The present invention is in the field of medicine. Particularly, the present invention relates to agonistic antibodies directed to human CD137, compositions comprising such agonistic anti-human CD137 antibodies, and methods of using such agonistic anti-human CD 137 antibodies for the treatment of solid and hematological tumors alone or in combination with chemotherapy and other cancer therapeutics.

It is now known that boosting the anti-tumor immune response can be an effective means of cancer therapy. In this regard, CD137, also known as 4-1BB, belongs to the TNF receptor family and plays a role in the activation of T cell immune responses such as by driving T cell proliferation and effector functions, promoting immunological memory, and inhibiting activation-induced cell death. Agonistic antibodies targeting CD137 have shown promise in murine tumor models as a monotherapy (Melero. I. et al., Nat. Med. 3(6):682-685 (1997)), however, agonist antibodies targeting human CD137 have not yet demonstrated sufficient responses as a monotherapy or combination therapy in human patients. In this regard, neither utomilumab (a fully human CD137 agonist IgG2 mAb) (Fisher, T.M. et al, Cancer Immunol. Immunother. (2012) 61 : 1721-1733) nor urelumab (a humanized CD137 agonist IgG4 mAb) (Segal, N.H. Clin. Cancer Res. (2017) 23(8): 1929-1936) have received regulatory approvals for use as a monotherapy or even as a combination therapy. Indeed, no agonistic antibody targeting human CD137 has been approved for therapeutic use in humans.

Thus, there exists a need for additional fully human antibodies that agonize the human CD 137 receptor and promote a robust anti-cancer immune response, but with acceptable toxiciticy profiles. There also remains a need for alternative anti-human agonistic CD 137 antibodies that can be combined with other therapeutics for the treatment of cancer. In particular, there also remains a need for anti-human CD137 antibodies that display sufficient potency as a cancer monotherapy and/or combination therapy.

Without being limited to theory, it is believed that the use of current agonistic antibodies targeting CD137 as a cancer monotherapy and/or combination agent is hampered by factors such as the agonistic strength of said antibodies and the immune- related adverse events that result from their use at higher, potentially efficacious doses. In particular, current antibodies are either too potent, leading to adverse events, or display sub-optimal efficacy.

The anti-human CD137 agonistic antibodies described herein are fully human, Fcy-receptor-mediated effector null antibodies that bind human CD137 and cynomolgus monkey CD 137, stimulate T cell activation in vitro, promote human CD 137 cell surface expression, enhance NF-kappa B activity, inhibit tumor growth in murine tumor models of non-small cell lung cancer as a monotherapy, inhibit T-regulatory cell mediated suppression in vitro, activate immune gene signatures, increase the frequency of intratumoral CD3+ T cells, compete with human CD137-Ligand for binding to human CD137, and bind to unique amino acid residues on human CD137.

The present disclosure provides an anti-human CD137 (SEQ ID NO: l) antibody comprising HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7.

The present disclosure provides an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9. The present disclosure provides an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12.

The present disclosure provides an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11. The present disclosure provides an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13.

The present disclosure provides a mammalian cell capable of expressing an antibody comprising HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid

sequence of SEQ ID NO: 4, LCDRl having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO:7.

The present disclosure provides a mammalian cell capable of expressing an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11 or the amino acid sequence of SEQ ID NO: 13.

The present disclosure provides a process for producing an antibody comprising cultivating a mammalian cell capable of expressing the antibody and recovering the antibody; wherein the antibody comprises HCDRl having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDRl having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7.

The present disclosure provides a process for producing an antibody comprising cultivating a mammalian cell capable of expressing the antibody and recovering the antibody; wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11 or the amino acid sequence of SEQ ID NO: 13.

The present disclosure provides an antibody produced by a process comprising cultivating a mammalian cell capable of expressing the antibody and recovering the antibody; wherein the antibody comprises HCDRl having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDRl having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7. The present disclosure provides an antibody produced by a process comprising cultivating a mammalian cell capable of expressing the antibody and recovering the antibody; wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11 or the amino acid sequence of SEQ ID NO:

The present disclosure provides a DNA molecule comprising a polynucleotide having the sequence of SEQ ID NO: 14 and one of SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17. The present disclosure provides a DNA molecule comprising a polynucleotide having the sequence of SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17. The present disclosure provides a mammalian cell comprising a DNA molecule comprising a polynucleotide having the sequence of SEQ ID NO: 14 and one of SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17. The present disclosure provides a mammalian cell comprising a DNA molecule comprising a polynucleotide having the sequence of SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17.

The present disclosure provides a pharmaceutical composition comprising an antibody disclosed herein and an acceptable carrier, diluent, or excipient. The present disclosure provides a pharmaceutical composition comprising an antibody and an acceptable carrier, diluent, or excipient; wherein the antibody comprises HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO:6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7. The present disclosure provides a pharmaceutical composition comprising an antibody and an acceptable carrier, diluent, or excipient; wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9. The present disclosure provides a pharmaceutical composition comprising an antibody and an acceptable carrier, diluent, or excipient; wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12. The present disclosure provides a pharmaceutical composition comprising an antibody and an acceptable carrier, diluent, or excipient; wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11. The present disclosure provides a pharmaceutical composition comprising an antibody and an acceptable carrier, diluent, or excipient; wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13.

The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an anti-human CD137 (SEQ ID NO: l) antibody comprising HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO:6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13.

The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an anti-human CD137 (SEQ ID NO: l) antibody comprising HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO:6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer.

The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an anti-human CD137 (SEQ ID NO: l) antibody comprising HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the

amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO:6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma.

The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma.

The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an anti-human CD137 (SEQ ID NO: l) antibody comprising HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO:6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation.

The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an anti-human CD137 (SEQ ID NO: l) antibody comprising HCDR1 having the amino acid sequence of SEQ

ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO:6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. The present disclosure provides a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents.

The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is bladder cancer. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is breast cancer. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is biliary tract cancer. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is colon cancer. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is endometrial cancer. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is esophageal cancer. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is gastric cancer. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is head and neck cancer. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is non-small cell lung cancer. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is prostate cancer. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is rectal cancer. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is thyroid cancer. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is head and neck squamous cell carcinoma. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is renal cell carcinoma. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is cholangiocarcinoma. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is lung adenocarcinoma. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is lung squamous cell carcinoma. The present disclosure provides an antibody disclosed herein for use in the treatment of cancer; wherein the cancer is clear cell renal carcinoma.

The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is bladder cancer. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is breast cancer. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is biliary tract cancer. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is colon cancer. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is endometrial cancer. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is esophageal cancer. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is gastric cancer. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is head and neck cancer. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is non-small cell lung cancer. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is prostate cancer. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is rectal cancer. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is thyroid cancer. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is head and neck squamous cell carcinoma. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is renal cell carcinoma. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is cholangiocarcinoma. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is lung adenocarcinoma. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is lung squamous cell carcinoma. The present disclosure provides the use of an antibody disclosed herein for the manufacture of a medicament for the treatment of cancer; wherein the cancer is clear cell renal carcinoma.

The present disclosure provides an anti-human CD137 (SEQ ID NO: l) antibody disclosed herein for use in therapy. The present disclosure provides an anti-human CD137 (SEQ ID NO: l) antibody disclosed herein for use in therapy; wherein the antibody comprises HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7. The present disclosure provides an anti-human CD137 (SEQ ID NO: l) antibody disclosed herein for use in therapy; wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11. The present disclosure provides an anti-human CD137 (SEQ ID NO: l) antibody disclosed herein for use in therapy; wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13.

The present disclosure provides an anti-human CD137 (SEQ ID NO: l) antibody for use in the treatment of cancer, wherein the antibody comprises HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO:6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11.

The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13.

The present disclosure provides an anti-human CD137 (SEQ ID NO: l) antibody for use in the treatment of cancer, wherein the antibody comprises HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDRl having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer.

The present disclosure provides an anti-human CD137 (SEQ ID NO: l) antibody for use in the treatment of cancer, wherein the antibody comprises HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDRl having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma.

The present disclosure provides an anti-human CD137 (SEQ ID NO: l) antibody for use in the treatment of cancer, wherein the antibody comprises HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDRl having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation.

The present disclosure provides an anti-human CD137 (SEQ ID NO: l) antibody for use in the treatment of cancer, wherein the antibody comprises HCDR1 having the

amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDRl having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. The present disclosure provides an antibody for use in the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents.

The present disclosure provides the use of an anti-human CD137 (SEQ ID NO: l) antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDRl having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13.

The present disclosure provides the use of an anti-human CD137 (SEQ ID NO: l) antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer .

The present disclosure provides the use of an anti-human CD137 (SEQ ID NO: l) antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9; wherein the cancer is cholangiocarcinoma, head

and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13; wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma.

The present disclosure provides the use of an anti-human CD137 (SEQ ID NO: l) antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13; wherein the antibody is administered in simultaneous, separate, or sequential combination with ionizing radiation.

The present disclosure provides the use of an anti-human CD137 (SEQ ID NO: l) antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises HCDR1 having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. The present disclosure provides the use of an antibody for the manufacture of a medicament for the treatment of cancer, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13; wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents.

The present disclosure provides an antibody that agonizes human CD137 (SEQ ID NO: 1) or a pharmaceutical composition comprising the antibody, wherein the antibody contacts human CD137 on at least one of the following amino acid residues: 55, 59, 63, 66, 72, 93-103 (inclusive); optionally, wherein the antibody contacts at least two of the residues, preferably at least three of the resides, more preferably at least four of the residues; more preferably at least five of the residues; more preferably at least six of the residues; more preferably at least seven of the residues; more preferably at least eight of the residues; more preferably at least nine of the residues; more preferably at least ten of the residues; more preferably at least eleven of the residues; more preferably at least twelve of the residues; more preferably at least thirteen of the residues; more preferably at least fourteen of the residues; more preferably at least fifteen of the residues; or more preferably all of the residues. The present disclosure provides an antibody that agonizes human CD137 (SEQ ID NO: 1) or a pharmaceutical composition comprising the antibody, wherein the antibody contacts human CD 137 on at least one of the following amino acid residues: 55, 59, 63, 66, 72, 93-103 (inclusive); optionally, wherein the antibody contacts at least two of the residues, preferably at least three of the resides, more preferably at least four of the residues; more preferably at least five of the residues; more preferably at least six of the residues; more preferably at least seven of the residues; more preferably at least eight of the residues; more preferably at least nine of the residues; more preferably at least ten of the residues; more preferably at least eleven of the residues; more preferably at least twelve of the residues; more preferably at least thirteen of the residues; more preferably at least fourteen of the residues; more preferably at least fifteen of the residues; or more preferably all of the residues; wherein contact is determined by X-ray crystallography and wherein the residues in contact are within six (6) angstroms or less of the antibody.

The present disclosure provides the use of an antibody that agonizes human CD 137 (SEQ ID NO: 1) for the treatment of cancer or for the manufacture of a medicament for the treatment of cancer, wherein the antibody contacts human CD 137 on at least one of the following amino acid residues: 55, 59, 63, 66, 72, 93-103 (inclusive); optionally, wherein the antibody contacts at least two of the residues, preferably at least three of the resides, more preferably at least four of the residues; more preferably at least five of the residues; more preferably at least six of the residues; more preferably at least seven of the residues; more preferably at least eight of the residues; more preferably at least nine of the residues; more preferably at least ten of the residues; more preferably at least eleven of the residues; more preferably at least twelve of the residues; more preferably at least thirteen of the residues; more preferably at least fourteen of the residues; more preferably at least fifteen of the residues; or more preferably all of the residues. The present disclosure provides the use of an antibody that agonizes human CD 137 (SEQ ID NO: 1) for the treatment of cancer or for the manufacture of a medicament for the treatment of cancer, wherein the antibody contacts human CD 137 on at least one of the following amino acid residues: 55, 59, 63, 66, 72, 93-103 (inclusive); optionally, wherein the antibody contacts at least two of the residues, preferably at least three of the resides, more preferably at least four of the residues; more preferably at least five of the residues; more preferably at least six of the residues; more preferably at least seven of the residues; more preferably at least eight of the residues; more preferably at least nine of the residues; more preferably at least ten of the residues; more preferably at least eleven of the residues; more preferably at least twelve of the residues; more preferably at least thirteen of the residues; more preferably at least fourteen of the residues; more preferably at least fifteen of the residues; or more preferably all of the residues; wherein contact is determined by X-ray crystallography and wherein the residues in contact are within six (6) angstroms or less of the antibody.

The present disclosure provides an antibody that agonizes human CD137 (SEQ ID NO: 1) or a pharmaceutical composition comprising the antibody, wherein the antibody contacts human CD137 at the following amino acid residues: 55, 59, 63, 66, 72, 93-103 (inclusive), and 112-116 (inclusive). The present disclosure provides an antibody that agonizes human CD137 (SEQ ID NO: 1) or a pharmaceutical composition comprising the antibody, wherein the antibody contacts human CD 137 at the following amino acid residues: 55, 59, 63, 66, 72, 93-103 (inclusive), and 112-116 (inclusive); wherein contact is determined by X-ray crystallography and wherein the residues in contact are within six (6) angstroms or less of the antibody.

The present disclosure provides an antibody that agonizes human CD137 (SEQ ID NO: 1) or a pharmaceutical composition comprising the antibody, wherein the antibody contacts human CD137 at the following amino acid residues: 55, 59, 63, 66, 72, 93-103 (inclusive), and 112-116 (inclusive); wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer . The present disclosure provides an antibody that agonizes human CD137 (SEQ ID NO: 1) or a pharmaceutical composition comprising the antibody, wherein the antibody contacts human CD137 at the following amino acid residues: 55, 59, 63, 66, 72, 93-103 (inclusive), and 112-116 (inclusive); wherein contact is determined by X-ray crystallography and wherein the residues in contact are within six (6) angstroms or less of the antibody; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer .

The present disclosure provides an antibody that agonizes human CD137 (SEQ ID NO: 1) for use in the treatment of cancer or for the manufacture of a medicament for the treatment of cancer, wherein the antibody contacts human CD 137 at the following amino acid residues: 55, 59, 63, 66, 72, 93-103 (inclusive), and 112-116 (inclusive). The present disclosure provides an antibody that agonizes human CD137 (SEQ ID NO: 1) for use in the treatment of cancer or for the manufacture of a medicament for the treatment of

cancer, wherein the antibody contacts human CD 137 at the following amino acid residues: 55, 59, 63, 66, 72, 93-103 (inclusive), and 112-116 (inclusive); wherein contact is determined by X-ray crystallography and wherein the residues in contact are within six (6) angstroms or less of the antibody.

The present disclosure provides an antibody that agonizes human CD137 (SEQ ID

NO: 1) for use in the treatment of cancer or the use of an antibody that agonizes human CD 137 (SEQ ID NO: 1) for the manufacture of a medicament for the treatment of cancer, wherein the antibody contacts human CD137 at the following amino acid residues: 55, 59, 63, 66, 72, 93-103 (inclusive), and 112-116 (inclusive); wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer. The present disclosure provides an antibody that agonizes human CD 137 (SEQ ID NO: 1) for use in the treatment of cancer or the use of an antibody that agonizes human CD 137 (SEQ ID NO: 1) for the manufacture of a medicament for the treatment of cancer, wherein the antibody contacts human CD 137 at the following amino acid residues: 55, 59, 63, 66, 72, 93-103 (inclusive), and 112-116 (inclusive); wherein contact is determined by X-ray crystallography and wherein the residues in contact are within six (6) angstroms or less of the antibody; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer .

The present disclosure provides an antibody that agonizes human CD137 (SEQ ID NO: 1) or a pharmaceutical composition comprising the antibody, wherein the antibody does not bind human FcyRI, human FcyRIIa, human FcyRIIb, human FcyRIIIa(F), human FcyRIIIaCV), or human Clq. The present disclosure provides an antibody that agonizes human CD 137 (SEQ ID NO: 1) for use in the treatment of cancer or for the manufacture of a medicament for the treatment of cancer, wherein the antibody does not bind human FcyRI, human FcyRIIa, human FcyRIIb, human FcYRIIIa(F), human FcyRIIIaCV), or human Clq.

The present disclosure provides an antibody that agonizes human CD137 (SEQ ID

NO: 1) or a pharmaceutical composition comprising the antibody, wherein the antibody does not bind human FcyRI, human FcyRIIa, human FcyRIIb, human FcyRIIIa(F), human FcyRIIIaCV), or human Clq; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer . The present disclosure provides an antibody that agonizes human CD137 (SEQ ID NO: 1) for use in the treatment of cancer or for the manufacture of a medicament for the treatment of cancer, wherein the antibody does not bind human FcyRI, human FcyRIIa, human FcyRIIb, human FcyRIIIa(F), human FcyRIIIaCV), or human Clq; wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer .

The present disclosure provides an antibody that is an agonist of human CD137 (SEQ ID NO: l), wherein the antibody comprises a heavy chain and a light chain; wherein the heavy chain contacts at least one amino acid residue of the following on human CD137: 55, 59, 63, 66, 72, 93-103 (inclusive), and 112-116 (inclusive); wherein the light chain contacts at least one amino acid residue of the following on human CD 137: 96-98 (inclusive), 100, and 114-116 (inclusive).

The present disclosure provides an antibody that is an agonist of human CD137 (SEQ ID NO: l), wherein the antibody comprises a heavy chain and a light chain; wherein the heavy chain contacts at least one amino acid residue of the following on human CD 137: 55, 59, 63, 66, 72, 93-103 (inclusive), and 112-116 (inclusive); wherein the light chain contacts at least one amino acid residue of the following on human CD 137: 96-98 (inclusive), 100, and 114-116 (inclusive); wherein the residues in contact are within six (6) angstroms or less of the antibody, as determined by X-ray crystallography.

WE CLAIM:

1. An anti-human CD137 (SEQ ID NO: 1) antibody comprising HCDRl having the amino acid sequence of SEQ ID NO: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7.

2. The antibody of claim 1, comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 9.

3. The antibody of claim 1, comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 and a light chain variable region having the amino acid sequence of SEQ ID NO: 12.

4. The antibody of claim 1, comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11.

5. The antibody of claim 1, comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 13.

6. A mammalian cell capable of expressing an antibody comprising HCDRl having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ

ID NO: 3, HCDR3 having the amino acid sequence of SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2 having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO:7.

7. A mammalian cell capable of expressing an antibody comprising a heavy chain

having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11 or the amino acid sequence of SEQ ID NO: 13.

8. A process for producing an antibody comprising cultivating a mammalian cell capable of expressing the antibody and recovering the antibody; wherein the antibody comprises HCDRl having the amino acid sequence of SEQ ID: 2, HCDR2 having the amino acid sequence of SEQ ID NO: 3, HCDR3 having the amino acid sequence of

SEQ ID NO: 4, LCDR1 having the amino acid sequence of SEQ ID NO: 5, LCDR2

having the amino acid sequence of SEQ ID NO: 6, and LCDR3 having the amino acid sequence of SEQ ID NO: 7.

9. A process for producing an antibody comprising cultivating a mammalian cell capable of expressing the antibody and recovering the antibody; wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 11 or the amino acid sequence of SEQ ID NO: 13.

10. The antibody produced by the process of any one of Claims 8-9.

11. A DNA molecule comprising a polynucleotide having the sequence of SEQ ID NO: 14 and one of SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17.

12. A DNA molecule comprising a polynucleotide having the sequence of SEQ ID

NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, or SEQ ID NO: 17.

13. A mammalian cell comprising the DNA molecule of Claim 1 1 or Claim 12.

14. A pharmaceutical composition, comprising the antibody of any one of Claims 1-5 and 10 and an acceptable carrier, diluent, or excipient.

15. A method of treating cancer, comprising administering to a patient in need thereof, an effective amount of the antibody of any one of Claims 1-5 and 10.

16. The method of Claim 15, wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer.

17. The method of Claim 15, wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, or clear cell renal carcinoma.

18. The method of Claim 15, wherein the cancer is bladder cancer, head and neck

squamous cell cancinoma, or renal cell carcinoma.

19. The method of any one of Claims 15-18, wherein the antibody is administered in combination with ionizing radiation.

20. The method of any one of Claims 15-19, wherein the antibody is administered in combination with one or more chemotherapeutic agents.

21. The antibody of any one of Claims 1-5 and 10, for use in therapy.

22. The antibody of any one of Claims 1-5 and 10, for use in the treatment of cancer.

23. The antibody for use of Claim 22, wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer.

24. The antibody for use of Claim 22, wherein the cancer is cholangiocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma.

25. The antibody for use of Claim 22, wherein the cancer is bladder cancer, head and neck squamous cell cancinoma, or renal cell carcinoma.

26. The antibody for use of any one of Claims 22-25, wherein the antibody is

administered in simultaneous, separate, or sequential combination with ionizing radiation.

27. The antibody for use of any one of Claims 22-26, wherein the antibody is

administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents.

28. The use of the antibody of any one of Claims 1-5 and 10 for the manufacture of a medicament for the treatment of cancer.

29. The use of Claim 28, wherein the cancer is bladder cancer, breast cancer, biliary tract cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, prostate cancer, rectal cancer, or thyroid cancer.

30. The use of Claim 28, wherein the cancer is cholangiocarcinoma, head and neck

squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, clear cell renal carcinoma, or head and neck squamous cell carcinoma.

31. The use of Claim 28, wherein the cancer is bladder cancer, head and neck squamous cell cancinoma, or renal cell carcinoma.

32. The use of any one of Claims 28-31, wherein the antibody is administered in

simultaneous, separate, or sequential combination with ionizing radiation.

33. The use of any one of Claims 28-32, wherein the antibody is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents.