLQMNSLRPEDTAVY YCAADSDLSTVTVGPHDYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKG QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 4780 T-005, ful-length VHH, camelid EVQLVESGGGLVQPGGSLRLSCAASGFTFDDIAMTWVRQAPGKGLEWVSSIYSYGPNTYYADSVKGRFTISTDSAKNTL YLQMNSLKPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVSS SEQ ID NO: 4781 T-004, ful-length VHH, camelid EVQLVESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTL YLQMNSLKPEDTAVYYCAADSDLSTVVVGPHDYWGQGTQVTVSS SEQ ID NO: 4782 T-004Hu1, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVVVGPHDYWGQGTQVTVSS SEQ ID NO: 4783 T-004.VTV, ful-length VHH, camelid EVQLVESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTL YLQMNSLKPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVSS SEQ ID NO: 4784 T-004Hu1.VTV, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGFTLDDYAMSWVRQAPGKGLEWVSTIFSYSSNTYYADSVKGRFTISTDSAKNTL YLQMNSLRPEDTAVYYCAADSDLSTVTVGPHDYWGQGTQVTVSS SEQ ID NO: 4785 T-009, ful-length VHH, camelid EVQLVESGGGLVQAGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNGRTTYADSVKGRFTISRDNAEN TGYLEMNSLKVEDTALYYCAATPTGKAYTYWGQGTQVTVSS SEQ ID NO: 4786 T-010, ful-length VHH, camelid EVQLVESGGGLVQAGGSLRLSCAASGRTFSDYGMGWFRQAPGKEHEFVASINWSNGRTSYADSAKGRFTISRDNAKN TGYLEMNSLKVEDTAVYYCAGTLSGKAYTYWGQGTQVTVSS 304 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 4787 CDR3 consensus sequence A(A/G)(T/A/S)(P/L)(S/T)GKAY(T/S)Y SEQ ID NO: 4788 T-009Hu1_QGR_CDR2 INWSQGRT SEQ ID NO: 4789 T-009Hu1_SGR_CDR2 INWSSGRT SEQ ID NO: 4790 T-007Hu1.S3.EGR_CDR2 INWSEGRT SEQ ID NO: 4791 T-007Hu1.S3.NSR_CDR2 INWSNSRT SEQ ID NO: 4792 T-007Hu1.S3.NTR_CDR2 INWSNTRT SEQ ID NO: 4793 T-007Hu1.S3.SAR_CDR2 INWSSART SEQ ID NO: 4794 T-009Hu1_QGR, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSQGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVSS SEQ ID NO: 4795 T-009Hu1_SGR, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNT GYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVSS SEQ ID NO: 4796 T-009Hu1_QGR_N/C, ful-length VHH, humanized DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSQGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVPAG SEQ ID NO: 4797 T-009Hu1_NAR_N/C, ful-length VHH, humanized DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSNARTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVPAG SEQ ID NO: 4798 T-009Hu1_SGR_N/C, ful-length VHH, humanized DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVPAG SEQ ID NO: 4799 T-007Hu1.S3.QGR, ful-length VHH, humanized 305 310886415v1 Attorney Docket No: 260525.000071 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSQGRTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAASPSGKAYSYWGQGTQVTVSS SEQ ID NO: 4800 T-007Hu1.S3.EGR, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSEGRTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAASPSGKAYSYWGQGTQVTVSS SEQ ID NO: 4801 T-007Hu1.S3.SGR, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSSGRTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAASPSGKAYSYWGQGTQVTVSS SEQ ID NO: 4802 T-007Hu1.S3.NSR, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNSRTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAASPSGKAYSYWGQGTQVTVSS SEQ ID NO: 4803 T-007Hu1.S3.NTR, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNTRTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAASPSGKAYSYWGQGTQVTVSS SEQ ID NO: 4804 T-007Hu1.S3.SAR, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSSARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAASPSGKAYSYWGQGTQVTVSS SEQ ID NO: 4805 T-007Hu1.EQ.QGR, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEQEFVAAINWSQGRTNYADSVKGRFTISRDNAK NTGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO: 4806 T-007Hu1.EQ.EGR, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEQEFVAAINWSEGRTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO: 4807 T-007Hu1.EQ.SGR, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEQEFVAAINWSSGRTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSYWGQGTQVTVSS SEQ ID NO: 4808 T-007Hu1.EQ.S3.NSR, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEQEFVAAINWSNSRTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAASPSGKAYSYWGQGTQVTVSS SEQ ID NO: 4809 CDR2 consensus sequence INWS(N/Q/E/S)(G/A)RT SEQ ID NO: 4810 T-016hu1.A1_CDR3 AASPTGRAFTY 306 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 4811 T-016hu1.G2_CDR3 VGSPTGRAFTY SEQ ID NO: 4812 T-016hu1.A3_CDR3 VAAPTGRAFTY SEQ ID NO: 4813 T-016hu1.A4_CDR3 VASATGRAFTY SEQ ID NO: 4814 T-016hu1.A5_CDR3 VASPAGRAFTY SEQ ID NO: 4815 T-016hu1.A6_CDR3 VASPTARAFTY SEQ ID NO: 4816 T-016hu1.A7_CDR3 VASPTGAAFTY SEQ ID NO: 4817 T-016hu1.A9_CDR3 VASPTGRAATY SEQ ID NO: 4818 T-016hu1.A10_CDR3 VASPTGRAFAY SEQ ID NO: 4819 T-016hu1.A11_CDR3 VASPTGRAFTA SEQ ID NO: 4820 T-016Hu1.A5.A7_CDR3 VASPAGAAFTY SEQ ID NO: 4821 T-016Hu1.A5.A1_CDR3 AASPAGRAFTY SEQ ID NO: 4822 T-016Hu1.A5.A3_CDR3 VAAPAGRAFTY SEQ ID NO: 4823 T-016Hu1.A5.A4_CDR3 VASAAGRAFTY SEQ ID NO: 4824 T-016Hu1.A5.A6_CDR3 VASPAARAFTY SEQ ID NO: 4825 T-016Hu1.A7.A1_CDR3 307 310886415v1 Attorney Docket No: 260525.000071 AASPTGAAFTY SEQ ID NO: 4826 T-016Hu1.A7.A3_CDR3 VAAPTGAAFTY SEQ ID NO: 4827 T-016Hu1.A7.A4_CDR3 VASATGAAFTY SEQ ID NO: 4828 T-016Hu1.A7.A6_CDR3 VASPTAAAFTY SEQ ID NO: 4829 T-016Hu1.A1.A4_CDR3 AASATGRAFTY SEQ ID NO: 4830 T-016Hu1.A1.A6_CDR3 AASPTARAFTY SEQ ID NO: 4831 T-016Hu1.A3.A4_CDR3 VAAATGRAFTY SEQ ID NO: 4832 T-016Hu1.A3.A6_CDR3 VAAPTARAFTY SEQ ID NO: 4833 T-016Hu1.A4.A6_CDR3 VASATARAFTY CDR3 consensus sequence (T/A/V)(A/G)(S/A)(A/P)(A/T)(A/G)(A/R)A(A/F)(T/N/A)(A/Y) SEQ ID NO: 4835 T-008Hu1.G1_CDR3 GATPSGKAYSY SEQ ID NO: 4836 T-008Hu1.G2_CDR3 AGTPSGKAYSY SEQ ID NO: 4837 T-008Hu1.A4_CDR3 AATASGKAYSY SEQ ID NO: 4838 T-008Hu1.A5_CDR3 AATPAGKAYSY SEQ ID NO: 4839 T-008Hu1.A6_CDR3 AATPSAKAYSY 308 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 4840 T-008Hu1.A7_CDR3 AATPSGAAYSY SEQ ID NO: 4841 T-008Hu1.G8_CDR3 AATPSGKGYSY SEQ ID NO: 4842 T-008Hu1.A9_CDR3 AATPSGKAASY SEQ ID NO: 4843 T-008Hu1.A10_CDR3 AATPSGKAYAY SEQ ID NO: 4844 T-008Hu1.A11_CDR3 AATPSGKAYSA SEQ ID NO: 4845 T-009Hu1_SGR.G1_CDR3 GATPTGKAYTY SEQ ID NO: 4846 T-009Hu1_SGR.G2_CDR3 AGTPTGKAYTY SEQ ID NO: 4847 T-009Hu1_SGR.A3_CDR3 AAAPTGKAYTY SEQ ID NO: 4848 T-009Hu1_SGR.A4_CDR3 AATATGKAYTY SEQ ID NO: 4849 T-009Hu1_SGR.A5_CDR3 AATPAGKAYTY SEQ ID NO: 4850 T-009Hu1_SGR.A6_CDR3 AATPTAKAYTY SEQ ID NO: 4851 T-009Hu1_SGR.A7_CDR3 AATPTGAAYTY SEQ ID NO: 4852 T-009Hu1_SGR.G8_CDR3 AATPTGKGYTY SEQ ID NO: 4853 T-009Hu1_SGR.A9_CDR3 AATPTGKAATY SEQ ID NO: 4854 T-009Hu1_SGR.A10_CDR3 AATPTGKAYAY 309 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 4855 T-009Hu1_SGR.A11_CDR3 AATPTGKAYTA CDR3 consensus sequence (A/G)(A/G)(T/A/S)(A/P/L)(A/S/T)(A/G)(A/K)(A/G)(A/Y)(A/T/S)(A/Y) SEQ ID NO: 4857 T-016hu1.A1, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCAASPTGRAFTYWGQGTQVTVSS SEQ ID NO: 4858 T-016hu1.G2, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVGSPTGRAFTYWGQGTQVTVSS SEQ ID NO: 4859 T-016hu1.A3, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVAAPTGRAFTYWGQGTQVTVSS SEQ ID NO: 4860 T-016hu1.A4, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASATGRAFTYWGQGTQVTVSS SEQ ID NO: 4861 T-016hu1.A5, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPAGRAFTYWGQGTQVTVSS SEQ ID NO: 4862 T-016hu1.A6, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTARAFTYWGQGTQVTVSS SEQ ID NO: 4863 T-016hu1.A7, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGAAFTYWGQGTQVTVSS SEQ ID NO: 4864 T-016hu1.A9, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAATYWGQGTQVTVSS SEQ ID NO: 4865 T-016hu1.A10, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFAYWGQGTQVTVSS SEQ ID NO: 4866 T-016hu1.A11, ful-length VHH, humanized 310 310886415v1 Attorney Docket No: 260525.000071 EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTAWGQGTQVTVSS SEQ ID NO: 4867 T-016Hu1.A5.A7, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPAGAAFTYWGQGTQVTVSS SEQ ID NO: 4868 T-016Hu1.A5.A1, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCAASPAGRAFTYWGQGTQVTVSS SEQ ID NO: 4869 T-016Hu1.A5.A3, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVAAPAGRAFTYWGQGTQVTVSS SEQ ID NO: 4870 T-016Hu1.A5.A4, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASAAGRAFTYWGQGTQVTVSS SEQ ID NO: 4871 T-016Hu1.A5.A6, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPAARAFTYWGQGTQVTVSS SEQ ID NO: 4872 T-016Hu1.A7.A1, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCAASPTGAAFTYWGQGTQVTVSS SEQ ID NO: 4873 T-016Hu1.A7.A3, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVAAPTGAAFTYWGQGTQVTVSS SEQ ID NO: 4874 T-016Hu1.A7.A4, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASATGAAFTYWGQGTQVTVSS SEQ ID NO: 4875 T-016Hu1.A7.A6, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTAAAFTYWGQGTQVTVSS SEQ ID NO: 4876 T-016Hu1.A1.A3, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCAAAPTGRAFTYWGQGTQVTVSS SEQ ID NO: 4877 T-016Hu1.A1.A4, ful-length VHH, humanized 311 310886415v1 Attorney Docket No: 260525.000071 EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCAASATGRAFTYWGQGTQVTVSS SEQ ID NO: 4878 T-016Hu1.A1.A6, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCAASPTARAFTYWGQGTQVTVSS SEQ ID NO: 4879 T-016Hu1.A3.A4, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVAAATGRAFTYWGQGTQVTVSS SEQ ID NO: 4880 T-016Hu1.A3.A6, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVAAPTARAFTYWGQGTQVTVSS SEQ ID NO: 4881 T-016Hu1.A4.A6, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASATARAFTYWGQGTQVTVSS SEQ ID NO: 4882 T-008Hu1.G1, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCGATPSGKAYSYWGQGTQVTVSS SEQ ID NO: 4883 T-008Hu1.G2, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAGTPSGKAYSYWGQGTQVTVSS SEQ ID NO: 4884 T-008Hu1.A4, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATASGKAYSYWGQGTQVTVSS SEQ ID NO: 4885 T-008Hu1.A5, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPAGKAYSYWGQGTQVTVSS SEQ ID NO: 4886 T-008Hu1.A6, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSAKAYSYWGQGTQVTVSS SEQ ID NO: 4887 T-008Hu1.A7, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGAAYSYWGQGTQVTVSS SEQ ID NO: 4888 T-008Hu1.G8, ful-length VHH, humanized 312 310886415v1 Attorney Docket No: 260525.000071 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKGYSYWGQGTQVTVSS SEQ ID NO: 4889 T-008Hu1.A9, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAASYWGQGTQVTVSS SEQ ID NO: 4890 T-008Hu1.A10, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYAYWGQGTQVTVSS SEQ ID NO: 4891 T-008Hu1.A11, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKDSEFVAAINWSNARTNYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPSGKAYSAWGQGTQVTVSS SEQ ID NO: 4892 T-009Hu1_SGR.G1, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNT GYLQMNSLRVEDTAVYYCGATPTGKAYTYWGQGTQVTVSS SEQ ID NO: 4893 T-009Hu1_SGR.G2, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNT GYLQMNSLRVEDTAVYYCAGTPTGKAYTYWGQGTQVTVSS SEQ ID NO: 4894 T-009Hu1_SGR.A3, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNT GYLQMNSLRVEDTAVYYCAAAPTGKAYTYWGQGTQVTVSS SEQ ID NO: 4895 T-009Hu1_SGR.A4, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNT GYLQMNSLRVEDTAVYYCAATATGKAYTYWGQGTQVTVSS SEQ ID NO: 4896 T-009Hu1_SGR.A5, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNT GYLQMNSLRVEDTAVYYCAATPAGKAYTYWGQGTQVTVSS SEQ ID NO: 4897 T-009Hu1_SGR.A6, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNT GYLQMNSLRVEDTAVYYCAATPTAKAYTYWGQGTQVTVSS SEQ ID NO: 4898 T-009Hu1_SGR.A7, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNT GYLQMNSLRVEDTAVYYCAATPTGAAYTYWGQGTQVTVSS SEQ ID NO: 4899 T-009Hu1_SGR.G8, ful-length VHH, humanized 313 310886415v1 Attorney Docket No: 260525.000071 EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNT GYLQMNSLRVEDTAVYYCAATPTGKGYTYWGQGTQVTVSS SEQ ID NO: 4900 T-009Hu1_SGR.A9, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNT GYLQMNSLRVEDTAVYYCAATPTGKAATYWGQGTQVTVSS SEQ ID NO: 4901 T-009Hu1_SGR.A10, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNT GYLQMNSLRVEDTAVYYCAATPTGKAYAYWGQGTQVTVSS SEQ ID NO: 4902 T-009Hu1_SGR.A11, ful-length VHH, humanized EVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNT GYLQMNSLRVEDTAVYYCAATPTGKAYTAWGQGTQVTVSS SEQ ID NO: 4903 T-036, multivalent construct DVQLLESGGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKN TGYLQMNSLRVEDTAVYYCAATPTGKAYTYWGQGTQVTVPAGGGGSGGGGSGGGGSDVQLLESGGGLVQPGGSLR LSCAASGRTFSDYGMGWFRQAPGKEREFVATINWSSGRTTYADSVKGRFTISRDNAKNTGYLQMNSLRVEDTAVYYC AATPTGKAYTYWGQGTQVTVPAGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK SEQ ID NO: 4904 DVQ-T-008hu1.A3.VPAG_nucleotide sequence GACGTGCAATTGCTGGAGTCCGGGGGCGGTTTGGTGCAGCCCGGGGGTAGCCTCAGATTGAGTTGCGCCGCATC CGGGCGAACATTCAGTGACTACGGGATGGGGTGGTTTAGACAGGCACCTGGCAAGGACAGTGAGTTTGTGGCTG CGATTAATTGGTCCAACGCTAGGACCAACTACGCGGATTCAGTCAAGGGACGCTTCACCATCTCCAGAGACAATGC CAAGAACACAGGGTACCTGCAAATGAACTCCCTCAGGGTGGAGGACACCGCAGTGTACTACTGCGCTGCAGCCCC GTCAGGAAAGGCCTATTCCTACTGGGGGCAGGGGACTCAAGTCACGGTACCAGCAGGA SEQ ID NO: 4905 DVQ-T-008hu1.A4.VPAG_nucleotide sequence GACGTCCAGTTGTTGGAGAGCGGAGGAGGCCTGGTCCAGCCGGGTGGCAGTCTTCGGCTGAGCTGTGCAGCCAG TGGACGAACATTCAGTGACTACGGGATGGGGTGGTTTCGCCAGGCACCGGGCAAAGATTCAGAGTTCGTTGCTGC GATCAATTGGTCCAACGCCAGGACAAATTACGCGGACTCCGTCAAGGGAAGATTCACTATATCCAGGGATAACGC TAAGAACACCGGGTACTTGCAGATGAATTCCCTGAGGGTCGAGGATACGGCTGTGTACTACTGTGCCGCAACGGC ATCCGGCAAGGCGTACAGCTATTGGGGGCAAGGCACCCAGGTGACGGTACCCGCCGGC SEQ ID NO: 4906 DVQ-T-008hu1.A5.VPAG_nucleotide sequence GACGTCCAGCTTCTCGAATCAGGTGGCGGACTGGTCCAGCCAGGGGGCTCTTTGCGGTTGTCTTGTGCCGCCAGC GGGAGAACCTTCTCAGACTACGGAATGGGGTGGTTTAGGCAGGCTCCTGGCAAAGACAGTGAGTTCGTGGCCGC GATCAATTGGTCCAATGCAAGGACGAACTACGCGGATTCCGTCAAGGGCCGGTTCACCATATCCCGGGATAATGC AAAGAATACGGGATACCTTCAGATGAATTCCTTGAGAGTGGAGGATACTGCCGTCTACTACTGCGCGGCCACCCC GGCAGGGAAAGCTTACTCCTATTGGGGGCAGGGGACACAGGTGACAGTACCTGCTGGT 314 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 4907 DVQ-T-008hu1.A6.VPAG_nucleotide sequence GACGTGCAGCTTCTTGAGTCCGGAGGGGGACTCGTCCAGCCGGGCGGATCCCTTAGGTTGAGCTGCGCCGCTTCA GGAAGAACGTTCAGCGACTATGGGATGGGGTGGTTTAGACAGGCACCCGGCAAAGATTCTGAGTTCGTTGCCGC GATTAACTGGTCCAATGCTAGAACAAACTACGCGGACTCTGTCAAGGGGCGATTCACAATTTCCAGAGACAACGC GAAGAACACTGGGTATCTCCAGATGAATTCCCTCAGAGTCGAAGATACGGCCGTATACTACTGCGCAGCCACGCC CAGTGCCAAGGCATATAGCTACTGGGGCCAAGGGACACAAGTAACAGTTCCAGCGGGC SEQ ID NO: 4908 DVQ-T-008hu1.A7.VPAG_nucleotide sequence GATGTGCAGCTTCTCGAGTCCGGCGGGGGATTGGTACAGCCCGGAGGGAGCCTGCGATTGAGTTGCGCCGCGAG TGGCAGGACTTTCAGTGACTATGGGATGGGGTGGTTTCGACAAGCCCCGGGTAAGGATTCAGAGTTTGTAGCCGC AATTAACTGGAGCAATGCGCGGACCAACTACGCAGACAGTGTCAAGGGAAGATTCACTATTTCCAGAGATAACGC CAAGAACACCGGCTACCTCCAGATGAATTCCCTCAGAGTTGAGGATACGGCCGTGTACTACTGCGCAGCTACGCCC AGCGGGGCCGCCTACAGCTACTGGGGGCAAGGAACTCAGGTGACGGTACCAGCTGGA SEQ ID NO: 4909 DVQ-T-008hu1.A9.VPAG_nucleotide sequence GACGTTCAGTTGCTCGAGTCCGGAGGGGGTCTGGTACAGCCCGGGGGATCCCTCCGCCTGTCTTGCGCGGCTTCC GGACGCACTTTCAGTGATTATGGGATGGGCTGGTTCAGGCAGGCCCCGGGGAAGGACAGCGAGTTTGTGGCTGC CATTAACTGGTCAAACGCGCGGACCAACTATGCGGACAGCGTCAAGGGACGATTCACTATCTCCAGAGATAATGC CAAGAACACAGGGTACTTGCAAATGAACAGTCTGCGAGTCGAAGATACGGCCGTTTACTACTGTGCTGCTACGCC GAGTGGCAAGGCCGCTAGCTACTGGGGCCAGGGGACCCAGGTAACGGTACCGGCGGGA SEQ ID NO: 4910 DVQ-T-008hu1.A10.VPAG_nucleotide sequence GACGTGCAGCTTCTTGAGAGTGGCGGGGGATTGGTGCAGCCTGGGGGCTCTTTGAGACTCAGTTGCGCTGCGAG CGGCCGCACCTTCTCAGACTATGGAATGGGGTGGTTTCGGCAGGCCCCAGGCAAGGATTCCGAGTTCGTGGCTGC GATTAATTGGTCCAACGCCAGGACCAACTATGCGGATTCTGTCAAGGGCCGCTTTACCATTTCCAGAGATAATGCT AAGAATACCGGGTACCTTCAAATGAATTCCCTGAGGGTGGAAGACACGGCTGTGTATTACTGCGCCGCAACGCCC TCCGGGAAGGCTTATGCCTATTGGGGACAGGGGACACAGGTGACCGTGCCCGCTGGA SEQ ID NO: 4911 DVQ-T-008hu1.A11.VPAG_nucleotide sequence GATGTGCAGCTCCTCGAGTCTGGTGGGGGCCTTGTTCAGCCCGGGGGTTCACTCCGATTGAGTTGCGCAGCCAGC GGAAGAACCTTCAGCGACTACGGCATGGGGTGGTTCCGACAGGCACCCGGCAAAGACTCCGAGTTCGTGGCCGC GATAAATTGGTCCAACGCTCGCACCAACTACGCGGACAGTGTCAAGGGTAGGTTCACGATCTCTCGGGACAATGC TAAGAATACAGGATACCTGCAGATGAACTCCTTGCGAGTGGAGGATACCGCTGTGTATTACTGTGCCGCAACGCC GAGTGGGAAGGCATACTCAGCATGGGGCCAGGGGACACAAGTGACGGTACCAGCGGGC SEQ ID NO: 4912 T-007Mu-2*01_nucleotide sequence GAGGTGCAACTGGTGGAGAGTGGCGGAGGGCTCGTGCAGCCAGGGGAGAGTTTGAAGCTGAGTTGCGAGGCGT CAGGGCGGACCTTCGGTTCCTACACAATGGGGTGGTTTCGGAAGACACCGGAAAAGGAGAGAGAGTTCTTGGCA TCTATTAGGTGGACAGGGGGCTCTACATCCTACCCAGACACGGTAGAGAGACGCTTTATCATTTCCCGGGACGAT GCAAAGAAGACCGTGTACCTGCAGATGTCCTCCCTGAGGCCAGAGGACACGGCTCTCTACTATTGCGTAGCAAGT CCCACCGGCAGGGCTTTTACTTACTGGGGCCAAGGGACCCAGGTAACGGTCTCTTCA SEQ ID NO: 4913 T-007Mu-4*01_nucleotide sequence 315 310886415v1 Attorney Docket No: 260525.000071 GAGGTGCAGCTTGTGGAGTCTGGGGGCGGACTGGTGAAGCCTGGGGGTAGTCTTAAACTCTCATGCGCTGCGTC TGGTAGGACCTTTGGCTCCTACACCATGGGGTGGTTTCGGCAGACCCCGGAAAAGGAGAGAGAATTTCTGGCTTC AATCCGATGGACAGGAGGGTCTACCAGCTACCCCGACAATGTGAAAGGCAGATTCACCATCTCCCGCGACGACGC AAAGAAGAACGTTTACCTCCAGATGTCCCACCTTAAGCCAGAAGACACTGCGATGTACTACTGCGTCGCCTCCCCT ACCGGCAGAGCATTTACGTATTGGGGCCAGGGCACCCAGGTGACAGTCTCATCA SEQ ID NO: 4914 T-007Mu-6*01_nucleotide sequence GAAGTGCAACTCGTGGAATCTGGGGGCGATCTTGTGAAGCCAGGGGGATCCCTGAAGCTTAGTTGCGCGGCTAG TGGGAGGACTTTCGGGTCCTACACGATGGGGTGGTTCCGCCAGACACCAGACAAAGAAAGAGAGTTTTTGGCCA GCATACGGTGGACTGGAGGGTCAACAAGCTACCCCGATTCTGTTAAGGGAAGATTTACTATCTCCAGGGATGACG CCAAAAAGACAGTGTATTTGCAGATGAGCTCCCTGAAGCCCGAGGACACCGCAATGTACTACTGCGTGGCGAGCC CCACCGGGCGCGCCTTTACATACTGGGGCCAAGGGACACAGGTGACGGTCTCCTCC SEQ ID NO: 4915 T-007Mu-9*01_nucleotide sequence GAGGTGATGCTGGTCGAATCTGGGGGTGGCCTTGTCAAGCCCGGAGGGTCCCTGAAGCTCAGCTGTGCCGCGAG TGGCCGGACGTTCGGCAGTTACACGATGGGCTGGTTCAGGCAGACACCCGAAAAGGAAAGGGAGTTCCTGGCGT CAATTAGATGGACAGGTGGATCCACAAGTTACCCGGACTCCGTTAAAGGGAGGTTCACCATATCCAGGGATGACG CAAAGAAAACCGTTTACCTTCAGATGTCCTCTCTTCGACCAGAGGACACGGCTCTCTACTACTGCGTGGCCAGTCCT ACAGGCAGAGCCTTCACTTACTGGGGGCAAGGGACACAGGTCACGGTAAGCTCA SEQ ID NO: 4916 T-007Mu-12*01_nucleotide sequence GAGGTGAAGCTGGTGGAGTCCGGGGGCGGCCTGGTACAACCAGGCGGCAGCCTGAAACTTTCCTGTGCCGCATC CGGCAGAACATTCGGGAGTTACACCATGGGGTGGTTTAGGCAGACACCGGAAAAGGAACGGGAATTCCTGGCGT CCATAAGGTGGACAGGTGGGTCCACCAGTTACCCTGACACAGTAAAAGGAAGATTTACTATCAGTCGAGATGACG CCAAGAAAACAGTCTACCTCCAAATGAGCCGCCTCAAGCCTGAAGACACCGCGATGTACTACTGTGTCGCGTCACC AACCGGGAGGGCCTTCACCTACTGGGGACAGGGGACGCAGGTAACGGTTTCCAGT SEQ ID NO: 4917 T-007Mu-15*01_nucleotide sequence GAAGTGAAACTGGTGGAAAGCGGGGGTGGACTTGTTCAGCCCGGAGGGTCCCTGAAGCTCAGCTGCGCAGCGTC AGGAAGGACATTTGGATCCTATACCATGGGGTGGTTCAGGCAGGCTCCGCGGAAGGAAAGAGAATTCCTGGCAA GTATTCGCTGGACCGGCGGGTCCACATCATACGCGGACACCGTGACCGGAAGATTTACCATTAGCCGGGATGATG CTAAGAAAACGGTCTACCTGGAGATGTCCAGCCTTCGCCCTGAAGATACGGCCATGTATTACTGTGTGGCATCCCC CACCGGAAGAGCATTCACTTACTGGGGGCAGGGGACACAGGTGACGGTAAGCTCT SEQ ID NO: 4918 T-007Mu-16*01_nucleotide sequence GAAGTGAAGCTTGTTGAAAGTGAGGGAGGTCTCGTGCAGCCCGGGAGCTCCTTGAAACTGTCCTGTACTGCGAGC GGCCGCACGTTTGGGAGTTACACGATGGGCTGGTTCCGACAGGTCCCGGAGAAAGAGAGGGAGTTCCTTGCAAG TATTCGATGGACCGGCGGGAGTACCTCATACCTGGACTCAGTAAAGTCCCGGTTCATCATCTCTAGAGACGATGCT AAGAAGATTGTCTACCTCCAAATGAGCTCCCTTAAACCCGAGGACACCGCTACCTACTACTGCGTGGCGAGCCCAA CAGGAAGGGCCTTTACCTACTGGGGTCAGGGGACTCAGGTAACGGTGAGTTCC SEQ ID NO: 4919 T-007Mu-17*01_nucleotide sequence GAGGTGCAGTTGGTGGAGAGCGGCGGCGGCCTCGTTAAGCCAGGGGGAAGTTTGAAGCTGAGCTGTGCCGCGT CTGGTAGGACCTTTGGCTCCTATACGATGGGGTGGTTCCGCCAAGCACCGGAAAAGGAGCGAGAATTCCTGGCTT 316 310886415v1 Attorney Docket No: 260525.000071 CCATTCGGTGGACCGGGGGATCTACAAGTTACGCAGACACCGTAAAAGGAAGATTCACAATCTCCCGGGACGACG CGAAGAAGACCGTGTACCTCCAAATGACATCCTTGCGGCCAGAAGATACGGCCATGTACTACTGCGTCGCCTCCCC TACCGGGCGCGCATTTACGTACTGGGGACAGGGGACCCAAGTGACGGTATCATCA SEQ ID NO: 4920 T-007Mu-Consensus_nucleotide sequence GAAGTCCAACTGGTAGAGTCCGGCGGCGGGTTGGTCCAGCCGGGAGGATCTCTCAAGCTCAGCTGCGCAGCTTCC GGACGCACGTTCGGGTCTTATACCATGGGTTGGTTCCGACAAACCCCGGAAAAGGAACGAGAGTTTCTTGCCAGC ATCAGATGGACAGGCGGGTCTACAAGCTACCCTGACACAGTCAAGGGTAGGTTTACTATTTCCAGGGATGATGCC AAGAAGACGGTGTACTTGCAGATGTCATCCTTGAGACCCGAGGACACGGCTATGTATTACTGCGTGGCTTCCCCAA CCGGCCGGGCTTTCACCTACTGGGGGCAAGGGACTCAGGTCACCGTGTCAAGT SEQ ID NO: 4921 T-007Mu-Graft-IGHV5-9*01_nucleotide sequence GAAGTGATGCTGGTAGAATCTGGGGGCGGCCTGGTCAAACCCGGGGGTTCCCTTAAATTGTCCTGCGCAGCGAGC GGAAGGACATTTGGGAGTTATACTATGAGTTGGGTCAGGCAAACGCCGGAGAAGCGGTTGGAGTGGGTGGCCAC CATAAGGTGGACAGGGGGCTCCACATACTACCCCGATAGCGTGAAGGGGCGCTTCACCATTTCCCGCGATAACGC CAAGAATACCCTGTATCTGCAAATGTCTAGTCTTCGATCCGAGGACACAGCGTTGTACTATTGCGTGGCTTCTCCGA CTGGAAGAGCTTTCACTTACTGGGGGCAGGGCACCAGTGTGACCGTGTCTAGT SEQ ID NO: 4922 DVQ-T-019hu1.VPAG_nucleotide sequence GATGTCCAGCTTGTTGAGAGTGGGGGTGGACTCGTGCAGCCAGGTGGTTCCCTGAGGCTGAGCTGCGCCGCGTCT GGGTCCATATTCCGCTTTCCTCCGATGGGCTGGTACCGGCAGGCACCCGGGAAGCAGCGAGAGCAGGTGGCTCA ACTGACAAGCGGCGGGAGCACAAACTACGCCGACTCAGTCAAAGGGCGGTTCACCATTAGTAGGGATAACGCGA AAAACACGTGGTACCTTCAGATGAATAGCCTTAGGCCCGAAGACACAGCCGTCTACTATTGCTCCGTCCTGGGCAG AGACATGGTCACGTATTGGGGGCAGGGGACTCAAGTGACGGTGCCAGCAGGA SEQ ID NO: 4923 DVQ-T-019hu1.LV.VPAG_nucleotide sequence GACGTCCAGCTTGTCGAGAGTGGAGGCGGCTTGGTTCAGCCTGGGGGCTCACTTCGGCTGTCATGTGCGGCGTCT GGGTCAATCTTCAGATTTCCGCCGATGGGGTGGTACCGACAGGCTCCGGGAAAACAAAGAGAACAGGTGGCGCA ACTGACATCTGGCGGAAGCACCAACTACGCAGACTCAGTCAAGGGGCGGTTTACGATCAGTAGAGATAACGCCAA GAATACCTGGTACCTGCAGATGAACAGTCTGAGGCCTGAAGACACGGCCGTTTACTACTGCTCCGTGCTGGGGCG GGACCTGGTAACGTATTGGGGTCAGGGTACACAGGTGACAGTGCCAGCCGGT SEQ ID NO: 4924 DVQ-T-019hu1.RV.VPAG_nucleotide sequence GACGTCCAGCTTGTGGAAAGCGGCGGCGGGCTTGTCCAGCCAGGGGGCTCACTCAGGCTTTCCTGCGCCGCGAGT GGATCCATATTCCGCTTTCCACCGATGGGATGGTACAGGCAGGCCCCAGGGAAACAGCGAGAACAAGTGGCACA GCTCACCTCCGGAGGGAGCACTAACTACGCTGACAGTGTTAAAGGGCGGTTTACCATTTCCCGCGACAACGCCAA GAATACCTGGTACCTGCAGATGAACAGCCTGAGACCAGAGGACACGGCGGTTTATTACTGTTCTGTCTTGGGCAG AGATCGAGTAACATACTGGGGGCAAGGGACGCAGGTGACGGTGCCAGCAGGT SEQ ID NO: 4925 DVQ-T-019hu1.IV.VPAG_nucleotide sequence GACGTTCAGCTCGTCGAATCAGGGGGAGGGCTCGTCCAGCCTGGGGGCAGTTTGCGCCTCAGTTGCGCCGCGAG TGGATCAATTTTCAGGTTCCCTCCTATGGGGTGGTACCGGCAGGCTCCCGGGAAACAGAGGGAGCAGGTGGCTCA ACTGACATCAGGTGGGTCTACAAACTATGCAGATTCTGTCAAGGGGAGGTTTACTATATCCAGAGATAATGCAAA 317 310886415v1 Attorney Docket No: 260525.000071 GAACACTTGGTACCTCCAGATGAACTCCCTCCGCCCAGAGGACACGGCTGTATACTACTGTTCCGTGTTGGGCCGC GACATCGTGACGTATTGGGGTCAGGGGACCCAGGTGACAGTACCAGCGGGA SEQ ID NO: 4926 T-009Hu1_QGR_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTGTTGCAACC ATTAATTGGAGCCAGGGTCGTACCACCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGAC CGGTAAAGCATATACCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4927 T-009Hu1_NAR_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTGTTGCAACC ATTAATTGGAGCAATGCACGTACCACCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGAC CGGTAAAGCATATACCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4928 T-009Hu1_SGR_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTGTTGCAACC ATTAATTGGAGCAGCGGTCGTACAACCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGAC CGGTAAAGCATATACCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4929 T-009Hu1_QGR_N/C_nucleotide sequence GATGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTGTTGCAACC ATTAATTGGAGCCAGGGTCGTACCACCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGAC CGGTAAAGCATATACCTATTGGGGTCAGGGTACCCAGGTTACCGTTCCGGCAGGT SEQ ID NO: 4930 T-009Hu1_NAR_N/C_nucleotide sequence GATGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTGTTGCAACC ATTAATTGGAGCAATGCACGTACCACCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGAC CGGTAAAGCATATACCTATTGGGGTCAGGGTACCCAGGTTACCGTTCCGGCAGGT SEQ ID NO: 4931 T-009Hu1_SGR_N/C_nucleotide sequence GATGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTGTTGCAACC ATTAATTGGAGCAGCGGTCGTACAACCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGAC CGGTAAAGCATATACCTATTGGGGTCAGGGTACCCAGGTTACCGTTCCGGCAGGT 318 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 4932 T-007Hu1.S3.QGR_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCCAGGGTCGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCATCTCCGAG CGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4933 T-007Hu1.S3.EGR_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCGAAGGTCGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCATCTCCGAG CGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4934 T-007Hu1.S3.SGR_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAGCGGTCGTACAAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCATCTCCGAG CGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4935 T-007Hu1.S3.NSR_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAATAGCCGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCATCTCCGAG CGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4936 T-007Hu1.S3.NTR_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAATACCCGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCATCTCCGAG CGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4937 T-007Hu1.S3.SAR_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAGCGCACGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCATCTCCGAG CGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4938 T-007Hu1.EQ.QGR_nucleotide sequence 319 310886415v1 Attorney Docket No: 260525.000071 GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACAGGAATTTGTTGCAGC AATTAATTGGAGCCAGGGTCGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCA AAAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGA GCGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4939 T-007Hu1.EQ.EGR_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACAGGAATTTGTTGCAGC AATTAATTGGAGCGAAGGTCGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCA AAAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGA GCGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4940 T-007Hu1.EQ.SGR_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACAGGAATTTGTTGCAGC AATTAATTGGAGCAGCGGTCGTACAAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCA AAAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGA GCGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4941 T-007Hu1.EQ.S3.NSR_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACAGGAATTTGTTGCAGC AATTAATTGGAGCAATAGCCGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCA AAAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCATCTCCGA GCGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4942 T-016hu1.A1_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTGGTAGCTATACCATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTCTGGCAAGC ATTCGTTGGACCGGTGGTAGCACCAGCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATGATGCAA AAAAAACCGTTTATCTGCAGATGAATAGCCTGCGTCCGGAAGATACCGCAGTTTATTATTGTGCAGCATCTCCGAC CGGTCGTGCCTTTACCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4943 T-016hu1.G2_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTGGTAGCTATACCATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTCTGGCAAGC ATTCGTTGGACCGGTGGTAGCACCAGCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATGATGCAA AAAAAACCGTTTATCTGCAGATGAATAGCCTGCGTCCGGAAGATACCGCAGTTTATTATTGTGTTGGTAGCCCGAC CGGTCGTGCCTTTACCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4944 T-016hu1.A3_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTGGTAGCTATACCATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTCTGGCAAGC 320 310886415v1 Attorney Docket No: 260525.000071 ATTCGTTGGACCGGTGGTAGCACCAGCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATGATGCAA AAAAAACCGTTTATCTGCAGATGAATAGCCTGCGTCCGGAAGATACCGCAGTTTATTATTGTGTTGCAGCACCGAC CGGTCGTGCCTTTACCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4945 T-016hu1.A4_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTGGTAGCTATACCATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTCTGGCAAGC ATTCGTTGGACCGGTGGTAGCACCAGCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATGATGCAA AAAAAACCGTTTATCTGCAGATGAATAGCCTGCGTCCGGAAGATACCGCAGTTTATTATTGTGTTGCAAGCGCAAC CGGTCGTGCCTTTACCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4946 T-016hu1.A5_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTGGTAGCTATACCATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTCTGGCAAGC ATTCGTTGGACCGGTGGTAGCACCAGCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATGATGCAA AAAAAACCGTTTATCTGCAGATGAATAGCCTGCGTCCGGAAGATACCGCAGTTTATTATTGTGTTGCAAGCCCGGC AGGTCGTGCCTTTACCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4947 T-016hu1.A6_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTGGTAGCTATACCATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTCTGGCAAGC ATTCGTTGGACCGGTGGTAGCACCAGCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATGATGCAA AAAAAACCGTTTATCTGCAGATGAATAGCCTGCGTCCGGAAGATACCGCAGTTTATTATTGTGTTGCAAGCCCGAC CGCACGTGCCTTTACCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4948 T-016hu1.A7_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTGGTAGCTATACCATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTCTGGCAAGC ATTCGTTGGACCGGTGGTAGCACCAGCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATGATGCAA AAAAAACCGTTTATCTGCAGATGAATAGCCTGCGTCCGGAAGATACCGCAGTTTATTATTGTGTTGCAAGCCCGAC CGGTGCAGCCTTTACCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4949 T-016hu1.A9_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTGGTAGCTATACCATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTCTGGCAAGC ATTCGTTGGACCGGTGGTAGCACCAGCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATGATGCAA AAAAAACCGTTTATCTGCAGATGAATAGCCTGCGTCCGGAAGATACCGCAGTTTATTATTGTGTTGCAAGCCCGAC CGGTCGTGCAGCAACCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4950 T-016hu1.A10_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTGGTAGCTATACCATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTCTGGCAAGC ATTCGTTGGACCGGTGGTAGCACCAGCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATGATGCAA 321 310886415v1 Attorney Docket No: 260525.000071 AAAAAACCGTTTATCTGCAGATGAATAGCCTGCGTCCGGAAGATACCGCAGTTTATTATTGTGTTGCAAGCCCGAC CGGTCGTGCATTTGCATATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4951 T-016hu1.A11_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTGGTAGCTATACCATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTCTGGCAAGC ATTCGTTGGACCGGTGGTAGCACCAGCTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATGATGCAA AAAAAACCGTTTATCTGCAGATGAATAGCCTGCGTCCGGAAGATACCGCAGTTTATTATTGTGTTGCAAGCCCGAC CGGTCGTGCCTTTACCGCATGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4952 T-016Hu1.A5.A7_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGATCTTTGAGGCTGAGCTGCGCCGCCAG CGGCAGGACCTTCGGCAGCTACACCATGGGCTGGTTCAGACAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCCA GCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACGAC GCCAAGAAGACCGTGTACCTGCAGATGAACAGCCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGTGGCCAG CCCCGCCGGAGCTGCCTTCACCTACTGGGGCCAGGGCACACAGGTGACCGTGAGCAGC SEQ ID NO: 4953 T-016Hu1.A5.A1_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGATCTTTGAGGCTGAGCTGCGCCGCCAG CGGCAGGACCTTCGGCAGCTACACCATGGGCTGGTTCAGGCAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCCA GCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGATTCACCATCAGCAGGGACGAC GCCAAGAAGACCGTGTACCTGCAGATGAACAGCCTGAGACCCGAGGACACCGCCGTGTACTACTGCGCCGCCTCT CCCGCCGGAAGGGCCTTCACCTACTGGGGCCAGGGCACACAGGTGACCGTGAGCAGC SEQ ID NO: 4954 T-016Hu1.A5.A3_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGAAGCTTGAGACTGAGCTGCGCCGCCA GCGGCAGAACCTTCGGCAGCTACACCATGGGCTGGTTCAGGCAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCC AGCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACGA CGCCAAGAAGACCGTGTACCTGCAGATGAACAGCCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGTGGCCG CCCCTGCTGGAAGGGCCTTCACCTACTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGC SEQ ID NO: 4955 T-016Hu1.A5.A4_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGAAGCTTGAGGCTGAGCTGCGCTGCCA GCGGCAGGACCTTCGGCAGCTACACCATGGGCTGGTTCAGGCAGGCCCCCGGCAAGGAGAGAGAGTTCCTGGCC AGCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACGA CGCCAAGAAGACCGTGTACCTGCAGATGAACAGCCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGTGGCCA GCGCCGCCGGAAGGGCCTTCACCTACTGGGGCCAGGGCACACAGGTGACCGTGAGCAGC SEQ ID NO: 4956 T-016Hu1.A5.A6_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGATCTTTGAGGCTGAGCTGCGCCGCCAG CGGCAGGACCTTCGGCAGCTACACCATGGGCTGGTTCAGGCAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCCA GCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGATTCACCATCAGCAGGGACGAC GCCAAGAAGACCGTGTACCTGCAGATGAACAGCCTGAGACCCGAGGACACCGCCGTGTACTACTGCGTGGCCAGC CCCGCCGCTAGGGCCTTCACCTACTGGGGCCAGGGCACACAGGTGACCGTGAGCAGC 322 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 4957 T-016Hu1.A7.A1_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGATCTTTGAGGCTGAGCTGCGCCGCCAG CGGCAGAACCTTCGGCAGCTACACCATGGGCTGGTTCAGGCAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCCA GCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACGAC GCCAAGAAGACCGTGTACCTGCAGATGAACAGCCTGAGACCCGAGGACACCGCCGTGTACTACTGCGCCGCCTCT CCCACCGGCGCTGCCTTCACCTACTGGGGCCAGGGCACACAGGTGACCGTGAGCAGC SEQ ID NO: 4958 T-016Hu1.A7.A3_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGATCTTTGAGGCTGAGCTGCGCCGCCAG CGGCAGGACCTTCGGCAGCTACACCATGGGCTGGTTCAGGCAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCCA GCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGATTCACCATCAGCAGGGACGAC GCCAAGAAGACCGTGTACCTGCAGATGAACAGCCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGTGGCCGC CCCCACCGGAGCTGCCTTCACCTACTGGGGCCAGGGCACACAGGTGACCGTGAGCAGC SEQ ID NO: 4959 T-016Hu1.A7.A4_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGAAGCTTGAGACTGAGCTGCGCCGCCA GCGGCAGGACCTTCGGCAGCTACACCATGGGCTGGTTCAGGCAGGCCCCCGGCAAGGAGAGAGAGTTCCTGGCC AGCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACGA CGCCAAGAAGACCGTGTACCTGCAGATGAACAGCCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGTGGCCA GCGCCACCGGCGCTGCCTTCACCTACTGGGGCCAGGGCACACAGGTGACCGTGAGCAGC SEQ ID NO: 4960 T-016Hu1.A7.A6_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGAAGCTTGAGGCTGAGCTGCGCTGCCA GCGGCAGGACCTTCGGCAGCTACACCATGGGCTGGTTCAGACAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCC AGCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGATTCACCATCAGCAGGGACGA CGCCAAGAAGACCGTGTATCTGCAGATGAACAGCCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGTGGCCA GCCCCACCGCCGCTGCCTTCACCTACTGGGGCCAGGGCACACAGGTGACCGTGAGCAGC SEQ ID NO: 4961 T-016Hu1.A1.A3_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGAAGCTTGAGGCTGAGCTGCGCTGCCA GCGGCAGAACCTTCGGCAGCTACACCATGGGCTGGTTCAGGCAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCC AGCATCAGATGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACGA CGCCAAGAAGACCGTGTATCTGCAGATGAACAGCCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGCCGCCGC CCCCACAGGCAGAGCCTTCACCTACTGGGGCCAGGGCACACAGGTGACCGTGAGCAGC SEQ ID NO: 4962 T-016Hu1.A1.A4_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGATCTTTGAGGCTGAGCTGCGCCGCCAG CGGCAGAACCTTCGGCAGCTACACCATGGGCTGGTTCAGGCAGGCCCCCGGCAAGGAGAGAGAGTTCCTGGCCA GCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACGAC GCCAAGAAGACCGTGTACCTGCAGATGAACAGCCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGCCGCCTCT GCCACCGGAAGGGCCTTCACCTACTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGC SEQ ID NO: 4963 T-016Hu1.A1.A6_nucleotide sequence 323 310886415v1 Attorney Docket No: 260525.000071 GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGAAGCTTGAGGCTGAGCTGCGCTGCCA GCGGCAGGACCTTCGGCAGCTACACCATGGGCTGGTTCAGACAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCC AGCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACGA CGCCAAGAAGACCGTGTATCTGCAGATGAACAGCCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGCCGCCAG CCCCACAGCTAGGGCCTTCACCTACTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGC SEQ ID NO: 4964 T-016Hu1.A3.A4_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGATCTTTGAGGCTGAGCTGCGCCGCCAG CGGCAGGACCTTCGGCAGCTACACCATGGGCTGGTTCAGACAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCCA GCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGATTCACCATCAGCAGGGACGAC GCCAAGAAGACCGTGTACCTGCAGATGAACAGCCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGTGGCCGC CGCCACAGGAAGGGCCTTCACCTACTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGC SEQ ID NO: 4965 T-016Hu1.A3.A6_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGATCTTTGAGGCTGAGCTGCGCCGCCAG CGGCAGGACCTTCGGCAGCTACACCATGGGCTGGTTCAGGCAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCCA GCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACGAC GCCAAGAAGACCGTGTACCTGCAGATGAACAGCCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGTGGCCGC CCCCACCGCCAGAGCCTTCACCTACTGGGGCCAGGGCACACAGGTGACCGTGAGCAGC SEQ ID NO: 4966 T-016Hu1.A4.A6_nucleotide sequence GAGGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGTGGAAGCTTGAGACTGAGCTGCGCCGCCA GCGGCAGGACCTTCGGCAGCTACACCATGGGCTGGTTCAGACAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCC AGCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGGTTCACCATTAGCAGAGACGA CGCCAAGAAGACCGTGTACCTGCAGATGAACTCTCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGTGGCCAG CGCCACCGCCAGAGCCTTCACCTACTGGGGCCAGGGCACCCAGGTGACCGTGAGCAGC SEQ ID NO: 4967 T-008Hu1.G1_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAATGCACGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGGTGCAACCCCGAG CGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4968 T-008Hu1.G2_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAATGCACGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGGTACCCCGAG CGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4969 T-008Hu1.A3_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA 324 310886415v1 Attorney Docket No: 260525.000071 ATTAATTGGAGCAATGCACGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAGCACCGAG CGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4970 T-008Hu1.A4_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAATGCACGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCGCAAG CGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4971 T-008Hu1.A5_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAATGCACGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGGC AGGTAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4972 T-008Hu1.A6_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAATGCACGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGAG CGCAAAAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4973 T-008Hu1.A7_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAATGCACGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGAG CGGTGCAGCATATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4974 T-008Hu1.G8_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAATGCACGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGAG CGGTAAAGGTTATAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4975 T-008Hu1.A9_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAATGCACGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA 325 310886415v1 Attorney Docket No: 260525.000071 AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGAG CGGTAAAGCAGCAAGCTATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4976 T-008Hu1.A10_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAATGCACGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGAG CGGTAAAGCATATGCATATTGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4977 T-008Hu1.A11_nucleotide sequence GAAGTTCAGCTGCTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGTGCAGCAAG CGGTCGTACCTTTAGCGATTATGGTATGGGTTGGTTTCGTCAGGCACCGGGTAAAGATAGCGAATTTGTTGCAGCA ATTAATTGGAGCAATGCACGTACCAATTATGCAGATAGCGTTAAAGGTCGTTTTACCATTAGCCGTGATAATGCAA AAAATACCGGTTATCTGCAGATGAATAGCCTGCGTGTTGAAGATACCGCAGTTTATTATTGTGCAGCAACCCCGAG CGGTAAAGCATATAGCGCATGGGGTCAGGGTACCCAGGTTACCGTTAGCAGC SEQ ID NO: 4978 T-022_nucleotide sequence GACGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGAGGAAGCTTGAGGCTGAGCTGCGCTGCCA GCGGCAGAACCTTCGGCAGCTACACCATGGGCTGGTTCAGGCAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCC AGCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACGA CGCCAAGAAGACCGTGTACCTGCAGATGAACAGCCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGTGGCCA GCCCCACCGGAAGGGCCTTCACCTACTGGGGCCAGGGCACCCAGGTGACCGTGCCCGCCGGAGGCGGATCTGAC AAGACCCACACCTGCCCTCCCTGCCCCGCCCCCGAGGCTGCTGGAGGACCTTCTGTGTTCCTGTTCCCTCCCAAGCC CAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCCG AGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGGGAGGAGCAGTA CAACAGCACCTACAGGGTGGTGAGCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGT GCAAGGTGAGCAACAAGGCCCTGGCCGCCCCCATCGAGAAGACCATCAGCAAGGCCAAGGGCCAGCCCAGGGA GCCCCAGGTGTACACCCTGCCCCCTAGCAGGGAGGAGATGACCAAGAACCAGGTGAGCCTGACCTGCCTGGTGA AGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACC CCTCCCGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGGTGGCAGCAG GGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAAAAATCTCTTTCTCTGTCTC CTGGAAAATGA SEQ ID NO: 4979 T-022_protein sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 4980 T-023_nucleotide sequence GACGTCCAGCTGCTCGAGTCAGGAGGCGGGCTTGTGCAACCTGGCGGCAGCCTGAGACTTTCTTGTGCCGCAAGT GGAAGGACCTTTGGTAGCTATACCATGGGTTGGTTTCGGCAGGCTCCCGGCAAAGAACGGGAGTTCCTGGCTTCT 326 310886415v1 Attorney Docket No: 260525.000071 ATAAGGTGGACAGGAGGCAGCACCAGCTATGCCGACTCCGTTAAGGGGAGGTTTACTATTAGTCGGGATGATGC AAAGAAGACAGTTTATCTGCAAATGAACAGCCTTCGCCCAGAAGATACTGCTGTGTACTATTGTGTGGCCTCACCC GCGGGCGCCGCATTCACCTACTGGGGGCAGGGAACCCAGGTCACAGTACCAGCCGGAGGCGGCTCCGATAAAAC TCATACGTGTCCCCCATGCCCTGCCCCGGAAGCCGCTGGGGGACCTTCAGTTTTCCTGTTTCCACCCAAGCCAAAA GACACACTCATGATCTCCAGAACCCCAGAAGTAACATGCGTCGTGGTGGACGTGTCTCATGAGGACCCAGAGGTC AAATTCAATTGGTACGTCGATGGCGTCGAGGTACACAACGCTAAAACTAAGCCCCGCGAAGAGCAATACAACTCT ACGTACCGAGTGGTGTCTGTCCTTACAGTGCTGCACCAGGACTGGCTGAACGGGAAAGAGTACAAGTGCAAAGT GTCAAACAAGGCACTCGCGGCCCCTATCGAAAAGACCATTTCCAAGGCAAAAGGCCAGCCTCGAGAGCCCCAGGT TTATACACTGCCGCCCTCCAGAGAAGAAATGACTAAGAATCAGGTTAGTCTGACGTGCCTCGTGAAAGGGTTCTAC CCCTCTGACATCGCCGTAGAGTGGGAGTCCAATGGGCAACCGGAGAATAATTATAAGACTACCCCTCCTGTTCTCG ATTCAGATGGTAGTTTCTTTCTGTACAGCAAGCTTACCGTGGACAAATCTCGCTGGCAGCAGGGAAATGTGTTTAG CTGTTCCGTGATGCATGAGGCTTTGCACAACCACTATACTCAGAAGAGCTTGTCCTTGAGTCCTGGTAAGTGA SEQ ID NO: 4981 T-023_protein sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPAGAAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 4982 T-024_nucleotide sequence GATGTCCAGCTGTTGGAAAGTGGCGGAGGGCTGGTGCAGCCAGGCGGCTCTCTTAGACTCTCATGCGCAGCAAGT GGACGCACGTTCGGTTCTTACACCATGGGCTGGTTCCGGCAGGCTCCCGGTAAAGAGAGGGAGTTCCTGGCATCC ATCCGCTGGACTGGCGGATCCACTTCTTATGCCGATTCCGTCAAGGGGCGGTTTACAATCTCACGAGATGACGCTA AAAAAACCGTTTATCTTCAAATGAATTCCCTGAGGCCTGAGGACACGGCGGTGTATTACTGCGCCGCATCCCCCGC CGGTCGAGCCTTTACTTACTGGGGACAAGGGACACAGGTGACAGTACCCGCCGGCGGCGGGAGCGACAAGACCC ATACTTGCCCACCCTGTCCCGCTCCCGAAGCCGCTGGTGGGCCATCTGTATTCTTGTTTCCACCGAAGCCAAAAGAC ACTCTCATGATCAGCAGGACACCTGAAGTTACCTGTGTGGTTGTTGACGTGAGCCACGAAGATCCTGAGGTGAAG TTTAATTGGTACGTGGATGGCGTGGAAGTGCACAACGCCAAAACCAAACCTCGGGAGGAGCAGTATAACTCAACA TATAGAGTAGTGTCTGTTCTTACGGTGTTGCATCAGGATTGGCTGAATGGGAAAGAGTACAAGTGTAAAGTAAGC AACAAAGCTCTGGCCGCCCCGATTGAGAAGACCATTTCCAAGGCTAAGGGACAGCCTAGGGAGCCTCAGGTCTAC ACCCTGCCCCCTAGTCGCGAGGAGATGACAAAGAACCAAGTCAGCTTGACCTGCCTCGTGAAGGGGTTCTATCCG TCTGACATAGCGGTCGAATGGGAATCTAATGGCCAACCCGAAAATAATTACAAGACTACTCCACCAGTGCTCGACT CCGATGGAAGTTTCTTTCTGTACAGCAAGTTGACCGTGGACAAATCAAGATGGCAGCAGGGAAACGTCTTTAGCT GTAGCGTCATGCACGAGGCACTGCACAACCATTATACACAGAAGTCACTCTCCCTGAGTCCAGGCAAGTGA SEQ ID NO: 4983 T-024_protein sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCAASPAGRAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 4984 T-025_nucleotide sequence 327 310886415v1 Attorney Docket No: 260525.000071 GACGTTCAACTGCTGGAAAGTGGCGGAGGTCTGGTCCAACCCGGGGGCAGCCTGCGCCTCAGCTGTGCAGCTAG TGGCAGAACCTTCGGCTCATACACAATGGGTTGGTTCCGCCAAGCCCCCGGGAAGGAACGGGAATTTCTCGCCTC CATCAGATGGACAGGAGGTAGTACCTCTTACGCCGACTCTGTCAAGGGGCGGTTCACTATAAGCAGGGACGACGC AAAGAAGACTGTGTACCTGCAGATGAATTCACTTCGCCCTGAGGATACAGCAGTCTACTACTGCGTGGCCGCCCCT GCCGGGAGGGCTTTCACATATTGGGGTCAGGGGACTCAGGTGACCGTACCAGCCGGAGGAGGATCAGATAAGAC TCACACGTGCCCTCCATGCCCAGCTCCGGAAGCTGCAGGCGGACCTAGCGTTTTTCTTTTTCCACCGAAGCCCAAA GACACCCTCATGATTAGCAGAACTCCGGAAGTGACCTGTGTAGTCGTGGATGTCTCCCACGAGGATCCCGAGGTG AAATTCAATTGGTACGTCGATGGAGTTGAAGTTCATAACGCCAAGACGAAGCCTCGGGAGGAGCAATACAATTCC ACATACAGGGTGGTGTCAGTGCTCACGGTGTTGCATCAGGACTGGCTGAACGGGAAAGAATATAAATGCAAGGT ATCCAATAAGGCGCTCGCTGCTCCCATTGAGAAGACCATCTCCAAAGCGAAAGGCCAGCCTCGAGAGCCCCAGGT TTATACTCTCCCTCCCTCACGAGAAGAGATGACAAAAAACCAGGTCAGCTTGACCTGTCTCGTGAAAGGCTTTTATC CATCCGACATCGCCGTTGAGTGGGAGAGCAACGGCCAGCCAGAGAATAATTATAAGACCACCCCTCCCGTGTTGG ATAGTGACGGCTCTTTTTTTCTGTATTCTAAACTGACAGTGGATAAGTCTAGGTGGCAGCAGGGCAACGTGTTCTC TTGTTCTGTAATGCATGAGGCACTGCACAACCACTATACTCAGAAGTCCCTTAGCCTGAGTCCAGGGAAATGA SEQ ID NO: 4985 T-025_protein sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVAAPAGRAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 4986 T-026_nucleotide sequence GACGTGCAGCTGCTGGAGAGCGGCGGCGGCCTGGTGCAGCCTGGAGGATCTCTGAGGCTGAGCTGCGCCGCCAG CGGCAGGACCTTCGGCAGCTACACCATGGGCTGGTTCAGGCAGGCCCCCGGCAAGGAGAGGGAGTTCCTGGCCA GCATCAGGTGGACCGGCGGCAGCACCAGCTACGCCGACAGCGTGAAGGGCAGGTTCACCATCAGCAGGGACGAC GCCAAGAAGACCGTGTACCTGCAGATGAACAGCCTGAGGCCCGAGGACACCGCCGTGTACTACTGCGTGGCCAG CGCCGCTGGAAGGGCCTTCACCTACTGGGGCCAGGGCACCCAGGTGACCGTGCCCGCCGGAGGCGGATCTGACA AGACCCACACCTGCCCTCCCTGCCCCGCCCCCGAGGCTGCTGGAGGACCTTCTGTGTTCCTGTTCCCTCCCAAGCCC AAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCCGA GGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGGGAGGAGCAGTAC AACAGCACCTACAGGGTGGTGAGCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGAGCAACAAGGCCCTGGCCGCCCCCATCGAGAAGACCATCAGCAAGGCCAAGGGCCAGCCCAGGGAGC CCCAGGTGTACACCCTGCCCCCTAGCAGGGAGGAGATGACCAAGAACCAGGTGAGCCTGACCTGCCTGGTGAAG GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCT CCCGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGGTGGCAGCAGGG CAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAAAAATCTTTGTCTTTGTCTCCTG GAAAATGA SEQ ID NO: 4987 T-026_protein sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASAAGRAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAA 328 310886415v1 Attorney Docket No: 260525.000071 PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 4988 T-027_nucleotide sequence GACGTGCAGCTCCTGGAGTCTGGGGGCGGGCTCGTTCAGCCGGGCGGGTCATTGCGACTCAGTTGTGCTGCGTCT GGCCGCACATTTGGCTCATACACTATGGGATGGTTTCGGCAGGCTCCTGGCAAGGAAAGAGAGTTCCTGGCTAGC ATCCGCTGGACTGGGGGTAGCACCTCATATGCCGATTCCGTGAAGGGCAGGTTTACCATTAGCAGAGACGACGCA AAAAAGACAGTATATCTTCAAATGAACTCTCTGCGCCCAGAGGATACAGCAGTGTACTATTGTGTGGCTAGCCCTG CAGCCAGGGCCTTTACCTACTGGGGGCAAGGAACACAGGTGACGGTGCCCGCCGGCGGGGGTAGTGATAAAACA CACACCTGCCCTCCTTGTCCTGCACCGGAAGCTGCTGGCGGTCCATCTGTATTCCTGTTTCCCCCTAAACCCAAAGA TACCCTGATGATCTCCCGGACACCCGAGGTAACCTGTGTGGTCGTCGACGTCAGCCACGAGGACCCTGAGGTCAA GTTCAATTGGTACGTGGATGGAGTGGAAGTTCACAACGCCAAGACTAAGCCACGGGAGGAACAGTACAATAGCA CCTATAGGGTCGTGAGCGTGCTGACTGTGTTGCATCAAGATTGGCTTAACGGAAAGGAGTATAAGTGCAAGGTTT CCAACAAAGCACTGGCGGCCCCCATTGAAAAGACGATCTCCAAAGCCAAAGGACAGCCCAGAGAGCCTCAGGTGT ACACACTCCCACCATCACGAGAGGAAATGACCAAGAACCAGGTTTCCCTTACTTGCCTGGTGAAGGGGTTTTATCC CAGTGATATAGCCGTTGAATGGGAGAGCAACGGCCAACCAGAGAATAATTATAAGACCACTCCGCCCGTTCTTGA CTCCGACGGAAGTTTCTTCCTTTACTCTAAGCTGACTGTCGACAAAAGTAGGTGGCAGCAGGGTAATGTCTTCTCCT GCTCAGTAATGCATGAAGCCCTCCACAATCATTACACGCAGAAATCTTTGTCCCTGTCTCCAGGAAAATGA SEQ ID NO: 4989 T-027_protein sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPAARAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 4990 T-028_nucleotide sequence GACGTCCAGCTGCTGGAATCTGGCGGTGGCCTTGTCCAGCCTGGAGGGTCCTTGAGACTCAGTTGCGCTGCCAGT GGGCGAACGTTTGGGTCATACACCATGGGATGGTTTAGGCAGGCCCCGGGTAAAGAAAGAGAGTTCCTTGCTAG TATCCGCTGGACCGGGGGTAGCACAAGCTACGCTGACTCCGTAAAGGGCCGCTTCACCATATCTCGCGATGATGC CAAGAAGACAGTGTACTTGCAAATGAACTCACTGCGACCCGAGGACACGGCCGTGTATTACTGTGTTGCAAGTGC AACTGGCGCGGCCTTCACTTACTGGGGCCAGGGCACCCAGGTGACAGTGCCAGCCGGAGGCGGCAGCGATAAAA CTCACACCTGTCCACCGTGCCCTGCTCCTGAGGCGGCAGGTGGACCCAGTGTGTTCCTGTTCCCACCCAAGCCAAA AGACACTCTGATGATCTCTAGGACGCCTGAGGTAACCTGCGTCGTCGTTGACGTTAGCCATGAGGACCCTGAGGTT AAGTTTAATTGGTATGTCGATGGCGTGGAGGTGCATAACGCCAAAACAAAGCCTCGGGAAGAACAGTACAACTCT ACCTATAGGGTTGTGAGCGTGTTGACTGTGCTGCACCAGGATTGGTTGAATGGGAAGGAGTATAAGTGCAAGGT ATCTAATAAAGCTCTCGCCGCCCCCATTGAAAAAACCATTTCCAAGGCTAAAGGACAGCCTAGAGAGCCCCAAGTA TATACACTTCCACCCTCACGGGAAGAGATGACCAAGAATCAGGTGTCCCTGACTTGTCTCGTCAAGGGGTTTTACC CCAGCGACATCGCAGTGGAGTGGGAATCCAACGGGCAACCGGAAAACAATTATAAAACAACTCCCCCAGTGCTCG ATTCCGACGGCTCCTTCTTTCTTTATTCTAAGCTGACCGTTGATAAATCACGGTGGCAGCAGGGAAATGTGTTTAGC TGTTCAGTCATGCACGAGGCACTCCATAACCACTACACACAAAAATCTCTGTCCCTGAGCCCAGGAAAGTGA SEQ ID NO: 4991 T-028_protein sequence 329 310886415v1 Attorney Docket No: 260525.000071 DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASATGAAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 4992 T-029_nucleotide sequence GACGTTCAACTCCTTGAGTCCGGAGGGGGCCTGGTTCAGCCAGGAGGCTCCCTTCGCCTCTCTTGTGCTGCTAGTG GTCGGACCTTCGGATCCTACACCATGGGGTGGTTCAGACAAGCACCTGGTAAGGAGAGGGAGTTTCTGGCCTCCA TCCGGTGGACAGGCGGATCAACCTCCTATGCGGACAGCGTCAAGGGGAGGTTCACAATTAGCCGCGACGATGCT AAAAAGACTGTCTACCTCCAGATGAACTCACTGAGGCCCGAAGACACCGCCGTATATTATTGCGCTGCTTCCGCCA CCGGCCGGGCCTTTACTTACTGGGGACAGGGGACCCAGGTGACAGTGCCCGCCGGGGGTGGAAGTGATAAGACT CACACATGTCCGCCCTGTCCTGCACCGGAGGCAGCCGGGGGCCCATCTGTGTTCCTGTTTCCCCCAAAACCGAAAG ACACTCTTATGATTTCCAGAACACCTGAGGTTACTTGCGTGGTCGTTGATGTGTCCCATGAGGATCCTGAAGTCAA ATTTAATTGGTATGTGGATGGCGTGGAGGTGCACAATGCAAAGACTAAGCCCCGAGAGGAGCAATACAATTCAAC ATACAGGGTGGTGTCAGTACTGACCGTACTGCATCAGGATTGGTTGAATGGAAAAGAGTACAAGTGCAAGGTGA GCAATAAGGCACTTGCTGCCCCAATAGAAAAGACCATCTCTAAGGCGAAAGGCCAGCCTAGAGAACCCCAGGTCT ATACGCTGCCCCCTAGTCGAGAGGAAATGACAAAAAACCAAGTCTCTTTGACCTGTCTCGTCAAGGGCTTTTATCC TAGCGACATCGCCGTGGAATGGGAAAGCAACGGCCAGCCAGAAAATAACTACAAGACGACACCCCCAGTGCTCG ATAGTGACGGTTCTTTTTTCCTGTACTCAAAGCTTACGGTTGACAAAAGCCGCTGGCAGCAGGGGAACGTGTTCAG CTGCTCTGTCATGCACGAGGCCCTGCATAACCACTATACTCAGAAATCTCTGAGTTTGAGCCCAGGCAAATGA SEQ ID NO: 4993 T-029_protein sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCAASATGRAFTYWGQGTQVTVPAGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 4994 monomer V-body in the fusion protein T-022_amino acid sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPTGRAFTYWGQGTQVTVPAG SEQ ID NO: 4995 monomer V-body in the fusion protein T-023_amino acid sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPAGAAFTYWGQGTQVTVPAG SEQ ID NO: 4996 monomer V-body in the fusion protein T-024_amino acid sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCAASPAGRAFTYWGQGTQVTVPAG SEQ ID NO: 4997 monomer V-body in the fusion protein T-025_amino acid sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVAAPAGRAFTYWGQGTQVTVPAG 330 310886415v1 Attorney Docket No: 260525.000071 SEQ ID NO: 4998 monomer V-body in the fusion protein T-026_amino acid sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASAAGRAFTYWGQGTQVTVPAG SEQ ID NO: 4999 monomer V-body in the fusion protein T-027_amino acid sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASPAARAFTYWGQGTQVTVPAG SEQ ID NO: 5000 monomer V-body in the fusion protein T-028_amino acid sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCVASATGAAFTYWGQGTQVTVPAG SEQ ID NO: 5001 monomer V-body in the fusion protein T-029_amino acid sequence DVQLLESGGGLVQPGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFLASIRWTGGSTSYADSVKGRFTISRDDAKKT VYLQMNSLRPEDTAVYYCAASATGRAFTYWGQGTQVTVPAG 331 310886415v1

Claims

Attorney Docket No: 260525.000071 Claims 1. An antigen-binding protein that specificaly binds tumor necrosis factor receptor 2 (TNFR2), comprising a complementarity determining region 3 (CDR3) comprising the amino acid sequence AADSDL(S/R)TV(V/T)VGPHDY (SEQ ID NO: 61), A(A/G)(T/A/S)(P/L)(S/T)GKAY(T/S)Y (SEQ ID NO: 4787), or (T/A/V)A(S/A)PTGRAF(T/N/A)Y (SEQ ID NO: 66), wherein one or more non-alanine residues in the CDR3 sequence are optionaly replaced with an alanine, and/or one or more alanine residues in the CDR3 sequence are optionaly replaced with a glycine. 2. The antigen-binding protein of claim 1, wherein the CDR3 comprises the amino acid sequence (T/A/V)(A/G)(S/A)(A/P)(A/T)(A/G)(A/R)A(A/F)(T/N/A)(A/Y) or (A/G)(A/G)(T/A/S)(A/P/L)(A/S/T)(A/G)(A/K)(A/G)(A/Y)(A/T/S)(A/Y). 3. The antigen-binding protein of claim 1, wherein the CDR3 comprises an amino acid sequence selected from SEQ ID NOs: 10, 34, 4524, 4530, 4774, 18, 4727, 4810-4833, and 4835-4855. 4. The antigen-binding protein of any one of claims 1-3, further comprising a CDR1 comprising the amino acid sequence GRTFSDYG (SEQ ID NO: 16), GRTF(G/R/S)(N/S)(Y/L)(T/F) (SEQ ID NO:73), or GFT(F/L)DD(I/Y)A (SEQ ID NO: 69). 5. The antigen-binding protein of claim 4, wherein the CDR1 comprises the amino acid sequence of SEQ ID NO: 16, 32, or 4061. 6. The antigen-binding protein of any one of claims 1-5, further comprising a CDR2 comprising the amino acid sequence INWS(N/Q/E/S)(G/A)RT (SEQ ID NO: 4809), IR(W/R/Y)(T/P)G(G/L)(S/I)T (SEQ ID NO: 80), or I(Y/F)SY(S/G)(S/P)NT (SEQ ID NO: 76). 7. The antigen-binding protein of claim 6, wherein the CDR2 comprises the amino acid sequence selected from SEQ ID NO: 4062, 4527, 4070, and 4788-4793. 8. The antigen-binding protein of any one of claims 1, 4, and 6, wherein the antigen-binding protein comprises 332 310886415v1 Attorney Docket No: 260525.000071 i. a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4809, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4787; i. a CDR1 comprising an amino acid sequence of SEQ ID NO: 69, a CDR2 comprising an amino acid sequence of SEQ ID NO: 76, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 61; ii. a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4809, and a CDR3 comprising an amino acid sequence of (A/G)(A/G)(T/A/S)(A/P/L)(A/S/T)(A/G)(A/K)(A/G)(A/Y)(A/T/S)(A/Y); or iv. a CDR1 comprising an amino acid sequence of SEQ ID NO: 73, a CDR2 comprising an amino acid sequence of SEQ ID NO: 80, and a CDR3 comprising an amino acid sequence of (T/A/V)(A/G)(S/A)(A/P)(A/T)(A/G)(A/R)A(A/F)(T/N/A)(A/Y). 9. The antigen-binding protein of any one of claims 1, 2-8, wherein the antigen-binding protein comprises i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10; ii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4061, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4062, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4524; iv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727; v) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4727; 333 310886415v1 Attorney Docket No: 260525.000071 vi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; vi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; vii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; ix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4791, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; x) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4792, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; xi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4793, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4774; xi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4788, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4790, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4810; 334 310886415v1 Attorney Docket No: 260525.000071 xvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4811; xvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4812; xvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4813; xix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4814; xx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4815; xxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4816; xxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4817; xxii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4818; xxiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4819; xxv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4820; 335 310886415v1 Attorney Docket No: 260525.000071 xxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4821; xxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4822; xxvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4823; xxix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4824; xxx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4825; xxxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4826; xxxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4827; xxxii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4828; xxxiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 34; xxxv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4829; Attorney Docket No: 260525.000071 xxxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4830; xxxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4831; xxxvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4832; xxxix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4070, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4833; xl) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4835; xli) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4836; xli) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4837; xlii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4838; xliv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4839; xlv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4840; 337 310886415v1 Attorney Docket No: 260525.000071 xlvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4841; xlvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4842; xlvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4843; xlix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4527, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4844; l) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4845; li) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4846; li) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4847; lii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4848; liv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4849; lv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4850; 338 310886415v1 Attorney Docket No: 260525.000071 lvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4851; lvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4852; lvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4853; lix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4854; or lx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4789, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4855. 10. The antigen-binding protein of any one of claims 1-9, wherein the antigen-binding protein is a single-domain antibody. 11. The antigen-binding protein of claim 10, wherein the single-domain antibody is a VHH, a VNAR, or a VH domain. 12. The antigen-binding protein of claim 11, wherein the VHH is a camelid VHH. 13. The antigen-binding protein of claim 12, wherein the VHH comprises the amino acid sequence of SEQ ID NO: 4781 or 4783, or a sequence having at least 75% identity thereto. 14. The antigen-binding protein of claim 11, wherein the VHH is a humanized VHH. 15. The antigen-binding protein of claim 14, wherein the humanized VHH comprises an amino acid sequence selected from any one of SEQ ID NOs: 4775, 4782, 4784, 4794-4808, 4857-4902, 4994- 5001, or a sequence having at least 75% identity thereto. 339 310886415v1 Attorney Docket No: 260525.000071 16. The antigen-binding protein of any one of claims 1-15, wherein the antigen-binding protein has an agonist efect upon binding to TNFR2. 17. The antigen-binding protein of any one of claims 1-16, wherein the antigen-binding protein binds to human TNFR2. 18. The antigen-binding protein of claim 17, wherein the antigen-binding protein binds to human TNFR2 with a K of about 1x10-8 M to a -6 D bout 2.7 x 10 M. binding protein of any one of claims 1-16, wherein the antigen-binding protein binds to cyno TNFR2. 20. The antigen-binding protein of claim 19, wherein the antigen-binding protein binds to cyno TNFR2 with a K of about 3x10-8 M to about 2.4 -6 D x 10 M. 21. The antigen-binding protein of any one of claims 1-20, wherein the antigen-binding protein increases expression of one or more proteins selected from a protein in the NF-kB pathway, FOXP3, HELIOS, EZH2, HLA-DR, ICAM-1, OX-40, ICOS, and CCR8. 22. The antigen-binding protein of any one of claims 1-21, wherein the antigen-binding protein comprises one or more modifications that reduce binding of said antigen-binding protein by pre- existing antibodies found in human blood or serum. 23. The antigen-binding protein of any one of claims 10-22, wherein the single-domain antibody comprises one or more modifications at the amino-terminus and/or the carboxy-terminus. 24. The antigen-binding protein of claims 23, wherein the single-domain antibody comprises the amino acid sequence VPAG (SEQ ID NO: 4698) or VAGG (SEQ ID NO: 4697) at the carboxy-terminus starting from position 111 according to Chothia. 25. The antigen-binding protein of claim 23 or 24, wherein the single-domain antibody comprises a substitution of amino acid residue Glu with Asp (E1D) at the first position of the amino-terminus. 340 310886415v1 Attorney Docket No: 260525.000071 26. An antigen-binding protein that specificaly binds tumor necrosis factor receptor 2 (TNFR2), comprising a means for binding an epitope within human TNFR2 bound by an antibody selected from T-004, T-004.VTV, T-007hu1 with CDR2 G/A, CDR3 T/S, T-009Hu1_QGR, T-009Hu1_SGR, T- 009Hu1_QGR_N/C, T-009Hu1_NAR_N/C, T-009Hu1_SGR_N/C, T-007Hu1.S3.QGR, T-007Hu1.S3.EGR, T-007Hu1.S3.SGR, T-007Hu1.S3.NSR, T-007Hu1.S3.NTR, T-007Hu1.S3.SAR, T-007Hu1.EQ.QGR, T- 007Hu1.EQ.EGR, T-007Hu1.EQ.SGR, T-007Hu1.EQ.S3.NSR, T-016hu1.A1, T-016hu1.G2, T-016hu1.A3, T-016hu1.A4, T-016hu1.A5, T-016hu1.A6, T-016hu1.A7, T-016hu1.A9, T-016hu1.A10, T-016hu1.A11, T-016Hu1.A5.A7, T-016Hu1.A5.A1, T-016Hu1.A5.A3, T-016Hu1.A5.A4, T-016Hu1.A5.A6, T- 016Hu1.A7.A1, T-016Hu1.A7.A3, T-016Hu1.A7.A4, T-016Hu1.A7.A6, T-016Hu1.A1.A3, T- 016Hu1.A1.A4, T-016Hu1.A1.A6, T-016Hu1.A3.A4, T-016Hu1.A3.A6, T-016Hu1.A4.A6, T-008Hu1.G1, T-008Hu1.G2, T-008Hu1.A4, T-008Hu1.A5, T-008Hu1.A6, T-008Hu1.A7, T-008Hu1.G8, T-008Hu1.A9, T-008Hu1.A10, T-008Hu1.A11, T-009Hu1_SGR.G1, T-009Hu1_SGR.G2, T-009Hu1_SGR.A3, T- 009Hu1_SGR.A4, T-009Hu1_SGR.A5, T-009Hu1_SGR.A6, T-009Hu1_SGR.A7, T-009Hu1_SGR.G8, T- 009Hu1_SGR.A9, T-009Hu1_SGR.A10, and T-009Hu1_SGR.A11. 27. A fusion protein that specificaly binds tumor necrosis factor receptor 2 (TNFR2), comprising one or more of said antigen-binding proteins of any one of claims 1-26. 28. The fusion protein of claim 27, which comprises two said antigen-binding proteins. 29. The fusion protein of claim 27, which comprises four said antigen-binding proteins. 30. The fusion protein of any one of claims 27-29, wherein the one or more antigen-binding proteins bind to the same epitope on TNFR2. 31. The fusion protein of any one of claims 27-29, wherein the one or more antigen-binding proteins bind to diferent epitopes on TNFR2. 32. The fusion protein of any one of claims 27-31, wherein the one or more antigen-binding proteins are one or more single-domain antibodies. 341 310886415v1 Attorney Docket No: 260525.000071 33. The fusion protein of claim 32, wherein the one or more single-domain antibodies are one or more VHHs. 34. The fusion protein of any one of claims 27-33, which further comprises an immunoglobulin Fc region. 35. The fusion protein of claim 34, wherein the immunoglobulin Fc region is an Fc region of a human immunoglobulin. 36. The fusion protein of claim 35, wherein the immunoglobulin Fc region is an Fc region of human IgG1, IgG2, IgG3 or IgG4, or a variant thereof. 37. The fusion protein of claim 36, wherein the immunoglobulin Fc region is an Fc region of human IgG1, or a variant thereof. 38. The fusion protein of claim 37, wherein the Fc region of human IgG1 comprises one or more mutations selected from L234A, L235A, G237A, M252Y, S254T, T256E, D265A, N297A, and/or P329A according to EU numbering. 39. The fusion protein of claim 38, wherein the Fc region of human IgG1 comprises a set of mutations selected from 1). L234A and L235A; 2). L234A, L235A, and P329A; 3). D265A, N297A and P329A; 4). L234A, L235A, and G237A; and 5). M252Y, S254T, and T256E. 40. The fusion protein of claim 39, wherein the Fc region of human IgG1 comprises L234A, L235A, and P329A. 41. The fusion protein of claim 39, wherein the Fc region of human IgG1 comprises M252Y, S254T, and T256E. 342 310886415v1 Attorney Docket No: 260525.000071 42. The fusion protein of claim 35, wherein the immunoglobulin Fc region is an Fc region of human IgG4, or a variant thereof. 43. The fusion protein of claim 42, wherein the Fc region of human IgG4 comprises one or more mutations selected from S228P, L235E, L235A, and/or F234A according to EU numbering. 44. The fusion protein of claim 43, wherein the Fc region of human IgG4 comprises a set of mutations selected from 1). S228P and L235E; 2). S228P and L235A; 3). S228P, F234A, and L235E; and 4). S228P, F234A, and L235A. 45. The fusion protein of claim 44, wherein the Fc region of human IgG4 comprises S228P and L235E. 46. The fusion protein of any one of claims 27-45, which further comprises a cytokine. 47. The fusion protein of claim 46, wherein the cytokine is IL-2, or a variant thereof. 48. The fusion protein of claim 47, wherein the cytokine is an IL-2 variant comprising a N88D mutation. 49. The fusion protein of any one of claims 27-48, which further comprises a moiety that binds to serum albumin. 50. The fusion protein of claim 27, which comprises the amino acid sequence of any one of SEQ ID Nos: 4772, 4773, 4776-4779, 4903, 4979, 4981, 4983, 4985, 4987, 4989, 4991, and 4993, or a sequence having at least 75% identity thereto. 51. The fusion protein of any one of claims 27-50, wherein the fusion protein has an agonist efect upon binding to TNFR2. 343 310886415v1 Attorney Docket No: 260525.000071 52. The fusion protein of any one of claims 27-51, wherein the fusion protein binds to human TNFR2. 53. The fusion protein of claim 52, wherein the fusion protein binds to human TNFR2 with a KD of about 3x10-12 M to about 1 x 10-7 M. 54. The fusion protein of any one of claims 27-51, wherein the fusion protein binds to cyno TNFR2. 55. The fusion protein of claim 54, wherein the fusion protein binds to cyno TNFR2 with a KD of about 1x10-12 M to about 5 x 10-8 M. 56. A conjugate comprising the antigen-binding protein of any one of claims 1-26 or the fusion protein of any one of claims 27-55, wherein the antigen-binding protein or fusion protein is conjugated to a second moiety. 57. The conjugate of claim 56, wherein the second moiety is selected from a detectable label, a drug, a toxin, a radionuclide, an enzyme, an immunomodulatory agent, a cytokine, a cytotoxic agent, a chemotherapeutic agent, and a diagnostic agent, or a combination thereof. 58. The conjugate of claim 57, wherein the second moiety is a cytokine. 59. The conjugate of claim 58, wherein the cytokine is IL-2, or a variant thereof. 60. The conjugate of claim 59, wherein the cytokine is IL-2 variant comprising a N88D mutation. 61. A polynucleotide molecule encoding the antigen-binding protein of any one of claims 1-26 or the fusion protein of any one of claims 27-55. 62. A recombinant vector comprising the polynucleotide molecule of claim 61. 63. A host cel comprising the polynucleotide molecule of claim 61, or the recombinant vector of claim 62. 344 310886415v1 Attorney Docket No: 260525.000071 64. A kit comprising the antigen-binding protein of any one of claims 1-26, the fusion protein of any one of claims 27-55, the conjugate of any one of claims 56-60, the polynucleotide molecule of claim 61, or the recombinant vector of claim 62, and optionaly, instructions and/or packaging for the same. 65. A pharmaceutical composition comprising the antigen-binding protein of any one of claims 1-26, the fusion protein of any one of claims 27-55, the conjugate of any one of claim 56-60, the polynucleotide molecule of claim 61, or the recombinant vector of claim 62, and a pharmaceuticaly acceptable carrier and/or excipient. 66. A method for preparing an antigen-binding protein or a fusion protein that specificaly binds tumor necrosis factor receptor 2 (TNFR2), comprising the steps of: (a) culturing the host cel of claim 63 in a culture medium under conditions suitable for expression of the antigen-binding protein or the fusion protein; and (b) isolating the antigen-binding protein or the fusion protein from the host cel and/or the culture medium. 67. A method for promoting proliferation, activating and/or enhancing suppressive function, and/or stabilizing immunosuppressive phenotype of a population of regulatory T cels (Treg) comprising contacting the population of Treg with the antigen-binding protein of any one of claims 1-26, the fusion protein of any one of claims 27-55, or the conjugate of any one of claim 56-60. 68. The method of claim 67, wherein said contacting occurs in vitro. 69. The method of claim 67, wherein said contacting occurs in vivo. 70. The method of claim 69, wherein the method further comprises administering the antigen-binding protein, the fusion protein, or the conjugate into a subject in need thereof. 71. A method of treating or preventing a disease or disorder in a subject in need thereof, said method comprising administering to the subject the antigen-binding protein of any one of claims 1-26, the fusion protein of any one of claims 27-55, or the conjugate of any one of claim 56-60. 345 310886415v1 Attorney Docket No: 260525.000071 72. The method of claim 71, wherein the disease or disorder is an immunological disease, inflammatory disease, cancer, cardiovascular disease, or an infertility and pregnancy-associated disease. 73. The method of claim 72, wherein the immunological disease is selected from an autoimmune disease, a neurological condition, an alergy, asthma, macular degeneration, muscular atrophy, a disease related to miscarriage, atherosclerosis, bone loss, a musculoskeletal disease, obesity, a graft- versus-host disease, and an alograft rejection. 74. The method of claim 73, wherein the autoimmune disease is selected from lupus, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, bulous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Goodpastures disease, Graves' disease, Guilain-Barré, Hashimoto's thyroiditis, hypothyroidism, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, juvenile arthritis, lichen planus, lichen sclerosis, IgG4-related disease, Meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disease, pemphigus vulgaris or related blistering skin disease, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, premature ovarian failure, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, primary ovarian insuficiency, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, spondyloarthritis, stif-man syndrome, type I diabetes, Takayasu arteritis, temporal arteritis/giant cel arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener's granulomatosis (Granulomatosis with polyangitis) or other immune vasculitis. 75. The method of claim 74, wherein the lupus is systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis, neonatal lupus, or drug-induced lupus. 346 310886415v1 Attorney Docket No: 260525.000071 76. The method of claim 75, wherein the cutaneous lupus is acute cutaneous lupus, chronic cutaneous lupus erythematosus, discoid lupus erythematosus (DLE), or subacute cutaneous lupus erythematosus. 77. The method of claim 73, wherein the neurological condition is selected from a brain tumor, a brain metastasis, a spinal cord injury, schizophrenia, epilepsy, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's disease, Parkinson's disease, and stroke. 78. The method of claim 73, wherein the alergy is selected from food alergy, seasonal alergy, pet alergy, hives, hay fever, alergic conjunctivitis, poison ivy alergy oak alergy, mold alergy, drug alergy, dust alergy, cosmetic alergy, and chemical alergy. 79. The method of claim 73, wherein the alograft rejection is selected from skin graft rejection, bone graft rejection, vascular tissue graft rejection, ligament graft rejection, and organ graft rejection. 80. The method of claim 73, wherein the ligament graft rejection is selected from cricothyroid ligament graft rejection, caudal cruciate ligament graft rejection, periodontal ligament graft rejection, suspensory ligament of the lens graft rejection, palmar radiocarpal ligament graft rejection, dorsal radiocarpal ligament graft rejection, ulnar colateral ligament graft rejection, radial colateral ligament graft rejection, suspensory ligament of the breast graft rejection, anterior sacroiliac ligament graft rejection, posterior sacroiliac ligament graft rejection, sacrotuberous ligament graft rejection, sacrospinous ligament graft rejection, inferior pubic ligament graft rejection, superior pubic ligament graft rejection, anterior cruciate ligament graft rejection, lateral colateral ligament graft rejection, posterior cruciate ligament graft rejection, medial colateral ligament graft rejection, cranial cruciate ligament graft rejection, and patelar ligament graft rejection. 81. The method of claim 73, wherein the organ graft rejection is selected from heart graft rejection, lung graft rejection, kidney graft rejection, liver graft rejection, pancreas graft rejection, intestine graft rejection, and thymus graft rejection. 82. The method of claim 73, wherein the graft-versus-host disease arises from a bone marrow transplant or one or more blood cels selected from B-cels, T-cels, basophils, common myeloid 347 310886415v1 Attorney Docket No: 260525.000071 progenitor cels, common lymphoid progenitor cels, dendritic cels, eosinophils, hematopoietic stem cels, neutrophils, natural kiler cels, megakaryocytes, monocytes, or macrophages. 83. The method of claim 73, wherein the inflammatory disease is acute or chronic inflammation. 84. The method of claim 73, wherein the inflammatory disease is selected from osteoarthritis, atopic dermatitis, endometriosis, polycystic ovarian syndrome, inflammatory bowel disease, fibrotic lung disease, and cardiac inflammation. 85. The method of claim 73, wherein the cancer is selected from adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer (sarcoma of bone), brain stem glioma, brain tumor, breast cancer, inflammatory breast cancer, metastatic breast cancer, male breast cancer, Carney complex, central nervous system tumors (brain and spinal cord), cervical cancer, childhood cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, desmoid tumor, desmoplastic infantile ganglioglioma, childhood tumor, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial pancreatic cancer, galbladder cancer, gastrointestinal stromal tumor (GIST), germ cel tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary difuse gastric cancer, hereditary leiomyomatosis and renal cel cancer, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papilary renal carcinoma, HIV/AIDS-related cancer, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumor, laryngeal and hypopharyngeal cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cel prolymphocytic leukemia and hairy cel leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cel lymphocytic leukemia, eosinophilic leukemia, Li-Fraumeni syndrome, liver cancer, lung cancer, non-smal cel lung cancer, smal cel lung cancer, hodgkin lymphoma, non- hodgkin lymphoma, lynch syndrome, mastocytosis, meduloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndromes (MDS), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumor of the gastrointestinal tract, neuroendocrine tumor of the lung, neuroendocrine tumor of the pancreas, 348 310886415v1 Attorney Docket No: 260525.000071 neuroendocrine tumors, neurofibromatosis type 1, neurofibromatosis type 2, nevoid basal cel carcinoma syndrome, oral and oropharyngeal cancer, osteosarcoma, ovarian, falopian tube, and peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma and paraganglioma, pituitary gland tumor, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Kaposi sarcoma, soft tissue sarcomas, skin cancer (non-melanoma), smal bowel cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis complex, uterine cancer, vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Waldenstrom macroglobulinemia (lymphoplasmacytic lymphoma), Werner syndrome, Wilms tumor, or xeroderma pigmentosum. 86. The method of claim 73, wherein the cardiovascular disease is selected from atherosclerosis, heart failure, left heart failure with reduced ejection fraction, left heart failure with preserved ejection fraction, right ventricular failure, congestive heart failure, restrictive cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, idiopathic cardiomyopathy, and hypertension. 87. The method of claim 73, wherein the infertility and pregnancy-associated diseases is selected from recurrent pregnancy loss, pre-eclampsia, preterm labor, fetal growth restriction, and intrauterine growth restriction. 88. A method of regenerating a tissue or organ comprising one or more TNFR2+ cels, said method comprising contacting the tissue or organ with an efective amount of the antigen-binding protein of any one of claims 1-26, the fusion protein of any one of claims 27-55, or the conjugate of any one of claim 56-60. 89. The method of claim 88, wherein said tissue or organ is selected from pancreas, salivary gland, pituitary gland, kidney, heart, lung, hematopoietic system, cranial nerves, heart, aorta, olfactory gland, ear, nerve, eye, thymus, tongue, bone, liver, smal intestine, large intestine, gastrointestinal, lung, brain, skin, peripheral nervous system, central nervous system, spinal cord, breast, embryonic structures, embryo, and testes tissue. 90. The method of claim 88 or 89, wherein said contacting occurs in vitro. 349 310886415v1 Attorney Docket No: 260525.000071 91. The method of claim 88 or 89, wherein said contacting occurs in vivo. 92. The method of claim 91, wherein the method further comprises administering the antigen-binding protein, the fusion protein, or the conjugate into a subject in need thereof. 93. A method for inducing tolerance to a foreign agent and/or preventing or reducing immune response to a foreign agent in a subject in need thereof, said method comprising administering to the subject the antigen-binding protein of any one of claims 1-26, the fusion protein of any one of claims 27- 55, or the conjugate of any one of claim 56-60. 94. The method of claim 93, wherein the foreign agent is a therapeutic protein or peptide, a viral vector, a bacterial vector, a fungal vector, a biochemical vector, a lipid, carbohydrate, a nucleic acid, a sperm, an oocyte, or an embryo. 95. The method of claim 94, wherein the viral vector is a DNA or RNA vector. 96. The method of any one of claims 70-87 and 92-95, wherein the subject is a mammal. 97. The method of claim 96, wherein the mammal is human. 350 310886415v1
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