The present invention relates to the use of anti-human human T-cell

immunoglobulin- and mucin-domain-containing protein-3 (TIM-3) antibodies for the treatment of cancer. More particularly, the present invention relates to dosing regimens for the use of anti-human TIM-3 antibodies for the treatment of cancer alone or in combination with other checkpoint inhibitors, such as an anti-human programmed cell death 1 ligand 1 (PD-L1) antibody or an anti-human programmed cell death protein 1 (PD-1) antibody.

Tumor cells escape detection and elimination by the immune system through multiple mechanisms some of which include the manipulation of immune checkpoint pathways. Immune checkpoint pathways are used in self-tolerance maintenance and in the regulation of T cell activation, but cancer cells can manipulate these pathways to prolong tumor survival. The PD-1/PD-L1 pathway is one such immune checkpoint. In addition to the PD-1/PD-L1 pathway, T cells recognizing tumor antigens can also express other checkpoint receptors, such as TIM-3. In particular, T cells expressing TIM-3 can exhibit an exhausted phenotype characterized by an impairment in cytotoxic functions, effector cytokine production, and proliferation. In this regard, it has been shown that anti-TIM-3 antibodies can restore anti-tumor immunity in some murine cancer models. Morever, it has also been shown that some patients who develop adaptive resistance to anti-PD-1 treatment display an upregulation of TIM-3 on their T cells.

Antibodies directed to human TIM-3 are known and have been described in W02018/039020. An anti-human TIM-3 antibody described in W02018/039020 is currently being tested in human clinical trials as a single agent and in combination with an anti-human PD-L1 antibody previously described in WO2017/034916

(NCT03099109). However, no antibody targeting TIM-3 has received regulatory approval for therapeutic use in humans alone or in combination with an anti-human PD-L1 or anti-human PD-1 antibody.

There remains a need for dosing regimens for anti-human TIM-3 antibodies.

There also remains a need for dosing regimens for anti-human TIM-3 antibodies in combination with anti-PD-Ll antibodies or anti-human PD-1 antibodies, for the treatment of cancer. In particular, there remains a need for dosing regimens for anti-human TIM-3 antibodies that optimize clinical benefit over clinical risk, such as regimens that produce nearly complete cell surface occupancy of TIM-3 or soluble TIM-3 target engagement during both the loading and maintenance phases for the patient using the regimen. There also remains a need to minimize the risk of non-linear pharmacokinetics in the tumor environment of patients using the regimen.

Accordingly, some embodiments of the present invention include dosing regimens for anti-human TIM-3 antibodies for the treatment of cancer. Further, some embodiments of the present invention include dosing regimens where the cancer is a solid tumor.

Embodiments of the present invention also include dosing regimens for the combination of anti-human TIM-3 antibodies and anti-human PD-L1 or anti -human PD-1 antibodies for the treatment of cancer. Further, embodiments of the present invention also include dosing regimens for the combination of anti-human TIM-3 antibodies and anti-human PD-L1 or anti-human PD-1 antibodies for the treatment of cancer, wherein the cancer is a solid tumor.

Further, in some embodiments of the present invention, the combination of anti human TIM-3 antibodies and anti-human PD-L1 or anti-human PD-1 antibodies as part of a treatment regimen for solid tumors are for patients whose tumors are MSI-H or MMR deficent. Embodiments of the present invention also include anti-human TIM-3 antibodies as a treatment regimen for solid tumors in patients whose tumors are MSI-H or MMR deficient and have previously been treated with an anti-human PD-L1 antibody or an anti-human PD-1 antibody. Embodiments of the present invention also include the combination of anti-human TIM-3 antibodies and anti-human PD-L1 or anti-human PD-1 antibodies as a treatment regimen for advanced solid tumors in patients whose tumors are MSI-H or MMR deficient and have previously been treated with an anti-human PD-L1 antibody or an anti-human PD-1 antibody. Embodiments of the invention also include anti-human TIM-3 antibodies as a treatment regimen for advanced solid tumors in patients whose tumors are MSI-H or MMR deficient and have not been previously treated with an anti-human PD-L1 antibody or an anti-human PD-1 antibody. Some embodiments of the present invention also include the combination of anti-human TIM-3 antibodies and anti-human PD-L1 or anti-human PD-1 antibodies as a treatment regimen for solid tumors in patients whose tumors are MSI-H or MMR deficient and have not been previously treated with an anti-human PD-L1 antibody or an anti-human PD-1 antibody.

Some embodiments of the present invention also include dosing regimens for the combination of anti-human TIM-3 antibodies and anti-human PD-L1 or anti-human PD-1 antibodies for the treatment of cancer, wherein the cancer is melanoma, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, gastric cancer, kidney cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, esophageal cancer, soft tissue sarcoma, liver cancer, gallbladder cancer, cervical cancer, duodenal cancer, bone cancer, neuroendocrine cancer, intestinal cancer.

In some embodiments of the present invention, the anti-human TIM-3 antibody binds the extracellular domain of human TIM-3 (SEQ ID NO: 1). Further, in some embodiments of the present invention, the anti-human TIM-3 antibody comprises a HCDR1 having the amino acid sequence of SEQ ID: 2, a HCDR2 having the amino acid sequence of SEQ ID NO: 3, a HCDR3 having the amino acid sequence of SEQ ID NO: 4, a LCDR1 having the amino acid sequence of SEQ ID NO: 5, a LCDR2 having the amino acid sequence of SEQ ID NO: 6, and a LCDR3 having the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-human TIM-3 antibody comprises a light chain variable region having the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 9. In some

embodiments, the anti-human TIM-3 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

In some embodiments, the anti-human TIM-3 antibody blocks the binding of human TIM-3 to human phosphatidylserine, but does not block binding of human TIM-3 to human CEACAM1. In some embodiments, the anti-human TIM-3 antibody blocks the binding of human TIM-3 to human phosphatidylserine, but does not block the binding of human TIM-3 to human CEACAMl, and also blocks the binding of human TIM-3 to human galectin-9. Anti-human TIM-3 antibodies that block the binding of human TIM-3 to human phosphatidylserine, but do not block the binding of human TIM-3 to human CEACAMl, and also block binding of human TIM-3 to human galectin-9 have been previously described in W02018/039020 and include antibodies that comprise a HCDR1

having the amino acid sequence of SEQ ID: 2, a HCDR2 having the amino acid sequence of SEQ ID NO: 3, a HCDR3 having the amino acid sequence of SEQ ID NO: 4, a LCDR1 having the amino acid sequence of SEQ ID NO: 5, a LCDR2 having the amino acid sequence of SEQ ID NO: 6, and a LCDR3 having the amino acid sequence of SEQ ID NO: 7.

Non-limiting examples of anti-human PD-L1 antibodies for use in the

combinations of the present invention include atezolizumab, durvalumab, avelumab, BMS-936559, and preferably those described in WO2017/034916. In some examples, the anti-human PD-L1 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 12 and a heavy chain having the amino acid sequence of SEQ ID NO: 13

Non-limiting examples of anti-human PD-1 antibodies for use in the combinations of the present invention include those as decribed in W02017025016, PDR001 (described in US20150210769; CAS registry number 1859072-53-9), MEDI0680, REGN2810, BGB-A317, nivolumab (CAS registry number 946414-94-4), pembrolizumab (CAS registry number 1374853-91-4), TSR-042, and those described in WO18085468.

Further, some embodiments of the present invention include the combination of chemotherapeutic agents. Non-limiting examples of useful chemotherapeutic agents for use herein include 5-fluorouracil, hydroxyurea, gemcitabine, methotrexate, doxorubicin, etoposide, carboplatin, cisplatin, cyclophosphamide, melphalan, dacarbazine, taxol, camptothecin, FOLFIRI, FOLFOX, docetaxel, daunorubicin, paclitaxel, oxaliplatin, and combinations thereof.

The present invention is derived from two Phase la/b clinical trials: a phase la/lb study of an anti-human TIM-3 antibody, administered alone or in combination with an anti-human PD-L1 antibody, in advanced relapsed/refractory solid tumors

(NCT03099109) and a phase la/lb study of a novel anti-human PD-L1 checkpoint antibody administered alone or in combination with other agents in advanced refractory solid tumors (NCT02791334).

The present invention provides a dosing regimen for the use of an anti-human TIM-3 antibody for the treatment of cancer, wherein the anti -human TIM-3 antibody is administered at a dose of 1 mg to 1800 mg, 30 mg to 1800 mg, 30 mg to 1800 mg once every three weeks, 30 mg to 1800 mg once every two weeks, 30 mg to 1200 mg once

every two weeks, 30 mg to 900 mg once every three weeks, 30 mg to 600 mg once every two weeks, 1 mg once every two weeks, 10 mg once every two weeks, 30 mg once every two weeks, 70 mg once every two weeks, 200 mg once every two weeks, 600 mg once every two weeks, 900 mg once every three weeks about 1000 mg once every three weeks, 1200 mg once every three weeks, or 1800 mg once every three weeks, and wherein the anti-human TIM-3 antibody comprises:

A.) a HCDR1 having the amino acid sequence of SEQ ID: 2, a HCDR2 having the amino acid sequence of SEQ ID NO: 3, a HCDR3 having the amino acid sequence of SEQ ID NO: 4, a LCDR1 having the amino acid sequence of SEQ ID NO: 5, a LCDR2 having the amino acid sequence of SEQ ID NO: 6, and a LCDR3 having the amino acid sequence of SEQ ID NO: 7,

B.) a light chain variable region having the amino acid sequence of SEQ ID NO:

8 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 9, or

C.) a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

The present invention provides a method of treating cancer comprising

administering an anti-human TIM-3 antibody to a human patient in need thereof with a dose in the range of 1 mg to 1800 mg, wherein the anti -human TIM-3 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

In some embodiments, the dose is administered once every two weeks. Further, in some embodiments, the dose is administered once every two weeks and the dose is in the range of 30 mg to 1200 mg, the dose is 30 mg, the dose is 70 mg, the dose is 200 mg, or the dose is 600 mg.

In some embodiments, the dose is administered once every three weeks. Further, in some embodiments, the dose is administered once every three weeks and the dose is in the range of 30 mg to 1800 mg, the dose is 900 mg, the dose is 1000 mg, the dose is 1200 mg, or the dose is 1800 mg.

In some embodiments of the present invention, the anti-TIM-3 antibody is administered with a loading dose followed by a maintenance dose, wherein the loading dose is administered once every two to three weeks for one to three cycles, the maintenance dose is administered once every two to three weeks following completion of the loading dose, the loading dose and the maintenance doses are in the range of 1 mg to 1800 mg, the maintenance dose is a lower dosage amount than the loading dose, and wherein the anti-human TIM-3 antibody comprises:

A.) a HCDR1 having the amino acid sequence of SEQ ID: 2, a HCDR2 having the amino acid sequence of SEQ ID NO: 3, a HCDR3 having the amino acid sequence of SEQ ID NO: 4, a LCDR1 having the amino acid sequence of SEQ ID NO: 5, a LCDR2 having the amino acid sequence of SEQ ID NO: 6, and a LCDR3 having the amino acid sequence of SEQ ID NO: 7,

B.) a light chain variable region having the amino acid sequence of SEQ ID NO:

8 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 9, or

C.) a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

Further, in some embodiments, the maintenance dose is half the dosage amount of the loading dose. In some embodiments, the loading dose is 1200 mg administered once every two weeks for two cycles, and the maintenance dose is 600 mg administered once every two weeks. In some embodiments, the loading dose is 1800 mg administered once every three weeks for three cycles, and the maintenance dose is 900 mg administered once every three weeks. Additionally, in some embodiments, the maintenance dose is administered up to two years.

The present disclosure provides a method of treating cancer comprising administering to a human patient whose cancer comprises a solid tumor that is mismatch repair deficient or exhibits a high degree of microsatellite instability, an effective amount of an anti-human TIM-3 (SEQ ID NO: 1) antibody.

The present disclosure provides a method of treating cancer comprising administering to a human patient whose cancer comprises a solid tumor that is mismatch repair deficient or exhibits a high degree of microsatellite instability, an effective amount of an anti-human TIM-3 (SEQ ID NO: 1) antibody; wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-

L1 (SEQ ID NO: 14) antibody or an effective amount of an anti-human PD-1 (SEQ ID NO: 15) antibody.

The present disclosure provides a method of treating cancer comprising administering to a human patient whose cancer comprises a solid tumor that is mismatch repair deficient or exhibits a high degree of microsatellite instability, an effective amount of an anti-human TIM-3 (SEQ ID NO: 1) antibody; wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti-human PD-1 (SEQ ID NO: 15) antibody; wherein the anti -human TIM-3 antibody comprises a HCDR1 having the amino acid sequence of SEQ ID: 2, a HCDR2 having the amino acid sequence of SEQ ID NO: 3, a HCDR3 having the amino acid sequence of SEQ ID NO: 4, a LCDR1 having the amino acid sequence of SEQ ID NO: 5, a LCDR2 having the amino acid sequence of SEQ ID NO: 6, and a LCDR3 having the amino acid sequence of SEQ ID NO: 7.

The present disclosure provides a method of treating cancer comprising administering to a human patient whose cancer comprises a solid tumor that is mismatch repair deficient or exhibits a high degree of microsatellite instability, an effective amount of an anti-human TIM-3 (SEQ ID NO: 1) antibody; wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti-human PD-1 (SEQ ID NO: 15) antibody; wherein the anti -human TIM-3 antibody comprises a light chain variable region having the amino acid sequence of SEQ ID NO: 8 and a heavy 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 human patient whose cancer comprises a solid tumor that is mismatch repair deficient or exhibits a high degree of microsatellite instability, an effective amount of an anti-human TIM-3 (SEQ ID NO: 1) antibody; wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti-human PD-1 (SEQ ID NO: 15) antibody; wherein the anti -human TIM-3 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

The present disclosure provides a method of treating cancer comprising administering an anti-human TIM-3 antibody to a human patient in need thereof, wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti human PD-1 (SEQ ID NO: 15) antibody, and wherein the anti-human PD-L1 antibody is administered at a dose of about 35 mg to about 1800 mg, about 70 mg to about 1400 mg, about 35 mg once every two weeks, about 70 mg once every three weeks, about 200 mg once every two weeks, 700 mg once every two weeks, about 1000 mg to about 100 mg, about 1000 mg once every three weeks, about 1400 mg once every three weeks, or about 1800 mg once every three weeks.

The present disclosure provides a method of treating cancer comprising administering an anti-human TIM-3 antibody to a human patient in need thereof, wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody, wherein the anti-human PD-L1 antibody is administered at a dose of 35 mg to 1800 mg, 70 mg to 1400 mg, 35 mg once every two weeks, 70 mg once every three weeks, 200 mg once every two weeks, 700 mg once every two weeks, 1000 mg to 100 mg, 1000 mg once every three weeks, 1400 mg once every three weeks, or 1800 mg once every three weeks, and wherein the anti-human PD-L1 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 12 and a heavy chain having the amino acid sequence of SEQ ID NO: 13.

The present disclosure provides a method of treating cancer comprising administering an anti-human TIM-3 antibody to a human patient in need thereof, wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti -human PD-1 (SEQ ID NO: 15) antibody, wherein the anti-human PD-1 antibody is administered at 200 mg once every 3 weeks, 240 mg administered once every 2 weeks, or 480 mg once every 4 weeks.

In some examples, the human patient receiving treatment with the anti-human TIM-3 antibody alone or in combination with an anti-human PD-L1 antibody or an anti human PD-1 antibody was previously treated with an anti-human PD-L1 antibody or an anti-human PD-1 antibody. In some examples, the human patient receiving treatment with the anti-human TIM-3 antibody alone or in combination with an anti-human PD-L1 antibody or an anti-human PD-1 antibody was not previously treated with an anti-human PD-L1 antibody or an anti-human PD-1 antibody. In some examples, the human patient receiving treatment with the anti-human TIM-3 antibody alone or in combination with an anti-human PD-L1 antibody or an anti-human PD-1 antibody has a solid tumor that is PD-L1 high. In some examples, the human patient receiving treatment with the anti-human TIM-3 antibody alone or in combination with an anti-human PD-L1 antibody or an anti human PD-1 antibody has a solid tumor that is PD-L1 low. In some examples, the human patient receiving treatment with the anti-human TIM-3 antibody alone or in combination with an anti-human PD-L1 antibody or an anti-human PD-1 antibody has a solid tumor that has a high degree of microsatellite instability. In some examples, the human patient receiving treatment with the anti-human TIM-3 antibody alone or in combination with an anti-human PD-L1 antibody or an anti-human PD-1 antibody has a solid tumor that is mismatch repair deficient.

In some examples, the human patient receiving treatment with the anti-human TIM-3 antibody alone or in combination with an anti-human PD-L1 antibody or an anti human PD-1 antibody has a cancer that is melanoma, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, gastric cancer, kidney cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, esophageal cancer, soft tissue sarcoma, liver cancer, gallbladder cancer, cervical cancer, duodenal cancer, bone cancer, neuroendocrine cancer, intestinal cancer. In some examples, the human patient receiving treatment with the anti-human TIM-3 antibody alone or in combination with an anti human PD-L1 antibody or an anti-human PD-1 antibody has a cancer that is melanoma or non-small cell lung cancer.

In some examples, the human patient receives ionizing radiation in simultaneous, separate, or sequential combination with their treatment with the anti-human TIM-3 antibody alone or in combination with an anti-human PD-L1 antibody or an anti-human PD-1 antibody. In some examples, the human patient receives one or more

chemotherapeutic agents in simultaneous, separate, or sequential combination with their treatment with the anti-human TIM-3 antibody alone or in combination with an anti human PD-L1 antibody or an anti-human PD-1 antibody.

In some examples, the anti-human TIM-3 antibody for use herein blocks binding of human TIM-3 to human phosphatidylserine, but does not block binding of human TIM-3 to human CEACAM1. In some examples, the anti-human TIM-3 antibody for use of herein blocks binding of human TIM-3 to human phosphatidylserine, but does not block binding of human TIM-3 to human CEACAM1, but also blocks binding of human TIM-3 to human galectin-9.

The present invention provides an anti -human TIM-3 (SEQ ID NO: 1) antibody for use in the treatment of a human patient whose cancer comprises a solid tumor. The present invention provides an anti-human TIM-3 antibody for use in the treatment of cancer.

The present invention provides an anti -human TIM-3 (SEQ ID NO: 1) antibody for use in the treatment of cancer, wherein the anti-human TIM-3 antibody is

administered at a dose in the range of 1 mg to 1800 mg, and the anti -human TIM-3 antibody comprises:

A.) a HCDR1 having the amino acid sequence of SEQ ID: 2, a HCDR2 having the amino acid sequence of SEQ ID NO: 3, a HCDR3 having the amino acid sequence of SEQ ID NO: 4, a LCDR1 having the amino acid sequence of SEQ ID NO: 5, a LCDR2 having the amino acid sequence of SEQ ID NO: 6, and a LCDR3 having the amino acid sequence of SEQ ID NO: 7,

B.) a light chain variable region having the amino acid sequence of SEQ ID NO:

8 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 9, or

C.) a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

In some embodiments of the present invention, the dose is administered once every two weeks. Further, in some embodiments, the dose is administered once every two weeks and the dose is in the range of 30 mg to 1200 mg, the dose is 30 mg, the dose is 70 mg, the dose is 200 mg, or the dose is 600 mg.

In some embodiments of the present invention, the dose is administered once every three weeks. Further, in some embodiments, the dose is administered once every three weeks and the dose is in the range of 30 mg to 1800 mg, the dose is 900 mg, the dose is 1000 mg, the dose is 1200 mg, or the dose is 1800 mg.

In some embodiments of the present invention, the anti-TIM-3 antibody is administered with a loading dose followed by a maintenance dose, wherein the loading dose is administered once every two to three weeks for one to three cycles, the maintenance dose is administered once every two to three weeks following completion of the loading dose, the loading dose and the maintenance doses are in the range of 1 mg to 1800 mg, the maintenance dose is a lower dosage amount than the loading dose, and wherein the anti-human TIM-3 antibody comprises:

A.) a HCDR1 having the amino acid sequence of SEQ ID: 2, a HCDR2 having the amino acid sequence of SEQ ID NO: 3, a HCDR3 having the amino acid sequence of SEQ ID NO: 4, a LCDR1 having the amino acid sequence of SEQ ID NO: 5, a LCDR2 having the amino acid sequence of SEQ ID NO: 6, and a LCDR3 having the amino acid sequence of SEQ ID NO: 7,

B.) a light chain variable region having the amino acid sequence of SEQ ID NO:

8 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 9, or

C.) a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

Further, in some embodiments, the maintenance dose is half the dosage amount of the loading dose. In some embodiments, the loading dose is 1200 mg administered once every two weeks for two cycles, and the maintenance dose is 600 mg administered once every two weeks. In some embodiments, the loading dose is 1800 mg administered once every three weeks for three cycles, and the maintenance dose is 900 mg administered once every three weeks. Additionally, in some embodiments, the the maintenance dose is administered up to two years.

The present invention provides anti-human TIM-3 antibody for use in the treatment of cancer, wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti-human PD-1 (SEQ ID NO: 15) antibody.

Further, in some embodiments, the anti-human PD-L1 antibody is durvalumab, atezolizumab, or avelumab. In some embodiments, the anti-human PD-L1 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 12 and a heavy chain having the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-human PD-L1 antibody is administered at a dose of about 35 mg to about 1800 mg. Further, in some embodiments, the dose of the anti-human PD-L1 antibody is

administered once every two weeks, and the dose is in the range of 70 mg to 700 mg, the dose is 35 mg, the dose is 70 mg, the dose is 200 mg, or the dose is 700 mg. In some embodiments, the dose of the anti-human PD-L1 antibody is administered once every three weeks, and the dose is in the range of 70 mg to 1400 mg, the dose is 1000 mg, the dose is 1200 mg, or the dose is 1400 mg. In some embodiments, the dose of the anti human PD-L1 antibody is administered once every four weeks, and the dose is 1800 mg.

Further, in some embodiments, the anti-human PD-1 antibody administered is pembrolizumab, nivolumab, or cemiplimab. In some embodiments, the dose of the anti human PD-1 antibody is 200 mg administered once every 3 weeks. In some

embodiments, the dose of the anti-human PD-1 antibody is 240 mg administered once every 2 weeks or 480 mg once every 4 weeks.

The present invention provides an anti -human TIM-3 (SEQ ID NO: 1) antibody for use in the treatment of cancer, wherein the anti-human TIM-3 antibody is

administered at a dose in the range of 1 mg to 1800 mg, and the anti -human TIM-3 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11, and wherein the cancer is melanoma, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, gastric cancer, kidney cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, esophageal cancer, soft tissue sarcoma, liver cancer, gallbladder cancer, cervical cancer, duodenal cancer, bone cancer, neuroendocrine cancer, intestinal cancer. Further, an embodiment of the present invention provides that the cancer melanoma or non-small cell lung cancer. Further, an embodiment of the present invention provides at least one of the anti-human TIM-3 antibody, anti-human PD-1 antibody, and anti-human PD-L1 antibody is administered with ionizing radiation.

The present invention provides an anti-human TIM-3 antibody for use in the treatment of cancer, wherein the anti-human TIM-3 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11, the anti-TIM-3 antibody is administered with a loading dose followed by a maintenance dose, wherein the loading dose is administered once every two to three weeks for one to three cycles, the maintenance dose is administered once every two to three weeks following completion of the loading dose, the loading dose and the maintenance doses are in the range of 1 mg to 1800 mg, the maintenance dose is a lower dosage amount than the loading dose, and wherein the the cancer is melanoma, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, gastric cancer, kidney cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, esophageal cancer, soft tissue sarcoma, liver cancer, gallbladder cancer, cervical cancer, duodenal cancer, bone cancer, neuroendocrine cancer, intestinal cancer. Further, an embodiment of the present invention provides that the cancer melanoma or non-small cell lung cancer.

The present invention provides an embodiment wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti-human PD-1 (SEQ ID NO: 15) antibody.

The present disclosure provides an anti-human TIM-3 (SEQ ID NO: 1) antibody for use in the treatment of a human patient whose cancer comprises a solid tumor that is mismatch repair deficient or exhibits a high degree of microsatellite instability; wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti human PD-1 (SEQ ID NO: 15) antibody.

The present disclosure provides an anti-human TIM-3 (SEQ ID NO: 1) antibody for use in the treatment of a human patient whose cancer comprises a solid tumor;

wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti-human PD-1 (SEQ ID NO: 15) antibody; wherein the anti-human TIM-3 antibody comprises a HCDR1 having the amino acid sequence of SEQ ID: 2, a HCDR2 having the amino acid sequence of SEQ ID NO: 3, a HCDR3 having the amino acid sequence of

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

The present disclosure provides an anti-human TIM-3 (SEQ ID NO: 1) antibody for use in the treatment of a human patient whose cancer comprises a solid tumor;

wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti-human PD-1 (SEQ ID NO: 15) antibody; wherein the anti-human TIM-3 antibody comprises a light chain variable region having the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 9.

The present disclosure provides an anti-human TIM-3 (SEQ ID NO: 1) antibody for use in the treatment of a human patient whose cancer comprises a solid tumor, an effective amount of an anti-human TIM-3 (SEQ ID NO: 1) antibody; wherein the anti human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti-human PD-1 (SEQ ID NO: 15) antibody; wherein the anti-human TIM-3 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

The present invention provides the use of an anti-human TIM-3 antibody for the manufacture of a medicament for the treatment of cancer comprising administering the anti-human TIM-3 antibody to a human patient in need thereof with a dose in the range of 1 mg to 1800 mg, and wherein the anti-human TIM-3 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

In some embodiments, the dose is administered once every two weeks. Further, in some embodiments, the dose is in the range of 30 mg to 1200 mg, the dose is 30 mg, the dose is 70 mg, the dose is 200 mg, or the dose is 600 mg.

In some embodiments, the dose is administered once every three weeks. Further, in some embodiments, the dose is in the range of 30 mg to 1800 mg, the dose is 900 mg, the dose is 1000 mg, the dose is 1200 mg, or the dose is 1800 mg.

The present invention provides the use of an anti-human TIM-3 antibody for the manufacture of a medicament for the treatment of cancer, wherein the anti-TIM-3 antibody is administered with a loading dose followed by a maintenance dose, wherein the loading dose is administered once every two to three weeks for one to three cycles, the maintenance dose is administered once every two to three weeks following completion of the loading dose, the loading dose and the maintenance doses are in the range of 1 mg to 1800 mg, the maintenance dose is a lower dosage amount than the loading dose, and wherein the anti-human TIM-3 antibody comprises:

A.) a HCDR1 having the amino acid sequence of SEQ ID: 2, a HCDR2 having the amino acid sequence of SEQ ID NO: 3, a HCDR3 having the amino acid sequence of SEQ ID NO: 4, a LCDR1 having the amino acid sequence of SEQ ID NO: 5, a LCDR2 having the amino acid sequence of SEQ ID NO: 6, and a LCDR3 having the amino acid sequence of SEQ ID NO: 7,

B.) a light chain variable region having the amino acid sequence of SEQ ID NO:

8 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 9, or

C.) a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

Further, in some embodiments, the maintenance dose is half the dosage amount of the loading dose. In some embodiments, the loading dose is 1200 mg administered once every two weeks for two cycles, and the maintenance dose is 600 mg administered once every two weeks. In some embodiments, the loading dose is 1800 mg administered once every three weeks for three cycles, and the maintenance dose is 900 mg administered once every three weeks. Additionally, in some embodiments, the the maintenance dose is administered up to two years.

The present disclosure provides the use of an anti-human TIM-3 antibody for the manufacture of a medicament for the treatment of cancer; wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti -human PD-1 (SEQ ID NO: 15) antibody.

The present disclosure provides the use of an anti-human TIM-3 antibody for the manufacture of a medicament for the treatment of a human patient; wherein the anti human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti-human PD-1 (SEQ ID NO: 15) antibody; wherein the anti-human TIM-3 antibody comprises a HCDR1 having the amino acid sequence of SEQ ID: 2, a HCDR2 having the amino acid sequence of SEQ ID NO: 3, a HCDR3 having the amino acid sequence of SEQ ID NO: 4, a LCDR1 having the amino acid sequence of SEQ ID NO: 5, a LCDR2 having the amino acid sequence of SEQ ID NO: 6, and a LCDR3 having the amino acid sequence of SEQ ID NO: 7.

The present disclosure provides the use of an anti-human TIM-3 antibody for the manufacture of a medicament for the treatment of a human patient whose cancer comprises a solid tumor that is mismatch repair deficient or exhibits a high degree of microsatellite instability; wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti-human PD-1 (SEQ ID NO: 15) antibody; wherein the anti-human TIM-3 antibody comprises a light chain variable region having the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 9.

The present disclosure provides the use of an anti-human TIM-3 antibody for the manufacture of a medicament for the treatment of a human patient whose cancer comprises a solid tumor that is mismatch repair deficient or exhibits a high degree of microsatellite instability, an effective amount of an anti-human TIM-3 (SEQ ID NO: 1) antibody; wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti-human PD-1 (SEQ ID NO: 15) antibody; wherein the anti-human TIM-3 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

The present provides a pharmaceutical composition comprising an anti-human TIM-3 antibody for use in the treatment of cancer in a human patient, wherein the anti human TIM-3 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11, and wherein the anti-human TIM-3 antibody is administered at a dose of about 1 mg to about 1800 mg.

In some embodiments, the dose is administered once every two weeks. Further, in some embodiments, the dose is in the range of 30 mg to 1200 mg, the dose is 30 mg, the dose is 70 mg, the dose is 200 mg, or the dose is 600 mg.

In some embodiments, the dose is administered once every three weeks. Further, in some embodiments, the dose is in the range of 30 mg to 1800 mg, the dose is 900 mg, the dose is 1000 mg, the dose is 1200 mg, or the dose is 1800 mg.

The present provides a pharmaceutical composition comprising an anti-human TIM-3 antibody for use in the treatment of cancer in a human patient, wherein the anti-TIM-3 antibody is administered with a loading dose followed by a maintenance dose, wherein the loading dose is administered once every two to three weeks for one to three cycles, the maintenance dose is administered once every two to three weeks following completion of the loading dose, the loading dose and the maintenance doses are in the range of 1 mg to 1800 mg, and the maintenance dose is a lower dosage amount than the loading dose., and wherein the anti-human TIM-3 antibody comprises:

A.) a HCDR1 having the amino acid sequence of SEQ ID: 2, a HCDR2 having the amino acid sequence of SEQ ID NO: 3, a HCDR3 having the amino acid sequence of SEQ ID NO: 4, a LCDR1 having the amino acid sequence of SEQ ID NO: 5, a LCDR2 having the amino acid sequence of SEQ ID NO: 6, and a LCDR3 having the amino acid sequence of SEQ ID NO: 7,

B.) a light chain variable region having the amino acid sequence of SEQ ID NO:

8 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 9, or

C.) a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

Further, in some embodiments, the maintenance dose is half the dosage amount of the loading dose. In some embodiments, the loading dose is 1200 mg administered once every two weeks for two cycles, and the maintenance dose is 600 mg administered once every two weeks. In some embodiments, the loading dose is 1800 mg administered once every three weeks for three cycles, and the maintenance dose is 900 mg administered once every three weeks. Additionally, in some embodiments, the the maintenance dose is administered up to two years.

The present disclosure further provides a pharmaceutical composition wherein the anti-human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti human PD-1 (SEQ ID NO: 15) antibody. Further, an embodiment of the present invention provides a pharmaceutical composition wherein the anti -human PD-L1 antibody is administered at a dose of about 35 mg to about 1800 mg, about 70 mg to about 1400 mg, about 35 mg once every two weeks, about 70 mg once every three weeks, about 200 mg once every two weeks, 700 mg once every two weeks, about 1000 mg to about 100 mg, about 1000 mg once every three weeks, about 1400 mg once every three weeks, or about 1800 mg once every three weeks.

WE CLAIM:

1. A method of treating cancer comprising administering an anti-human TIM-3 antibody to a human patient in need thereof with a dose in the range of 1 mg to 1800 mg, wherein the anti-human TIM-3 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11.

2. The method of Claim 1, wherein the dose is administered once every two weeks.

3. The method of Claim 2, wherein the dose is in the range of 30 mg to 1200 mg.

4. The method of Claim 2, wherein the dose is 30 mg.

5. The method of Claim 2, wherein the dose is 70 mg.

6. The method of Claim 2, wherein the dose is 200 mg.

7. The method of Claim 2, wherein the dose is 600 mg.

8. The method of Claim 1, wherein the dose is administered once every three weeks.

9. The method of Claim 8, wherein the dose is in the range of 30 mg to 1800 mg.

10. The method of Claim 8, wherein the dose is 900 mg.

11. The method of Claim 8, wherein the dose is 1000 mg.

12. The method of Claim 8, wherein the dose is 1200 mg.

13. The method of Claim 8, wherein the dose is 1800 mg.

14. The method of Claim 1, wherein the anti-TIM-3 antibody is administered with a loading dose followed by a maintenance dose, wherein the loading dose is administered once every two to three weeks for one to three cycles, the maintenance dose is administered once every two to three weeks following completion of the loading dose, the loading dose and the maintenance doses are in the range of 1 mg to 1800 mg, and the maintenance dose is a lower dosage amount than the loading dose.

15. The method of Claim 14, wherein the maintenance dose is half the dosage amount of the loading dose.

16. The method of Claim 14, wherein the loading dose is 1200 mg administered once every two weeks for two cycles, and the maintenance dose is 600 mg administered once every two weeks.

17. The method of Claim 14, wherein the loading dose is 1800 mg administered once every three weeks for three cycles, and the maintenance dose is 900 mg administered once every three weeks.

18. The method of any one of Claims 14-17, wherein the maintenance dose is

administered up to two years.

19. The method of any one of Claims 1-18, wherein the anti -human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti-human PD-1 (SEQ ID NO: 15) antibody.

20. The method of Claim 19, wherein the anti-human PD-L1 antibody is durvalumab, atezolizumab, or avelumab.

21. The method of Claim 19, wherein the anti-human PD-L1 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 12 and a heavy chain having the amino acid sequence of SEQ ID NO: 13.

22. The method of any one of Claims 19-21, wherein the anti-human PD-L1 antibody is administered at a dose of about 35 mg to about 1800 mg.

23. The method of Claim 22, wherein the dose of the anti-human PD-L1 antibody is

administered once every two weeks.

24. The method of Claim 23, wherein the dose of the anti-human PD-L1 antibody is in the range of 70 mg to 700 mg.

25. The method of Claim 23, wherein the dose of the anti-human PD-L1 antibody is 35 mg.

26. The method of Claim 23, wherein the dose of the anti-human PD-L1 antibody is 70 mg.

27. The method of Claim 23, wherein the dose of the anti-human PD-L1 antibody is 200 mg.

28. The method of Claim 23, wherein the dose of the anti-human PD-L1 antibody is 700 mg.

29. The method of Claim 22, wherein the dose of the anti-human PD-L1 antibody is

administered once every three weeks.

30. The method of Claim 29, wherein the dose of the anti-human PD-L1 antibody is in the range of 70 mg to 1400 mg.

31. The method of Claim 29, wherein the dose of the anti-human PD-L1 antibody is 1000 mg.

32. The method of Claim 29, wherein the dose of the anti-human PD-L1 antibody is 1200 mg.

33. The method of Claim 29, wherein the dose of the anti-human PD-L1 antibody is 1400 mg.

34. The method of Claim 22, wherein the dose of the anti-human PD-L1 antibody is

administered once every four weeks.

35. The method of Claim 34, wherein the dose of the anti-human PD-L1 antibody is 1800 mg.

36. The method of Claim 19, wherein the anti-human PD-1 antibody is administered and is pembrolizumab, nivolumab, or cemiplimab.

37. The method of Claim 36, wherein the dose of the anti-human PD-1 antibody is

administered once every 2 to 4 weeks.

38. The method of Claim 37, wherein the dose of the anti-human PD-1 antibody is 200 mg administered once every 3 weeks.

39. The method of Claim 37, wherein the dose of the anti-human PD-1 antibody is 240 mg administered once every 2 weeks or 480 mg once every 4 weeks.

40. The method of any one of Claims 1-39, wherein the patient was previously treated with an anti-human PD-L1 antibody or an anti-human PD-1 antibody.

41. The method of any one of Claims 1-39, wherein the patient has not been previously treated with an anti-human PD-L1 antibody or an anti-human PD-1 antibody.

42. The method of any one of Claims 1-39, wherein the cancer is a solid tumor.

43. The method of Claim 42, wherein the solid tumor is PD-L1 high.

44. The method of Claim 42, wherein the solid tumor is PD-L1 low.

45. The method of Claim 42, wherein the solid tumor has a high degree of microsatellite instability.

46. The method of Claim 42, wherein the solid tumor is mismatch repair deficient.

47. The method of Claim 42, wherein the solid tumor has a high degree of microsatellite instability and is mismatch repair deficient.

48. The method of any one of Claims 1-39, wherein the cancer is melanoma, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, gastric cancer, kidney cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, esophageal cancer, soft tissue sarcoma, liver cancer, gallbladder cancer, cervical cancer, duodenal cancer, bone cancer, neuroendocrine cancer, intestinal cancer.

49. The method of Claim 48, wherein the cancer is melanoma or non-small cell lung cancer.

50. The method of any one of Claims 1-39, wherein at least one of the anti-human TIM-3 antibody, anti -human PD-1 antibody, and anti-human PD-L1 antibody is

administered with ionizing radiation.

51. An anti -human TIM-3 antibody for use in the treatment of cancer wherein the anti human TIM-3 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO:

11, and wherein the anti-human TIM-3 antibody is administered at a dose in the range of 1 mg to 1800 mg.

52. The anti-human TIM-3 antibody for use of Claim 51, wherein the dose is

administered once every two weeks.

53. The anti-human TIM-3 antibody for use of Claim 52, wherein the dose is in the range of 30 mg to 1200 mg.

54. The anti-human TIM-3 antibody for use of Claim 52, wherein the dose is 30 mg.

55. The anti-human TIM-3 antibody for use of Claim 52, wherein the dose is 70 mg.

56. The anti-human TIM-3 antibody for use of Claim 52, wherein the dose is 200 mg.

57. The anti-human TIM-3 antibody for use of Claim 52, wherein the dose is 600 mg.

58. The anti-human TIM-3 antibody for use of Claim 51, wherein the dose is

administered once every three weeks.

59. The anti-human TIM-3 antibody for use of Claim 58, wherein the dose is in the range of 30 mg to 1800 mg.

60. The anti-human TIM-3 antibody for use of Claim 58, wherein the dose is 900 mg.

61. The anti-human TIM-3 antibody for use of Claim 58, wherein the dose is 1000 mg.

62. The anti-human TIM-3 antibody for use of Claim 58, wherein the dose is 1200 mg.

63. The anti-human TIM-3 antibody for use of Claim 58, wherein the dose is 1800 mg.

64. The anti-human TIM-3 antibody for use of Claim 51, wherein the anti-TIM-3

antibody is administered with a loading dose followed by a maintenance dose, wherein the loading dose is administered once every two to three weeks for one to three cycles, the maintenance dose is administered once every two to three weeks following completion of the loading dose, the loading dose and the maintenance doses are in the range of 1 mg to 1800 mg, and the maintenance dose is a lower dosage amount than the loading dose.

65. The anti-human TIM-3 antibody for use of Claim 64, wherein the maintenance dose is half the dosage amount of the loading dose.

66. The anti-human TIM-3 antibody for use of Claim 64, wherein the loading dose is 1200 mg administered once every two weeks for two cycles, and the maintenance dose is 600 mg administered once every two weeks.

67. The anti-human TIM-3 antibody for use of Claim 64, wherein the loading dose is 1800 mg administered once every three weeks for three cycles, and the maintenance dose is 900 mg administered once every three weeks.

68. The anti-human TIM-3 antibody for use of any one of Claims 64-67, wherein the maintenance dose is administered up to two years.

69. The anti-human TIM-3 antibody for use of any one of Claims 51-68, wherein the anti human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti human PD-1 (SEQ ID NO: 15) antibody.

70. The anti-human TIM-3 antibody for use of Claim 69, wherein the anti-human PD-L1 antibody is durvalumab, atezolizumab, or avelumab.

71. The anti-human TIM-3 antibody for use of Claim 69, wherein the anti-human PD-L1 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 12 and a heavy chain having the amino acid sequence of SEQ ID NO: 13.

72. The anti-human TIM-3 antibody for use of any one of Claims 69-71, wherein the anti human PD-L1 antibody is administered at a dose of about 35 mg to about 1800 mg.

73. The anti-human TIM-3 antibody for use of Claim 72, wherein the dose of the anti human PD-L1 antibody is administered once every two weeks.

74. The anti-human TIM-3 antibody for use of Claim 73, wherein the dose of the anti human PD-L1 antibody is in the range of 70 mg to 700 mg.

75. The anti-human TIM-3 antibody for use of Claim 73, wherein the dose of the anti human PD-L1 antibody is 35 mg.

76. The anti-human TIM-3 antibody for use of Claim 73, wherein the dose of the anti human PD-L1 antibody is 70 mg.

77. The anti-human TIM-3 antibody for use of Claim 73, wherein the dose of the anti human PD-L1 antibody is 200 mg.

78. The anti-human TIM-3 antibody for use of Claim 73, wherein the dose of the anti human PD-L1 antibody is 700 mg.

79. The anti-human TIM-3 antibody for use of Claim 72, wherein the dose of the anti human PD-L1 antibody is administered once every three weeks.

80. The anti-human TIM-3 antibody for use of Claim 79, wherein the dose of the anti human PD-L1 antibody is in the range of 70 mg to 1400 mg.

81. The anti-human TIM-3 antibody for use of Claim 79, wherein the dose of the anti human PD-L1 antibody is 1000 mg.

82. The anti-human TIM-3 antibody for use of Claim 79, wherein the dose of the anti human PD-L1 antibody is 1200 mg.

83. The anti-human TIM-3 antibody for use of Claim 79, wherein the dose of the anti human PD-L1 antibody is 1400 mg.

84. The anti-human TIM-3 antibody for use of Claim 72, wherein the dose of the anti human PD-L1 antibody is administered once every four weeks.

85. The anti-human TIM-3 antibody for use of Claim 84, wherein the dose of the anti human PD-L1 antibody is 1800 mg.

86. The anti-human TIM-3 antibody for use of Claim 69, wherein the anti-human PD-1 antibody is administered and is pembrolizumab, nivolumab, or cemiplimab.

87. The anti-human TIM-3 antibody for use of Claim 86, wherein the dose of the anti human PD-1 antibody is administered once every 2 to 4 weeks.

88. The anti-human TIM-3 antibody for use of Claim 87, wherein the dose of the anti human PD-1 antibody is 200 mg administered once every 3 weeks.

89. The anti-human TIM-3 antibody for use of Claim 87, wherein the dose of the anti human PD-1 antibody is 240 mg administered once every 2 weeks or 480 mg once every 4 weeks.

90. The anti-human TIM-3 antibody for use of any one of Claims 51-89, wherein the patient was previously treated with an anti-human PD-L1 antibody or an anti-human PD-1 antibody.

91. The anti-human TIM-3 antibody for use of any one of Claims 51-89, wherein the patient has not been previously treated with an anti -human PD-L1 antibody or an anti human PD-1 antibody.

92. The anti-human TIM-3 antibody for use of any one of Claims 51-89, wherein the cancer is a solid tumor.

93. The anti-human TIM-3 antibody for use of Claim 92, wherein the solid tumor is PD- L1 high.

94. The anti-human TIM-3 antibody for use of Claim 92, wherein the solid tumor is PD- L1 low.

95. The anti-human TIM-3 antibody for use of Claim 92, wherein the solid tumor has a high degree of microsatellite instability.

96. The anti-human TIM-3 antibody for use of Claim 92, wherein the solid tumor is mismatch repair deficient.

97. The anti-human TIM-3 antibody for use of Claim 92, wherein the solid tumor has a high degree of microsatellite instability and is mismatch repair deficient.

98. The anti-human TIM-3 antibody for use of any one of Claims 51-89, wherein the cancer is melanoma, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, gastric cancer, kidney cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, esophageal cancer, soft tissue sarcoma, liver cancer, gallbladder cancer, cervical cancer, duodenal cancer, bone cancer, neuroendocrine cancer, intestinal cancer.

99. The anti-human TIM-3 antibody for use of Claim 98, wherein the cancer is melanoma or non-small cell lung cancer.

100. The anti-human TIM-3 antibody for use of any one of Claims 51-89, wherein at least one of the anti-human TIM-3 antibody, anti-human PD-1 antibody, and anti human PD-L1 antibody is administered with ionizing radiation.

101. A pharmaceutical composition comprising an anti -human TIM-3 antibody for use in the treatment of cancer in a human patient, wherein the anti-human TIM-3 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 10 and a heavy chain having the amino acid sequence of SEQ ID NO: 11, wherein the anti human TIM-3 antibody is administered at a dose of about 1 mg to about 1800 mg.

102. The pharmaceutical composition of Claim 101, wherein the dose is administered once every two weeks.

103. The pharmaceutical composition of Claim 102, wherein the dose is in the range of 30 mg to 1200 mg.

104. The pharmaceutical composition of Claim 102, wherein the dose is 30 mg.

105. The pharmaceutical composition of Claim 102, wherein the dose is 70 mg.

106. The pharmaceutical composition of Claim 102, wherein the dose is 200 mg.

107. The pharmaceutical composition of Claim 102, wherein the dose is 600 mg.

108. The pharmaceutical composition of Claim 101, wherein the dose is administered once every three weeks.

109. The pharmaceutical composition of Claim 108, wherein the dose is in the range of 30 mg to 1800 mg.

110. The pharmaceutical composition of Claim 108, wherein the dose is 900 mg.

111. The pharmaceutical composition of Claim 108, wherein the dose is 1000 mg.

112. The pharmaceutical composition of Claim 108, wherein the dose is 1200 mg.

113. The pharmaceutical composition of Claim 108, wherein the dose is 1800 mg.

114. The pharmaceutical composition of Claim 101, wherein the anti-TIM-3 antibody is administered with a loading dose followed by a maintenance dose, wherein the loading dose is administered once every two to three weeks for one to three cycles, the maintenance dose is administered once every two to three weeks following completion of the loading dose, the loading dose and the maintenance doses are in the range of 1 mg to 1800 mg, and the maintenance dose is a lower dosage amount than the loading dose.

115. The pharmaceutical composition of Claim 114, wherein the maintenance dose is half the dosage amount of the loading dose.

116. The pharmaceutical composition of Claim 114, wherein the loading dose is 1200 mg administered once every two weeks for two cycles, and the maintenance dose is 600 mg administered once every two weeks.

117. The pharmaceutical composition of Claim 114, wherein the loading dose is 1800 mg administered once every three weeks for three cycles, and the maintenance dose is 900 mg administered once every three weeks.

118. The pharmaceutical composition of any one of Claims 114-117, wherein the

maintenance dose is administered up to two years.

119. The pharmaceutical composition of any one of Claims 101-118, wherein the anti human TIM-3 antibody is administered in combination with an effective amount of an anti-human PD-L1 (SEQ ID NO: 14) antibody or an effective amount of an anti human PD-1 (SEQ ID NO: 15) antibody.

120. The pharmaceutical composition of Claim 119, wherein the anti-human PD-L1 antibody is durvalumab, atezolizumab, or avelumab.

121. The pharmaceutical composition of Claim 119, wherein the anti-human PD-L1 antibody comprises a light chain having the amino acid sequence of SEQ ID NO: 12 and a heavy chain having the amino acid sequence of SEQ ID NO: 13.

122. The pharmaceutical composition of any one of Claims 119-121, wherein the anti human PD-L1 antibody is administered at a dose of about 35 mg to about 1800 mg.

123. The pharmaceutical composition of Claim 122, wherein the dose of the anti

human PD-L1 antibody is administered once every two weeks.

124. The pharmaceutical composition of Claim 123, wherein the dose of the anti

human PD-L1 antibody is in the range of 70 mg to 700 mg.

125. The pharmaceutical composition of Claim 123, wherein the dose of the anti

human PD-L1 antibody is 35 mg.

126. The pharmaceutical composition of Claim 123, wherein the dose of the anti

human PD-L1 antibody is 70 mg.

127. The pharmaceutical composition of Claim 123, wherein the dose of the anti

human PD-L1 antibody is 200 mg.

128. The pharmaceutical composition of Claim 123, wherein the dose of the anti human PD-L1 antibody is 700 mg.

129. The pharmaceutical composition of Claim 122, wherein the dose of the anti

human PD-L1 antibody is administered once every three weeks.

130. The pharmaceutical composition of Claim 129, wherein the dose of the anti

human PD-L1 antibody is in the range of 70 mg to 1400 mg.

131. The pharmaceutical composition of Claim 129, wherein the dose of the anti

human PD-L1 antibody is 1000 mg.

132. The pharmaceutical composition of Claim 129, wherein the dose of the anti

human PD-L1 antibody is 1200 mg.

133. The pharmaceutical composition of Claim 129, wherein the dose of the anti

human PD-L1 antibody is 1400 mg.

134. The pharmaceutical composition of Claim 122, wherein the dose of the anti

human PD-L1 antibody is administered once every four weeks.

135. The pharmaceutical composition of Claim 134, wherein the dose of the anti

human PD-L1 antibody is 1800 mg.

136. The pharmaceutical composition of Claim 119, wherein the anti-human PD-1 antibody is administered and is pembrolizumab, nivolumab, or cemiplimab.

137. The pharmaceutical composition of Claim 136, wherein the dose of the anti

human PD-1 antibody is administered once every 2 to 4 weeks.

138. The pharmaceutical composition of Claim 137, wherein the dose of the anti

human PD-1 antibody is 200 mg administered once every 3 weeks.

139. The pharmaceutical composition of Claim 137, wherein the dose of the anti

human PD-1 antibody is 240 mg administered once every 2 weeks or 480 mg once every 4 weeks.

140. The pharmaceutical composition of any one of Claims 101-139, wherein the patient was previously treated with an anti-human PD-L1 antibody or an anti-human PD-1 antibody.

141. The pharmaceutical composition of any one of Claims 101-139, wherein the patient has not been previously treated with an anti -human PD-L1 antibody or an anti human PD-1 antibody.

142. The pharmaceutical composition of any one of Claims 101-139, wherein the cancer is a solid tumor.

143. The pharmaceutical composition of Claim 42, wherein the solid tumor is PD-L1 high.

144. The pharmaceutical composition of Claim 42, wherein the solid tumor is PD-L1 low.

145. The pharmaceutical composition of Claim 42, wherein the solid tumor has a high degree of microsatellite instability.

146. The pharmaceutical composition of Claim 42, wherein the solid tumor is

mismatch repair deficient.

147. The pharmaceutical composition of Claim 42, wherein the solid tumor has a high degree of microsatellite instability and is mismatch repair deficient.

148. The pharmaceutical composition of any one of Claims 101-139, wherein the

cancer is melanoma, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, gastric cancer, kidney cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, esophageal cancer, soft tissue sarcoma, liver cancer, gallbladder cancer, cervical cancer, duodenal cancer, bone cancer, neuroendocrine cancer, intestinal cancer.

149. The pharmaceutical composition of Claim 148, wherein the cancer is melanoma or non-small cell lung cancer.

150. The pharmaceutical composition of any one of Claims 101-139, wherein at least one of the anti-human TIM-3 antibody, anti -human PD-1 antibody, and anti -human PD-L1 antibody is administered with ionizing radiation.