Anti-TNFR2 antigen-binding proteins and uses thereof

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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 e35 310886415v1Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 Non-humanized VHH Humanized VHH Antibody ID Group DNA A i id DNA e310886415v1Attorney Docket No: 260525.000071 CDR1 CDR2 CDR3 Non-humanized VHH Humanized VHH Antibody ID Group DNA A i id DNA e37 310886415v1Attorney 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 Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence310886415v1Attorney Docket No: 260525.000071 Group Non-humanized VHH Humanized VHH Amino Acid Sequence Amino Acid Sequence

[0191] In someembodiments, 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 Contact127 310886415v1Attorney Docket No: 260525.000071 CDR Kabat Chothia AbM Contact (Kabatindividual 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 310886415v1Attorney 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 310886415v1Attorney 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 exampl...

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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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 310886415v1Attorney 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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