Antagonistic anti-tumor necrosis factor receptor 2 antibodies

1. A humanized, human, or chimeric antibody or antigen-binding fragment thereof capable of specifically binding human TNFR2, wherein the antibody or antigen-binding fragment thereof comprises the following complementarity-determining regions (CDRs):

(I)

(a) a CDR-H1 having the amino acid sequence GYTFTDYX (SEQ ID NO: 257);

(b) a CDR-H2 having the amino acid sequence VDPEYGST (SEQ ID NO: 258);

(c) a CDR-H3 having the amino acid sequence ARDDGSYSPFDYWG (SEQ ID NO: 259);

(d) a CDR-L1 having the amino acid sequence QNINKY (SEQ ID NO: 260);

(e) a CDR-L2 having the amino acid sequence TYS or YTS; and

(f) a CDR-L3 having the amino acid sequence CLQYVNLXT (SEQ ID NO: 261);

or

(II)

(a) a CDR-H1 having the amino acid sequence GFTFSSY (SEQ ID NO: 23);

(b) a CDR-H2 having the amino acid sequence SSGGSY (SEQ ID NO: 24);

(c) a CDR-H3 having the amino acid sequence QRVDGYSSYWYFDV (SEQ ID NO: 25);

(d) a CDR-L1 having the amino acid sequence SASSSVYYMY (SEQ ID NO: 26);

(e) a CDR-L2 having the amino acid sequence STSNLAS (SEQ ID NO: 27); and

(f) a CDR-L3 having the amino acid sequence QQRRNYPYT (SEQ ID NO: 28);

wherein

each X is independently leucine or isoleucine;

and wherein the antibody or antigen-binding fragment thereof inhibits T regulatory (Treg) cell proliferation in the presence of TNFα.

2. The antibody or antigen-binding fragment thereof of claim 1 , wherein:

(a) said CDR-H1 has the amino acid sequence GYTFTDYX (SEQ ID NO: 257);

(b) said CDR-H2 has the amino acid sequence VDPEYGST (SEQ ID NO: 258);

(c) said CDR-H3 has the amino acid sequence ARDDGSYSPFDYWG (SEQ ID NO: 259);

(d) said CDR-L1 has the amino acid sequence QNINKY (SEQ ID NO: 260);

(e) said CDR-L2 has the amino acid sequence TYS or YTS; and

(f) said CDR-L3 has the amino acid sequence CLQYVNLXT (SEQ ID NO: 261),

wherein each X is independently leucine or isoleucine.

3. The antibody or antigen-binding fragment thereof of claim 2 , wherein said CDR-H1 has the amino acid sequence GYTFTDYL (SEQ ID NO: 274), said CDR-L2 has the amino acid sequence YTS, and said CDR-L3 has the amino acid sequence CLQYVNLIT (SEQ ID NO: 273).

4. The antibody or antigen-binding fragment thereof of claim 1 , wherein:

(a) said CDR-H1 has the amino acid sequence GFTFSSY (SEQ ID NO: 23);

(b) said CDR-H2 has the amino acid sequence SSGGSY (SEQ ID NO: 24);

(c) said CDR-H3 has the amino acid sequence QRVDGYSSYWYFDV (SEQ ID NO: 25);

(d) said CDR-L1 has the amino acid sequence SASSSVYYMY (SEQ ID NO: 26);

(e) said CDR-L2 has the amino acid sequence STSNLAS (SEQ ID NO: 27); and

(f) said CDR-L3 has the amino acid sequence QQRRNYPYT (SEQ ID NO: 28).

5. The antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen-binding fragment thereof comprises a heavy chain amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 2 and/or a light chain amino acid sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 4.

6. The antibody or antigen-binding fragment thereof of claim 5 , wherein said light chain amino acid sequence is the amino acid sequence of SEQ ID NO: 4, and said heavy chain amino acid sequence is the amino acid sequence of SEQ ID NO: 2.

7. The antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen-binding fragment thereof:

(a) comprises a framework region comprising the amino acid sequence LLIR (SEQ ID NO: 262) bound to the N-terminus of said CDR-L2; and/or

(b) comprises a framework region comprising the amino acid sequence TLE bound to the C-terminus of said CDR-L2.

8. The antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen-binding fragment thereof is selected from the group consisting of a monoclonal antibody or antigen-binding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a bispecific antibody or antigen-binding fragment thereof, a multi-specific antibody or antigen-binding fragment thereof, a dual-variable domain immunoglobulin, a monovalent antibody or antigen-binding fragment thereof, a single-chain Fv molecule (scFv), a diabody, a triabody, an antibody-like protein scaffold, a FY fragment, a Fab fragment, a F(ab′)2 molecule, and a tandem scFv (taFv).

9. A construct comprising a first polypeptide domain and a second polypeptide domain, wherein said first polypeptide domain and said second polypeptide domain each independently comprise a single-chain polypeptide comprising the antibody or antigen-binding fragment thereof of claim 1 , and wherein said construct lacks a murine Fc domain.

10. The construct of claim 9 , wherein said first polypeptide domain and said second polypeptide domain are bound by a covalent linker selected from an amide bond and a disulfide bond.

11. The antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen-binding fragment thereof is conjugated to a therapeutic agent.

12. The antibody or antigen-binding fragment thereof of claim 11 , wherein said therapeutic agent is a cytotoxic agent.

13. The antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen-binding fragment thereof is a single-chain polypeptide.

14. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof has an isotype selected from the group consisting of IgG, IgA, IgM, IgD, and IgE.

15. The antibody or antigen-binding fragment thereof of claim 14 , wherein the antibody or antigen-binding fragment thereof has an IgG isotype.

16. The antibody or antigen-binding fragment thereof of claim 15 , wherein the antibody or antigen-binding fragment thereof has an IgG2 isotype.