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 method of slowing progression of a cancer in a human that is undergoing treatment with an anti-cancer agent, said method comprising administering to the human an antibody or antigen-binding fragment thereof capable of specifically binding human tumor necrosis factor receptor 2 (TNFR2), wherein the antibody or antigen-binding fragment thereof comprises 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-light chain 1 (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), and
wherein each X is independently leucine or isoleucine.
2 . The method of claim 1 , wherein the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, or a chimeric antibody or antigen-binding fragment thereof.
3 . The method of claim 1 , wherein the 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, an Fab, a bispecific antibody or antigen-binding fragment thereof, a monovalent antibody or antigen-binding fragment thereof, a single-chain Fv molecule, a bispecific single chain Fv ((scFv′) 2) molecule, a domain antibody, a diabody, a triabody, a SMIP, a Fv fragment, a Fab fragment, a F(ab′) 2 molecule, and a tandem scFv (taFv) fragment.
4 . The method of claim 1 , wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related lymphoma, anal cancer, astrocytoma, bile duct cancer, bladder cancer, osteosarcoma, malignant fibrous histiocytoma, brain stem glioma, visual pathway and hypothalamic glioma, bronchial adenomas/carcinoids, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, clear cell sarcoma of tendon sheaths, colon cancer, colorectal cancer, T-cell lymphoma, epithelial cancer, Ewing's family of tumors, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, hairy cell leukemia, Hodgkin's lymphoma, hypopharyngeal cancer, Kaposi's sarcoma, laryngeal cancer, pituitary cancer, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, small cell lung cancer, small intestine cancer, squamous neck cancer, testicular cancer, thyroid cancer, urethral cancer, uterine sarcoma, and vaginal cancer.
5 . The method of claim 1 , wherein the cancer is selected from the group consisting of breast cancer, endometrial cancer, esophageal cancer, gastric cancer, hepatocellular cancer, kidney cancer, multiple myeloma, skin cancer, lung cancer, ovarian cancer, brain cancer, lymphoid cancer, pharyngeal cancer, and prostate cancer.
6 . The method of claim 1 , wherein the cancer is selected from the group consisting of ocular cancer, bone cancer, head and neck cancer, and soft tissue sarcoma.
7 . The method of claim 1 , wherein the CDR-H1 has the amino acid sequence GYTFTDYL (SEQ ID NO: 274) or GYTFTDYI (SEQ ID NO: 275), and/or the CDR-L2 has the amino acid sequence YTS.
8 . The method of claim 1 , wherein the CDR-H1 has the amino acid sequence GYTFTDYL (SEQ ID NO: 274), the CDR-L2 has the amino acid sequence YTS, the CDR-L3 has the amino acid sequence CLQYVNLIT (SEQ ID NO: 273).
9 . The method of claim 1 , wherein the antibody or antigen-binding fragment thereof further comprises a framework region comprising:
(a) the amino acid sequence LLIR (SEQ ID NO: 262) bound to the N-terminus of the CDR-L2; and/or
(b) the amino acid sequence TLE bound to the C-terminus of the CDR-L2.
10 . The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a non-native constant region.
11 . The method of claim 10 , wherein the non-native constant region is a human constant region.
12 . The method of claim 1 , wherein the antibody or antigen-binding fragment thereof lacks all or a portion of an Fc domain.
13 . The method of claim 1 , wherein the antibody or antigen-binding fragment thereof is conjugated to an additional therapeutic agent.
14 . The method of claim 1 , wherein the anti-cancer agent is an immunotherapy agent.
15 . The method of claim 14 , wherein the immunotherapy agent is an anti-CTLA-4 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, an anti-PD-L1 antibody or antigen-binding fragment thereof, an anti-PD-L2 antibody or antigen-binding fragment thereof, a TNF-α cross-linking antibody or antigen-binding fragment thereof, a TRAIL cross-linking antibody or antigen-binding fragment thereof, an anti-CD27 antibody or antigen-binding fragment thereof, an anti-CD30 antibody or antigen-binding fragment thereof, an anti-CD40 antibody or antigen-binding fragment thereof, an anti-4-1BB antibody or antigen-binding fragment thereof, an anti-GITR antibody or antigen-binding fragment thereof, an anti-OX40 antibody or antigen-binding fragment thereof, an anti-TRAILR1 antibody or antigen-binding fragment thereof, an anti-TRAILR2 antibody or antigen-binding fragment thereof, or an anti-TWEAKR antibody or antigen-binding fragment thereof.
16 . The method of claim 8 , wherein the antibody or antigen-binding fragment thereof is conjugated to an additional therapeutic agent.
17 . The method of claim 8 , wherein the anti-cancer agent is an immunotherapy agent.
18 . The method of claim 17 , wherein the immunotherapy agent is an anti-CTLA-4 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, an anti-PD-L1 antibody or antigen-binding fragment thereof, an anti-PD-L2 antibody or antigen-binding fragment thereof, a TNF-α cross-linking antibody or antigen-binding fragment thereof, a TRAIL cross-linking antibody or antigen-binding fragment thereof, an anti-CD27 antibody or antigen-binding fragment thereof, an anti-CD30 antibody or antigen-binding fragment thereof, an anti-CD40 antibody or antigen-binding fragment thereof, an anti-4-1BB antibody or antigen-binding fragment thereof, an anti-GITR antibody or antigen-binding fragment thereof, an anti-OX40 antibody or antigen-binding fragment thereof, an anti-TRAILR1 antibody or antigen-binding fragment thereof, an anti-TRAILR2 antibody or antigen-binding fragment thereof, or an anti-TWEAKR antibody or antigen-binding fragment thereof.
19 . A method of slowing progression of a cancer in a human comprising administering to the human a combination comprising an antibody or antigen-binding fragment thereof capable of specifically binding human TNFR2 and an additional immunotherapy agent, wherein the antibody or antigen-binding fragment thereof comprises the following CDRs:
(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),
and wherein each X is independently leucine or isoleucine.
20 . The method of claim 19 , wherein the CDR-H1 has the amino acid sequence GYTFTDYL (SEQ ID NO: 274), the CDR-L2 has the amino acid sequence YTS, the CDR-L3 has the amino acid sequence CLQYVNLIT (SEQ ID NO: 273).
21 . The method of claim 19 , wherein the method comprises administering the antibody or antigen-binding fragment thereof and to the human prior to or after the additional immunotherapy agent.
22 . The method of claim 21 , wherein the method comprises administering the antibody or antigen-binding fragment thereof to the human prior to the additional immunotherapy agent.
23 . The method of claim 21 , wherein the method comprises administering the antibody or antigen-binding fragment thereof to the human after the additional immunotherapy agent.
24 . The method of claim 19 , wherein the method comprises simultaneously administering the antibody or antigen-binding fragment thereof and the additional immunotherapy agent to the human.
25 . The method of claim 20 , wherein the antibody or antigen-binding fragment thereof is conjugated to an additional therapeutic agent.
26 . The method of claim 20 , wherein the additional immunotherapy agent is an anti-CTLA-4 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, an anti-PD-L1 antibody or antigen-binding fragment thereof, an anti-PD-L2 antibody or antigen-binding fragment thereof, a TNF-α cross-linking antibody or antigen-binding fragment thereof, a TRAIL cross-linking antibody or antigen-binding fragment thereof, an anti-CD27 antibody or antigen-binding fragment thereof, an anti-CD30 antibody or antigen-binding fragment thereof, an anti-CD40 antibody or antigen-binding fragment thereof, an anti-4-1BB antibody or antigen-binding fragment thereof, an anti-GITR antibody or antigen-binding fragment thereof, an anti-OX40 antibody or antigen-binding fragment thereof, an anti-TRAILR1 antibody or antigen-binding fragment thereof, an anti-TRAILR2 antibody or antigen-binding fragment thereof, or an anti-TWEAKR antibody or antigen-binding fragment thereof.