Multispecific molecules binding TNFR2 and CD25 and uses thereof

Abstract

The present application provides multispecific antigen-binding proteins (e.g., antibodies) that specifically bind tumor necrosis factor receptor 2 (TNFF52) and cluster of differentiation 25 (CD25). The application also provides conjugates comprising the multispecific antigen-binding proteins, polynucleotides and recombinant vectors encoding the multispecific antigen-binding proteins, as well as host cells and methods for preparing the multispecific antigen-binding proteins. The application further provides pharmaceutical compositions comprising the multispecific antigen-binding proteins and methods for treating a disease or disorder using the multispecific antigen-binding proteins.

Description

MULTOPECIFiC MOLECULES BINDING TNFR2 AND CD25 AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS(OOOl)This application claims priority to U.S. Provisional Patent Application No. 63 / 665,064, filed on June 27, 2024, the disclosure of which is herein incorporated by reference in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on June 26, 2025, is named 260525_.000075__SL.xml and is 10,679,494 bytes in size.FIELD OF THE INVENTION

[0003] The present invention relates to multispecific antigen-binding proteins, and methods of use thereof. The multispecific antigen-binding proteins, including bispecific molecules, may comprise one or more antigen-binding domains that specifically bind tumor necrosis factor receptor 2 (TNFR2), and one or more antigen-binding domains that specifically bind cluster of differentiation 25 (CD25).BACKGROUND OF THE INVENTION

[0004] Regulatory T cells (Tregs) are a subset of T ceils 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] While Tregs can support immune homeostasis under normal, healthy conditions, and their activation can be beneficial in the context of autoimmune disease, during proliferative diseases (e.g., cancer), Tregs can accumulate within the tumor microenvironment where they can hamper antitumor responses mounted by infiltrating immune cells, effectively protecting the cancer cells from immune attack. Tregs are capable of suppressing most types of immune cells including CD4+ and CDS-i- T cells, B cells, and antigen-presenting cells (APCs) (e.g., dendritic cells macrophages and monocytes), natural killer (NK) cells, and NKT cells. The number of Tregs is higher in tumors and peripheral bloodmononuclear cells (PBMCs) of many cancer patients, and high Treg levels can be associated with poor prognosis, e.g., in solid tumors including breast, cervical, renal, melanomas, ovarian, hepatocellular, gastric, and pancreatic cancers.

[0006] There is a need in the art to develop therapies that can induce a stable immunosuppressive Tregs phenotype for the treatment of diseases such as autoimmune diseases.SUMMARY OF THE INVENTION[0007jAs mentioned in the background section above, there is an unmet need in the art to develop therapies that can induce a stable immunosuppressive Tregs phenotype. This application provides compositions and methods to address this and other related needs.

[0008] ln an aspect, provided herein is a multispecific antigen-binding protein comprising one or more binding domains that specifically bind tumor necrosis factor receptor 2 (TNFR2), and one or more binding domains that specifically bind cluster of differentiation 25 (CD25). In some embodiments, the multispecific antigen-binding protein further comprises one or more binding domains that binds to another antigen, e.g., human serum albumin.

[0009] ln some embodiments, the multispecific antigen-binding protein is multivalent, e.g., bivalent, trivalent, tetravalent, pentavalent, hexavalent, septivalent, or octavalent for both antigens.[OOlOjln some embodiments, the multispecific antigen-binding protein comprises at least one of the anti-TNFR2 antigen-binding domains described herein. In some embodiments, the multispecific antigenbinding protein comprises two of the anti-TNFR2 antigen-binding domains described herein. In some embodiments, the multispecific antigen-binding protein comprises three of the anti-TNFR2 antigenbinding domains described herein. In some embodiments, the multispecific antigen-binding protein comprises four of the anti-TNFR2 antigen-binding domains described herein. In some embodiments, the multispecific antigen-binding protein comprises five of the anti-TNFR2 antigen-binding domains described herein. In some embodiments, the multispecific antigen-binding protein comprises six of the anti-TNFR2 antigen-binding domains described herein.[OOlljln some embodiments, the multispecific antigen-binding protein comprises at least one of the anti-CD25 antigen-binding domains described herein. In some embodiments, the multispecific antigenbinding protein comprises two of the anti-CD25 antigen-binding domains described herein, in some embodiments, the multispecific antigen-binding protein comprises three of the anti-CD25 antigenbinding domains described herein. In some embodiments, the multispecific antigen-binding proteincomprises four of the anti-CD25 antigen-binding domains described herein. In some embodiments, the multispecific antigen-binding protein comprises five of the anti-CD25 antigen-binding domains described herein, in some embodiments, the multispecific antigen-binding protein comprises six of the anti-CD25 antigen-binding domains described herein.

[0012] ln some embodiments of the multispecific antigen-binding protein described herein, the one or more anti-TNFR2 antigen-binding domains and / or the one or more anti-CD25 antigen-binding domains are linked by a flexible linker. In some embodiments of the multispecific antigen-binding protein described herein, the one or more anti-TNFR2 antigen-binding domains and / or the one or more anti- CD25 antigen-binding domains are linked by a rigid linker,

[0013] ln some embodiments of the multispecific antigen-binding protein described herein, the one or more anti-TNFR2 antigen-binding domains may bind to the same epitope on TNFR2. In other embodiments, the one or more anti-TNFR2 antigen-binding domains may bind to different epitopes on TNFR2.

[0014] in some embodiments of the multispecific antigen-binding protein described herein, the one or more anti-CD25 antigen-binding domains may bind to the same epitope on CD25. In other embodiments, the one or more anti-CD25 antigen-binding domains may bind to different epitopes on CD25,

[0015] !n one aspect, the present disclosure provides one or more antigen-binding domains that specifically bind TNFR2, comprising a complementarity determining region 3 (CDR3) comprising an amino acid sequence selected from a) (Y / F)¥Q(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)(V / T)GPHDY (SEQ ID NO: 61); c) AKDAG(S / G)WG(T / R)GPFG(Y / F)(E / D)¥D¥ (SEQ ID NO: 62); d) A(A / G)(T / A / S)(P / L)(S / T)GKAY(T / S)Y (SEQ ID NO: 10387); e) ATPGPY(T / S / M)YCAPYGSSWSRG¥DY (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)¥ (SEQ ID NO: 66); 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: 6635); and k) AAD(L / V)G(F / V / ¥)L¥(A / T / V)DYV(P / R)LH(M / T)HHFGS (SEQ ID NO: 7086);wherein one or more non-alanine residues in the CDR3 sequence are optionally replaced with an alanine, and / or one or more alanine residues in the CDR3 sequence are optionally replaced with a glycine.

[0016] ln some embodiments, the CDR3 of the one or more anti-TNFR2 antigen-binding domains comprises an amino acid sequence a). (T / A / V)(A / G)(S / A)(A / P)(A / T / S)(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).

[0017] ln some embodiments, the CDR3 of the one or more anti~TNFR2 antigen-binding domains comprises an amino acid sequence selected from SEQ ID NOs: 3, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 63, 6635, 6639, 6643, 7093, 7099, 7289-7292, 7333, 10374, 10410-10433, 10435-10455, and 10811.

[0018] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains further comprise a CDR1 comprising an amino acid sequence selected from 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)FSM¥S (SEQ ID NO: 72); g) GRTF(G / R / S)(N / S)(Y / L)(T / F) (SEQ ID NO: 73); h) GASLSRNA (SEQ ID NO: 40); i) GS(I / T)FRFPP (SEQ ID NO: 74); and j) G(F / V)(S / T)LD(D / Y)(H / Y)T (SEQ ID NO: 7088).

[0019] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains comprise a CORI comprising an amino acid sequence selected from SEQ ID NOs: 1, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 6633, 6637, 6641, 7089, and 7281-7284.

[0020] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains comprise a CDR2 comprising an amino add sequence selected from a) IRSDGF(T / I) (SEQ ID NO: 75); b) l(Y / F)SY(S / G)(S / P)NT (SEQ ID NO: 76); c) l(Y / S)(S / D)DGS(E / D)T (SEQ ID NO: 77); d) INWS(N / Q / E / S)(G / A)RT (SEQ ID NO: 10409); e) l(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); and j) l(N / S)SNDG(S / T)(T / V) (SEQ ID NO: 7087).

[0021] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains comprise a CDR2 comprises an amino acid sequence selected from SEQ ID NOs: 2, 9, 13, 17, 21, 25, 23, 33, 37, 41, 45, 6634, 6638, 6642, 7096, 7268, and 7285-7288, and 10388-10393.

[0022] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains comprise 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; ii)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; iii)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: 7268, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10387; v)a CDR1 comprising an amino acid sequence of SEQ ID NQ: 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; vii)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; viii)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; ix)a CDR1 comprising an amino acid sequence of SEQ ID NQ: 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: 6633, a CDR2 comprising an amino acid sequence of SEQ iD NO: 6634, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6635; xi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7088, a CDR2 comprising an amino acid sequence of SEQ !D NO: 7087, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7086;xli)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10409, 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)(WS)(A / Y); or xiii)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 / S)(A / G)(A / R)A(A / F)(T / N / A)(A / Y).[0023)ln some embodiments, the one or more anti-TNFR2 antigen-binding domains comprise 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: 7268, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10387; 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: 7268, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 63; or e)a CDR1 comprising an amino acid sequence of SEQ ID NG: 16, a CDR2 comprising an amino acid sequence of SEQ !D NO: 7268, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7333;

[0024] !n some embodiments, the one or more anti-TNFR2 antigen-binding domains comprise 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 ¥¥Q(S / A)LSSPNYGQ(V / F)F (SEQ ID NO: 7270); ii)a CDR1 comprising an amino acid sequence of GFT(F / L)DD(I / Y)A (SEQ !D NO: 69), a CDR2 comprising an amino acid sequence of l(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: 7271); iii)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: 7268), and a CDR3 comprising an amino acid sequence of A(A / G)(T / A / S)(P / L)(S / T)GKA¥(T / S)¥ (SEQ ID NO: 10387);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 ofATPGPYTYCAPYGSSWSRGYDY (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: 7273); vii)a CDR1 comprising an amino acid sequence of GRTF(G / S)S(Y / L)(T / F) (SEQ ID NO: 7274), 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: 7276); viii)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: 7277), 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: 7275); x)a CDR1 comprising an amino acid sequence of GFTLDDYA (SEQ ID NO: 6633), a CDR2 comprising an amino acid sequence of IFSYSSNT (SEQ ID NO: 6634), and a CDR3 comprising an amino acid sequence of AVGDFEGELVLKGDY (SEQ ID NO: 6635);or xi)a CDR1 comprising an amino acid sequence of GFTLDYYT (SEQ ID NO: 6637), a CDR2 comprising an amino acid sequence of ISSNDGSV (SEQ ID NO: 6638), and a CDR3 comprising an amino acid sequence of AADLGYLYVDYVRLHTHHFGS (SEQ ID NO: 6639).

[0025] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains comprise a)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 l(¥ / F)S¥(S / G)(S / P)NT (SEQ ID NO: 76), and a CDR3 comprising an amino acid sequence of AADSDLSTW(V / T)GPHDY (SEQ ID NO: 7271); 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: 7268), and a CDR3 comprising an amino acid sequence of A(A / G)(T / A / S)(P / L)(S / T)GKAY(T / S)Y (SEQ ID NO: 10387); or c)a CDR1 comprising an amino acid sequence of GRTF(G / S)S(¥ / L)(T / F) (SEQ ID NO: 7274), 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 (AAf)A(A / S)PTGRAF(T / N)¥ (SEQ ID NO: 7276).

[0026] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains comprisei)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; ii) 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; iii)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; vii)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; viii)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; xiija CDR1 comprising an amino acid sequence of SEQ ID NO: 44, a CDR2 comprising an amino add sequence of SEQ ID NO: 45, and a CDR3 comprising an amino add sequence of SEQ ID NO: 46 xiii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 6633, a CDR2 comprising an amino add sequence of SEQ ID NO: 6634, and a CDR3 comprising an amino add sequence of SEQ ID NO: 6635; xiv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 6637, a CDR2 comprising an amino add sequence of SEQ ID NO: 6638, and a CDR3 comprising an amino add sequence of SEQ ID NO: 6639; xv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino add sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino add sequence of SEQ ID NO: 6643; xvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7089, a CDR2 comprising an amino add sequence of SEQ ID NO: 45, and a CDR3 comprising an amino add sequence of SEQ ID NO: 46;xvii)s 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: 7093; xviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, 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: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7099; xx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7285, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289; xxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289; xxi i)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7285, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7291; xxiiija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7291; xxiv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 6633, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6634, 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: 6633, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6634, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7093; xxvii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10388, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289; xxviiija CDR1 comprising an amino acid sequence of SEQ ID NO: IS, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289; xxix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10388, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10390, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374;xxxii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10391, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxiiija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10392, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxiv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10393, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10388, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xxxvQa CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10390, 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: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xxxviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ iD NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10410; xxxixja CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10411; xl)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10412; xli)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10413; xlii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10414; xliiija CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10415; xlivja CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10416; xlv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10417; xlvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10418;xlvii)a CDRI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10419; xlviiija CDRI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10420; xlix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10421; l)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10422; li)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10423; lii)a CDRI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10424; liii)a CDRI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10425; liv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10426; lv)a CDRI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10427; lvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10428; lvii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 34;Iviiija CDRi comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10429; lix)a CDRI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10430; lx)a CDRI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10431; lxi)a CDRI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NQ: 10432; lxii)a CDRI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10433;Ixiii) CDR1 comprising an amino add sequence of SEQ ID NO: 32, a CDR2 comprising an amino add sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10811; lxiv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10435; lxv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10436; lxvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10437; lxvii)a CDR1 comprising an amino add sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10438;Ixvi ii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10439;Ixvixja CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10440; lxx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10441; lxxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10442;Ixxiija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10443; lxxiii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10444;Ixxivja CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10445; lxxv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10446;Ixxvija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10447;Ixxviija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino add sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10448;Ixxviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10449; ixxvix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10450; lxxx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10451;Ixxxija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10452; lxxxii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ !D NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10453;Ixxxiiija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10454; orIxxxivja CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10455.

[0027] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains comprise 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; b)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, 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: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7099; d)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7285, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289; e)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino add sequence of SEQ ID NO: 7289; f)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7285, and a CDR3 comprising an amino add sequence of SEQ ID NO: 7291;g)a CDR1 comprising an amino acid sequence of SEQ. ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7291; h)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; i)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: 7093; j)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6643; k)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10414; l)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10421; m)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10422; n)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10423; o)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10429; p)a CDR1 comprising an amino acid sequence of SEQ ID NQ: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10811; q)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; r)a CDR1 comprising an amino acid sequence of SEQ ID NO: 6633, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6634, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10; or s)a CDR1 comprising an amino acid sequence of SEQ ID NO: 6633, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6634, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7093.

[0028] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains comprise a CDR1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 1128-1686, 6745-6806, and 7102-7125; a CDR2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 1687- 2245, 6807-6868, and 7126-7149; and / or a CDR3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 2246-2804, 6869-6930, and 7150-7173.

[0029] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains is a singie-domain antibody. In some embodiments, the single-domain antibody is a VHH, a VNAR, or a VH domain.

[0030] ln some embodiments, the VHH of the one or more anti-TNFR2 antigen-binding domains is a cameiid VHH. In some embodiments, the VHH of the one or more anti-TNFR2 antigen-binding domains comprises an amino acid sequence selected from any one of SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 93-640, 2805-3363, 6636, 6640, 6644, 7090, 6651-6697, 6931-6992, 7174-7197, 10380, 10381, 10383, 10385, and 10386, or a sequence having at least 75% identity thereto, in some embodiments, the VHH of the one or more anti-TNFR2 antigen-binding domains comprises an amino acid sequence selected from any one of SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 6636, 6640, 6644, 7090, 10380, 10381, 10383, 10385, and 10386, or a sequence having at least 75% identity thereto.

[0031] ln some embodiments, the VHH of the one or more anti-TNFR2 antigen-binding domains is a humanized VHH. In some embodiments, the VHH of the one or more anti-TNFR2 antigen-binding domains comprises an amino acid sequence selected from any one of SEQ ID NOs: 81-92, 6648, 6649, 6650, 7092, 7095, 7098, 7101,7293-7296, 641-1127, 6698-6744, 10375, 10382, 10384, 10394-10408, 10457-10502, 10720-10727, and 10812, or a sequence having at least 75% identity thereto. In some embodiments, the VHH of the one or more anti-TNFR2 antigen-binding domains comprises an amino acid sequence selected from any one of SEQ ID NOs: 81-92, 6648, 6649, 6650, 7092, 7095, 7098, 7101, 7293-7296, 10375, 10382, 10384, 10394-10408, 10457-10502, 10720-10727, and 10812 or a sequence having at least 75% identity thereto.

[0032] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains of the present disclosure comprise TNF or a variant thereof.

[0033] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains bind to human TNFR2. in some embodiments, the one or more anti-TNFR2 antigen-binding domains bind to human TNFR2 with a KD of less than about 3xl0’6M. in some embodiments, the one or more anti-TNFR2 antigen-binding domains bind to human TNFR2 with a KD of about IxiO"10to 5xWsM.

[0034] In some embodiments, the one or more anti-TNFR2 antigen-binding domains bind to cyno TNFR2. In some embodiments, the one or more anti-TNFR2 antigen-binding domains bind to cyno TNFR2 with a KD of less than about 3xl0"6M. In some embodiments, the one or more anti-TNFR2 antigen-binding domains bind to cyno TNFR2 with a KDof about IxlO’9to 2xW7M,[0035)1 n some embodiments, the one or more anti-TNFR2 antigen-binding domains bind to the same epitope(s) on TNFR2 as antibody clone MR2-1. In some embodiments, the one or more anti-TNFR2 antigen-binding domains do not bind to the same epitope(s) on TNFR2 as antibody clone MR2-1.

[0036] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains have an agonist effect upon binding to TNFR2. In some embodiments, the one or more anti-TNFR2 antigen-binding domains have an agonist effect upon binding to TNFR2 with an EC50 of about 1-100 nM (e.g., l-10nM, 10-100 nM).[0037jln some embodiments, the one or more anti-TNFR2 antigen-binding domains increase expression of one or more proteins selected from a protein in the NF-kB pathway, F0XP3, HELIOS, EZH2, HLA-DR, ICAM-1, OX-40, ICOS, and CCR8.

[0038] ln one aspect, the present disclosure provides one or more antigen-binding domains that specifically binds CD25, comprising a complementarity determining region 3 (CDR3) comprising an amino acid sequence selected from a) NAL(G / L / P / Q / W)¥ (SEQ ID NO: 4131); b) NALR(D / H / N / F) (SEQ ID NO: 4134); c) (K / S / T)TLRY (SEQ ID NO: 4136); d). (A / V / S)(K / T)G(R / A / K)(G / H / N / R)SG(S / G)YYP(W / F / L)(D / E)(D / E)(Y / V) (SEQ ID NO: 10219); e). AA(S / T)(D / N / Y / K)(F / V)(L / P)(I / L)A(T / I / A)(T / S / A)IS(A / G)(Y / H)DY (SEQ ID NO: 10308); f) AAYVYPDYYCS(D / E)YVLL(K / R)YD¥ (SEQ ID NO: 7363); g) NIYR(P / S)QVP(P / S / T)TR¥S (SEQ ID NO: 7365); and h) AAKRLGP(M / I / A / L)VH(Q / R)YSLEVLTPLFLDEYDY (SEQ ID NO: 9423), wherein one or more non-alanine residues in the CDR3 sequence are optionally replaced with an alanine, and / or one or more alanine residues in the CDR3 sequence are optionally replaced with a glycine.

[0039] ln some embodiments, the CDR3 comprises an amino acid sequence a).(A / V / S)(A / K / T)(A / G)(A / R / K)(A / G / H / N / R)(A / S)(A / G)(A / S / G)(A / Y)(A / Y)(A / P)(A / W / F / L)(A / D / E)(A / D / E)(A / Y / V); or b). (A / G)(A / G)(A / K)(A / R)(A / L)(A / G)(A / P)(M / I / A / L)(A / V)(A / H)(A / R / Q)(A / Y)(A / S)(A / L)(A / E){A / V) (A / L)(A / T)(A / P)(A / L)(A / F)(A / L)(A / D)(A / E)(A / ¥)(A / D)(A / Y).

[0040] ln some embodiments, the CDR3 comprises an amino acid sequence selected from a). NAL(G / L / P / Q / W)Y (SEQ ID NO: 4131); b). NALR(D / H / N / F) (SEQ ID NO: 4134); c). (K / S / T)TLRY (SEQ ID NO: 4136);d). AKGR(H / N)SGSYYPWD(D / E)Y (SEQ ID NO: 4139); e). (A / V)KGR(G / H / N)SGSYYP(W / F)D(D / E)Y (SEQ ID NO: 9440); f). AA(S / T)(D / N / Y)FL(i / L)ATTIS(A / G)YDY (SEQ ID NO: 4141); g). AAYVYPDYYCS(D / E)YVLL(K / R)YDY (SEQ ID NO: 7363); h). NIYR(P / S)QVP(P / S / T)TRYS (SEQ ID NO: 7365); and i). AAKRLGPMVH(Q / R)YSLEVLTPLFLDEYDY (SEQ ID NO: 7367).(0041]ln some embodiments, the CDR3 of the one or more anti~CD25 antigen-binding domains comprises an amino acid sequence selected from SEQ ID NOs: 4103, 4107, 4111, 4115, 4119, 4139,4141, 5337, 5339, 5371, 5375, 5398, 5401, 5431, 5515, 5519, 5521, 5528, 5532, 5542, 5544, 5545, 5547, 5548, 7344, 7347, 7349, 7350, 7367, 9411-9416, 9436, 9440, 9887, 9966, 9975, 9978, 9979, 9980, and 10504-10544.

[0042] ln some embodiments, the CDR3 of the one or more anti-CD25 antigen-binding domains comprises an amino acid sequence selected from SEQ ID NOs: 4103, 4107, 4111, 4115, 4119, 5337, 5339, 5371, 5375, 5398, 5401, 5431, 5515, 5519, 5521, 5528, 5532, 5542, 5544, 5545, 5547, 5548, 7344, 7347, 7349, 7350, 9411-9416, 9436, 9887, 9966, 9975, 9978, 9979, 9980, and 10504-10544.

[0043] ln some embodiments, the CDR3 of the one or more anti-CD25 antigen-binding domains comprises an amino acid sequence selected from SEQ ID NOs: 4103, 4107, 4111, 4115, 4119, 7344, 7347, 7349, 7350, 9411-9416, 9436, and 10504-10544.

[0044] ln some embodiments, the one or more anti-CD25 antigen-binding domains described herein may further comprise a CDR1 comprising an amino acid sequence selected from a) GR(K / R / S)FSTLI (SEQ ID NG: 4137); b) GFTFS(N / S)YA (SEQ ID NO: 4140); c) GRTF(A / S)(S / W / D)(F / N / Y)G (SEQ ID NO: 10309); d) GFTLDYYA (SEQ ID NO: 7342); and e) G(I / M)P(F / -)(A / -)L(P / V / Y)A (SEQ ID NO: 7366).

[0045] ln some embodiments, the CDR1 of the one or more anti-CD25 antigen-binding domains comprises an amino acid sequence selected from SEQ ID NOs: 4101, 4105, 4109, 4113, 4117, 4132,4142, 4905, 4909, 4918, 7342, and 7345.

[0046] ln some embodiments, the CDR1 of the one or more anti-CD25 antigen-binding domains comprises an amino acid sequence selected from SEQ ID NOs: 4101, 4105, 4109, 4113, 4117, 4132, 7342, and 7345.

[0047] In some embodiments, the one or more anti-CD25 antigen-binding domains described herein may further comprise a CDR2 comprising an amino acid sequence selected from a) (l / V)(D / E)R(D / G)(D / G)T(A / P / T); b) l¥SD(G / S)SGT (SEQ ID NO: 9441); c) IS(Q / R / G)(S / G)GGRT (SEQ ID NO: 10310); d) IS(R / S)(D / S)G(D / G)ST (SEQ ID NO: 7364); e) ISSGGNT {SEQ ID NO: 7346); and f) ISSTDGRT (SEQ ID NO: 7348).

[0048] ln some embodiments, the CDR2 of the one or more anti-CD25 antigen-binding domains comprises an amino acid sequence seiected from a) (l / V)(D / E)R(D / G)GT(A / P / T); b) l(D / E)RDGT(T / P) (SEQ ID NO: 4135); c) l(D / E)R(D / G)(D / G)T(P / T); d) IYSDGSGT (SEQ ID NO: 4114); e) ISQSGGRT (SEQ ID NO: 4118) f). !S(R / S)(D / S)G(D / G)ST (SEQ ID NO: 7364); g). ISSGGNT (SEQ ID NO: 7346); and h). ISSTDGRT (SEQ ID NO: 7348).

[0049] ln some embodiments, the CDR2 of the one or more anti-CD25 antigen-binding domains comprises an amino acid sequence seiected from SEQ ID NOs: 4102, 4106, 4110, 4114, 4118, (l / V)(D / E)R(D / G)GT(A / P / T), 4135, l(D / E)R(D / G)(D / G)T(P / T), 5042, 5046, 5059, 5067, 5092, 5214, 5215, 5216, 1117, 7343, 7346, 7348, and 9435.

[0050] ln some embodiments, the CDR2 of the one or more anti-CD25 antigen-binding domains comprises an amino acid sequence selected from SEQ ID NOs: 4102, 4106, 4110, 4114, 4118, 7343, 7346, 7348, and 9435.

[0051] In some embodiments, the one or more anti-CD25 antigen-binding domains comprise i) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4137, a CDR2 comprising an amino acid sequence of (l / V)(D / E)R(D / G](D / G)T(A / P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4131; ii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4137, a CDR2 comprising an amino acid sequence of (l / V)(D / E)R(D / G)(D / G)T(A / P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4134;in) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4137, a CDR2 comprising an amino acid sequence of (l / V){D / E)R(D / G)(D / G)T(A / P / T), and a CDR3 comprising an amino acid sequence of SEQID NO: 4136; iv) a CORI comprising an amino acid sequence of SEQ iD NO: 4137, a CDR2 comprising an amino acid sequence of (l / V)( D / E) R(D / G)GT(A / P / T), and a CDR3 comprising an amino acid sequence of SEQ iD NO: 4131; v) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4137, a CDR2 comprising an amino acid sequence of SEQ iD NO: 4135, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 4134; vi) a CDR1 comprising an amino acid sequence of SEQ iD NO: 4137, a CDR2 comprising an amino acid sequence of l(D / E)R(D / G)(D / G)T(P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4136; vii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4132, a CDR2 comprising an amino acid sequence of (l / V)(D / E)R(D / G)(D / G)T(A / P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4131; viii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino acid sequence of (l / V)(D / E)R(D / G)(D / G)T(A / P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4134; ix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4132, a CDR2 comprising an amino acid sequence of (l / V)(D / E)R(D / G)GT(A / P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4131; x) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4135, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4134; xi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4140, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9441, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10219; xii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4140, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9441, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9440; xiii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4140, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4114, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4139; xiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 10309, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10310, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10308;xv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4142, a CDR2 comprising an amino acid sequence of SEQ iD NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 4141; xvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7364, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7363; xvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7366, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7346, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7365; xviii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9423; xix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7367. xx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4140, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9441, and a CDR3 comprising an amino acid sequence of {A / V / S)(A / K / T)(A / G)(A / R / K)(A / G / H / N / RHA / S){A / G)(A / S / G)(A / Y)(A / Y)(A / P)(A / W / F / L){A / D / E)(A / D / E)(A / Y / V); or xxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of (A / G)(A / G)(A / K)(A / R)(A / L)(A / G)(A / P)(M / I / A / L)(A / V)(A / H)(A / R / Q)(A / ¥)(A / S)(A / L)(A / E)(A / V)(A / L)(A / T){A / P )(A / L)(A / F)(A / L)(A / D)(A / E)(A / Y)(A / D)(A / Y).

[0052] ln some embodiments, the one or more CD25 antigen-binding domains comprise i) a CDR1 comprising an amino add sequence of SEQ ID NO: 4101, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4102, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4103; ii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4106, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4107; ill) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4109, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4110, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4111; ivj a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4114, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4115;v) a CDR1 comprising an amino add sequence of SEQ ID NO: 4117, a CDR2 comprising an amino acid sequence of SEQ iD NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 4119; vi) a CDR1 comprising an amino acid sequence of SEQ iD NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7343, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 7344; vii) a CDR1 comprising an amino acid sequence of SEQ iD NO: 7345, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7346, and a CDR3 comprising an amino acid sequence of SEQ !D NO: 7347; viii) a CDR1 comprising an amino add sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 7349; ix) a CDR1 comprising an amino acid sequence of SEQ iD NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7350; x) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9411; xi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9412; xii) a CDR1 comprising an amino add sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9413; xiii) a CDR1 comprising an amino acid sequence of SEQ iD NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9414; xiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9415; xv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ, ID NO: 9416; xvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4114, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9975; xvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4114, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5431;xviii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4114, and a CDR3 comprising an amino acid sequence of SEQ ID NO:9887; xix) a CDR1 comprising an amino acid sequence of SEQ iD NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 4114, and a CDR3 comprising an amino add sequence of SEQ ID NO: 9966; xx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9436; xxi) a CDR1 comprising an amino add sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9978; xxii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino add sequence of SEQ ID NO: 9979; xxiii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9980; xxiv) a CDR1 comprising an amino add sequence of SEQ ID NO: 4105, a CDR2 comprising an amino add sequence of SEQ ID NO: 4110, and a CDR3 comprising an amino add sequence of SEQ ID NO: 5339; xxv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5046, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5339; xxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino add sequence of SEQ ID NO: 5059, and a CDR3 comprising an amino add sequence of SEQ ID NO: 5337; xxvi!) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5046, and a CDR3 comprising an amino add sequence of SEQ ID NO: 5337; xxviii) a CDR1 comprising an amino add sequence of SEQ ID NO: 4101, a CDR2 comprising an amino add sequence of SEQ ID NO: 5067, and a CDR3 comprising an amino add sequence of SEQ ID NO: 5371;xxix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino acid sequence of SEQ iD NO: 504S, and a CDR3 comprising an amino acid sequence of SEQ iD NO:5375; xxx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4109, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4110, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4111; xxxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4101, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5092, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4111; xxxii) a CDR1 comprising an amino acid sequence of SEQ ID NQ: 4101, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5092, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5398; xxxiii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4101, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5042, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4111; xxxiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5059, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4111; xxxv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4101, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5042, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5401; xxxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5515; xxxvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4909, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5214, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5519; xxxviii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5216, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5521;xxxix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4909, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5217, and a CDR3 comprising an amino acid sequence of SEQ ID NO:5519; xl) a CDR1 comprising an amino acid sequence of SEQ, ID NO: 4918, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5215, and a CDR3 comprising an amino acid sequence of SEQ, ID NO: 5528; xli) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5532; xlii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5542; xliii) a CDR1 comprising an amino acid sequence of SEQ ID NG: 4905, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5544; xliv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5545; xlv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5547; xlvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5548. xlviija CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino add sequence of SEQ ID NG: 10504; xlviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10505; xl ix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10506; l)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10507; li)a CDR1 comprising an amino add sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10508;lii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10509; liii)a CDR1 comprising an amino add sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10510; livja CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10511; lv)a CDR1 comprising an amino add sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10512; lvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10513; lvii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ !D NO: 10514;Iviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10515; lix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10516; lx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10517; lxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10518; lxii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10519;Ixi ii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10520;Ixivja CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10521; lxv)a CDR1 comprising an amino add sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10522;Ixvija CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10523;Ixvi i)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10524;Ixviiija CDR1 comprising an amino acid sequence of SEQ !D NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10525; lxix)a CDR1 comprising an amino acid sequence of SEQ iD NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 9414; lxx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ !D NO: 10526; lxxi)a CDR1 comprising an amino acid sequence of SEQ iD NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10527; lxxii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10528; lxxiii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10529;Ixxivja CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10530;Ixxvja CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10531; lxxvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10532;Ixxviija CDR1 comprising an amino acid sequence of SEQ ID NO; 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10533;Ixxviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10534; lxxix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ !D NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10535; ixxx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10536; lxxxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10537;Ixxxiija CDR1 comprising an amino add sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10538;Ixxxiiija CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10539;Ixxxivja CDRI comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10540;Ixxxvja CDRI comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10541;Ixxxvija CDRI comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10542;Ixxxviija CDRI comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10543; or lxxxviii)a CDRi comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10544,

[0053] ln some embodiments, the one or more anti-CD25 antigen-binding domains comprise a CDRI comprising an amino acid sequence selected from any one of SEQ ID NOs: 4726-5030, 7931-8226, and 9660-9770; a CDR2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 5031- 5335, 8227-8522, and 9771-9880; and / or a CDR3 comprising an amino acid sequence selected from any one of SEQ ID Nos: 5336-5640, 8523-8818, and 9881-9991.

[0054] ln some embodiments, the one or more anti-CD25 antigen-binding domains include a singledomain antibody. In some embodiments, the single-domain antibody is a VHH, a VNAR, or a VH domain. In some embodiments, the VHH of the one or more anti-CD25 antigen-binding domains is a camelid VHH.

[0055] ln some embodiments, the VHH of the one or more anti-CD25 antigen-binding domains comprises an amino acid sequence selected from any one of SEQ ID NOs: 4104, 4108, 4112, 4116, 4120, 4143- 4442, 5641-5945, 7351-7354, 7368-7659, 8819-9114, 9437, 9442-9551, 9992-10102, and 10246-10276, or a sequence having at least 75% identity thereto.

[0056] ln some embodiments, the VHH of the one or more anti-CD25 antigen-binding domains comprises an amino acid sequence selected from any one of SEQ ID NOs: 4104, 4108, 4112, 4116, 4120, 7351- 7354, 9437, and 10246-10276, or a sequence having at least 75% identity thereto.

[0057] ln some embodiments, the humanized VHH of the one or more anti-CD25 antigen-binding domains comprises an amino acid sequence selected from any one of SEQ ID NOs: 4126-4130, 4443- 4725, 7359-7362, 7660-7930, 9417-9422, 9439, 9552-9659, 10214-10245, and 10545-10585, or a sequence having at least 75% identity thereto.

[0058] ln some embodiments, the humanized VHH of the one or more anti~CD25 antigen-binding domains comprises an amino acid sequence selected from any one of SEQ, ID NOs: 4126-4130, 7359- 7362, 9417-9422, 9439, 10214-10245, and 10545-10585, or a sequence having at least 75% identity thereto.

[0059] ln some embodiments, the one or more anti-CD25 antigen-binding domains of the present disclosure comprise IL-2 or a variant thereof.[0060)ln some embodiments, the one or more anti-CD25 antigen-binding domains bind to human CD25. in some embodiments, the one or more anti-CD25 antigen-binding domains bind to human CD25 with a KD of less than about 3.5 x!0~7M. in some embodiments, the one or more anti-CD25 antigen-binding domains bind to human CD25 with a KD of about lxl0“Mto about 5xl0~8M.[OOSljln some embodiments, the one or more antl-CD25 antigen-binding domains bind to cyno CD25. In some embodiments, the one or more anti-CD25 antigen-binding domains bind to cyno CD25 with a KD of less than about l*10~6M, In some embodiments, the one or more anti-CD25 antigen-binding domains bind to cyno CD25 with a KD of about lxl0“9to about 2xl0“7M.

[0062] ln some embodiments, the one or more anti-CD25 antigen-binding domains bind to the same epitope(s) on CD25 as i L-2, In some embodiments, the one or more anti-CD25 antigen-binding domains compete for binding to CD25 with IL-2. In some embodiments, the one or more anti-CD25 antigenbinding domains have an antagonistic effect upon binding to CD25. In some embodiments, the one or more anti-CD25 antigen-binding domains do not bind to the same epitope(s) as IL-2. In some embodiments, the one or more anti-CD25 antigen-binding domains do not compete for binding to CD25 with IL-2.

[0063] ln some embodiments, the one or more anti-TNFR2 antigen-binding domains and / or the one or more CD25 antigen-binding domains comprise one or more modifications that reduce binding of said antigen-binding protein by pre-existing antibodies found in human blood or serum.

[0064] ln some embodiments, the anti-TNFR2 single-domain antibody and / or the anti-CD25 singledomain antibody comprises one or more modifications at the amino-terminus and / or the carboxyterminus.

[0065] ln some embodiments, the anti-TNFR2 single-domain antibody and / or the anti~CD25 singledomain antibody comprises the amino acid sequence VPAG (SEQ ID NO: 7267) or VAGG (SEQ ID NO: 7266) at the carboxy-terminus starting from position ill according to Chothia.

[0066] ln some embodiments, the anti-TNFR2 single-domain antibody and / or the anti-CD25 singledomain antibody comprises a substitution of amino acid residue Glu with Asp (EID) at the first position of the amino-terminus.[0067pn some embodiments of the muitispecific antigen-binding protein described herein, the one or more anti-TNFR2 antigen-binding domains and / or the one or more CD25 antigen-binding domains are one or more single-domain antibodies. In some embodiments, the one or more single-domain antibodies are one or more VHHs.

[0068] ln some embodiments of the multispecific antigen-binding protein described herein, the multispecific antigen-binding protein further comprises an immunoglobulin Fc region, in some embodiments, the immunoglobulin Fc region is an Fc region of a human immunoglobulin. In some embodiments, the immunoglobulin Fc region is an Fc region of human IgGl, lgG2, lgG3 or lgG4, or a variant thereof.

[0069] ln some embodiments, the immunoglobulin Fc region is an Fc region of human IgGl, or a variant thereof. In some embodiments, the Fc region of human IgGl comprises one or more mutations selected from Leu234Ala (L234A), Leu234Gly (L234G), Leu234Ser (L234S), Leu234Thr (L234T), Leu234Ala (L234A), Leu235Ala (L235A), Leu235Glu (L235E), Leu235Ser (L235S), Leu235Thr (L235T), Leu235Val (L235V), Leu235Gln (L235Q), Gly236Arg (G236R), Met252Tyr (M252Y), Ser254Thr (S254T), Thr256Glu (T256E), Asp265Asn (D265N), Asp265Ala (D265A), Asp270Asn (D270N), Ser298Asn (S298N), Asn297Ala (N297A), Pro329Ala (P329A), Pro239Gly (P329G), Asn325Glu (N325E), and / or Ala327Ser (A327S) according to EU numbering. In some embodiments, the Fc region of human IgGl comprises a set of mutations selected from:1JL234A and L235A;2JL234A, L235A, and P329A;3JD265A, N297A and P329A;4)L234A, L235A, and G237A;5)L234G, L235S, and G236R;6) L234S, L235T, and G236R;7)L234S, L235V, and G236R;8)L234T, L235Q, and G236R;9)L234T, L235T, and G236R;10JL234A, L235A, and P329G; and11)M252Y, S254T, and T25SE.

[0070] ln some embodiments, the immunoglobulin Fc region is an Fc region of human IgGl comprising L234A, L235A, and P329A.

[0071] ln some embodiments, the immunoglobulin Fc region is an Fc region of human lgG4, or a variant thereof. In some embodiments, the Fc region of human lgG4 comprises one or more mutations selected from Ser228Pro (S228P), Leu235Glu (L235E), Leu235Ala (L235A), Phe234Ala (F234A), and / or Pro329Gly (P329G) according to EU numbering. In some embodiments, the Fc region of human lgG4 comprises a set of mutations selected from:1) S228P and L235E;2JS228P and L235A;3)S228P, F234A, and L235E;4JS228P, F234A, and L235A; and5)P329G, S228P, and L235E.

[0072] ln some embodiments, the immunoglobulin Fc region is an Fc region of human lgG4 comprising S228P and L235E.

[0073] ln some embodiments, the multispecific antigen-binding protein comprises at least one linker, optionally selected from the group consisting of SEQ ID NOs: 3969-4027, and 6261-6362.

[0074] ln some embodiments, the at least one linker is a rigid linker.

[0075] ln some embodiments, the at least one rigid linker is selected from the group consisting of PAPAPAPAPAPAPAPAP (SEQ ID NO: 4009), GGGGSPAPAPAPAPAPAPAPAPGGGGS (SEQ ID NO: 4012), GGGGSPAPAPAPAPGGGGS (SEQ ID NO: 6361), GGGGSPAPAPAPAPAPAPAPAPAPAPAPAPGGGGS (SEQ ID NO: 6362), and A(EAAAK)nA (SEQ ID NO: 4027), where n is any integer, e.g., 1, 2, 3, 4, 5, 6, or 7, 8, 9 or 10,

[0076] ln some embodiments, the at least one linker is a flexible linker.

[0077] ! n some embodiments, the at least one flexible linker is selected from the group consisting of GnS (SEQ ID NO: 4013), SGn(SEQ ID NO: 4014), where n is any integer, e.g., 1, 2, 3, 4, 5, 6, or 7, 8, 9 or 10, and (GGGGS)n (SEQ ID NO: 4015), where n is any integer, e.g., 1, 2, 3, 4, 5, 6, or 7, 8, 9 or 10.

[0078] ! n some embodiments, the multispecific antigen-binding protein comprises the amino acid sequence of any one of SEQ ID NOs: 6401-6520 and 10792-10810, or a sequence having at least 70% identity thereto.

[0079] ln another aspect, provided herein is a conjugate comprising the multispecific antigen-binding protein described herein, wherein the multispecific antigen-binding protein is conjugated to a second moiety. In some embodiments, the second moiety is selected from a detectable label, a drug, a toxin, aradionuclide, an enzyme, an immunomodulatory agent, a cytokine, a cytotoxic agent, a chemotherapeutic agent, and a diagnostic agent, or a combination thereof,

[0080] ln another aspect, provided herein is a polynucleotide molecule encoding the muitispecific antigen-binding protein described herein,

[0081] ln some embodiments, the polynucleotide molecule comprises a nucleotide sequence encoding any of the amino acid sequences selected from SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 93-640, 2805-3363, 6636, 6640, 6644, 7090, 6651-6697, 6931-6992, 7174-7197, 10380, 10381, 10383, 10385, and 10386, encoding an anti-TNFR2 VHH, or a sequence having at least 70% identity thereto, in some embodiments, the polynucleotide molecule comprises encoding any of the amino acid sequences selected from SEQ ID NOs: 81-92, 6648, 6649, 6650, 7092, 7095, 7098, 7101,7293-7296, 641-1127, 6698-6744, 10375, 10382, 10384, 10394-10408, 10457-10502, 10720-10727, and 10812, encoding an anti-TNFR2 VHH, or a sequence having at least 70% identity thereto.

[0082] ln some embodiments, the polynucleotide molecule comprises the nucleotide sequence of any one of SEQ ID NOs: 48-59, 3364-3922, 6645-6647, 7091, 7094, 7097, 7100, 6993-7054, 7198-7221, and 10611-10661, encoding an anti-TNFR2 VHH, or a sequence having at least 70% identity thereto. In some embodiments, the polynucleotide molecule comprises the nucleotide sequence of any one of SEQ ID NOs: 48-59, 6645-6647, 7091, 7094, 7097, and 7100, and 10611-10661, encoding an anti-TNFR2 VHH, or a sequence having at least 70% identity thereto.

[0083] ln some embodiments, the polynucleotide molecule comprises a nucleotide sequence encoding any one of the amino acid sequences selected from SEQ, ID NOs: 4104, 4108, 4112, 4116, 4120, 4143- 4442, 5641-5945, 7351-7354, 7368-7659, 8819-9114, 9437, 9442-9551, 9992-10102, and 10246-10276, encoding an anti-CD25 VHH, or a sequence having at least 70% identity thereto.

[0084] ln some embodiments, the polynucleotide molecule comprises the nucleotide sequence of any one of SEQ ID NOs: 4121-4125, 5946-6250, 7355-7358, 9115-9410, 9438, and 10103-10213, encoding an anti-CD25 VHH, or a sequence having at least 70% identity thereto.

[0085] ln an embodiment provided herein, the polynucleotide molecule comprises the nucleotide sequence encoding an amino acid sequence selected from SEQ ID NOs: 4126-4130, 4443-4725, 7359- 7362, 7660-7930, 9417-9422, 9439, 10214-10245, and 9652-9659, encoding a humanized anti-CD25 VHH, or a sequence having at least 70% identity thereto.

[0086] ln an embodiment provided herein, the polynucleotide molecule comprises the nucleotide sequence encoding an amino acid sequence selected from SEQ ID NOs: 9438, 10277-10307, and 10662- 10703 encoding a humanized anti-CD25 VHH, or a sequence having at least 70% identity thereto.

[0087] In an embodiment provided herein, the polynucleotide molecule comprises a nucleotide sequence selected from SEQ ID NOs: 6521-6632, or a similar sequence thereof having at least 70% identity thereto.

[0088] ln an embodiment provided herein, the polynucleotide molecule comprises the nucleotide sequence of any one of SEQ ID NOs- 6521-6632 encoding a multispecific antigen-binding protein.

[0089] ln another aspect, provided herein is a recombinant vector comprising the polynucleotide molecule described herein.

[0090] in another aspect, provided herein is a host cell comprising the polynucleotide molecule described herein, or the recombinant vector described herein.

[0091] ln another aspect, provided herein is a kit comprising the multispecific antigen-binding protein, the conjugate, the polynucleotide molecule, the recombinant vector, or the host cell described herein, and optionally, instructions and / or packaging for the same.

[0092] ln another aspect, provided herein is a pharmaceutical composition comprising the multispecific antigen-binding protein, the conjugate, the polynucleotide molecule, or the recombinant vector described herein, and a pharmaceutically acceptable carrier and / or excipient.

[0093] ln another aspect, provided herein is a method for preparing a multispecific antigen-binding protein that specifically binds TNFR2 and CD25, comprising the steps of:(a) culturing the host cell described herein in a culture medium under conditions suitable for expression of the multispecific antigen-binding protein, and(bj isolating the multispecific antigen-binding protein from the host cell and / or the culture medium.

[0094] ln another aspect, provided herein is a method for promoting proliferation, activating and / or enhancing suppressive function, and / or stabilizing immunosuppressive phenotype of a population of regulatory T cells (Treg) comprising contacting the population of Treg with the multispecific antigenbinding protein or the conjugate described herein. In some embodiments, said contacting occurs in vitro, in some embodiments, said contacting occurs in vim. In some embodiments wherein the method occurs in vivo, the method further comprises administering the multispecific antigen-binding protein or the conjugate into a subject in need thereof.

[0095] ln another aspect, provided herein is a method of treating or preventing a disease or disorder in a subject in need thereof, said method comprising administering to the subject an effective amount of the multispecific antigen-binding protein or the conjugate described herein. In some embodiments, thedisease or disorder is an immunological disease, inflammatory disease, cancer, cardiovascular disease, or an infertility and pregnancy-associated disease.

[0096] ln some embodiments, the immunological disease is selected from an autoimmune disease, a neurological condition, an allergy, asthma, macular degeneration, muscular atrophy, a disease related to miscarriage, atherosclerosis, bone loss, a musculoskeletal disease, obesity, a graft-versus-host disease, and an allograft rejection.

[0097] ln 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, bullous 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, Guillain-Barre, Hashimoto's thyroiditis, hypothyroidism, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, juvenile arthritis, lichen planus, lichen sclerosis, lgG4-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 insufficiency, Raynaud’s phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthritis, stiff-man syndrome, type I diabetes, Takayasu arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener's granulomatosis (Granulomatosis with polyangiitis) or other immune vasculitis.

[0098] ln some embodiments, the lupus is systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis, neonatal lupus, or drug-induced lupus. In some embodiments, the cutaneous lupus is acute cutaneous lupus, chronic cutaneous lupus erythematosus, discoid lupus erythematosus (DLE), or subacute cutaneous lupus erythematosus.[0099jln some embodiments, the autoimmune disease is atopic dermatitis, psoriasis, systemic lupus erythematosus, or arthritis.[OlOOjln 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.[OlOlJIn some embodiments, the allergy is selected from food allergy, seasonal allergy, pet allergy, hives, hayfever, allergic conjunctivitis, poison ivy allergy oak allergy, mold allergy, drug allergy, dust allergy, cosmetic allergy, and chemical allergy.[O1O2J8 n some embodiments, the allograft rejection is selected from skin graft rejection, bone graft rejection, vascular tissue graft rejection, ligament graft rejection, and organ graft rejection,

[0103] ! n 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 collateral ligament graft rejection, radial collateral 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 collateral ligament graft rejection, posterior cruciate ligament graft rejection, medial collateral ligament graft rejection, cranial cruciate ligament graft rejection, , and patellar ligament graft rejection.

[0104] ln 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.

[0105] ln some embodiments, the graft-versus-host disease arises from a bone marrow transplant or one or more blood cells selected from B-cells, T-cells, basophils, common myeloid progenitor cells, common lymphoid progenitor cells, dendritic cells, eosinophils, hematopoietic stem cells, neutrophils, natural killer cells, megakaryocytes, monocytes, or macrophages.[OlOSjln some embodiments, the Inflammatory disease is acute or chronic inflammation.

[0107] ! n some embodiments, the inflammatory disease is selected from osteoarthritis, atopic dermatitis, endometriosis, polycystic ovarian syndrome, inflammatory bowel disease, fibrotic lung disease, and cardiac inflammation.[OlOSJin 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-Dube 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, gallbladder cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis and renal cell cancer, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary 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-cell proiymphocytic leukemia and hairy cell leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CIVIL), chronic T-cell lymphocytic leukemia, eosinophilic leukemia, Li-Fraumeni syndrome, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, hodgkin lymphoma, non-hodgkin lymphoma, lynch syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, multiple myeloma, MUTYH (or M¥H)-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, neuroendocrine tumors, neurofibromatosis type 1, neurofibromatosis type 2, nevoid basal cell carcinoma syndrome, oral and oropharyngeal cancer, osteosarcoma, ovarian, fallopian 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), small 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,

[0109] ln 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. [OllOjln 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.[OlllJIn another aspect provided herein is a method of regenerating a tissue or organ comprising one or more TNFR2+ and / or CD25+ cells, said method comprising contacting the tissue or organ with an effective amount of the multispecific antigen-binding protein or the conjugate described herein. In another aspect, provided herein is a method of regenerating a tissue or organ comprising one or more TNFR24- cells, said method comprising contacting the tissue or organ with an effective amount of the multispecific antigen-binding protein or the conjugate described herein. In another aspect, provided herein is a method of regenerating a tissue or organ comprising one or more CD25+ cells, said method comprising contacting the tissue or organ with an effective amount of the multispecific antigen-binding protein or the conjugate described herein.

[0112] ! n some embodiments, the 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, small intestine, large intestine, gastrointestinal, lung, brain, skin, peripheral nervous system, central nervous system, spinal cord, breast, embryonic structures, embryo, and testes tissue. In some embodiments, said contacting occurs m vitro. In some embodiments, said contacting occurs in vivo. In some embodiments wherein the method occurs in vivo, the method further comprises administering the multispecific antigen-binding protein or the conjugate into a subject in need thereof.

[0113] ! n various embodiments of the above-described methods, the subject is a mammal. In some embodiments, the mammal is human.

[0114] ! n another aspect, provided herein is 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, comprising an administering to the subject an effective amount of the multispecific antigen-binding protein, or the conjugate described herein.

[0115] ln some embodiments, the foreign agent is a therapeutic protein, a peptide, a vector, a biochemical vector, a lipid, a carbohydrate, a nucleic acid, a sperm, an oocyte, or an embryo. In some embodiments, the vector is a viral vector, a bacterial vector, or a fungal vector. In some embodiments, the viral vector is a DNA or RNA vector.BRIEF DESCRIPTION OF DRAWINGS[OllSjFsgure 1 shows the therapeutic rational of the multispecific antigen-binding proteins of the present disclosure. An exemplary bispecific format is depicted.

[0117] Fsgure 2A depicts an exemplary general panning strategy for isolation of tumor necrosis factor (INF) 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.

[0118] Figure 2B 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 million, 2 million, and 2 million 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.[O119]F8gure 3 shows a schematic diagram of an exemplary NGS workflow. Following phage display, the VHH region of the phage eluate was amplified via polymerase chain reaction (PCR). Unique and samplespecific barcodes were then fused, and NGS was subsequently performed using the Illumina 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 CDRS identity, V-body sequences were clustered, thereby allowing for detailed analysis of, e.g,, V-body enrichment during phage display, sequence diversity, CDR3 length distribution, and cluster abundance. Based on such analyses, more than 600 candidates were selected for DNA synthesis (Twist) and further characterization.

[0120] F8gure§ 4A~4B illustrate human TNFR2 (hTNFR2) V-body binding validation at a fixed concentration of 1 pM V-body. The bar histogram (Figure 4A) and table (Figure 4B) show the percentage of Alexa488-positive cells for all VHHs tested. For the bar histogram, the lower dotted line indicates background staining, and the upper 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". Shading within the table indicates binders to hTNFR2.

[0121] Figures 5A-5B illustrate human TNFR2 (hTNFR2) V-body binding validation at a fixed concentration of 100 nM V-body. The bar histogram (Figure 5A) and table (Figure SB) show the percentage of Alexa488-positive cells for all VHHs tested. For the bar histogram, the lower dotted line indicates background staining (~5%), and the upper 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". Shading within the table indicates binders to hTNFR2,

[0122] Figures SA-6C depict cross-specificity of V-body binding to mouse TNFR2 (mTNFR2) (Figure SA) and cynomolgus TNFR2 (cTNFR2) (Figure SB) at a fixed concentration of WO nM. The bar histograms (Figure 6A-6B) and table (Figure 6C) show the percentage of Aiexa488-positive cells for all VHHs tested. For the bar histogram, the lower dotted line indicates background staining, and the upper dotted line indicates two times the background level.

[0123] 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. V-bodies were tested at molar concentrations of 100 nM, 50 nM, 25 nM, 12.5 nM, 6.25 nM, 3.12 nM and 1.55 nM.[0124)Figure 8 shows a schematic diagram of an exemplary experimental setup for determination of binding affinities 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: 7279.

[0125] 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.

[0126] Fsgure 10 shows a summary of binding affinities of 16 selected anti-TNFR2 V-bodies to human, cynomolgus and mouse TNFR2. Cyno, cynomolgus.

[0127] Fsgure 11 demonstrates that some humanized anti-TNFR2 V-bodies targeted the epitope recognized by a MR2-1 bivalent agonist. T-013hul and T-018hul may recognize the same epitope as MR2-1. MR2-1 binding enhanced binding of T-015hul, T-017hul and T-Ollhul to TNFR2.

[0128] 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-KB reporter HEK293 cells 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 cell lines specific for each signaling pathway. RLU, relative luminescence unit.

[0129] Figure 13 depicts HEK293 TNFR2 NF-KB (LUC) reporter gene assay controls. Anti-hTNFR2 agonist MR2-1 monoclonal antibodies were tested on NF-xB reporter (Luc) HEK293 reporter cell-line stably expressing TN FR2 (clone 25) versus parental cell line (PCL). RLU, relative luminescence unit.[O13O]F8gures 14A-14C shows HEK293 TNFR2 NF-KB (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 isdepicted in Figure MB. A bar graph showing RLUs for V-body constructs and respective controls tested on a PCL control is depicted in Figure 14C.

[0131] Figures 15A-15B depict concentration range curve data generated using MR2-1 (Figure ISA) and TNFa (Figure 15B) controls for four assay plates.

[0132] Flgures 1SA-1SC 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 crysta lliza ble (Fc) region of a lgG4 variant comprising S228P, L235E and P329G mutations.

[0133] 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 lgG4 variant comprising S228P, L235E and P329G mutations.

[0134] 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.

[0135] Figures 29A-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.

[0136] 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-xB reporter (Luc) HEK293 reporter cell-line stably expressing TNFR2 (clone 8).[O137]F8gure 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 cells (PBMCs) and cluster of differentiation 4 positive (CD4+) CD25* CD127dim regulatory T cells (Tregs).

[0138] Fsgure 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.

[0139] Fjgure 23 illustrates 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 cell and CD4 gating were based on Fluorescence Minus One (FMO) FMO control determination of the cut-off point between background fluorescence and positive cell 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%.

[0140] 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 lreg 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.

[0141] Figure 25A-25B demonstrate 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.

[0142] 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.

[0143] Fsgure 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 (bottom panel).

[0144] 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 (bottom panel),

[0145] Fsgure 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).

[0146] 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: 7280.[O147]F8gure 31 shows assessment of tetravalent-Fc VHH activity on naive CD4+CD25-rCD45RA+ human Treg. HLA-DR and CCR8 expression on CD4+FQXIP3+ and expansion after 5 day stimulation with anti- CD3 / IL-2 plus VHH or MR2-1 are shown.

[0148] Figure 32A shows the ability of TNFR2 VHH to stabilize Treg. Naive CD4+CD25-KD45RA+ human Treg from healthy donors were stimulated with IL-2 and anti-CD3 in the presence of TNFR2 agonist VHH or TNFR2 monoclonal agonist MR2-1 for 5 days. Figure 328 shows the effect of TNFR2 VHH on early markers of Treg stability. Naive CD4*CD25+CD45RA* human Treg from healthy donors were stimulated with IL-2 and anti-CD3 in the presence of TNFR2 agonist VHH or IL-2 mutein for 5 days.

[0149] Fjgures 33A-33B show additional results of in vitro treatment of human Treg (CD4+ FQXP3+) 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.

[0150] Hgures 34A-34C show the effect of TNFR2 VHH on Treg stability under inflammatory conditions. Human Treg were expanded with IL-2 mutein or TNFR2 VHH in the presence of anti~CD3 and IL-2 for 5 days and then cultured with proinflammatory cytokines (IL-lb, IL-21, and IL-23 + / - TGFb) for 11 to 12 days; IL-17A or IFNy production after PMA / ionomycin stimulation was assessed together with FOXP3 by flow cytometry. The conversion of human Treg in vitro to cells that produce Thl / 17 cytokines (IFNy / IL- 17A) triggered by the inflammatory cytokines shown was prevented by co-stimulation with TNFR2 VHH but not with IL-2 mutein. P~vaiues indicate results of a paired T-test; * = p < 0.05; ** = p < 0.01; Fc = human lgG4 mutant Fc.[OlSljFigure 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 cells were incubated with cel! tracer-labeled autologous responder cells (na'ive CD4+ T cells); bar graph shows effector CD4 cell proliferation measured as % dividing CD4+FOXP3- cells; FACS histograms show dilution of the cell tracer at different Treg:CD4 (responder) ratios of one of four donors. T-007__2xVHH-Fc induces Treg that are better able to restrain effector CD4 cell proliferation than IL-2 mutein.

[0152] Figure 36A-36B show the effect of TNFR2 agonist VHH on Treg population size in mice. An exemplary design of the experimental procedure is shown. CD4+FOXP3+ Treg expansion in the spleen of mice 5 days after a single injection of 2,5 mg / kg control VHH or TNFR2-specific VHH T-007__2xVHH-Fc is shown.

[0153] Figure 37 shows that TNFR2 agonist VHH activates Treg in vivo. CCR§ is a chemokine receptor expressed on highly suppressive Treg and involved in cell 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):1033). Proportion of Treg (CD4+ CD25+ F0XP3+) 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 differences are shown; **“ = p < 0.0001.

[0154] Figure 38 shows that TNFR2 agonist VHH selectively expands Treg in the spleen. Cell subsets as percentage of CD45+ cells in the spleen 5 days after single injection of TNFR2-specific VHH T- 007__2xVHH-Fc or control VHH are shown.

[0155] Fsgure 39 shows that TNFR2 agonist VHH increases serum level of IL-10. IL-10 is a key antiinflammatory cytokine (Saraiva et al., J Exp Med 2020;217(l):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 differences are shown; **** = p < 0.0001.

[0156] Figure 40A-40R show frequency of Treg (CD4+ FOXP3+) among total immune cells (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.

[0157] Fsgure§ 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 FQXP3 and surface markers (F0XP3, ICAM-1, OX-40, ICOS, and CCR8), consistent with superior function and stability. One-way ANOVA test: **** p < 0.0001; n = 4.

[0158] Fsgure§ 42A~42B show that Treg expansion in the spleen as well as increased expression of F0XP3, linked to Treg stability and function, and Treg activation shown by up-regulation of ICAM-1 and ICOS.

[0159] Fsgure§ 43A-43C show that reduction of arthritis, measured by paw volume and arthritis score, in a model of collagen-antibody induced arthritis upon treatment with TNFR2 agonists T-037 and T-043.

[0160] Figure§ 44A~448 show Treg expansion by TNFR2 agonist without inducing proinflammatory cytokines when compared to CD28 agonist.

[0161] Fsgure 45 depicts an exemplary general panning strategy for isolation of CD25-specific variable domain of heavy chain (VHH) antibodies, also referred to herein as V-bodies (Vbs). Binders to human and rodent CD25 were enriched from VHH immune libraries by two rounds of phage display. BM, bone marrow.

[0162] Figure 46 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 million, 2 million, and 2 million 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.[OlSSjFsgure 47 shows a schematic diagram of an exemplary NGS workflow. Following phage display, the VHH region of the phage eluate was amplified via polymerase chain reaction (PCR). Unique andsample-specific barcodes were then fused, and NGS was subsequently performed using the Illumina NovaSeq platform (Genewiz). The raw data were de-multiplexed, and then processed by the MGS 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 allowing for detailed analysis of, e.g., V-body enrichment during phage display, sequence diversity, CDR3 length distribution, and cluster abundance. Based on such analyses, up to ~300 candidates were selected for DNA synthesis (Twist) and further characterization.

[0164] Figure 48 illustrates human CD25 (hCD25) V-body binding validation at a fixed concentration of 100 nM V-body, The bar histogram shows the mean fluorescence intensity (MFI) of Alexa488-positive cells for V-bodies C-004 and C-006 versus an anti-His only control condition.

[0165] Figure 49 illustrates V-body binding to cynomolgus (cCD25) (left panel) and mouse CD25 (mCD25) (right panel) at a fixed concentration of 100 nM V-body. The bar histograms show the mean fluorescence intensity (MFI) of Alexa488-positive cells for tested-bodies C-004 and C-006 versus an anti- His only control condition.

[0166] Fsgure§ 50A-50B show testing of human CD25 V-body binding across a range of concentrations for V-bodies C-004 and C-006. V-bodies were tested at molar concentrations of 100 nM, 50 nM, 25 nM, 12.5 nM, 6.25 nM, 3.125 nM, 1.5625 nM, 0.78125 nM, and 0.390625 nM (shown from left to right). The bar histogram in Figure 50A shows the percentage of Alexa488 positive cells for C-004 and C-006. The bar histogram in Figure 503 shows the mean fluorescent intensity (MFI) of Alexa488 positive cells for C-004 and C-006.

[0167] Figure 51 shows a schematic diagram of an exemplary experimental setup for determination of binding affinities of the anti-CD25 V-bodies for their respective target via surface plasmon resonance (SPR). Figure discloses "HHHHHH" as SEQ ID NO: 9425.

[0163] Figures 52A-52C depict surface plasmon resonance (SPR) sensorgrams of VHH binding to human, cynomolgus, and mouse CD25 for anti-CD25 V-bodies C-004 and C-006. Fitted binding curves and calculated dissociation constants (KD) are included. Data corresponding to an anti-CD25 IgG (aCD25 IgG) control condition are also included (Figure 52C). Figure discloses "HHHHHH" as SEQ ID NO: 9425.

[0169] Figure S3 shows a summary of binding affinities of two candidate anti~CD25 V-bodies to human, cynomolgus and mouse CD25. Data corresponding to an anti-CD25 IgG (aCD25 IgG) control condition are also included. MB, no binding.

[0170] F!gures 54A-54B demonstrate that some humanized anti-CD25 V-bodies targeted the epitope recognized by H--2. Data are shown for a first experiment 1 (Expl) and second experiment 2 (Exp2) performed using V-bodies C-004 (Figure 54A) and C-006 (Figure 548).

[0171] Fsgures 55A-55B demonstrate humanized anti-CD25 V-bodies C-OOlhul, C-002Hul, and C-003 are non-competitive binders. Data are shown for a first experiment 1 (Figure 55A) and second experiment 2 (Figure 55B).

[0172] Figures 56A-56C depict SPR sensorgrams of VHH binding to human, cynomolgus, and mouse CD25 for anti-CD25 V-bodies C-008Hul, C-OlOHul, and C-009Hul. Fitted binding curves and caicuiated dissociation constants (KD) are included.

[0173] Figure§ 57A-57C illustrate ligand (IL-2) competition by SPR. Each panel represents a sensorgram overlay plot for a single V-body captured onto a discrete spot. The sensorgrams display I L-2-Fc competition: association of the human CD25-extracellular domain (CD25-ECD) to the V-body was followed either by additional binding by IL2-Fc, indicating an unoccupied epitope (non-overlapping epitopes), or no i L2-Fc binding, indicating epitope blocking (overlapping epitopes), and a buffer control, association and dissociation of human CD25-ECD in the absence of I L2-Fc.

[0174] Fsgure 58 shows binding of His-tagged anti-CD25 VHHs to Human Embryonic Kidney (HEK) cells transfected with human or cyno CD25 detected by flow cytometry using a fluorescently-labelled secondary anti-His antibody. Binding is expressed as mean fluorescent intensity.

[0175] Figures 59A-59C depict SPR sensorgrams of VHH binding to human, cynomolgus, and mouse CD25 for anti-CD25 V-bodies C-010Hul.A8, C-010Hul.L8, and C-009Hul.L8. Fitted binding curves and calculated dissociation constants (KD) are included.[017S]Fsgure§ 6QA-60C illustrate exemplary multispecific antibody-binding proteins encompassed by the present invention. Figures 6QB-60C are adapted from C. Spiess et al. Molecular Immunology S7 (2015) 95-106, which is incorporated herein by reference in its entirety.

[0177] Figures S1A-618 show that a TNFR2 / CD25 bispecific V-body is able to bind to Treg. Healthy donor PBMC were incubated with mono- (TNFR2 or CD25) or bispecific (TNFR2 and CD25) VHHs and stained for CD4, F0XP3, CD8 and CD14. VHH binding was detected after washing with a secondary fluorescently- labelled anti VHH antibody. Plots show binding to Treg (mean fluorescent intensity) from 2 different donors for molecules that are monospecific for TNFR2 or bispecific for TNFR2 and CD25.

[0178] Hgure§ 62A-62B show that different anti-TNFR2 / anti-CD25 multispecific antibodies are able to bind to Treg. Healthy donor PBMC were incubated with mono or bispecific VHHs and stained for CD4, FOXP3, CD8 and CD14. VHH binding was detected after washing with a secondary fluorescently-labelledanti VHH antibody. Histograms show bispecific binding on CD4*FOXP3 Treg, CD4+FOXP3- CD4 effector, CD8 effector and CD.I.4+ monocytes. Insertion of a CD25 VHH at the N- or C-terminus of the Fc portion drastically increases binding to Treg.

[0179] Fsgures 63A-63B shows that a TNFR2 / CD25 bispecific V-body is able to activate a reporter cell. Figure 63A shows the results of TNFR2 agonism tested at 3 different dilutions on HEK NF-kB -Luciferase reporter cells expressing TNFR2. Y axis shows maximum agonism / reporter activity in relative luminescence unit (R.L.U.). Antibody formats are described above the respective data points. Figure §38 shows the results of TNFR2 agonism on HEK NF-kB -Luciferase reporter cells expressing TNFR2 only (Clone 18) or both TNFR2 and CD25 (Subcione 48 derived from clone 18). Monospecific and bispecific VHH were tested on TNFR2+ HEK and TNFR2*CD25+ HEK. Plot show equal TNFR2 agonism by TNFR2 VHH on both cells. In contrast, bispecific VHHs induced stronger agonism on reporter expressing CD25 (clone 48) compared to cells not expressing CD25 (clone 18).

[0180] Figures &4A-64B show that Tregs can be activated by mono- and bispecific tetravalent V-bodies. Figure S4A shows the results of total CD4 T cells isolated from PBMC from healthy donors stimulated with anti-CD3 / CD28 beads and IL-2 in the presence or absence of mono or bispecific VHHs. Mono and bispecific VHHs led to increased activation as measured by HLA-DR upregulation in Treg after 5 days of stimulation. Figure 648 shows the results of total CD4 T cells isolated from PBMC from healthy donors stimulated with anti-CD3 / CD28 beads and IL-2 in the presence or absence of mono or bispecific VHHs, Mono and bispecific VHHs led to increase percentage of FOXP3+ cells among CD4 after 5 days of stimulation.

[0181] Figures 65A-65C depict SPR sensorgrams of VHH binding to human, cynomolgus, and mouse CD25 for anti-CD25 V-bodies C-OllHul, C-012Hul, C-013Hul, C-014Hul, C-015Hul, C-005Hul, C-016Hul, C- 017Hul, and C-018Hul. Fitted binding curves and calculated dissociation constants (KD) are included.

[0182] Figures 66A-66C depict SPR sensorgrams of VHH binding to human, cynomolgus, and mouse CD25 for anti-CD25 V-bodies C-031Hul, C-032Hul, C-033Hul, C-034Hul, C-035Hul, C-036Hul, C-037Hul, C- 038Hul, C-039Hul, C~040Hul, and C-041Hul. Fitted binding curves and calculated dissociation constants (KD) are included.

[0183] Figure 67 depicts SPR sensorgrams of VHH binding to human, cynomolgus, and mouse CD25 for anti-CD25 V-bodies C~019Hul, C-020Hul, and C-022Hul. Fitted binding curves and calculated dissociation constants (KD) are included.

[0184] Figure 68 depicts SPR sensorgrams of VHH binding to human, cynomolgus, and mouse CD25 for anti-CD25 V-bodies C-023Hul and C-024Hul. Fitted binding curves and calculated dissociation constants (Ko) are included.

[0185] Fsgures 69A-69B depict SPR sensorgrams of VHH binding to human, cynomolgus, and mouse CD25 for anti-CD25 V-bodies C-025Hul, C-026Hul, C-027Hul, C-028Hul, C-029Hul, and C-030Hul. Fitted binding curves and calculated dissociation constants (KD) are included.

[0186] Rgures 70A-7GF depict SPR sensorograms of VHH binding to human and cynomolgus TNFR2 for anti-TNFR2 V-bodies . Fitted binding curves and calculated dissociation constants (Ko) are included.

[0187] Figures 71A-71J depict SPR sensorograms of VHH (obtained by alanine scanning mutagenesis) binding to human and cynomolgus TNFR2 for anti-TNFR2 V-bodies. Fitted binding curves and calculated dissociation constants (KD) are included.

[0188] Fsgure§ 72A-72B 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 (Ko) are included.

[0189] Figures 73A-73B depict flow cytometry plots (Figure 73A) and luminescence plots (Figure 73B) upon incubation of TNFR2 HEK reporter cells with the Fc-tagged bivalent V-bodies.

[0190] Figures 74A-74D depict binding of His-tagged VHHs to CD25+ human embryonic kidney (HEK) cells analyzed via flow cytometry. Figures 74A-74B show binding of His-tagged VHH to CD25+ HEK cells detected after washing with secondary anti-His antibody. Figures 74C-74D show binding measured by incubation of pre-incubated VHH / anti-His antibody complex to CD25+ HEK cells.

[0191] Figure 75 depicts Treg cell activation in the presence of a TNFR2 / CD25 bispecific V-body compared to a TNFR2 / control antibody. Data shows the average of 4 donors + / - SEM.[O192]F8gure 76 depicts Treg cell expansion upon Injection in human TNFR2 / human CD25 double knock- in mice with a TNFR2 / CD25 bispecific V-body compared to a TNFR2 / control antibody. Data shows the average of 3 replicates + / - STD.

[0193] Figures 77A-77B depict stable TNFR2* HEK cells incubated with a dose range of bispecific TNFR2 / CD25 antibodies or control antibodies comprising control VHH with irrelevant specificity in place of the TNFR2 and / or the CD25 VHH.

[0194] Figures 78A-78C depict stable CD25-r / low TNFR2 HEK cells incubated with a dose range of blspecific TNFR2 / CD25 antibodies or control antibodies comprising control VHH with irrelevant specificity in place of the TNFR2 and / or the CD25 VHH.

[0195] Fsgures 79A-79B depict NF-kB luciferase reporter activity in TNFR2+ HEX cells upon 16-20 hours of incubation with a dose range of bispecific TNFR2 / CD25 antibodies or control antibodies comprising control VHH with irrelevant specificity in place of the TNFR2 and / or the CD25 VHH.

[0196] Fsgures 80A-80B depict binding of bispecific TNFR2 / CD25 antibodies or control antibodies comprising control VHH with irrelevant specificity in place of the TNFR2 and / or the CD25 VHH to Treg cells (CD4+ FOXP3+) or monocytes (CD14+) from human PBMC.DETAILED DESCRIPTION OF THE INVENTION

[0197] The present application provides, among other things, multispecific antigen-binding proteins protein comprising: one or more antigen-binding domains that specifically bind to tumor necrosis factor receptor 2 (TNFR2); and one or more antigen-binding domains that specifically bind to cluster of differentiation 25 (CD25).

[0198] TNFR2 signaling has been shown to induce proliferation, sustained suppressive function and FOXP3 promoter demethylation in Tregs (Tseng et al., 2019). TNFR2 signaling also induces the expression of EZH2 (Urbano et al., 2018), a histone methyl transferase involved in the repression of the effector transcriptomic program and stabilization of the Treg phenotype (DuPage et al., 2015). Because of its role in Tregs biology and FOXP3 promoter demethylation, TNFR2 signaling can be leveraged to induce a stable immunosuppressive phenotype and enhance their function to the benefit of autoimmune diseases.

[0199] CD25, also called interleukin-2 receptor subunit alpha (IL-2Ra or IL2RA), is the alpha chain component of the high-affinity heterotrimeric interleukin-2 (IL-2) receptor, a type I transmembrane protein highly expressed on the surface of the majority of Tregs. IL-2 activation of CD25 can facilitate immune tolerance in Tregs. High cell surface expression of CD25 can also occur in malignant cells, e.g., in several lymphomas and leukemias,

[0200] TNFR2 is highly expressed on CD25-f- Tregs and has been shown to induce their expansion, enhance their function and stabilize their suppressive phenotype. While not wishing to be bound by any particular theory, Tregs are believed to be the only cells that express both TNFR2 and CD25 constitutively. In some embodiments, the multispecific antigen-binding proteins described herein can specifically agonize TNFR2 on Tregs using CD25 as an anchor (see Figure 1).Definitions[02(31] U n less defined otherwise, ail technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. For purposes of interpreting this specification, the following description of terms will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. All 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 shall control.

[0202] 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 all values in between (e.g., 96, 97, 98, 99, etc.).

[0203] The term "antigen" encompasses any agent (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleotide, portions thereof, or combinations thereof) that may be specifically bound by the products of specific humoral or cellular immunity, such as an antibody molecule or T-cell receptor. In various embodiments of the present disclosure, the antigens described herein include TNFR2, including human, cynomolgus, and / or mouse TNFR2, and / or CD25, including human CD25.

[0204] 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, different antibodies may bind to different areas on an antigen and may have different biological effects (e.g., agnostic or antagonistic effects). Epitopes may be either conformational or linear. A conformational epitope is formed by spatially juxtaposed amino acids from different segments of the linear polypeptide chairs. 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.

[0205] The term "antigen-binding protein" refers in the broadest sense to a protein that specifically binds an antigen (e.g., TNFR2 and / or CD25). In certain embodiments, an antigen-binding protein comprises 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 IgGl antibody; an lgG2 antibody; an lgG3 antibody; or an lgG4 antibody, andfragments thereof. The term "antigen-binding protein" also encompasses, for example, an alternative protein scaffold or artificial scaffold with grafted CDRs or CDR derivatives. Such scaffolds include, but are not limited to, antibody-derived scaffolds comprising mutations introduced to, for example, stabilize the three-dimensional structure of the antigen-binding protein as well as wholly synthetic scaffolds comprising, for example, a biocompatible polymer. In addition, peptide antibody mimetics can be used, as well as scaffolds based on antibody mimetics utilizing fibronectin components (e.g., fibronectin type III domain (FN3)) as a scaffold.

[0206] The term "antigen-binding domain" refers to the portion of the antigen-binding protein that is capable of specifically binding to an antigen or epitope. An antigen-binding protein may comprise more than one antigen-binding domains, for example, two, three, four, five, six, seven, eight or more antigenbinding domains. For example, antigen-binding domains may comprise at least one variable region (either a heavy chain or light chain variable region) or one or more CDRs of an antibody that can bind a particular antigen, Examples of suitable antigen-binding domains include, without limitation, singledomain antibodies (e.g., VHH), single-chain antibodies (e.g., single chain fragment variable (scFv)), Fab fragments, F(ab')2 fragments, and protein scaffolds.

[0207] 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, full 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-ld) antibodies, and antigen-binding fragments of antibodies, as described below. An antibody can be human, humanized, camellzed, recombinantly produced, chimeric, synthetic, affinity de-matured and / or affinity matured as well as an antibody from other species, for example mouse, camel, llama, rabbit, etc. In specific embodiments, the specific target antigen that can be bound by an antibody provided herein includes a TNFR2 polypeptide, TNFR2 fragment orTNFR2 epitope. In specific embodiments, the specific target antigen that can be bound by an antibody provided herein includes a CD25 polypeptide, CD25 fragment or CD25 epitope. An "antigen-binding fragment" generally refers a portion of an antibody heavy and / or light chain polypeptide that retains some or all 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 andminibody, or a chemically modified derivative thereof. In particular, antibodies provided herein include immunoglobulin molecules and molecules that contain immunologically active portion(s) of an immunoglobulin molecule, for example, one or more complementarity determining regions (CDRs) of an antibody that binds to TNFR2 and / or CD25. 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., Cell Biophysics, 22:189-224 (1993); Pluckthun 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., IgGl, lgG2, lgG3, lgG4, IgAl and lgA2), or any subclass (e.g., lgG2a and lgG2b) of immunoglobulin molecule.

[0208] 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 naturally 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 scaffolds other than those derived from antibodies. Single domain antibodies may be derived from any species including, but not limited to mouse, human, camel, llama, shark, goat, rabbit, and / or bovine. In some embodiments, a single domain antibody as used herein is a naturally 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 naturally 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, llama, dromedary, alpaca and guanaco. Other species besides Camelidae may produce heavy chain antibodies naturally 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.

[0209] The term "specifically 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 (KD) of about Ix.lO'6M or iess (e.g., less than 1G5M, less than 5xl0'7M, less than 1£T7M, less than 5xl0'sM, less than 10'8M, less than 5xl0‘9M, less than 10‘9M, or less than 1O'WM). Methods for determining the binding affinity of an antigen-binding protein, e.g., an antibody or an antibody fragment, to a target antigen are well 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 cell 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 specifically bind to the analogous target from a different species. For example, specific binding to human TNFR2 does not exclude that the antigen-binding protein can also specifically bind to TNFR2 from cynomolgus monkeys ("cyno") or mouse.

[0210] 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 partially free of other biological molecules from the cells or cell 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 cellular debris and growth medium. An isolated antigen-binding protein may further be at least partially free of expression system components such as biological molecules from a host cell or of the growth medium thereof. Generally, 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, buffers, or salts or to components of a pharmaceutical formulation that includes the antigen-binding proteins (e.g., antibodies, such as single-domain antibodies).

[0211] 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,

[0212] 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 thathas 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 multispecific antigen-binding protein or polypeptide comprising the polypeptide it is a variant or derivative of,

[0213] The term "substantial identity" or "substantially identical," when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 95%, and more preferably at least about 96%, 97%, 98%, or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or Gap, as discussed below. A nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in certain instances, encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.

[0214] As applied to polypeptides, the term "substantial similarity" or "substantially similar" means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 95% sequence identity, even more preferably at least 98% or 99% sequence identity. Preferably, residue positions which are not identical differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making thisadjustment are well-known to those of skill in the art, See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331, herein incorporated by reference. Examples of groups of amino acids that have side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartate and glutamate, and (7) sulfur- containing side chains are cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamateaspartate, and asparagine-giutamine. 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.

[0215] Sequence similarity for polypeptides, which is also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions, and other modifications, including conservative amino acid substitutions. For instance, GCG software contains programs such as Gap and Bestfit which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild-type protein and a mutein thereof. See, e.g., GCG Version 6.1. Polypeptide sequences also can be compared using FASTA using default or recommended parameters, a program in GCG Version 6.1. FASTA (e.g,, FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence of the disclosure to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402, each herein incorporated by reference.[021S]The terms "enhance" or "promote / ' or "increase," or "expand," or "improve" refer generally to the ability of a composition contemplated herein to produce, elicit, or cause a greater physiological response (i.e., downstream effects) compared to the response caused by either vehicle or a control molecule / composition. A measurable physiological response may include an increase in immune cell expansion, activation, effector function, persistence, and / or an increase in tumor celi death killingability, among others apparent from the understanding in the art and the description herein, in certain embodiments, an "increased" or "enhanced" amount can be a "statistically 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 ail 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.

[0217] The terms "decrease" or "lower," or "lessen," or "reduce," or "abate" refer generally to the ability of composition contemplated herein to produce, elicit, or cause a lesser physiological response (i.e., downstream effects) compared to the response caused by either vehicle or a control molecule / composition. In certain embodiments, a "decrease" or "reduced" amount can be a "statistically 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 all 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.

[0218] The terms "treat” or "treatment" of a state, disease, 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 afflicted with or predisposed to the state, disease, disorder or condition, but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder or condition; or (2) inhibiting the state, disease, disorder or condition, e.g., arresting, reducing or delaying the development of the state, disease, disorder, or condition or a relapse thereof or at least one clinical or sub-clinical symptom of the state, disease, disorder, or condition; or (3) relieving the state, disease, disorder, or condition, e.g., causing regression of the state, disease, disorder or condition or at least one of its clinical or sub-clinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.

[0219] The terms "effective amount" or "therapeutically effective amount" refer to a quantity and / or concentration of a composition containing an active ingredient (e.g., multispecific 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 the progression of the state, disease, disorder, or condition, as, for example, by ameliorating or eliminating symptoms and / or the cause of the state, disease, disorder, or condition. An effective amount may be an amount that relieves, lessens, or alleviates at least one symptom or biological response or effect associated with a state, disease, disorder, or condition, prevents progression of the state, disease, disorder, or condition, or improvesphysical functioning of the patient. A therapeutically effective 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 therapeutically effective amount is also one in which any toxic or detrimental effects of the active agent are outweighed by the therapeutically beneficial effects. A therapeutically effective amount may be delivered in one or more administrations. A therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic and / or prophylactic result.[0220jThe 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.Muitispecific Antigen-Binding Proteins[0221pn one aspect, provided herein are multispecific antigen-binding proteins comprising one or more anti-TNFR2 antigen-binding domains and one or more anti CD25 antigen-binding domains that are linked, directly or indirectly, to one another. The multispecific antigen-binding proteins may comprise one or more additional domains or moieties.

[0222] ln some embodiments, the multispecific antigen-binding protein of the present disclosure may be, for example, bispecific, trispecific, tetraspecific, pentaspecific, etc. The terms "bispecific", "trispecific", "tetraspecific", "pentaspecific", etc., all fall under the term "multispecific" and refer to binding to two, three, four, five, etc., different target molecules, respectively. In specific embodiments, the multispecific antigen-binding protein of the present disclosure are bispecific.

[0223] ln some embodiments, the multispecific antigen-binding protein of the present disclosure comprises one or more anti-TNFR2 antigen-binding domains (e.g., single-domain antibodies) and one or more anti CD25 antigen-binding domains (e.g., single-domain antibodies) as described herein. In some embodiments, the multispecific antigen-binding protein is multivalent. For example, the multispecificantigen-binding protein or conjugate of the present disclosure may be at least bivalent, but can also be e.g., trivalent, tetravalent, pentavalent, hexavalent, septivalent, octavalent, etc. The multispecific antigen-binding protein can be bivalent, trivalent, tetravalent, pentavalent, hexavalent, septivalent, or octa va Sent for the different antigens. The terms "bivalent", "trivalent", "tetravaient", "pentavalent", "hexavalent", "septivalent", "octavalent" all fall under the term "multivalent" and indicate the presence of two, three, four, five six, seven, or eight binding domains (e.g., single-domain antibodies), respectively.

[0224] ln some embodiments, the multispecific antigen-binding protein can comprise two or more anti- TNFR2 antigen-binding domains and two or more anti-CD25 binding domains. In some embodiments, the multispecific antigen-binding protein can comprise four or more anti-TNFR2 antigen-binding domains and two or more anti-CD25 binding domains. In some embodiments, the multispecific antigenbinding protein can comprise six or more anti-TNFR2 antigen-binding domains and two or more anti- CD25 binding domains.

[0225] ln some embodiments, the multispecific antigen-binding protein of the present disclosure comprises a single polypeptide. In other embodiments, the multispecific antigen-binding protein or conjugate of the present disclosure comprises more than one polypeptide. In some embodiments, the multispecific antigen-binding protein of the present disclosure comprises two polypeptides.

[0226] ln some embodiments, the multispecific antigen-binding protein can comprise an anti-TNFR2 antigen-binding domain operably connected to an anti-CD25 antigen-binding domain.

[0227] ! n certain embodiments, the one or more additional domain or moieties may be one or more additional binding domain that binds to one or more further antigen or protein.

[0228] When two or more anti-TNFR2 antigen-binding domains are included in a multispecific antigenbinding protein, the two or more anti-TNFR2 antigen-binding domains may comprise the same sequence or may comprise different sequences. In such embodiments, the two or more anti-TNFR2 antigenbinding domains may bind to the same epitope on TNFR2 or different epitopes on TNFR2. For example, a multispecific antigen-binding protein or conjugate of the present disclosure may be biparatopic, e.g., if two VHHs bind two different epitopes on TNFR2.[0229jln various embodiments, multispecific antigen-binding protein of the present disclosure can comprise two or more anti-TNFR2 antigen-binding domains each comprising an amino acid sequence selected from any of the CDR1, CDR2, and / or CDR3 amino acid sequences listed in Table 1-1, Table 5, Table 11, or Table 13, or any combination thereof, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity, or any combination thereof. In various relatedembodiments, multispecific antigen-binding protein of the present disclosure can comprise two or more anti-TNFR2 antigen-binding domains each comprising a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within any of the exemplary anti-TNFR2 VHH antibodies listed in Table 1-1, Table 1-2, Table 5, Table 11, or Table 13. In some embodiments, the two or more anti-TNFR2 antigen-binding domains can comprise the same set of three CDRs. in some embodiments, the two or more anti-TNFR2 antigenbinding domains can comprise different sets of three CDRs.

[0230] When two or more anti-CD25 antigen-binding domains are included in a multispecific antigenbinding protein or conjugate, the two or more anti-CD25 antigen-binding domains may comprise the same sequence or may comprise different sequences. In such embodiments, the two or more anti-CD25 antigen-binding domains may bind to the same epitope on CD25 or different epitopes on CD25. For example, a multispecific antigen-binding protein or conjugate of the present disclosure may be biparatopic, e.g., if two VHHs bind two different epitopes on CD25.

[0231] ln various embodiments, multispecific antigen-binding protein of the present disclosure can comprise two or more anti-CD25 antigen-binding domains each comprising an amino acid sequence selected from any of the CDR1, CDR2, and / or CDRS amino acid sequences listed in Table 1-3 or Table 9, or any combination thereof, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity, or any combination thereof. In various related embodiments, multispecific antigen-binding protein of the present disclosure can comprise two or more anti-CD25 antigen-binding domains each comprising a set of three CDRs (i.e., CDR1-CDR2-CDR3) contained within any of the exemplary anti-CD25 VHH antibodies listed in Table 1-3, Table 1-4, or Table 9. In some embodiments, the two or more anti-CD25 antigen-binding domains can comprise the same set of three CDRs. In some embodiments, the two or more anti-CD25 antigen-binding domains can comprise different sets of three CDRs.

[0232] Exemplary designs of bispecific constructs comprising one or more anti-TNFR2 binding domain (e.g., VHHs) and one or more anti-CD25 binding domain (e.g., VHHs) are shown in Figure SOA.[O233]8n some embodiments, a multispecific antigen-binding protein of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the following structure from N- terminus to C-terminus: (anti-TNFR2 VHH)n- first linker - Fc region- second linker - (anti-CD25 VHH)m, wherein n and m can independently be any integral number (e.g., 1, 2, 3, 4, 5, etc.). When n>2, each anti-TNFR2 VHH may be optionally operably linked to another anti-TNFR2 VHH via a linker. When m>2, each anti-TNFR2 VHH may be optionally operably linked to another anti-TNFR2 VHH via a linker. Themultiple linkers used in the multispecific antigen-binding protein are not necessarily the same or different.

[0234] ln some embodiments, a multispecific antigen-binding protein or conjugate of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the following structure from N-terminus to C-terminus: (anti-CD25 VHH)n- first linker- Fc - second linker - (anti-TNFR2 VHH)m, wherein n and m can independently be any integral number (e.g., 1, 2, 3, 4, 5, etc.). When n>2, each anti-CD25 VHH may be optionally operably linked to another anti-CD25 VHH via a linker. When m>2, each anti-TNFR2 VHH may be optionally operably linked to another anti-TNFR2 VHH via a linker. The multiple linkers used in the multispecific antigen-binding protein are not necessarily the same or different.

[0235] ln some embodiments, a multispecific antigen-binding protein of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the following structure from N- terminus to C-terminus: (anti- CD25 VHH)i- (anti~TNFR2 VHH)n- first linker - Fc region- second linker - (anti-TNFR2 VHH)m, wherein I, n, and m can independently be any integral number (e.g., 1, 2, 3, 4, 5, etc.). The adjacent anti- CD25 VHH and anti-TNFR2 VHH may be optionally operably linked to one another via a linker. When I >2, each anti- CD25 VHH may be optionally operably linked to another anti- CD25 VHH via a linker. When n>2, each anti-TNFR2 VHH may be optionally operably linked to another anti-TNFR2 VHH via a linker. When m>2, each anti-TNFR2 VHH may be optionally operably linked to another anti-TNFR2 VHH via a linker. The multiple linkers used in the multispecific antigen-binding protein are not necessarily the same or different.

[0236] ln some embodiments, a multispecific antigen-binding protein of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the following structure from N- terminus to C-terminus: (anti-TNFR2 VHH)r (anti-CD25 VHH)n- first linker - Fc region- second linker - (anti-TNFR2 VHH)m, wherein I, n, and m can independently be any integral number (e.g., 1, 2, 3, 4, 5, etc.). The adjacent anti-TNFR2 VHH and anti-CD25 VHH may be optionally operably linked to one another via a linker. When I >2, each anti-TNFR2 VHH may be optionally operably linked to another anti- TNFR2 VHH via a linker. When n>2, each anti-CD25 VHH may be optionally operably linked to another anti-CD25 VHH via a linker. When m>2, each anti-TNFR2 VHH may be optionally operably linked to another anti-TNFR2 VHH via a linker. The multiple linkers used in the multispecific antigen-binding protein are not necessarily the same or different.

[0237] ln a specific embodiment, a multispecific antigen-binding protein of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the following structure from N-terminus to C-terminus: anti-TNFR2 VHH - first linker - Fc region- second linker - anti-CD25 VHH. The multiple linkers used in the multispecific antigen -binding protein are not necessarily the same or different.[O23S]8n a specific embodiment, a multispecific antigen-binding protein of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the following structure from N- terminus to C-terminus: (anti-TNFR2 VHH)?- first linker - Fc region- second linker - anti-CD25 VHH. The two anti-TNFR2 VHHs may be optionally operably linked to each another via a linker. The multiple linkers used in the multispecific antigen-binding protein are not necessarily the same or different. The two anti- TNFR2 VHHs may bind to the same epitope on TNFR2 or different epitopes on TNFR2.

[0239] ln a specific embodiment, a multispecific antigen-binding protein of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the following structure from N- terminus to C-terminus: anti-CD25 VHH - first linker - Fc region- second linker - (anti-TNFR2 VHH)?.. The two anti-TNFR2 VHHs may be optionally operably linked to each another via a linker. The multiple linkers used in the multispecific antigen-binding protein are not necessarily the same or different, The two anti- TNFR2 VHHs may bind to the same epitope on TNFR2 or different epitopes on TNFR2.

[0240] !n a specific embodiment, a multispecific antigen-binding protein of the present disclosure may comprise two polypeptide chains, each polypeptide chain having the following structure from N- terminus to C-terminus: anti-CD2S VHH - anti-TNFR2 VHH - first linker - Fc region- second linker - anti- TNFR2 VHH. The adjacent anti-TNFR2 VHH and anti-CD25 VHH may be optionally operably linked to one another via a linker. The multiple linkers used in the multispecific antigen-binding protein are not necessarily the same or different. The two anti-TNFR2 VHHs may bind to the same epitope on TNFR2 or different epitopes on TNFR2.

[0241] ln some embodiments, the one or more antl-TNFR2 antigen-binding domains (e.g., VHHs) and one or more anti CD25 antigen-binding domains (e.g., VHHs) may be operably linked to one another in tandem. The adjacent antigen-binding domains (e.g., VHHs) may be optionally operably linked to one another via a linker. The linkers may be a flexible Sinker or a rigid linker.

[0242] ln some embodiments, a multispecific antigen-binding protein of the present disclosure may comprise the following structure from N-terminus to C-terminus: (anti-TNFR2 VHH),,-- linker - (anti- CD25 VHH)m, wherein n and m can independently be any integral number (e.g., 1, 2, 3, 4, 5, etc.). When n>2, each anti-TNFR2 VHH may be optionally operably linked to another anti-TNFR2 VHH via a linker. When m>2, each anti-CD25 VHH may be optionally operably linked to another anti-CD25 VHH via alinker. The multiple linkers used in the multispecific antigen-binding protein are not necessarily the same or different.

[0243] Sn some embodiments, a multispecific antigen-binding protein of the present disclosure may comprise the following structure from N-terminus to C-terminus: (anti-CD25 VHH)n- linker - (anti-TNFR2 VHH)m, wherein n and m can independently be any integral number (e.g., 1, 2, 3, 4, 5, etc.). When n>2, each anti-CD25 VHH may be optionally operably linked to another anti-CD25 VHH via a linker. When m>2, each anti-TNFR2 VHH may be optionally operably linked to another anti-TNFR2 VHH via a linker. The multiple linkers used in the multispecific antigen-binding protein are not necessarily the same or different.

[0244] ln some specific embodiments, a multispecific antigen-binding protein of the present disclosure may comprise the following structure from N-terminus to C-terminus: anti-CD25 VHH - linker - (anti- TNFR2 VHH)?.. The two anti-TNFR2 VHHs may bind to the same epitope on TNFR2 or different epitopes on TNFR2. In one embodiment, the linker between anti-CD25 VHH and the adjacent anti-TNFR2 VHH is a flexible linker. In one embodiment, the linker between the two anti-TNFR2 VHH is a rigid linker.

[0245] ln some specific embodiments, a multispecific antigen-binding protein of the present disclosure may comprise the following structure from N-terminus to C-terminus: anti~CD25 VHH - linker - (anti- TNFR2 VHHh. The four anti-TNFR2 VHHs may bind to the same epitope on TNFR2 or different epitopes on TNFR2. In one embodiment, the linker between the anti-CD25 VHH and the adjacent anti-TNFR2 VHH is a flexible linker. In one embodiment, the linker between each of the anti-TNFR2 VHHs is a flexible linker.

[0246] The multispecific antigen-binding protein may also adopt any of the alternative molecular formats shown in Figures 60B-60C and / or described in C. Spiess et al. Molecular Immunology 67 (2015) 95-106, which is Incorporated herein by reference in its entirety.Antigen-binding Domains

[0247] The antigen-binding domains of the present disclosure can include an antibody or an antigenbinding 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 IgGl antibody; an lgG2 antibody; an lgG3 antibody; or an lgG4 antibody, and fragments thereof.

[0248] ln some embodiments, an antigen-binding domain that binds to TNFR2 or CD25 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 (naturally 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 conventionally heterodimeric VH and VL domains, including interface engineering and selection of specific germline families. In some embodiments, sdAbs of the present invention are human or humanized.

[0249] ! n 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 naturally occurring VH domain or engineered VH domain.

[0250] 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 typically contains 4 framework regions interspaced by 3 CDR regions, resulting in the following typical antibody variable domain structure: FR1- CDR1-FR2-CDR2-FR3-CDR3-FR4. CDRs and / or FRs of the single-domain antibody of the present disclosure may be fragments or derivatives from a naturally occurring antibody variable domain or may be synthetic.

[0251] Binding affinity of a molecular Interaction between two molecules, e.g., for an antigen recognized by a multispecific antigen as described herein, 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 cell sorting (FACS), or flow cytometry binding assays and the like. Surface plasmon resonance is a biosensor technique that allows 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 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 ISA system. Another biosensor technique that can be used to determine affinities of biomolecular interactions is bio-layerinterferometry (Bid) (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 affinities can be determined. BLI can for example be performed using the Octet® Systems. Alternatively, affinities 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 affinity and kinetics of unmodified molecules. Equilibrated solutions of an antibody / antigen complex are passed over a column with beads precoated with antigen (or antibody), allowing 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).Anti-TNFR2 Antigen-binding Domain

[0252] The present disclosure provides one or more antigen binding domains (e.g., antibodies, such as single-domain antibodies) that bind to tumor necrosis factor receptor 2 (TNFR2).

[0253] TNFR2 is a single pass type-1 membrane protein belonging to the TNFR superfamily. It consists of an extracellular domain with four cysteine rich domains (CRD) and an intracellular domain that is involved in signaling. The cysteine rich domains contain a total of 10 disulfide bonds stabilizing the elongated structure of the protein. Unlike TNFR1 which is widely expressed, the expression of TNFR2 is restricted on immune cells including Tregs, myeloid cells, CD8 and NK cells but also glial cells, endothelial cells and fibroblasts (Medler and Wajant, 2019).

[0254] ln some embodiments, the human TNFR2 protein is encoded by the human TNF receptor superfamily member IB (TNFRSF1B) gene (NCBI Gene ID: 7133) and has the amino acid sequence of MAPVAVWAALAVGLELWAAAHALPAQVAFTPYAPEPGSTCRLREY¥DQTAQMCCSKCSPGQHAKVFCTKTSDTVCD SCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCAL5KQEGCRLCAPLRKCRPGFGVARPG TETSDWCKPCAPGTFSNTTSSTDICRPHQICNWAIPGNASMDAVCTSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPE PSTAPSTSFLLPMGPSPPAEGSTGDFALPVGLIVGVTALGLLIIGWNCVIMTQVKKKPLCLQREAKVPHLPADKARGTQ GPEQQHLLITAPSSSSSSLESSASALDRRAPTRNQPQAPGVEASGAGEARASTGSSDSSPGGHGTQVNVTCIVNVCSSS DHSSQCSSQASSTMGDTDSSPSESPKDEQVPFSKEECAFRSQLETPETLLGSTEEKPLPLGVPDAGMKPS (UniProtKB Accession No. P20333) (SEQ ID NO: 4028)

[0255] I n some embodiments, the cyno TNFR2 protein is encoded by the Cyno TNF receptor superfamily member IB (TNFRSF1B) gene (Gene ID: 102144224) and has the amino acid sequence of MVTRRGGDDRRRLKGHRVLGVTLEVLARRCWGGRVGGPAEAGEGRGGGVSKAGWPRPAPPRCLASGPLQRGLSLS VAAGWRAQRSLGRRRCAARARGREGRGNRIPPAPMAPAAVWAALAVGLELWAAGHALPAQVAFTPYAPEPGGTCR LREYYDQTAQMCCSKCPPGQHAKVFCTKTSDTVCDSCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRIC TCRPGWYCALSKQEGCRLCAQLRKCRPGFGVARPGTETSDWCKPCAPGTFSNTTSSTDICRPHQICHWAIPGNASM DAVCTSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPAPSTAPGTSFLLPVGPSPPAEGSTGDIVLPVGLIVGVTALGLLIIG WNCVIMTQVKKKPLCLQRETKVPHLPADKARGAQGPEQQHLLTTVPSSSSSSLESSASALDRRAPTRNQPQAPGAEK ASGAGEARASTGSSDSSPGGHGTQVNVTCIVNVCSSSDHSSQCSSQASSTMGDTDASPSGSPKDEQVPFSKEECAFRS QLETPETLLGSTEEKPLPLGVPDAGMKPS (UniProtKB Accession No. A0A2K5VET2) (SEQ ID NO: 4029)

[0256] ln some embodiments, the mouse TNFR2 protein is encoded by the mouse TNF receptor superfamily member IB (Tnfrsflb) gene (Gene ID: 21938) and has the amino acid sequence of MAPAALWVALVFELQLWATGHTVPAQWLTPYKPEPGYECQISQEYYDRKAQMCCAKCPPGQYVKHFCNKTSDTVC ADCEASMYTQVWNQFRTCLSCSSSCTTDQVEIRACTKQQNRVCACEAGRYCALKTHSGSCRQCMRLSKCGPGFGVAS SRAPNGNVLCKACAPGTFSDTTSSTDVCRPHRICSILAIPGNASTDAVCAPESPTLSAIPRTLYVSQPEPTRSQPLDQEPG PSQTPSILTSLGSTPIIEQSTKGGISLPIGLIVGVTSLGLLMLGLVNCIILVQRKKKPSCLQRDAKVPHVPDEKSQDAVGLEQ QHLLTTAPSSSSSSLESSASAGDRRAPPGGHPQARVMAEAQGFQEARASSRISDSSHGSHGTHVNVTCIVNVCSSSDHS SQCSSQASATVGDPDAKPSASPKDEQVPFSQEECPSQSPCETTETLQSHEKPLPLGVPDMGMKPSQAGWFDQIAVKV A (UniProtKB Accession No. P25119) (SEQ ID NO: 4030)

[0257] ln various embodiments, antigen-binding domains of the present disclosure have an agonist effect 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 cells. Agonistic TNFR2 binders may promote or increase TNFR2 activation by binding TNFR2, e.g., to induce a conformational change that renders the receptor biologically 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 domains of the present disclosure may be capable of inducing the proliferation of Treg ceils (e.g., CD4+, CD25+, FOXP3+ Treg cells).Agonistic TNFR2 binding domains of the present disclosure may also be capable of suppressing the proliferation of cytotoxic T lymphocytes (e.g., CDB-r T-cells), e.g., through activation of immunomodulatory Treg cells or by directly binding TNFR2 on the surface of an autoreactive cytotoxic T- cell and inducing apoptosis.[025S]ln some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure comprise TNF or a variant thereof.

[0259] ln some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure do not impair the binding of its cognate ligand, tumor necrosis factor (TN F), to TNFR2 upon binding to TNFR2. In some embodiments, anti-TNFR2 antigen-binding domain of the present disclosure do not have overlapping epitopes with TNF or do not bind to the same epitope(s) as TNF. In some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure have overlapping epitopes with TNF or bind to the same epitope(s) as TNF. in some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure upon binding to TNFR2 promote or facilitate TNFR2 oligomerization (in the presence or absence of TNF, respectively). In some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure upon binding to TNFR2 multimerize (e.g., dimerize) the TNFR2 trimers to induce intracellular signaling. In some embodiments, the one or more anti-TNFR2 antigen-binding domains compete with binding of TNF to TNFR2, In some embodiments, the one or more anti-TNFR2 antigenbinding domains have an antagonistic effect upon binding to TNFR2. In some embodiments, the one or more anti-TNFR2 antigen-binding domains do not compete with binding of TNF to TNFR2. In some embodiments, the one or more anti-TNFR2 antigen-binding domains have an agonistic effect upon binding to TNFR2.

[0260] ln some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure may have an agonist effect upon binding to TNFR2 with an ECso from about 0.1 - 1 nM, about 1 - 10 nM, about 10 - 100 nM, about 100 nM - 1 pM, or above 1 pM. In some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure may have an agonist effect upon binding to TNFR2 with an ECso from about 1- 100 nM. In some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure may have an agonist effect upon binding to TNFR2 with an ECso from about 1 - 10 nM or about 10 - 100 nM, In some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure may have an agonist effect upon binding to TNFR2 with an ECso of about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 15 nM, about 20 nM, about 25 nM, about 30 nM, about 35 nM, about 40 nM, about 45 nM, about 50 nM, about 55 nM, about 60 nM, about 65 nM, about 70 nM, about 75 nM, about 80 nM, about 85 nM, about 90 nM, about 95 nM, or about 100 nM.

[0261] ln some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure bind to human TNFR2. In some embodiments, anti-TNFR2 antigen-binding domains (e.g., antibodies such as single-domain antibodies) of the present disclosure may bind to human TNFR2 with a KD of less than about IxlO”6M, for example, less than about 5xl0~7M, less than about 3xl0’7M, less than about1x107M, less than about 3x10sM, less than about 5x108M, less than about 3x108M, less than about1x108M, less than about 8x109M, less than about 5x109M, less than about 3x109M, less than about IxlO"3M, about IxlO’10to IxlO’9M, about IxlO’10to 5xl0~9M, about IxlO’10to IxlO"8IM, about IxlO’10to 5xl0~sM, about IxlO’9to IxlO’8M, about IxlO’9to 5xl0’sM, about IxlO’9to lx IQ"7M, or about IxlO"8to IxlO"7M. 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 Ko of about IxlO'12M to about IxlO”6M. In certain embodiments, antigen-binding proteins (e.g., antibodies such as singledomain antibodies) of the present disclosure may bind to human TNFR2 with a KB of about 1 xiO"8M to about 2.7 xl0“® M.

[0262] ln some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure bind to cynomolgus monkey ("cyno") TNFR2, In some embodiments, anti-TNFR2 antigen-binding domains (e.g., antibodies such as single-domain antibodies) of the present disclosure may bind to cyno TNFR2 with a KB of less than about IxlO"6M, for example, less than about SxlO"7M, less than about 3xl0~7M, less than about IxlO”7M, less than about 8x10“* M, less than about 5xl0~8M, less than about 3xl0”8M, less than about IxlO"8IM, less than about 8xl0"9IM, less than about 5xl0"9IM, less than about 3xl0"9IM, less than about IxlO"9M, about IxlO"10to IxlO"3IM, about IxlO"1'5to 5xl0"sM, about IxlO"10to IxlO"8M, about IxlO"10to SxlO”8M, about IxlO"9to IxlO"8M, about 1x10"® to SxlO"8M, about IxlO"9to IxlO"7M, about IxlO"3to 2x107M, about IxlO"3to 5xl0’7M, about 1x108to IxlO"7M, about IxlO"8to 2xl0"7M, about IxlO"8to 5xl0"7M, or about IxlO"8to IxlO"6M. In certain embodiments, antigenbinding proteins (e.g., antibodies such as single-domain antibodies) of the present disclosure may bind to cyno TNFR2 with a KB of about 1x1012M to about IxlO"6M. 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 Ko of about 3xl0"8M to about 2.4 xlO"6IM.

[0263] ln some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure bind to mouse TNFR2. In some embodiments, antl-TNFR2 antigen-binding domains of the present disclosure may bind to mouse TNFR2 with a KD of less than about IxlO"6IM, far example, less than about 5xl0”7M, less than about 3xl0"7IM, less than about IxlO"7IM, less than about 8x10sM, less than about 5xl0"8IM, less than about 3xl0"8M, less than about IxlO"8IM, less than about 8xl0"9M, less than about 5xl0"9M, less than about 3xl0"9M, less than about IxlO"9M, about IxlO"10to IxlO"9M, about IxlO"10to 5xl0"9IM, about IxlO"10to IxlO"8M, about IxlO"10to 5xl0"8M, about IxlO"9to IxlO"8IM, about IxlO"9to 5xl0~sIM, about IxlO"9to IxlO’7M, about IxlO’9to 2xl0’7IM, about IxlO’9to 5xl0’7IM, about IxlO’8to IxlO”7M, about IxlO’8to 2xl0"7M, about IxlO”8to 5xl0’7M, or about IxlO’8to IxlO”6M. In someembodiments, anti-TNFR2 antigen-binding domains of the present disclosure do not bind to mouse TNFR2.

[0264] ln some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure may bind to TNFR2 with an ECso from about 0.1 - 1 nM, about 1 - 10 nM, about 10 - 100 nM, about 100 nM - 1 pM, or above 1 pM, In some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure may bind to TNFR2 with an ECsofrom about 1- 100 nM. In some embodiments, anti-TNFR2 antigenbinding domains of the present disclosure may bind to TNFR2 with an EC$o from about 1 - 10 nM or about 10 - 100 nM. in some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure may bind to TNFR2 with an ECso of about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 15 nM, about 20 nM, about 25 nM, about 30 nM, about 35 nM, about 40 nM, about 45 nM, about 50 nM, about 55 nM, about 60 nM, about 65 nM, about 70 nM, about 75 nM, about 80 nM, about 85 nM, about 90 nM, about 95 nM, or about 100 nM.

[0265] ln some embodiments, anti-TNFR2 antigen-binding domains of the present disclosure may specifically bind TNFR2 without exhibiting specific binding for another receptor of the tumor necrosis factor receptor (TNFR) superfamily,

[0266] The variable domain of an anti-TNFR2 antigen-binding domain (e.g., antibody such as a singledomain 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 typically contains 4 framework regions interspaced by 3 CDR regions, resulting in the following 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 naturally occurring antibody variable domain or may be synthetic.

[0267] 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 DMA sequences of the full-length camelid VHH antibodies, as well as amino acid sequences of corresponding humanized VHH antibodies. In the present disclosure, the suffix "-Hui" 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 antibodiesTable 1-2. Sequence Identifiers for additional exemplary anti-TNFR2 VHH antibodies and humanized anti-THFR2 VHH antibodies

[0268] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as a singledomain antibody) of the present disclosure comprises a 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); h) GASLSRNA (SEQ ID NO: 40); i) GS(I / T)FRFPP (SEQ ID NO: 74); j) GFTLDDYA (SEQ ID NO: 6633); and k) G(F / V)(S / T)LD(D / Y)(H / Y)T (SEQ ID NO: 7088)

[0269] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g,, antibody such as a singledomain antibody) of the present disclosure comprises a 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) l(Y / F)SY(S / G)(S / P)NT (SEQ ID NO: 76); c) l(Y / S)(S / D)DGS(E / D)T (SEQ ID NO: 77); d) INWSN(G / A)RT (SEQ ID NO: 7268); e) l(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: 6634); k) l(N / S)SNDG(S / T)(T / V) (SEQ ID NO: 7087); and l) INWS(N / Q / E / S)(G / A)RT (SEQ ID NQ:10409).

[0270] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as a singledomain antibody) of the present disclosure comprises a 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)(V / T)GPHDY (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); 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: 6635); k) AAD(L / V)G(F / V / Y)LY(A / T / V)DYV(P / R)LH(M / T)HHFGS (SEQ ID NO: 7086); l) A(A / G)(T / A)(P / L)(S / T)GKAY(T / S)Y (SEQ ID NQ: 7333); and m) A(A / G)(T / A / S)(P / L)(5 / T)GKAY(T / S)Y (SEQ ID NO: 10387), wherein one or more non-alanine residues in the CDR3 sequence are optionally replaced with an alanine, and / or one or more alanine residues in the CDR3 sequence are optionally replaced with a glycine.

[0271] ! n certain embodiments, the CDR3 sequence of an anti-TNFR2 antigen-binding domain (e.g., antibody such as a single-domain antibody) of the present disclosure comprises the amino acid sequence: a). (WV)(A / G)(S / A)(A / P)(A / T / S)(A / G)(A / R)A(A / F)(T / N / A)(A / Y); or b). (A / G)(A / G)(WS)(A / P / L){A / S / T)(A / G)(A / K)(A / G)(A / Y)(A / T / S)(A / Y).

[0272] in certain embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as a singledomain antibody) of the present disclosure comprisesi)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 ofSEQ ID NO: 60; ii)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; iii)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: 7268, 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: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7268, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 7333; vi)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; vii)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; viii)a CDR1 comprising an amino acid sequence of SEQ ID NG: 73, a CDR2 comprising an amino acid sequence of SEQ !D NO: 80, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 66; ix)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; x)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; xi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 6633, a CDR2 comprising an amino acid sequence of SEQ iD NO: 6634, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6635; xii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7088, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7087, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7086; xiii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7268, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10387; xivja CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10409, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10387;xv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10409, 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)(WS)(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 / 6)(S / A)(A / P)(An / S)(A / G)(A / R)A(A / F)(T / N / A)(A / Y).

[0273] ln certain embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as a singledomain 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: 7268, 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: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7268, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7333; - d)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; e)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7268, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10387; f) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10409, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10387; g) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10409, 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 h) 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 / S)(A / G)(A / R)A(A / F){T / N / A)(A / ¥).

[0274] ln certain embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as a singledomain 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: 7270);ii)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 AADSDLSTW(V / T)GPHDY (SEQ ID NO: 7271); iii)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: 7268), and a CDR3 comprising an amino acid sequence of AA(T / A)PSGKAYSY (SEQ ID NO: 7272); v)a CDR1 comprising an amino acid sequence of GRTFSDYG (SEQ ID NQ: 16), a CDR2 comprising an amino acid sequence of INWSN(G / A)RT (SEQ ID NO: 7268), 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: 7333); vi)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); vii)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: 7273); viii)a CDR1 comprising an amino acid sequence of GRTF(G / S)S(Y / L)(T / F) (SEQ ID NO: 7274), 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: 7276); ix)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); x)a CDR1 comprising an amino acid sequence of GS(T / i)FRFPP (SEQ ID NO: 7277), a CDR2 comprising an amino add sequence of LTSGGST (SEQ ID NO: 45), and a CDR3 comprising an amino acid sequence of SVLGRDM(M / V)TY (SEQ ID NO: 7275); xi)a CDR1 comprising an amino acid sequence of GFTLDDYA (SEQ ID NO: 6633), a CDR2 comprising an amino acid sequence of IFSYSSNT (SEQ ID NO: 6634), and a CDR3 comprising an amino add sequence of AVGDFEGELVLKGDY (SEQ ID NO: 6635);xii)a CDR1 comprising an amino acid sequence of GFTLDYYT (SEQ ID NO: 6637), a CDR2 comprising an amino acid sequence of ISSNDGSV (SEQ, iD NO: 6638), and a CDR3 comprising an amino acid sequence of AADLGYLYVDYVRLHTHHFGS (SEQ ID NO: 6639); xiii)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: 7268), and a CDR3 comprising an amino acid sequence of A(A / G)(T / A / S)(P / L)(S / T)GKAY(T / S)Y (SEQ ID NO: 10387); or xiv)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 AADSDLSTW(V / T)GPHDY (SEQ ID NO: 7271).

[0275] ! n certain embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as a singledomain antibody) of the present disclosure comprises 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 AADSDLSTW(V / T)GPHDY (SEQ ID NO: 7271); 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: 7268), and a CDR3 comprising an amino acid sequence of AA(T / A)PSGKAYSY (SEQ ID NO: 7272); c)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: 7268), 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: 7333); d)a CDR1 comprising an amino acid sequence of GRTF(G / S)S(Y / L)(T / F) (SEQ ID NO: 7274), 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: 7276); e)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: 7268), and a CDR3 comprising an amino acid sequence of A(A / G)(T / A / S)(P / L)(S / T)GKAY(T / S)Y (SEQ ID NO: 10387); or f)a CDR1 comprising an amino acid sequence of GFT(F / L)DD(I / Y)A (SEQ ID NO: 69), a CDR2 comprising an amino add sequence of l(Y / F)SY(S / G)(S / P)NT (SEQ ID NO: 76), and a CDR3 comprising an amino acid sequence of AADSDLSTW(V / T)GPHDY (SEQ ID NO: 7271).

[0276] lncluded herein are anti-TNFR2 antigen-binding domains (e.g., antibodies such as single-domain antibodies) comprising a CDR1 (CDR1) comprising an amino add sequence selected from any of theCDR1 ammo acid sequences listed in Table 1-1, Table 5, Table 11, or Table IB, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity.

[0277] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain 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, 6633, 6637, 6641, 7089, 7281-7284, 1128-1686, 6745-6806, and 7102-7125, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity.

[0278] lncluded herein are anti~TNFR2 antigen-binding domains (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 11, or Table 13, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity.

[0279] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g,, antibody such as singledomain 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, 6634, 6638, 6642, 7096, 7285-7288, 1687-2245, 6807-6868, 7126-7149, and 10388-10393, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity.

[0280] lncluded herein are anti-TNFR2 antigen-binding domains (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 11, or Table 13, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity.

[0281] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain 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, 6635, 6639, 6643, 7093, 7099, 2246-2804, 6869-6930, 7150-7173, 7289-7292, 7333, 10374, 10410-10433, 10435-10455, and 10811, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity.

[0282] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR3 comprising an amino acid sequence selected from SEQ ID Nos: 34, 7099, 10410-10433, 10435-10455, and 10811, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity.

[0283] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR3 comprising an amino acid sequence selected from SEQ ID Nos:10414, 10421, 10422, 10423, 10429, and 10811, or a similar sequence thereof having at least 70%, at least 80%, at least 90%, or at least 95% sequence identity.

[0284] lnciuded herein are anti-TNFR2 antigen-binding domains (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 Table 1-1, Table 1-2, Table 5, Table 21, or Table 13. In certain embodiments, an anti-TNFR2 antigen-binding domain (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; ii) a CDR1 comprising an amino acid sequence of SEQ !D 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; iii)a CDR1 comprising an amino acid sequence of SEQ !D 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 CORI 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; vii)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; viii)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 CDRS comprising an amino acid sequence of SEQ ID NO: 42; xii) 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;xiii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 6633, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6634, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6635; xiv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 6637, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6638, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6639; xv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6643; xvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7089, a CDR2 comprising an amino acid sequence of SEQ ID NO: 45, and a CDR3 comprising an amino acid sequence of SEQ !D NO: 46; xvii)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: 7093; xvii i)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, 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: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7099; xx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7285, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289; xxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289; xxii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7285, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7291; xxiii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7291; xxiv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 6633, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6634, 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: 6633, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6634, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7093; xxviija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10388, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289; xxviiija CDR1 comprising an amino add sequence of SEQ ID NO: 16, a CDR2 comprising an amino add sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289;xxix)a CDR1 comprising an amino acid sequence of SEQ iD NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10388, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10374; xxx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10390, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10391, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxiii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10392, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxivja CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10393, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxvja CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10338, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xxxvija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10390, 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: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xxxviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10410; xxxixja CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10411; xl)a CDR1 comprising an amino acid sequence of SEQ. ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10412; xli)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10413; xlii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10414; xliiija CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10415;xilv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10416; xlv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10417; xlvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10418; xlvii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10419; xlviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10420; xlix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10421; l)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10422; li)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10423; lii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10424; liii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10425; livja CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10426; lv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10427;Ivija CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10428; lvii)a CDR1 comprising an amino add sequence of SEQ ID NO: 32, a CDR2 comprising an amino add sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino add sequence of SEQ ID NO: 34;Ivii i)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10429; lixja CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10430;lx)a CDR1 comprising an amino add sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ iD NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10431; lxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ iD NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10432; bcii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ iD NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10433;IxliiJCDRl comprising an amino acid sequence of SEQ iD NO: 32, a CDR2 comprising an amino acid sequence of SEQ iD NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10811; lxiv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10435; lxv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10436; lxvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10437; lxvii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10438;Ixviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10439; lxix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10440; lxx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10441; lxxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10442; ixxii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10443; ixxiiija CDR1 comprising an amino acid sequence of SEQ iD NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10444; ixxivja CDR1 comprising an amino acid sequence of SEQ iD NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10445; lxxv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10446;Ixxvija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10447;Ixxviija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10448; lxxviii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ !D NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10449;Ixxixja CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10450; lxxx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10451; lxxxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10452;Ixxxiija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10453;Ixxxiiija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10454; 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: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10455.

[0285] ! n some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain 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; b)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, 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: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7099;d)a CDR1 comprising an amino acid sequence of SEQ iD NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7285, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 7289; e)a CDR1 comprising an amino acid sequence of SEQ iD NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 7289; f)a CDR1 comprising an amino acid sequence of SEQ iD NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7285, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 7291; g)a CDR1 comprising an amino acid sequence of SEQ iD NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 7291; h)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; i)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: 7093; j)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6643; k)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ iD NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ !D NO: 10414; l) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ iD NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10421; m) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ iD NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10422; n) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ iD NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10423; o) a CDR1 comprising art amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10429; p) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10811; q) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino add sequence of SEQ iD NO: 7096, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10374; r) a CDR1 comprising an amino acid sequence of SEQ ID NO: 6633, a CDR2 comprising an amino add sequence of SEQ ID NO: 6634, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10; or s) a CDR1 comprising an amino acid sequence of SEQ ID NO: 6633, a CDR2 comprising art amino acid sequence of SEQ !D NO: 6634, and a CDR3 comprising an amino add sequence of SEQ ID NO: 7093.

[0286] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain 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: 6642, and a CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 34, 7099, 10410-10433, 10435-10455, and 10811.

[0287] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain 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: 6642, and a CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 10414, 10421, 10422, 10423, 10429, and 10811.

[0288] in a related embodiment, included herein are anti-TNFR2 antigen-binding domainsje.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 11, or Table 13. 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, 6636, S640, 6644, 7090, 10380, 10381, 10383, 10385, 10386, 81-92, 6648, 6649, 6650, 7095, 7098, 7101, 7092, 93-640, 641-1127, 2805-3363, 3364-3922, 6651-6697, 6698-6744, 6931-6992, 7174-7197, 10375, 10382, 10384, 10394-10408, 10457-10502, 10720-10727, and 10812.

[0289] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as a singledomain 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; 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: 6636; n)a variable domain that comprises a CDR1;CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 6640; o)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 6644; p)a variable domain that comprises a CDR1;CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7090; q)a variable domain that comprises a CORI, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7095; r)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7098; s)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7101; t)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 6650; u)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7293; v)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7294;w)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7295; x)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7296; y) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10375; z) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10382; aa) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10384; bb) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10380; cc) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10381; dd) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NG: 10383; ee) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10385; ff) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NG: 10386; gg) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10394; hh) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NG: 10395; ii) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10396; jj) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10397; kk) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NG: 10398;II) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10399;mm) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10400; nn) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10401; oo) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10402; pp) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10403; qq) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10404; rr) a variable domain that comprises a CDR1,. CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10405; ss) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10406; tt) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10407; uu) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10408; w) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10457; ww) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10458; xx) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10459; yy) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10460; zz) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10461; aaa) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10462; bbb) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10463;ccc) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10464; ddd) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10465; eee) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10466; fff) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10467; ggg) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10468; hhh) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10469; iii) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10470; jjj) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10471; kkk) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10472;III) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10473; mmm) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10474; nnn) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino add sequence of SEQ ID NO: 10475; ooo) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10476; ppp) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10477; qqq) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10478; nr) a variable domain that comprises a CDRl, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10479;sss) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10480; ttt) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10481; uuu) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10482; vw) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10483; www) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10484; xxx) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10485; yyy) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10486; zzz) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10487; aaaa) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10488; bbbb) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10489; cccc) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10490; dddd) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10491; eeee) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10492; ffff) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10493; gggg) 3 variable domain that comprises a CDR1;CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10494; hhhh) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10495;iiii) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10496; jjjj) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10497; kkkk) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10498;Illi) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10499; mmmm) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10500; nnnn) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10501; oooo) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10502; pppp) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10720; qqqq) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10721; rrrr) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10722; ssss) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10723; tttt) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10724; uuuu) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10725; vwv) a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10726; 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: 10727.

[0290] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as a singledomain antibody) of the present disclosure can includea)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: 6644; c)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7095; d)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7098; e)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7101; f)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7293; g)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7294; h)a variable domain that comprises a CDR1;CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7295; i)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 7296; j)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10375; k)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10382; l)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10384; m)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10380; n)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10381; o)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10383; p)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10385; orq)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10386; r)a variable domain that comprises a CDR1;CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10394; s)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10395; t)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10396; u)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10397; v)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10398; w)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10399; x)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10400; y)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10401; z)a variable domain that comprises a CDR1?CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10402; aa)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10403; bb)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10404; cc)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10405; dd)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10406; ee)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10407; ff)a variable domain that comprises a CDR1, CDR2?and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10408;ggja variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10457; hh)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10458; ii)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10459; jj)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10460; kk)a variable domain that comprises a CDR1, CDR2?and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10461; ll)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10462; mm)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10463; nn)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10464; oo)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10465; pp)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10466; qq)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10467; rr)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10468; ss)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10469; tt)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10470; uu)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NQ: 10471; vv)a variable domain that comprises a CORI, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10472;ww)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10473; xx)a variable domain that comprises a CDR1;CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10474; yy)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10475; zz)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10476; aaa)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10477; bbb)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10478; ccc)a variable domain that comprises a CDR1;CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10479; ddd)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10480; eee)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10481; fff)a variable domain that comprises a CDR1;CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10482; ggg)a variable domain that comprises a CDR1, CDR2?and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10483; hhh)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10484; iii)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10485; jjj)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10486; kkk)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NQ: 10487; lil)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10488;mmm)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10489; nnn)a variable domain that comprises a CDR1;CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10490; oooja variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10491; ppp)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10492; qqq)a variable domain that comprises a CDR1;CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10493; rrr)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10494; sss)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10495; ttt)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10496; utiuja variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10497; vw)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10498; www)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10499; xxx)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino add sequence of SEQ ID NO: 10500; yyy)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10501; m)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10502; aaaa)a variable domain that comprises a CDR1, COR2,. and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10720; bbbb)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10721;cccc)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10722; dddd)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10723; eeee)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10724; ffff)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10725; gggg)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10726; hhhh)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10727; or iiii)a variable domain that comprises a CDR1, CDR2, and CDR3 contained within a VHH comprising the amino acid sequence of SEQ ID NO: 10812.

[0291] ln an embodiment provided herein, an anti-TNFR2 antigen-binding domain (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, 6636, 6640, 6644, 7090, 93-640, 2805-3363, 6651-6697, 6931-6992, 7174-7197, 7222-7254, 10380, 10381, 10383, 10385, and 10386, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0292] ln an embodiment provided herein, an anti-TNFR2 antigen-binding domain (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, 6636, 6640, 6644, 7090, 7222-7254, 10380, 10381, 10383, 10385, and 10386, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0293] ln an embodiment provided herein, an anti-TNFR2 antigen-binding domain (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, 6648, 6649, 6650, 7092, 7095, 7098, 7101, 7293-7296, 641-1127, 6698-6744, 10375, 10382, 10384, 10394-10408, 10457-10502, 10720-10727, 10812, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%,at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0294] ln an embodiment provided herein, an anti-TNFR2 antigen-binding domain (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: 10461, 10468, 10469, 10470, 10477, and 10812, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0295] ! n an embodiment provided herein, an anti-TNFR2 antigen-binding domain (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, 6644, 6650, 7095, 7098, 7101, 7293-7296, 7222-7254, 10375, 10382, 10384, 10380, 10381, 10383, 10385, and 10386, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0296] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ, ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 6643. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 6650 or 10720. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDR3 comprising an amino add sequence of SEQ ID NO: 6643. In some embodiments, an anti-TNFR2 antigenbinding domain (e.g., antibody such as single-domain antibody) comprises the amino add sequence of SEQ ID NO: 6650 or 10720, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0297] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In someIllembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10388. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289. In some embodiments, an anti~TNFR2 antigenbinding domain (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 !D NO: 10394. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 10388, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10394, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0298] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 7294. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 7294, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0299] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In someembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289. In some embodiments, an anti~TNFR2 antigenbinding domain (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 !D NO: 10395. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10395, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0300] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10388. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10396. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10388, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10396, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0301] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In someembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289. In some embodiments, an anti~TNFR2 antigenbinding domain (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 !D NO: 10397. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 7096, and a CDRS comprising an amino acid sequence of SEQ ID NO: 7289. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10397, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0302] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10398. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10398, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0303] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In someembodiments, an antl-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10388. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. In some embodiments, an antl-TNFR2 antigenbinding domain (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 !D NO: 10399. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 10388, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10399, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0304] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10390. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10400. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10390, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ, ID NO: 10400, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0305] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In someembodiments, an antl-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. In some embodiments, an antl-TNFR2 antigenbinding domain (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 !D NO: 10401. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10401, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0306] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10391. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10402. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10391, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ, ID NO: 10402, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0307] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In someembodiments, an antl-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10392. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. In some embodiments, an antl-TNFR2 antigenbinding domain (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 !D NO: 10403. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 10392, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10403, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0308] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10393. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10404. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10393, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ, ID NO: 10404, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0309] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In someembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10388. In some embodiments, an anti-TNFR2 antigen-binding domain (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 antigenbinding domain (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 !D NO: 10405. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 10388, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10405, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0310] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10390. In some embodiments, an anti-TNFR2 antigen-binding domain (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 antigenbinding domain (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: 10406. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10390, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10406, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0311] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In someembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389. In some embodiments, an anti-TNFR2 antigen-binding domain (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 antigenbinding domain (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 !D NO: 10407. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10407, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0312] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 10391. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10408. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10391, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ, ID NO: 10408, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0313] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In someembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10410. In some embodiments, an anti-TNFR2 antigenbinding domain (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 !D NO: 10457. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDRS comprising an amino acid sequence of SEQ ID NO: 10410. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10457, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0314] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10411. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10458. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10411. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ, ID NO: 10458, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0315] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In someembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10412. In some embodiments, an anti-TNFR2 antigenbinding domain (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 !D NO: 10459. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDRS comprising an amino acid sequence of SEQ ID NO: 10412. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10459, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0316] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10413. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10460. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10413. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ, ID NO: 10460, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0317] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In someembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10414. In some embodiments, an anti-TNFR2 antigenbinding domain (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 !D NO: 10461. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDRS comprising an amino acid sequence of SEQ ID NO: 10414. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10461, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0318] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10415. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10462. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10415. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ, ID NO: 10462, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0319] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In someembodiments, an antl-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10416. In some embodiments, an antl-TNFR2 antigenbinding domain (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 !D NO: 10463. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDRS comprising an amino acid sequence of SEQ ID NO: 10416. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10463, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0320] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10417. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10464. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10417. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ, ID NO: 10464, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.[0321pn some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In someembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10418. In some embodiments, an anti-TNFR2 antigenbinding domain (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 !D NO: 10465. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDRS comprising an amino acid sequence of SEQ ID NO: 10418. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10465, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0322] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10419. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10466. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10419. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ, ID NO: 10466, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0323] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In someembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10420. In some embodiments, an anti-TNFR2 antigenbinding domain (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 !D NO: 10467 or 10721, In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDRS comprising an amino acid sequence of SEQ ID NO: 10420. In some embodiments, an anti-TNFR2 antigenbinding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10467 or 10721, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0324] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10421. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10468 or 10722. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10421. In some embodiments, an anti-TNFR2 antigenbinding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10468 or 10722, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0325] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In someembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10422. In some embodiments, an anti-TNFR2 antigenbinding domain (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 !D NO: 10469 or 10723. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDRS comprising an amino acid sequence of SEQ ID NO: 10422. In some embodiments, an anti-TNFR2 antigenbinding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10469 or 10723, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0326] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10423. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10470 or 10724. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10423. In some embodiments, an anti-TNFR2 antigenbinding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10470 or 10724, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0327] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In someembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10424. In some embodiments, an anti-TNFR2 antigenbinding domain (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 !D NO: 10471 or 10725. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDRS comprising an amino acid sequence of SEQ ID NO: 10424. In some embodiments, an anti-TNFR2 antigenbinding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10471 or 10725, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0323] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10425. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10472. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10425. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10472, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0329] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In someembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10426. In some embodiments, an anti-TNFR2 antigenbinding domain (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 !D NO: 10473. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDRS comprising an amino acid sequence of SEQ ID NO: 10426. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10473, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0330] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10427. In some embodiments, an anti-TNFR2 antigenbinding domain (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: 10474 or 10726. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CORI comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10427. In some embodiments, an anti-TNFR2 antigenbinding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10474 or 10726, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0331] ln some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In someembodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as singie-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. in some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR3 comprising an amino acid sequence of SEQ ID NO: 10428. In some embodiments, an anti-TNFR2 antigenbinding domain (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 !D NO: 10475. In some embodiments, an anti-TNFR2 antigen-binding domain (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: 6642, and a CDRS comprising an amino acid sequence of SEQ ID NO: 10428. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises the amino acid sequence of SEQ ID NO: 10475, or a similar sequence thereof having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.

[0332] ln some embodiments, an anti~TNFR2 antigen-binding domain (e.g., antibody such as singledomain antibody) comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibody such as single-domain antibody) comprises a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642. In some embodiments, an anti-TNFR2 antigen-binding domain (e.g., antibo...

Claims

□aims1. A multispecific antigen-binding protein comprising: a) one or more antigen-binding domains that specifically bind to tumor necrosis factor receptor 2 (TNFR2); and b) one or more antigen-binding domains that specifically bind to cluster of differentiation 25 (CD25).

2. The multispecific antigen-binding protein of claim 1, wherein the multispecific antigen-binding protein is bivalent, trivalent, tetravalent, pentavalent, hexavalent, septivalent, or octavalent for both antigens.

3. The multispecific antigen-binding protein of claim 1 or claim 2, wherein the multispecific antigenbinding protein comprises at least two, at least four, or at least six TNFR2 antigen-binding domains, and at least two CD25 antigen-binding domains.

4. The multispecific antigen-binding protein of any of claims 1-3, wherein the one or more anti-TNFR2 antigen-binding domains comprise a complementarity determining region 3 (CDR3) comprising an amino acid sequence selected from: 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)(V / T)GPHDY (SEQ. ID NO: 61); c) AKDAG(S / G)WG(T / R)GPFG(Y / F)(E / D)YDY (SEQ ID NO: 62); d) A(A / G)(T / A / S)(P / L)(S / T)GKAY(T / S)Y (SEQ ID NO: 10387); 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); 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: 6635); and k) AAD(L / V)G(F / V / Y)LY(A / T / V)DYV(P / R)LH(M / T)HHFGS (SEQ ID NO: 7086);wherein one or more non-alanine residues in the CDR3 sequence are optionally replaced with an alanine, and / or one or more alanine residues In the CDR3 sequence are optionally replaced with a glycine.

5. The multispecific antigen-binding protein of ciaim 4, wherein the CDR3 of the one or more anti- TNFR2 antigen-binding domains comprises an amino acid sequence a). {T / A / V)(A / G)(S / A)(A / P){A / T / S)(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).

6. The multispecific antigen-binding protein of claim 4, wherein the CDR3 of the one or more anti- TNFR2 antigen-binding domains comprises an amino acid sequence selected from SEQ ID NOs: 3, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 63, 6635, 6639, 6643, 7093, 7099, 7289-7292, 7333, 10374, 10410-10433, 10435-10455, and 10811.

7. The multispecific antigen-binding protein of any of claims 1-6, wherein the one or more anti-TNFR2 antigen-binding domains further comprise a CDR1 comprising an amino acid sequence selected from: a) GS!(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); h) GASLSRNA (SEQ ID NO: 40); i) GS(I / T)FRFPP (SEQ ID NO: 74); and k). G(F / V)(S / T)LD(D / Y)(H / Y)T (SEQ ID NO: 7088).

8. The multispecific antigen-binding protein of claim 7, wherein the CDR1 of the one or more anti- TNFR2 antigen-binding domains comprises an amino acid sequence selected from SEQ ID NOs: 1, 5, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 6633, 6637, 6641, 7089, and 7281-7284.

9. The multispecific antigen-binding protein of any one of claims 1-8, wherein the one or more anti- TNFR2 antigen-binding domains further comprise a CDR2 comprising an amino acid sequence selected from: a) IRSDGF(T / I) (SEQ ID NO: 75); b) l(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) INWS(N / Q / E / S)(G / A)RT (SEQ ID NO: 10409); e) l(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);and j) l(N / S)SNDG(S / T)(T / V) (SEQ ID NO: 7087).

10. The multispecific antigen-binding protein of claim 9, wherein the CDR2 of the one or more anti- TNFR2 antigen-binding domains comprises an amino acid sequence selected from SEQ ID Nos: 2, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 6634, 6638, 6642, 7096, 7268, 7285-7288, and 10388-10393.

11. The multispecific antigen-binding protein of any one of claims 4, 7, and 9, wherein the one or more anti-TNFR2 antigen-binding domains comprise 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; ii) 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; iii) 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: 10409, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10387; 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; vii) 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; x) 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; 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: 6633, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6634, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6635; xi). a CDR1 comprising an amino acid sequence of SEQ ID NO: 7088, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7087, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7086; xii). a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10409, 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 xiii) , 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 / S)(A / G)(A / R)A(A / F)(T / N / A){A / Y).12, The multispecific antigen-binding protein of claim 11, wherein the one or more anti-TNFR2 antigenbinding domains comprise 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: 7263, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10387; 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: 7263, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 63; or e) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7263, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7333,13. The multispecific antigen-binding protein of any one of claims 4, 7, 9, and 11, wherein the one or more anti-TNFR2 antigen-binding domains comprise 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: 7270); ii) 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 AADSDLSTW(V / T)GPHDY (SEQ ID NO: 7271); iii) 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: 7268), and a CDR3 comprising an amino acid sequence of A(A / G)(T / A / S)(P / L)(S / T)GKAY(T / S)Y (SEQ ID NO: 10387); 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)P¥EY(N / G)Y (SEQ ID NO: 7273); vii) a CDR1 comprising an amino acid sequence of GRTF(G / S)S(Y / L)(T / F) (SEQ ID NO: 7274), 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: 7276); x) 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: 7277), 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: 7275);x) a CORI comprising an amino acid sequence of GFTLDDYA (SEQ ID NO: 6633), a CDR2 comprising an amino acid sequence of IFSYSSNT (SEQ ID NO: 6634), and a CDR3 comprising an amino acid sequence of AVGDFEGELVLKGDY (SEQ ID NO: 6635); or xi) a CDR1 comprising an amino acid sequence of GFTLDYYT (SEQ ID NO: 6637), a CDR2 comprising an amino acid sequence of ISSNDGSV (SEQ ID NO: 6638), and a CDR3 comprising an amino acid sequence of AADLGYLYVDYVRLHTHHFGS (SEQ ID NO: 6639).

14. The multispecific antigen-binding protein of claim 11 or claim 12, wherein the antigen-binding protein comprise comprises a) 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 l(Y / F)SY(S / G)(S / P) NT (SEQ ID NO: 76), and a CDR3 comprising an amino acid sequence of AADSDLSTW(V / F)GPHD¥ (SEQ ID NO: 7271); 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: 7268), and a CDR3 comprising an amino acid sequence of A(A / G)(T / A / S)(P / L)(S / T)GKAY(T / S)Y (SEQ ID NO: 10387); or c) a CDR1 comprising an amino acid sequence of GRTF(G / S)S(Y / L)(T / F) (SEQ ID NO: 7274), 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: 7276).

15. The multispecific antigen-binding protein of any one of claims 1-14, wherein the one or more anti-TNFR2 antigen-binding domains comprise: 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; ii) 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; iii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 8, a CDR2 comprising an amino acid sequence of SEQ ID NQ: 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; vii) 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; viii) 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; xii) 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; xiii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 6633, a CDR2 comprising an amino acid sequence of SEQ iD NO: 6634, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6635; xiv). a CDR1 comprising an amino acid sequence of SEQ ID NO: 6637, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6638, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6639; xv). a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6643; xvi) . a CDR1 comprising an amino acid sequence of SEQ ID NO: 7089, 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; xvii). 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: 7093; xviii). a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, 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: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7099; xx). a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7285, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289;xxi), a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289; xxi i) . a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7285, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7291; xxiii). a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ !D NO: 7291; xxiv). a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxv). a CDR1 comprising an amino acid sequence of SEQ ID NO: 6633, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6634, 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: 6633, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6634, and a CDR3 comprising an amino acid sequence of SEQ !D NO: 7093; xxviija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10388, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289; xxviii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289; xxix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10388, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10390, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10391, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxiiija CDR1 comprising an amino acid sequence of SEQ ID NO: 1S, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10392, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxiv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10393, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; xxxv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino add sequence of SEQ ID NO: 10338, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18;xxxvija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10390, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xxxviija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 18; xxxviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10410; xxxixja CDR1 comprising an amino acid sequence of SEQ ID NQ: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10411; xl)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10412; xli)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10413; xlii)a CDR1 comprising an amino acid sequence of SEQ ID NQ: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10414; xliiija CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10415; xliv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10416; xlv)a CDR1 comprising an amino acid sequence of SEQ ID NQ: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10417; xlvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10418; xlviija CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10419; xlviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10420; xlix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10421; l)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10422;li)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10423; lii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10424; liiija CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10425; liv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10426; lv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10427; lvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10428; lvii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 34; lviii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10429; lix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10430; lx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10431; lxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10432; lxii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10433;Ixiii) CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10811; lxiv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10435; lxv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10436;lxvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10437; lxvii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10438; ixviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10439;Ixvixja CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10440; ixx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10441; lxxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10442;Ixxiija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10443;Ixxilija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10444; lxxiv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10445; lxxv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NQ: 10446; lxxvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10447; lxxvii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10448;Ixxviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10449; lxxvix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ ID NO:lxxx)a CDR1 comprising an amino acid sequence of SEQ iD NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10451; lxxxi)a CDR1 comprising an amino acid sequence of SEQ iD NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10452; ixxxiija CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10453;Ixxxiiija CDR1 comprising an amino acid sequence of SEQ iD NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10454; orIxxxivja CDR1 comprising an amino acid sequence of SEQ iD NO: 16, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10389, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10455.

16. The multispecific antigen-binding protein of any one of claims 1-15, wherein the one or more anti-TNFR2 antigen-binding domains comprise 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; b) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, 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: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7099; d) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7285, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289; e) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7289; f) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino add sequence of SEQ ID NO: 7285, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7291; g) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7291;h) 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; i) 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: 7093; j) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6643; k) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10414; l) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10421; m) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10422; n) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10423; o) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10429; p) a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6642, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10811; q) a CDR1 comprising an amino acid sequence of SEQ ID NO: 16, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7096, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10374; r) a CDR1 comprising an amino acid sequence of SEQ ID NO: 6633, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6634, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10; or s) a CDR1 comprising an amino acid sequence of SEQ ID NO: 6633, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6634, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7093,17. The multispecific antigen-binding protein of any one of claims 1-3, wherein the one or more anti- TNFR2 antigen-binding domains comprise a CDR1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 1128-1686, 6745-6806, and 7102-7125; a CDR2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 1637-2245, 6807-6863, and 7126-7149; and / or a CDR3 comprising an amino acid sequence selected from any one of SEQ ID NOs: 2246-2804, 6869- 6930, and 7150-7173.

18. The multispecific antigen-binding protein of any one of claims 1-17, wherein the one or more anti- TNFR2 antigen-binding domains comprise at least one anti-TNFR2 single-domain antibody.

19. The multispecific antigen-binding protein of claim 18, wherein the anti~TNFR2 single-domain antibody is an anti-TNFR2 VHH, an anti-TNFR2 VNAR, or an anti-TNFR2 VH domain.

20. The multispecific antigen-binding protein of claim 19, wherein the anti-TNFR2 VHH is a camelid anti- TNFR2 VHH.

21. The multispecific antigen-binding protein of claim 20, wherein the anti-TNFR2 VHH comprises an amino acid sequence selected from any one of SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 93-640, 2805-3363, 6636, 6640, 6644, 7090, 6651-6697, 6931-6992, 7174-7197, 10380, 10381, 10383, 10385, and 10386, or a sequence having at least 75% identity thereto.

22. The multispecific antigen-binding protein of claim 20 or 21, wherein the anti-TNFR2 VHH comprises an amino acid sequence selected from any one of SEQ ID NOs: 4, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43 47, 6636, 6640, 6644, 7090, 10380, 10381, 10383, 10385, and 10386, or a sequence having at least 75% identity thereto,23. The multispecific antigen-binding protein of claim 19, wherein the anti-TNFR2 VHH is a humanized anti-TNFR2 VHH.

24. The multispecific antigen-binding protein of claim 23, wherein the humanized anti-TNFR2 VHH comprises an amino acid sequence selected from any one of SEQ ID NOs: 81-92, 6648, 6649, 6650, 7092, 7095, 7098, 7101,7293-7296, 641-1127, 6698-6744, 10375, 10382, 10384, 10394-10408, 10457-10502, 10720-10727, and 10812, or a sequence having at least 75% identity thereto.

25. The multispecific antigen-binding protein of claim 24, wherein the humanized anti-TNFR2 VHH comprises an amino acid sequence selected from any one of SEQ ID NOs: 81-92, 6648, 6649, 6650,7092, 7095, 7098, 7101, 7293-7296, 10375, 10382, 10384, 10394-10408, 10457-10502, 10720-10727, and 10812, or a sequence having at least 75% identity thereto. , The multispecific antibody of any of ciaims 1-3, wherein the one or more antigen-binding domains that specifically bind to TNFR2 comprise TNF or a variant thereof. , The multispecific antigen-binding protein of any one of claims 1-26, wherein the one or more anti- TNFR2 antigen-binding domains have an agonist effect upon binding to TNFR2. , The mu Itispecif ic antigen-binding protein of claim 27, wherein the one or more anti-TNFR2 antigenbinding domains have an agonist effect upon binding to TNFR2 with an ECso of about 1-100 nM. , The multispecific antigen-binding protein of any one of claims 1-28, wherein the one or more anti- TNFR2 antigen-binding domains bind to human TNFR2. , The multispecific antigen-binding protein of claim 29, wherein the one or more anti-TNFR2 antigenbinding domains bind to human TNFR2 with a Ko of less than about 3xl0'6M. , The multispecific antigen-binding protein of claim 30, wherein the one or more anti-TNFR2 antigenbinding domains bind to human TNFR2 with a fo of about IxiO"10to 5x10sM. , The multispecific antigen-binding protein of any one of claims 1-28, wherein the one or more anti- TNFR2 antigen-binding domains bind to cyno TNFR2. , The multispecific antigen-binding protein of ciaim 32, wherein the one or more anti-TNFR2 antigenbinding domains bind to cyno TNFR2 with a KD of less than about 3xl0"6M. , The multispecific antigen-binding protein of claim 33, wherein the at least one or more anti-TNFR2 antigen-binding domains bind to cyno TNFR2 with a Ka of about IxlO"9to 2xl0”7M.

35. The multispecific antigen-binding protein of any one of claims 1-34, wherein the one or more anti- TNFR2 antigen-binding domains bind to the same epitope(s) on TNFR2 as antibody clone MR2-1.

36. The multispecific antigen-binding protein of any one of claims 1-35, wherein the one or more anti- TNFR2 antigen-binding domains do not bind to the same epitope(s) on TNFR2 as antibody clone MR2-1.

37. The multispecific antigen-binding protein of any one of claims 1-36, wherein the one or more anti- TNFR2 antigen-binding domains increase 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.

33. The multispecific antigen-binding protein of any one of claims 1-37, wherein the one or more anti- TNFR2 antigen-binding domains comprise one or more modifications that reduce binding of said TNFR2 antigen-binding domain by pre-existing antibodies found in human blood or serum.

39. The multispecific antigen-binding protein of any one of claims 19-38, wherein the anti-TNFR2 singledomain antibody comprises one or more modifications at the amino-terminus and / or the carboxyterminus.

40. The multispecific antigen-binding protein of claim 39, wherein the anti-TNFR2 single-domain antibody comprises the amino acid sequence VP AG (SEQ, ID NO: 7267) or VAGG (SEQ ID NO: 7266) at the carboxy-terminus starting from position 111 according to Chothia.

41. The multispecific antigen-binding protein of claim 39 or 40, wherein the anti-TNFR2 single-domain antibody comprises a substitution of amino acid residue Glu with Asp (EID) at the first position of the amino-terminus,42. The multispecific antigen-binding protein of any one of claims 1-41, wherein the one or more anti- TNFR2 antigen-binding domains bind to the same epitope on TNFR2.

43. The multispecific antigen-binding protein of any one of claims 1-41, wherein the one or more anti- TNFR2 antigen-binding domains bind to different epitopes on TNFR2.

44. The multispecific antigen-binding protein of any one of claims 1-43, wherein the one or more anti- CD25 antigen-binding domain comprises a complementarity determining region 3 (CDR3) comprising an amino add sequence selected from: a) NAL(G / L / P / Q / W)Y (SEQ ID NO: 4131); b) NALR(D / H / N / F) (SEQ ID NO: 4134); c) (K / S / T)TLRY (SEQ ID NO: 4136); d) (A / V / S)(K / T)G(R / A / K)(G / H / N / R)SG(S / G)YYP(W / F / L)(D / E)(D / E)(Y / V) (SEQ ID NO: 10219); e) AA(S / T)(D / N / Y / K)(F / V)(L / P)(I / L)A(T / I / A)(T / S / A)IS(A / G)(Y / H)DY (SEQ ID NO: 10308); f) AAYVYPDYYCS(D / E)YVLL(K / R)YDY (SEQ ID NO: 7363); g) NIYR(P / S)QVP(P / S / T)TRYS (SEQ ID NO: 7365); and h) AAKRLGP(M / I / A / L)VH(Q / R)YSLEVLTPLFLDEYDY (SEQ ID NO: 9423), wherein one or more non-alanine residues in the CDR3 sequence are optionally replaced with an alanine, and / or one or more alanine residues in the CDR3 sequence are optionally replaced with a glycine.

45. The multispecific antigen-binding protein of claim 44, wherein the CDR3 comprises an amino acid sequence a).(A / V / S)(A / K / T)(A / G)(A / R / K)(A / G / H / N / R)(A / S)(A / G)(A / S / G)(A / Y)(A / Y)(A / P)(A / W / F / L)(A / D / E)(A / D / E )(A / Y / V); or b). (A / G)(A / G)(A / K)(A / R)(A / L)(A / G)(A / P)(M / I / A / L)(A / V)(A / H)(A / R / Q)(A / Y)(A / S)(A / L)(A / E)(A / V) (A / L)(A / T)(A / P)(A / L)(A / F)(A / L)(A / D)(A / E)(A / Y)(A / D)(A / Y).

45. The multispecific antigen-binding protein of claim 44, wherein the CDR3 of the one or more anti- CD25 antigen-binding domains comprises an amino acid sequence selected from SEQ ID NOs: 4103, 4107, 4111, 4115, 4119, 4139, 4141, 5337, 5339, 5371, 5375, 5398, 5401, 5431, 5515, 5519, 5521, 5528, 5532, 5542, 5544, 5545, 5547, 5548, 7344, 7347, 7349, 7350, 7367, 9411-9416, 9436, 9440, 9887, 9966, 9975, 9978, 9979, 9980, and 10504-10544.

47. The multispecific antigen-binding protein of any one of claims 1-46, wherein the one or more anti-CD25 antigen-binding domains further comprises a CDR1 comprising an amino acid sequence selected from: a) GR(K / R / S)FSTU (SEQ ID NO: 4137); b) GFTFS(N / S)YA (SEQ ID NO: 4140); c) GRTF(A / S)(S / W / D)(F / N / Y)G (SEQ ID NO: 10309); d) GFTLDYYA (SEQ ID NO: 7342); and e) G(I / M)P(F / -)(A / -)L(P / V / Y)A (SEQ ID NO: 7366).48, The mu Itispecif ic antigen-binding protein of claim 47, wherein the CDR1 of the one or more anti- CD25 antigen-binding domains comprises an amino acid sequence selected from SEQ ID NOs: 4101,4105, 4109, 4113, 4117, 4132, 4142, 4905, 4909, 4918, 7342, and 7345.

49. The multispecific antigen-binding protein of any one of claims 1-48, wherein the one or more anti- CD25 antigen-binding domains further comprises a CDR2 comprising an amino acid sequence selected from: a) (l / V)(D / E)R(D / G)(D / G)T(A / P / T); b) IYSD(G / S)SGT (SEQ ID NO: 9441); c) IS(Q / R / G)(S / G)GGRT (SEQ ID NO: 10310); d) IS(R / S)(D / S)G(D / G)ST (SEQ ID NO: 7364); e) ISSGGNT (SEQ ID NO: 7346); and f) ISSTDGRT (SEQ ID NO: 7348).50, The multispecific antigen-binding protein of claim 49, wherein the CDR2 of the one or more anti- CD25 antigen-binding domains comprises an amino acid sequence selected from SEQ ID NOs: 4102,4106, 4110, 4114, 4118, (i / V)(D / E)R(D / G)GT(A / P / T), 4135, l(D / E)R(D / G)(D / G)T(P / T), 5042, 5046, 5059, 5067, 5092, 5214, 5215, 5216, 5217, 7343, 7346, 7348, and 9435,51. The multispecific antigen-binding protein of any one of claims 44, 45, 47, and 49, wherein the one or more anti-CD25 antigen-binding domains comprisei) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4137, a CDR2 comprising an amino acid sequence of (l / V)(D / E)R(D / G)(D / G)T(A / P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4131; ii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4137, a CDR2 comprising an amino acid sequence of (l / V)(D / E)R(D / G)(D / G)T(A / P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4134; iii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4137, a CDR2 comprising an amino acid sequence of (l / V)(D / E)R(D / G)(D / G)T(A / P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4136; iv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4137, a CDR2 comprising an amino acid sequence of (l / V)(D / E)R(D / G)GT(A / P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4131; v) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4137, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4135, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4134; vi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4137, a CDR2 comprising an amino acid sequence of l(D / E)R(D / G)(D / G)T(P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4136; viij a CDR1 comprising an amino acid sequence of SEQ ID NO: 4132, a CDR2 comprising an amino acid sequence of (l / V)(D / E)R(D / G)(D / G)T(A / P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4131; viii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino acid sequence of (l / V)(D / E)R(D / G)(D / G)T(A / P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4134; lx) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4132, a CDR2 comprising an amino acid sequence of (l / V)(D / E)R(D / G)GT(A / P / T), and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4131; x) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino add sequence of SEQ ID NO: 4135, and a CDR3 comprising an amino add sequence of SEQ ID NO: 4134; xi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4140, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9441, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10219;xii) a CDRI comprising an amino acid sequence of SEQ ID NO: 4140, a CDR2 comprising an amino acid sequence of SEQ iD NO: 9441, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9440; xiii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4140, a CDR2 comprising an amino acid sequence of SEQ iD NO: 4114, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4139; xiv) a CDR1 comprising an amino acid sequence of SEQ iD NO: 10309, a CDR2 comprising an amino acid sequence of SEQ iD NO: 10310, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10308; xv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4142, a CDR2 comprising an amino acid sequence of SEQ iD NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4141; xvi) a CDRI comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7364, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7363; xvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7366, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7346, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7365; xviii) a CDRi comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9423; xix) a CDRI comprising an amino acid sequence of SEQ iD NO: 7342, a CDR2 comprising an amino acid sequence of SEQ !D NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7367; xx) a CDRI comprising an amino acid sequence of SEQ ID NO: 4140, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9441, and a CDR3 comprising an amino acid sequence of (A / V / S){A / K / T){A / G){A / R / K)(A / G / H / N / R){A / S)(A / G)(A / S / G)(A / Y)(A / Y)(A / P)(A / W / F / L)(A / D / EKA / D / E){A / Y / V); or xxi) a CDRI comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of (A / G)(A / G)(A / K){A / R)(A / L)(A / G)(A / P)(M / I / A / L)(A / V)(A / H){A / R / Q)(A / Y)(A / S)(A / L)(A / E)(A / V)(A / L)(A / T)(A / P )(A / L)(A / F)(A / L){A / D)(A / E)(A / Y)(A / D)(A / Y).

52. The multispecific antigen-binding protein of any one of claims 1-51, wherein the one or more anti- CD25 antigen-binding domains comprise: i) a CDRI comprising an amino acid sequence of SEQ ID NO: 4101, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4102, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4103;ii) a CDR1 comprising an amino add sequence of SEQ ID NO: 4105, a CDR2 comprising an amino add sequence of SEQ ID NO: 410S, and a CDR3 comprising an amino add sequence of SEQ ID NO: 4107; iii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4109, a CDR2 comprising an amino add sequence of SEQ ID NO: 4110, and a CDR3 comprising an amino add sequence of SEQ ID NO: 4111; iv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 4114, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4115; v) a CDR1 comprising an amino add sequence of SEQ ID NO: 4117, a CDR2 comprising an amino add sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4119; vi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7343, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7344; vii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7345, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7346, and a CDR3 comprising an amino acid sequence of SEQ !D NO: 7347; viii) a CDR1 comprising an amino add sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7349; ix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 7350; x) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 9411; xi) a CDR1 comprising an amino add sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 9412; xii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9413; xiii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9414; xiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9415; xv) a CDR1 comprising an amino add sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 9416; xvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 4114, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9975;xvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ iD NO: 4114, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 5431; xviii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ iD NO: 4114, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 9887 xix) a CDR1 comprising an amino acid sequence of SEQ iD NO: 4113, a CDR2 comprising an amino acid sequence of SEQ iD NO: 4114, and a CDR3 comprising an amino acid sequence of SEQ !D NO: 9966; xx) a CDR1 comprising an amino acid sequence of SEQ ID NQ: 4113, a CDR2 comprising an amino acid sequence of SEQ iD NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 9436; xxi) a CDR1 comprising an amino acid sequence of SEQ iD NO: 4113, a CDR2 comprising an amino acid sequence of SEQ iD NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 9978; xxii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ iD NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 9979; xxi si) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ iD NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9980; xxiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino acid sequence of SEQ iD NO: 4110, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5339; xxv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino acid sequence of SEQ iD NO: 5046, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5339; xxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino acid sequence of SEQ iD NO: 5059, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 5337; xxvii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino acid sequence of SEQ iD NO: 5046, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 5337; xxvlii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4101, a CDR2 comprising an amino add sequence of SEQ ID NO: 5067, and a CDR3 comprising an amino add sequence of SEQ ID NO: 5371; xxix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino add sequence of SEQ ID NO: 5046, and a CDR3 comprising an amino add sequence of SEQ ID NO: 5375; xxx) a CDR1 comprising an amino add sequence of SEQ ID NO: 4109, a CDR2 comprising an amino add sequence of SEQ iD NO: 4110, and a CDR3 comprising an amino add sequence of SEQ ID NO: 4111; xxxi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4101, a CDR2 comprising an amino add sequence of SEQ ID NO: 5092, and a CDR3 comprising an amino add sequence of SEQ ID NO: 4111;xxxii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4101, a CDR2 comprising an amino acid sequence of SEQ iD NO: 5092, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5398; xxxiii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4101, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5042, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4111; xxxiv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4105, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5059, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 4111; xxxv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4101, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5042, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5401; xxxvi) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5515; xxxvii) a CDR1 comprising an amino acid sequence of SEQ, ID NO: 4909, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5214, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5519; xxxviii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5216, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5521; xxxix) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4909, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5217, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5519; xl) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4918, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5215, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5528; xii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5532; xlii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino acid sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5542; xliii) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino add sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino add sequence of SEQ ID NO: 5544; xliv) a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino add sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino add sequence of SEQ ID NO: 5545; xiv) a CDR1 comprising an amino add sequence of SEQ ID NO: 4905, a CDR2 comprising an amino add sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino add sequence of SEQ ID NO: 5547; xlvij a CDR1 comprising an amino acid sequence of SEQ ID NO: 4905, a CDR2 comprising an amino add sequence of SEQ ID NO: 4118, and a CDR3 comprising an amino add sequence of SEQ ID NO: 5548;xlvii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ iD NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10504; xlviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ iD NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10505; xlix)a CDR1 comprising an amino acid sequence of SEQ iD NO: 4113, a CDR2 comprising an amino acid sequence of SEQ iD NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ !D NO: 10506; l)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10507; li)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10508; lii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10509; liii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10510; liv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10511; lv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10512; lvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10513; lvii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ iD NO: 9435, and a CDR3 comprising an amino acid sequence of SEQ iD NO: 10514; lviil)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10515; lix)a CDR1 comprising an amino add sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10516; lx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 4113, a CDR2 comprising an amino add sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10517; lxi)a CDR1 comprising an amino add sequence of SEQ ID NO: 4113, a CDR2 comprising an amino acid sequence of SEQ ID NO: 9435, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10518;Ixi i)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10519;Ixiiija CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10520; lxiv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10521; lxv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10522; lxvi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10523;Ixvi i)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10524;Ixviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10525; lxix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 9414; lxx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10526; lxxi)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10527; lxxii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10528;Ixxiiija CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10529;Ixxivja CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10530; lxxv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10531;Ixxvija CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino add sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino add sequence of SEQ ID NO: 10532;Ixxviija CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10533;Ixxviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10534; lxxix)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10535; lxxx)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10536;Ixxxija CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10537; lxxxii)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ !D NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10533;Ixxxiiija CDR1 comprising an amino acid sequence of SEQ iD NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10539;Ixxxivja CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10540; lxxxv)a CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10541;Ixxxvija CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ !D NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10542;Ixxxviija CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ iD NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10543; orIxxxviiija CDR1 comprising an amino acid sequence of SEQ ID NO: 7342, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7348, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 10544,53. The multispecific antigen-binding protein of any one of claims 1-3, wherein the one or more anti- CD25 antigen-binding domains comprise a CDR1 comprising an amino acid sequence selected from any one of SEQ ID NOs: 4726-5030, 7931-8226, and 9660-9770; a CDR2 comprising an amino acid sequence selected from any one of SEQ ID NOs: 5031-5335, 8227-8522, and 9771-9880; and / or aCDR3 comprising an amino acid sequence selected from any one of SEQ ID Nos: 5336-5640, 8523- 8818, and 9881-9991.

54. The multispecific antigen-binding protein of any one of claims 1-53, wherein the one or more anti- CD25 antigen-binding domains comprise at least one anti-CD25 single-domain antibody.

55. The multispecific antigen-binding protein of claim 54, wherein the anti-CD25 single-domain antibody is an anti-CD25 VHH, an anti-CD25 VNAR, or an anti-CD25 VH domain.

56. The multispecific antigen-binding protein of claim 55, wherein the anti-CD25 VHH is a camelid anti- CD25 VHH.

57. The multispecific antigen-binding protein of claim 56, wherein the anti-CD25 VHH comprises an amino acid sequence selected from any one of SEQ ID NOs: 4104, 4108, 4112, 4116, 4120, 4143- 4442, 5641-5945, 7351-7354, 7368-7659, 8819-9114, 9437, 9442-9551, 9992-10102, and 10246- 10276, or a sequence having at least 75% identity thereto.

53. The multispecific antigen-binding protein of claim 56 or 57, wherein the anti-CD25 VHH comprises an amino acid sequence selected from any one of SEQ ID NOs: 4104, 4108, 4112, 4116, 4120, 7351- 7354, 9437, and 10246-10276, or a sequence having at least 75% identity thereto.

59. The multispecific antigen-binding protein of claim 55, wherein the anti-CD25 VHH is a humanized antl-CD25 VHH.

60. The multispecific antigen-binding protein of claim 59, wherein the humanized anti-CD25 VHH comprises an amino acid sequence selected from any one of SEQ ID NOs: 4126-4130, 4443-4725, 7359-7362, 7660-7930, 9417-9422, 9439, 9552-9659, 10214-10245, and 10545-10585, or a sequence having at least 75% identity thereto.

61. The multispecific antigen-binding protein of claim 59, wherein the humanized anti-CD25 VHH comprises an amino acid sequence selected from any one of SEQ ID NOs: 4126-4130, 7359-7362,9417-9422, 9439, 10214-10245, and 1054540585, or a sequence having at least 75% identity thereto.

62. The multispecific antibody of any of claims 1-43, wherein the one or more antigen-binding domains that specifically bind to CD25 comprise IL-2 or a variant thereof.

63. The multispecific antigen-binding protein of any one of claims 1-62, wherein the one or more anti- CD25 antigen-binding domains bind to human CD25.

64. The mu Itispecific antigen-binding protein of claim 63, wherein the one or more anti-CD25 antigenbinding domains bind to human CD25 with a KB of less than about 3.5 xlO”7M.

65. The multispecific antigen-binding protein of ciaim 64, wherein the one or more anti-CD25 antigenbinding domains bind to human CD25 with a KD of about lxlO“10to about 5xl0~8M.

66. The multispecific antigen-binding protein of any one of claims 1-65, wherein the one or more anti- CD25 antigen-binding domains bind to cyno CD25.

67. The multispecific antigen-binding protein of ciaim 66, wherein the one or more anti-CD25 antigenbinding domains bind to cyno CD25 with a KB of less than about IxlO"6M.

68. The multispecific antigen-binding protein of claim 67, wherein the one or more anti-CD25 antigenbinding domains bind to cyno CD25 with a KD of about 1x10sto about 4xl0"7M.

69. The multispecific antigen-binding protein of any one of claims 1-61 and 63-68, wherein the one or more anti-CD25 antigen-binding domains bind to the same epitope(s) on CD25 as IL-2.

70. The multispecific antigen-binding protein of any one of claims 1-61 and 63-69, wherein the one or more anti-CD25 antigen-binding domains compete for binding to CD25 with IL-2 .

71. The multispecific antigen-binding protein of claim 69 or 70, wherein the one or more anti-CD25 antigen-binding domains have an antagonistic effect upon binding to CD25.

72. The muitispecific antigen-binding protein of any one of ciaims 1-61 and 63-71, wherein the one or more anti~CD25 antigen-binding domains do not bind to the same epitope(s) on CD25 as I L-2.

73. The multispecific antigen-binding protein of any one of claims 1-61, 63-68 and 72, wherein the one or more anti-CD25 antigen-binding domains do not compete for binding to CD25 with IL-2.

74. The multispecific antigen-binding protein of any one of claims 1-73, wherein the one or more a nt i- CD25 antigen-binding domains comprise one or more modifications that reduce binding of said antigen-binding domains by pre-existing antibodies found in human blood or serum.

75. The multispecific antigen-binding protein of any one of claims 54-74, wherein the anti-CD25 singledomain antibody comprises one or more modifications at the amino-terminus and / or the carboxyterminus.

76. The multispecific antigen-binding protein of claim 75, wherein the anti-CD25 single-domain antibody comprises the amino acid sequence VPAG (SEQ. ID NO: 7267) or VAGG (SEQ ID NO: 7266) at the carboxy-terminus starting from position 111 according to Chothia.

77. The multispecific antigen-binding protein of claim 75 or 76, wherein the anti-CD25 single-domain antibody comprises a substitution of amino acid residue Glu with Asp (EID) at the first position of the amino-terminus.

78. The multispecific antigen-binding protein of any one of claims 1-77, wherein the one or more anti- CD25 antigen-binding domains bind to the same epitope on CD25.

79. The multispecific antigen-binding protein of any one of claims 1-77, wherein the one or more a nt i-CD25 antigen-binding domains bind to different epitopes on CD25.

80. The multispecific antigen-binding protein of any one of claims 1-79, further comprising at least one antigen-binding domain that binds to another antigen.

81. The multispecific antigen-binding protein of claim 80, wherein the other antigen comprises serum albumin.

82. The multispecific antigen-binding protein of any one of claims 1-81, which further comprises an immunoglobulin Fc region.

83. The multispecific antigen-binding protein of claim 80, wherein the immunoglobulin Fc region is an Fc region of a human immunoglobulin.

84. The multispecific antigen-binding protein of claim 83, wherein the immunoglobulin Fc region is an Fc region of human IgGl, lgG2, lgG3 or lgG4, or a variant thereof.

85. The multispecific antigen-binding protein of claim 84, wherein the immunoglobulin Fc region is an Fc region of human IgGl, or a variant thereof.

86. The multispecific antigen-binding protein of ciaim 85, wherein the Fc region of human IgGl comprises one or more mutations selected from Leu234Ala (L.234A), Leu234Gly (L234G), Leu234Ser (L234S), Leu234Thr (L234T), Leu234Ala (L234A), Leu235Ala (L235A), Leu235Giu (L235E), Leu235Ser (L235S), Leu235Thr (L235T), Leu235Val (L235V), Leu235Gin (L235Q), Giy236Arg (G236R), Met252Tyr (M252Y), Ser254Thr (S254T), Thr256Giu (T256E), Asp265Asn (D265N), Asp265Aia (D265A), Asp270Asn (D270N), Ser298Asn (S298N), Asn297Ala (N297A), Pro329Ala (P329A), Pro239Gly (P329G), Asn325Giu (N325E) and / or Ala327Ser (A327S) according to EU numbering.

87. The multispecific antigen-binding protein of claim 86, wherein the Fc region of human IgGl comprises a set of mutations selected from1JL234A and L235A;2)L234A, L.235A, and P329A;3JD265A, N297A and P329A;4JL234A, L235A, and G237A;5)L234G, L235S, and G236R;6) L234S, L235T, and G236R;7)L234S, L235V, and G236R;8)L234T, L235Q, and G236R;9)L234T, L235T, and G236R;10JL234A, L235A, and P329G; and11JM252Y, S254T, and T256E. , The mu Itispecif ic antigen-binding protein of any one of claims 85-87, the immunoglobulin Fc region is an Fc region of human SgGl comprising L234A, L235A, and P329A. , The multispecific antigen-binding protein of claim 84, wherein the immunoglobulin Fc region is an Fc region of human lgG4, or a variant thereof. , The multispecific antigen-binding protein of claim 89, wherein the Fc region of human lgG4 comprises one or more mutations selected from Ser228Pro (S228P), Leu235Glu (L235E), Leu235Ala (L235A), Phe234Ala (F234A), and / or Pro329Gly (P329G) according to EU numbering. , The multispecific antigen-binding protein of claim 90, wherein the Fc region of human lgG4 comprises a set of mutations selected from1).S228P and L235E;2J.S228P and L235A;3J.S228P, F234A, and L235E;4J.S228P, F234A, and L235A; and5) P329G, S228P, and L235E. , The multispecific antigen-binding protein of any of claims 1-91, wherein the multispecific antigenbinding protein comprises at least one linker, optionally selected from the group consisting of SEQ ID NOs: 3969-4027, and 6261-6362.

93. The multispecific antigen-binding protein of claim 92, wherein the at least one linker is a rigid linker.

94. The multispecific antigen-binding protein of ciaim 93, wherein the at least one rigid linker is selected from the group consisting of PAPAPAPAPAPAPAPAP (SEQ ID NO: 4009), GGGGSPAPAPAPAPAPAPAPAPGGGGS (SEQ ID NO: 4012), GGGGSPAPAPAPAPGGGGS (SEQ ID NO: 6361), GGGGSPAPAPAPAPAPAPAPAPAPAPAPAPGGGGS (SEQ ID NO: 6362), and A(EAAAK)nA (SEQ ID NO: 4027), where n is any integer, e.g., 1, 2, 3, 4, 5, 6, or 7, 8, 9 or 10.

95. The multispecific antigen-binding protein of claim 92, wherein the at least one linker is a flexible linker.

96. The multispecific antigen-binding protein of claim 95, wherein the at least one flexible linker is selected from the group consisting of GnS (SEQ ID NO: 4013), SGn(SEQ ID NO: 4014), where n is any integer, e.g,, 1, 2, 3, 4, 5, 6, or 7, 8, 9 or 10, and (GGGGS)n(SEQ ID NO: 4015), where n is any integer, e.g,, 1, 2, 3, 4, 5, 6, or 7, 8, 9 or 10.

97. The multispecific antigen-binding protein of any of claims 1-96, wherein the multispecific antigenbinding protein comprises the amino acid sequence of any one of SEQ ID NOs: 6401-6520 and 10792-10810, or a sequence having at least 70% identity thereto.

98. A conjugate comprising the multispecific antigen-binding protein of any one of claims 1-97, wherein the multispecific antigen-binding protein is conjugated to a second moiety.

99. The conjugate of claim 98, 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.100.A polynucleotide molecule encoding the muitispecific antigen-binding protein of any one of claims 1-97.101.The polynucleotide molecule of claim 100, which comprises the nucleotide sequence of any one of SEQ ID NOs: 6521-6632 encoding a multispecific antigen-binding protein, or a sequence having at least 70% identity thereto.102.A recombinant vector comprising the polynucleotide molecule of any one of claims 100-101.103.A host cell comprising the polynucleotide molecule of any one of claims 100-101, or the recombinant vector of claim 102.104.A kit comprising the multispecific antigen-binding protein of any one of claims 1-97, the conjugate of any one of claims 98-99, the polynucleotide molecule of any one of claims 100-101, the recombinant vector of claim 102, or the host cell of claim 103, and optionally, instructions and / or packaging for the same.105.A pharmaceutical composition comprising the multispecific antigen-binding protein of any one of claims 1-97, the conjugate of any one of claims 98-99, the polynucleotide molecule of any one of claims 100-101, or the recombinant vector of claim 94, and a pharmaceutically acceptable carrier and / or excipient,106. A method for preparing a multispecific antigen-binding protein that specifically binds TNFR2 and CD25, comprising the steps of:(a) culturing the host cell of claim 103 in a culture medium under conditions suitable for expression of the multispecific antigen-binding protein, and(b) isolating the multispecific antigen-binding protein from the host cell and / or the culture medium.107.A method for promoting proliferation, activating and / or enhancing suppressive function, and / or stabilizing immunosuppressive phenotype of a population of regulatory T cells (Treg) comprising contacting the population of Treg with the multispecific antigen-binding protein of any one of claims 1-97, or the conjugate of any one of claim 98-99. lOS.The method of claim 107, wherein said contacting occurs in vitro.109.The method of claim 107, wherein said contacting occurs in vivo.110.The method of claim 109, wherein the method further comprises administering the multispecific antigen-binding protein or the conjugate into a subject in need thereof.111.A method of treating or preventing a disease or disorder in a subject in need thereof, said method comprising administering to the subject an effective amount of the multispecific antigen-binding protein of any one of claims 1-97, or the conjugate of any one of claim 98-99.112.The method of claim 111, wherein the disease or disorder is an immunological disease, inflammatory disease, cancer, cardiovascular disease, or an infertility and pregnancy-associated disease.113.The method of claim 112, wherein the immunological disease is selected from an autoimmune disease, a neurological condition, an allergy, asthma, macular degeneration, muscular atrophy, a disease related to miscarriage, atherosclerosis, bone loss, a musculoskeletal disease, obesity, a graft- versus-host disease, and an allograft rejection.

114. The method of claim 113, 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, bullous 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, Guillain-Barre, Hashimoto's thyroiditis, hypothyroidism, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, juvenile arthritis, lichen planus, lichen sclerosis, lgG4-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, polymyalgiarheumatics, polymyositis and dermatomyositis, premature ovarian failure, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, primary ovarian insufficiency, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthritis, stiff-man syndrome, type I diabetes, Takayasu arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener's granulomatosis (Granulomatosis with polyangiitis) or other immune vasculitis.IlS.The method of claim 114, wherein the lupus is systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis, neonatal lupus, or drug-induced lupus.IlS.The method of claim 115, wherein the cutaneous lupus is acute cutaneous lupus, chronic cutaneous lupus erythematosus, discoid lupus erythematosus (DIE), or subacute cutaneous lupus erythematosus,IlT.The method of claim 113, 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.118.The method of claim 113, wherein the allergy is selected from food allergy, seasonal allergy, pet allergy, hives, hay fever, allergic conjunctivitis, poison ivy allergy oak allergy, mold allergy, drug allergy, dust allergy, cosmetic allergy, and chemical allergy.119.The method of claim 113, wherein the allograft rejection is selected from skin graft rejection, bone graft rejection, vascular tissue graft rejection, ligament graft rejection, and organ graft rejection.120.The method of claim 119, 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 collateral ligament graft rejection, radial collateral ligament graft rejection, suspensory ligament of the breast graft rejection, anterior sacroiliac ligament graft rejection, posterior sacroiliac ligament graft rejection, sacrotuberousligament graft rejection, sacrospinous ligament graft rejection, inferior pubic ligament graft rejection, superior pubic ligament graft rejection, anterior cruciate ligament graft rejection, lateral collateral ligament graft rejection, posterior cruciate ligament graft rejection, medial collateral ligament graft rejection, cranial cruciate ligament graft rejection, and patellar ligament graft rejection.IZl.The method of claim 119, 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.122.The method of claim 113, wherein the graft-versus-host disease arises from a bone marrow transplant or one or more blood cells selected from B-cells, T-cells, basophils, common myeloid progenitor cells, common lymphoid progenitor cells, dendritic cells, eosinophils, hematopoietic stem cells, neutrophils, natural killer cells, megakaryocytes, monocytes, or macrophages.123.The method of claim 112, wherein the inflammatory disease is acute or chronic inflammation.124, The method of claim 112, wherein the inflammatory disease is selected from osteoarthritis, atopic dermatitis, endometriosis, polycystic ovarian syndrome, inflammatory bowel disease, fibrotic lung disease, and cardiac inflammation.125,The method of claim 112, 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-Dube 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, gallbladder cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, gestationaltrophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary diffuse gastric cancer, hereditary leiomyomatosis and renal cell cancer, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papillary 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~cell prolymphocytic leukemia and hairy ceil leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic T-cell lymphocytic leukemia, eosinophilic leukemia, Li-Fraumeni syndrome, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, hodgkin lymphoma, non- hodgkin lymphoma, lynch syndrome, mastocytosis, medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, multiple myeloma, MUTYH (or M¥H)-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, neuroendocrine tumors, neurofibromatosis type 1, neurofibromatosis type 2, nevoid basal cell carcinoma syndrome, oral and oropharyngeal cancer, osteosarcoma, ovarian, fallopian 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), small 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. .The method of claim 112, 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.127.The method of claim 112, wherein the infertility and pregnancy-associated diseases is selected from recurrent pregnancy loss, pre-eclampsia, preterm labor, fetal growth restriction, and intrauterine growth restriction.

128. A method of regenerating a tissue or organ comprising one or more TNFR2+ and / or CD25+ cells, said method comprising contacting the tissue or organ with an effective amount of the multispecific antigen-binding protein of any one of claims 1-97, or the conjugate of any one of claim 98-99.129.The method of claim 128, 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, small intestine, large intestine, gastrointestinal, lung, brain, skin, peripheral nervous system, central nervous system, spinal cord, breast, embryonic structures, embryo, and testes tissue.130.The method of claim 128 or 129, wherein said contacting occurs in vitro.131.The method of claim 128 or 129, wherein said contacting occurs in vivo.132.The method of claim 131, wherein the method further comprises administering the multispecific antigen-binding protein, or the conjugate into a subject in need thereof.133.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 an effective amount of the multispecific antigen-binding protein of claim 1-97, or the conjugate of any one of claims 98-99.134.The method of claim 133, wherein the foreign agent is a therapeutic protein or peptide, a viral, bacterial, or fungal vector, a biochemical vector, a lipid, carbohydrate, a nucleic acid, a sperm, an oocyte, or an embryo.135.The method of claim 134, wherein the viral vector is a DNA or RNA vector.136.The method of any one of claims 111-127 and 131-135, wherein the subject is a mammal.137,The method of claim 136, wherein the mammal is human.

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