Antagonistic anti-tumor necrosis factor receptor 2 antibodies
The present invention relates to antagonistic TNFR2 polypeptides, such as antibodies and antigen-binding fragments thereof, and the use of these polypeptides to inhibit the proliferation of regulatory T cells (T-regs) and/or expand T effector cell populations or function. For example, antibodies of the invention include antagonistic TNFR2 antibodies and antigen-binding fragments thereof, and can be used to suppress the T-reg-mediated deactivation of tumor reactive T-lymphocytes, as well as to treat a wide variety of cancers and infectious diseases.
1. A humanized or chimeric antibody or antigen-binding fragment thereof comprising a non-native constant region and each of the following complementarity determining regions (CDRs)
(a) a CDR heavy chain 1 (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);
(d) a CDR-L2 having the amino acid sequence TYS or YTS; and
(e) a CDR-L3 having the amino acid sequence CLQYVNLXT (SEQ ID NO: 261);
wherein each X is independently leucine or isoleucine; and wherein the antibody or antigen-binding fragment thereof specifically binds human tumor necrosis factor receptor 2 (TNFR2) and inhibits TNFR2 signaling.
2. The antibody or antigen-binding fragment thereof of claim 1 , wherein said CDR-H1 has the amino acid sequence GYTFTDYL (SEQ ID NO: 274) or GYTFTDYI (SEQ ID NO: 275), and/or wherein said CDR-L2 has the amino acid sequence YTS.
3. The antibody or antigen-binding fragment thereof of claim 2 , wherein said antibody or antigen-binding fragment thereof further comprises a framework region comprising (i) the amino acid sequence LLIR (SEQ ID NO: 262) bound to the N-terminus of said CDR-L2 and/or (ii) the amino acid sequence TLE bound to the C-terminus of said CDR-L2.
4. The antibody or antigen-binding fragment thereof of claim 1 , wherein said non-native constant region is a human constant region.
5. The antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen-binding fragment thereof lacks all or a portion of an Fc domain.
6. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier or excipient.
7. The antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or antigen-binding fragment thereof is conjugated to a therapeutic agent.
8. A kit comprising an agent selected from the group consisting of
(a) the antibody or antigen-binding fragment thereof of claim 1 ; and
(b) a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier or excipient,
wherein the kit further comprises instructions for administering said agent to a human patient.
9. A method of treat slowing progression of a cell proliferation disorder in a human, said method comprising administering to the human the antibody or antigen-binding fragment thereof of claim 1 , wherein the cell proliferation disorder is a cancer.