EA050059B1 - CANCER TREATMENT METHODS USING TIM-3 ANTIBODIES - Google Patents

Abstract

The present invention provides methods for administering certain TIM-3 binding agents to patients with cancer. Dosage regimens for compositions containing a TIM-3 binding agent are also detailed.

Description

Cross-reference to related applications

This application claims priority to U.S. Provisional Patent Application No. 62/444,354, filed January 9, 2017, and U.S. Provisional Patent Application No. 62/582,272, filed November 6, 2017, each of which is incorporated by reference in its entirety.

List of sequences

This description refers to a sequence listing provided in electronic form as an ASCII.txt file named TSR-002 SEQ LISTST25, which was created on January 8, 2018 and has a size of 39647 bits.

Prerequisites for the creation of an invention

Cancer is a major public health problem, with approximately 600,920 people expected to die from cancer in the United States in 2017 alone according to the American Cancer Society, Cancer Facts & Figures 2017 (https://www.cancer.org/research/cancer-factsstatistics/all-cancer-facts-figures/cancer-facts-figures-2017.html). Consequently, there remains a need for effective therapies to treat patients with cancer.

Brief description of the invention

The present invention embraces the recognition that certain dosage regimens for agents that are capable of suppressing T-cell immunoglobulin and mucin domain 3 (TIM-3) signaling (e.g., anti-TIM-3 antibody agents) are useful for treating disorders such as cancer.

In some embodiments, the present invention provides methods for treating disorders, such as cancer, that comprise administering compositions that deliver specific TIM-3 inhibitors (e.g., TIM-3 antibody agents) according to dosage regimens that can achieve clinical benefit in at least some patients.

In embodiments, the TIM-3 inhibitor is a TIM-3 binding agent. In embodiments, the TIM-3 binding agent is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. In embodiments, the TIM-3 binding agent is an antibody-based agent (i.e., an anti-TM-3 antibody-based agent).

In embodiments, the anti-TIM-3 antibody agent comprises a heavy chain variable region with one or more CDR sequences selected from SEQ ID NOs: 21, 22, and 23, and/or a light chain variable region with one or more CDR sequences selected from SEQ ID NOs: 24, 25, and 26. In embodiments, the anti-TIM-3 antibody agent comprises a heavy chain variable region with two or three CDR sequences selected from SEQ ID NOs: 21, 22, and 23, and/or a light chain variable region with two or three CDR sequences selected from SEQ ID NOs: 24, 25, and 26. In embodiments, the anti-TIM-3 antibody agent comprises a heavy chain variable region with three CDR sequences of SEQ ID NOs: 21, 22, and 23, and/or a light chain variable region with three CDRs of SEQ ID NOs: 24, 25, and 26. In embodiments, the anti-TIM-3 antibody agent comprises a heavy chain variable region with three CDR sequences of SEQ ID NOs: 21, 22, and 23, and a light chain variable region with three CDR sequences of SEQ ID NOs: 24, 25, and 26.

In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence has at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:1 or SEQ ID NO:7. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin light chain variable domain whose amino acid sequence has at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:2 or SEQ ID NO:8. In some embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7 and/or an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7 and an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8.

In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain polypeptide comprising an amino acid sequence having about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 3. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin light chain polypeptide comprising an amino acid sequence having about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain

- 1 050059 noglobulin, the amino acid sequence of which comprises SEQ ID NO: 3, and/or an immunoglobulin light chain, the amino acid sequence of which comprises SEQ ID NO: 4. In some embodiments, the TIM-3 antibody-based agent comprises an immunoglobulin heavy chain, the amino acid sequence of which comprises SEQ ID NO: 3, and an immunoglobulin light chain, the amino acid sequence of which comprises SEQ ID NO: 4.

In some embodiments, the present invention provides methods of treating a disorder in a subject that is capable of responding to suppression of T cell immunoglobulin mucin 3 (TIM-3) protein comprising administering a therapeutically effective dose of an agent that is capable of suppressing TIM-3 signaling. In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of a TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 100-1500 mg of a TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 100 mg; a constant dose of about 200 mg; a constant dose of about 300 mg; a constant dose of about 400 mg; a constant dose of about 500 mg; a constant dose of about 600 mg; a constant dose of about 700 mg; a constant dose of about 800 mg; a constant dose of about 900 mg; a constant dose of about 1000 mg; a constant dose of about 1100 mg; a constant dose of about 1200 mg; a constant dose of about 1300 mg; a constant dose of about 1400 mg; or a constant dose of about 1500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 1 mg/kg. In embodiments, the therapeutically effective dose is about 3 mg/kg. In embodiments, the therapeutically effective dose is about 10 mg/kg. In embodiments, the therapeutically effective dose is a constant dose of about 100 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 300 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 1200 mg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is any anti-TIM-3 antibody agent described herein.

In some embodiments, the present invention provides methods of enhancing T cell activation or T cell effector function in a subject that is capable of responding to T cell immunoglobulin mucin 3 (TIM-3) protein suppression comprising administering a therapeutically effective dose of an agent that is capable of suppressing TTM-3 signaling. In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of a TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 100-1500 mg of a TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 100 mg; a constant dose of about 200 mg; a constant dose of about 300 mg; a constant dose of about 400 mg; a constant dose of about 500 mg; a constant dose of about 600 mg; a constant dose of about 700 mg; a constant dose of about 800 mg; a constant dose of about 900 mg; a constant dose of about 1000 mg; a constant dose of about 1100 mg; a constant dose of about 1200 mg; a constant dose of about 1300 mg; a constant dose of about 1400 mg; or a constant dose of about 1500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 1 mg/kg. In embodiments, the therapeutically effective dose is about 3 mg/kg. In embodiments, the therapeutically effective dose is about 10 mg/kg. In embodiments, the therapeutically effective dose is a constant dose of about 100 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 300 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 900 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 1200 mg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is any TIM-3 antibody agent described herein.

In some embodiments, the present invention provides methods of reducing tumors or suppressing tumor cell growth in a subject that is capable of responding to suppression of T cell immunoglobulin mucin 3 (TIM-3) protein comprising administering a therapeutically effective dose of an agent that is capable of suppressing TTM-3 signaling. In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of a TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 100 to 1500 mg of a TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 100 mg; a constant dose of about 200 mg; a constant dose of about 300 mg; a constant dose of about 400 mg; a constant dose of about 500 mg; a constant dose of about 600 mg; a constant dose of about 700 mg; a constant dose of about 800 mg; constant dose of approximately 900 mg; constant dose of approximately 1000 mg; constant dose of approximately 1100 mg; constant dose of approximately 1200 mg; constant dose at

- 2 050059 about 1300 mg; a constant dose of about 1400 mg, or a constant dose of about 1500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 1 mg/kg. In embodiments, the therapeutically effective dose is about 3 mg/kg. In embodiments, the therapeutically effective dose is about 10 mg/kg. In embodiments, the therapeutically effective dose is a constant dose of about 100 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 300 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 900 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 1200 mg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is any TIM-3 antibody agent described herein.

In some embodiments, the present invention provides methods of inducing an immune response in a subject that is capable of responding to T cell immunoglobulin mucin 3 (TIM-3) protein suppression comprising administering a therapeutically effective dose of an agent that is capable of suppressing TIM-3 signaling. In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of a TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 100-1500 mg of a TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 100 mg; a constant dose of about 200 mg; a constant dose of about 300 mg; a constant dose of about 400 mg; a constant dose of about 500 mg; a constant dose of about 600 mg; a constant dose of about 700 mg; a constant dose of about 800 mg; a constant dose of about 900 mg; a constant dose of about 1000 mg; a constant dose of about 1100 mg; a constant dose of about 1200 mg; a constant dose of about 1300 mg; a constant dose of about 1400 mg; or a constant dose of about 1500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 1 mg/kg. In embodiments, the therapeutically effective dose is about 3 mg/kg. In embodiments, the therapeutically effective dose is about 10 mg/kg. In embodiments, the therapeutically effective dose is a constant dose of about 100 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 300 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 900 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 1200 mg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is any TIM-3 antibody agent described herein.

In some embodiments, the present invention provides methods of enhancing an immune response or increasing immune cell activity in a subject that is capable of responding to a T cell immunoglobulin mucin 3 (TIM-3) protein suppression comprising administering a therapeutically effective dose of an agent that is capable of suppressing TM-3 signaling. In embodiments, the immune response is a humoral or cell-mediated immune response. In embodiments, the immune response is a CD4 or CD8 T cell response. In embodiments, the immune response is a B cell response. In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 100-1500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 100 mg; a constant dose of about 200 mg; a constant dose of about 300 mg; a constant dose of about 400 mg; a constant dose of about 500 mg; a constant dose of about 600 mg; a constant dose of about 700 mg; a constant dose of about 800 mg; a constant dose of about 900 mg; a constant dose of about 1000 mg; a constant dose of about 1100 mg; a constant dose of about 1200 mg; a constant dose of about 1300 mg; a constant dose of about 1400 mg; or a constant dose of about 1500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 1 mg/kg. In embodiments, the therapeutically effective dose is about 3 mg/kg. In embodiments, the therapeutically effective dose is about 10 mg/kg. In embodiments, the therapeutically effective dose is about 100 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 300 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 900 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 1200 mg of the TIM-3 inhibitor. In embodiments, the inhibitor

- 3 050059 TIM-3 inhibitor is any TIM-3 antibody-based agent described herein.

In some embodiments, the present invention provides methods of treating cancer that comprise administering to a patient in need of treatment, an agent directed against T cell immunoglobulin and mucin domain 3 (TIM-3) in a therapeutically effective dose. In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 100 to 1500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 100 mg; a constant dose of about 200 mg; a constant dose of about 300 mg; a constant dose of about 400 mg; a constant dose of about 500 mg; a constant dose of about 600 mg; a constant dose of about 700 mg; a constant dose of about 800 mg; a constant dose of about 900 mg; a constant dose of about 1000 mg; a constant dose of about 1100 mg; a constant dose of about 1200 mg; a constant dose of about 1300 mg; a constant dose of about 1400 mg; or a constant dose of about 1500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 1 mg/kg. In embodiments, the therapeutically effective dose is about 3 mg/kg. In embodiments, the therapeutically effective dose is about 10 mg/kg. In embodiments, the therapeutically effective dose is a constant dose of about 100 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 300 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 900 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 1200 mg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is any TIM-3 antibody agent described herein.

In some embodiments, the present invention provides methods of treating cancer comprising administering to a patient in need of treatment an antibody to a T cell immunoglobulin and mucin domain 3 (TIM-3) at a therapeutically effective dose at an administration interval for a period sufficient to provide clinical benefit. In embodiments, the antibody to TIM-3 comprises a heavy chain comprising three CDRs that have the sequences of SEQ ID NO: 21, 22, or 23; and/or a light chain comprising three CDRs that have the sequences of SED ID NO: 24, 25, or 26. In embodiments, the anti-TIM-3 antibody comprises an immunoglobulin heavy chain variable domain comprising SEQ ID NO: 1 or SEQ ID NO: 7 and an immunoglobulin light chain variable domain comprising SEQ ID NO: 2 or SEQ ID NO: 8. In embodiments, the anti-TIM-3 antibody comprises a heavy chain polypeptide comprising SEQ ID NO: 3 and a light chain polypeptide comprising SEQ ID NO: 4. In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of the anti-TIM-3 antibody. In embodiments, the therapeutically effective dose is about 100 to 1500 mg of the anti-TIM-3 antibody. In embodiments, the therapeutically effective dose is a constant dose of about 100 mg; a constant dose of about 200 mg; a constant dose of about 300 mg; a constant dose of about 400 mg; a constant dose of about 500 mg; a constant dose of about 600 mg; a constant dose of about 700 mg; a constant dose of about 800 mg; a constant dose of about 900 mg; a constant dose of about 1000 mg; a constant dose of about 1100 mg; a constant dose of about 1200 mg; a constant dose of about 1300 mg; a constant dose of about 1400 mg; or a constant dose of about 1500 mg of the anti-TIM-3 antibody. In embodiments, the therapeutically effective dose is about 1 mg/kg of the anti-TIM-3 antibody. In embodiments, the therapeutically effective dose is about 3 mg/kg of the anti-TIM-3 antibody. In embodiments, the therapeutically effective dose is about 10 mg/kg of the anti-TIM-3 antibody. In embodiments, the therapeutically effective dose is a constant dose of about 100 mg of the anti-TIM-3 antibody. In embodiments, the therapeutically effective dose is a constant dose of about 300 mg of the anti-TIM-3 antibody. In embodiments, the therapeutically effective dose is a constant dose of about 500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 900 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a constant dose of about 1200 mg of the anti-TIM-3 antibody.

In any of the methods described herein, the therapeutically effective dose is about 1 mg/kg of the TTM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 3 mg/kg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 5 mg/kg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is any TIM-3 antibody agent described herein.

In any of the methods described herein, the therapeutically effective dose is approximately 100 mg of the TIM-3 inhibitor. In any of the methods described herein,

- 4 050059 ment, the therapeutically effective dose is about 200 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 300 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 400 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 500 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 600 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 700 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 800 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 900 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 1000 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 1100 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 1200 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 1300 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 1400 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 1500 mg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is any TIM-3 antibody agent described herein.

In embodiments, the TIM-3 inhibitor is administered at an administration interval (or treatment cycle) of once per week (Q1W), once every 2 weeks (Q2W), once every 3 weeks (Q3W), once every 4 weeks (Q4W), once every 5 weeks (Q5W), or once every 6 weeks (Q6W). In embodiments, the TIM-3 inhibitor is administered over a period of at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks or more. In embodiments, the TIM-3 inhibitor is administered at an administration interval (or treatment cycle) of once per week (Q1W). In embodiments, the TIM-3 inhibitor is administered at an administration interval (or treatment cycle) of once every 2 weeks (Q2W). In embodiments, the TIM-3 inhibitor is administered at an administration interval (or treatment cycle) of once every three weeks (Q3W). In embodiments, the TIM-3 inhibitor is administered at an administration interval (or treatment cycle) of once every 4 weeks (Q4W). In embodiments, the TIM-3 inhibitor is administered at an administration interval (or treatment cycle) of once every 5 weeks (Q5W). In embodiments, the TIM-3 inhibitor is administered at an administration interval (or treatment cycle) of once every 6 weeks (Q6W).

In embodiments, a TIM-3 inhibitor (e.g., a therapeutically effective dose of about 100 mg, 300 mg, 500 mg, or 900 mg) is administered at an administration interval (or treatment cycle) of once every 3 weeks. In embodiments, a therapeutically effective dose of about 100 mg is administered at an administration interval (or treatment cycle) of once every 3 weeks. In embodiments, a therapeutically effective dose of about 300 mg is administered at an administration interval (or treatment cycle) of once every 3 weeks. In embodiments, a therapeutically effective dose of about 500 mg is administered at an administration interval (or treatment cycle) of once every 3 weeks. In embodiments, a therapeutically effective dose of about 900 mg is administered at an administration interval (or treatment cycle) of once every 3 weeks.

In embodiments, the TIM-3 inhibitor is administered on day 1 of a treatment cycle or within 1, 2, or 3 days of day 1 of a treatment cycle. In embodiments, the TIM-3 inhibitor is any TIM-3 antibody agent described herein.

In embodiments, the TIM-3 inhibitor described herein is administered according to dosing regimens that have been shown to achieve clinical benefit in some patients (e.g., according to a regimen determined by a physician, including dosing modifications). In embodiments, the TIM-3 inhibitor described herein is administered until treatment is discontinued due to, for example, disease progression or an adverse reaction, or as determined by a physician. In embodiments, the clinical benefit is stable disease (SD), a partial response (PR), and/or a complete response (CR). In embodiments, the clinical benefit is stable disease (SD). In embodiments, the clinical benefit is a partial response (PR). In embodiments, the clinical benefit is a complete response (CR). In embodiments, PR or CR are determined according to Response Evaluation Criteria in Solid Tumors (RECIST). In embodiments, the TIM-3 inhibitor is administered for a longer period to maintain clinical benefit. In embodiments, the TIM-3 inhibitor is any TIM-3 antibody agent described herein.

In embodiments, the TIM-3 inhibitor is administered to the subject periodically at a dose of about 100 mg, about 300 mg, or about 1200 mg. In embodiments, the inhibitor

- 5 050059

TIM-3 is administered to the subject periodically at a dose of about 100 mg (e.g., once every three weeks (Q3W) and/or for 2, 3, 4, 5, 6, or more cycles). In embodiments, the TIM-3 inhibitor is administered to the subject periodically at a dose of about 300 mg (e.g., once every three weeks (Q3W) and/or for 2, 3, 4, 5, 6, or more cycles). In embodiments, the TIM-3 inhibitor is administered to the subject periodically at a dose of about 1200 mg (e.g., once every three weeks (Q3W) and/or for 2, 3, 4, 5, 6, or more cycles). In embodiments, the TIM-3 inhibitor is any anti-TIM-3 antibody agent described herein.

In embodiments, the subject has been or will be further administered an additional therapeutic agent, whereby the subject receives a TIM-3 inhibitor (e.g., any TIM-3 antibody agent described herein) and an additional therapeutic agent (e.g., one, two, three, four, or more additional therapies).

In embodiments, the subject has additionally been or will be administered an immune checkpoint inhibitor, whereby the subject receives a TIM-3 inhibitor (e.g., any TIM-3 antibody agent described herein) and an immune checkpoint inhibitor. Thus, the subject may be administered a TIM-3 inhibitor in combination with at least one immune checkpoint inhibitor.

In embodiments, the checkpoint inhibitor is an agent capable of inhibiting any of the following: PD-1 (e.g., inhibition by anti-PD-1, anti-PD-L1, or anti-PD-L2 therapies), CTLA-4, TIM-3, TIGIT, LAG (e.g., LAG-3), CEACAM (e.g., CEACAM-1, -3, and/or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (e.g., TGFR beta), B7-H1, B7-H4 (VTCN1), OX-40, CD137, CD40, IDO, or CSF-1R. In embodiments, the checkpoint inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the checkpoint inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.

In embodiments, the immune checkpoint inhibitor is an agent that inhibits programmed death protein 1 (PD-1) signaling, cytotoxic T lymphocyte-associated protein 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin and ITIM domain (TIGIT), indoleamine 2,3-dioxygenase (IDO), or colony stimulating factor 1 receptor (CSF1R).

In embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. In embodiments, the PD-1 inhibitor is a PD-1 binding agent (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the PD-1 binding agent is nivolumab, pembrolizumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, AMP-514/MEDI-0680, AGEN-2034, CS1001, TSR-042, Sym-021, PF-06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), AK 104 or GLS-010 or derivatives thereof. In embodiments, the PD-1 inhibitor is a PD-L1 or PD-L2 binder (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the PD-1 inhibitor is a PD-L1 or PD-L2 binder such as durvalumab, atezolizumab, avelumab, BGB-A333, SHR-1316, FAZ-053, CK-301, or an anti-PD-L1 millimolecule, or derivatives thereof. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered to the subject periodically at a dose of about 500 mg or 1000 mg. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered to the subject periodically at a dose of about 500 mg or 1000 mg. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered to the subject periodically at a dose of about 500 mg. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered to the subject once every 3 weeks. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered for 2, 3, 4, 5, 6, or more cycles. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered for 4 cycles. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered to the subject periodically at a dose of about 1000 mg. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered to the subject once every 6 weeks. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered at a first dose of about 500 mg once every 3 weeks for 4 cycles, followed by a second dose of about 1000 mg once every 6 weeks (e.g., until treatment is discontinued).

In embodiments, the immune checkpoint inhibitor is a CTLA4 inhibitor (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the CTLA-4 inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the CTLA4 inhibitor is a small molecule. In embodiments, the CTLA-4 inhibitor is a CTLA-4 binding agent. In embodiments, the CTLA-4 inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. In embodiments, the inhibitor

- 6 050059

CTLA-4 is ipilimumab (Yervoy), AGEN1884, or tremelimumab.

In embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the LAG-3 inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the LAG-3 inhibitor is a small molecule. In embodiments, the LAG-3 inhibitor is a LAG-3 binding agent. In embodiments, the LAG-3 inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. In embodiments, the LAG-3 inhibitor is IMP321, BMS-986016, GSK2831781, Novartis LAG525, or a LAG-3 inhibitor described in WO 2016/126858, WO 2017/019894, or WO 2015/138920, each of which is incorporated herein by reference in its entirety.

In embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the TIGIT inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the TIGIT inhibitor is a small molecule. In embodiments, the TIGIT inhibitor is a TIGIT binding agent. In embodiments, the TIGIT inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. In embodiments, the TIGIT inhibitor is MTIG7192A, BMS-986207, or OMP-31M32.

In embodiments, the immune checkpoint inhibitor is an IDO inhibitor. In embodiments, the IDO inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the IDO inhibitor is a small molecule. In embodiments, the IDO inhibitor is an IDO binding agent. In embodiments, the IDO inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.

In embodiments, the immune checkpoint inhibitor is a CSF1R inhibitor. In embodiments, the CSF1R inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the CSF1R inhibitor is a small molecule. In embodiments, the inhibitor

CSF1R is a CSF1R binding agent. In embodiments, the CSF1R inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.

In embodiments, the method comprises administering a TIM-3 inhibitor (e.g., any anti-TIM-3 antibody agent described herein) with at least two immune checkpoint inhibitors. In embodiments, the method comprises administering a third checkpoint inhibitor. In embodiments, the method comprises administering a TIM3 inhibitor with a PD-1 inhibitor and a LAG-3 inhibitor, such that the subject receives all three. In embodiments, the method comprises administering a TIM-3 inhibitor with a PD-1 inhibitor, a LAG-3 inhibitor, and a CTLA-4 inhibitor, such that the subject receives all four.

In embodiments, the subject has additionally been or will be administered an agent that inhibits poly(ADP-ribose) polymerase (PARP), resulting in the subject receiving treatment with a TIM-3 inhibitor and a PARP inhibitor.

In embodiments, the PARP inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the PARP inhibitor is selected from the group consisting of: ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib, IMP 4297, INO1001, JPI 289, JPI 547, B3-LysPE40 monoclonal antibody conjugate, MP 124, niraparib, NU 1025, NU 1064, NU 1076, NU1085, olaparib, ONO2231, PD 128763, R 503, R554, rucaparib, SBP 101, SC 101914, simmiparib, talazoparib, veliparib, WW 46, 2-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3D]pyrimidin-4-ol, and salts or derivatives thereof. In embodiments, the PARP inhibitor is nirapirib, olaparib, rucaparib, talazoparib, or veliparib. In embodiments, the PARP inhibitor is niraparib (e.g., niraparib free base, niraparib tosylate, or niraparib tosylate monohydrate, or any combination thereof).

In embodiments, the subject is further administered or will be administered one or more immune checkpoint inhibitors (e.g., a PD-1 inhibitor and/or a LAG-3 inhibitor), whereby the subject is treated with a TIM-3 inhibitor, a PARP inhibitor (e.g., niraparib), and one or more immune checkpoint inhibitors. In embodiments, the subject is administered a TIM-3 inhibitor, a PD-1 inhibitor (e.g., TSR-042), and a PARP inhibitor (e.g., niraparib). In embodiments, the subject is administered a TIM-3 inhibitor, a PD-1 inhibitor (e.g., TSR042), a LAG-3 inhibitor, and a PARP inhibitor (e.g., niraparib).

In embodiments, the patient has a disorder that is a dysfunctional T cell disorder.

In embodiments, the patient has a disorder that is cancer.

- 7 050059

In embodiments, the cancer is associated with a high tumor mutational burden (TMB).

In embodiments, the cancer is microsatellite stable (MSS).

In embodiments, the cancer is characterized by microsatellite instability.

In embodiments, the cancer has a microsatellite instability-high (MSI-H) status.

In embodiments, the cancer has a microsatellite instability-low (MSI-L) status.

In embodiments, cancer is associated with high TMB and MSI-H.

In embodiments, the cancer is associated with high TMB and MSI-L or MSS.

In embodiments, the cancer is associated with high TMB and MSI-L.

In embodiments, the cancer is associated with high TMB and MSS.

In embodiments, the cancer has a defective DNA mismatch repair system.

In embodiments, the cancer is characterized by a defect in a DNA mismatch repair gene.

In embodiments, the cancer is a hypermutated cancer.

In embodiments, the cancer is characterized by homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer involves a mutation in polymerase delta (POLD).

In embodiments, the cancer involves a mutation in polymerase epsilon (POLE).

In embodiments, the cancer is endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, testicular cancer, primary peritoneal cancer, colon cancer, colorectal cancer, gastric cancer, small bowel cancer, squamous cell carcinoma of the anogenital region (e.g., squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), soft tissue sarcoma (e.g., leiomyosarcoma), melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell carcinoma of the lung, gastric cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, hematological cancer, multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma (HL)/primary mediastinal B-cell lymphoma, chronic myelogenous leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, neuroblastoma, CNS tumor, diffuse intrinsic glioma of the brainstem (DIPG), Ewing's sarcoma, embryonal rhabdomyosarcoma, osteosarcoma, or Wilms' tumor. In embodiments, the cancer is MSS or MSI-L, has microsatellite instability, is MSI-H, has high TMB, has high TMB and is MSS or MSI-L, has high TMB and is MSI-H, has a defective DNA mismatch repair system, has a defect in a DNA mismatch repair gene, is a hypermutated cancer, is an HRD cancer, has a mutation in polymerase delta (POLD), or has a mutation in polymerase epsilon (POLE).

In embodiments, the cancer is endometrial cancer (e.g., MSI-H or MSS/MSI-L endometrial cancer). In embodiments, the cancer is MSI-H cancer that has a mutation in POLE or POLD (e.g., MSI-H non-endometrial cancer that has a mutation in POLE or POLD). In embodiments, the cancer is breast cancer (triple-negative breast cancer (TNBC)). In embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer). In embodiments, the cancer is melanoma. In embodiments, the cancer is colorectal cancer. In embodiments, the cancer is squamous cell carcinoma of the anus, squamous cell carcinoma of the penis, squamous cell carcinoma of the cervix, squamous cell carcinoma of the vagina, or squamous cell carcinoma of the vulva.

In embodiments, the cancer is characterized by homologous recombination repair deficiency/homologous repair deficiency (HRD). In embodiments, the cancer is acute myeloid leukemia. In embodiments, the cancer is acute lymphoblastic leukemia. In embodiments, the cancer is non-Hodgkin lymphoma. In embodiments, the cancer is Hodgkin lymphoma. In embodiments, the cancer is neuroblastoma. In embodiments, the cancer is a CNS tumor. In embodiments, the cancer is diffuse intrinsic glioma (DIPG). In embodiments, the cancer is Ewing's sarcoma. In embodiments, the cancer is embryonal rhabdomyosarcoma. In embodiments, the cancer is osteosarcoma. In embodiments, the cancer is Wilms tumor. In embodiments, the cancer is a soft tissue sarcoma (e.g., leiomyosarcoma).

In some embodiments, the patient has a cancer such as non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cell carcinoma, melanoma, cervical cancer, colorectal cancer, anogenital squamous cell carcinoma, head and neck cancer, triple-negative breast cancer, ovarian cancer, or endometrial cancer. In some embodiments, the patient has

- 8 050059 cancer with microsatellite instability. In some embodiments, microsatellite instability is considered high, wherein the instability is significantly higher than the instability observed in a control cell (e.g., MSI-H status). In some embodiments, the patient has a solid tumor. In some embodiments, the patient has an advanced solid tumor. In some embodiments, the patient has an advanced solid tumor, such as non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cancer, melanoma, cervical cancer, colorectal cancer, anogenital squamous cell carcinoma, head and neck cancer, triple-negative breast cancer, ovarian cancer, or endometrial cancer. In some embodiments, the patient has an advanced solid tumor with microsatellite instability.

In some embodiments, the patient has a hematological cancer. In some embodiments, the patient has a hematological cancer such as diffuse large B cell lymphoma (DLBCL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), follicular lymphoma (FL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM). In some embodiments, the patient has a hematological cancer with microsatellite instability.

In some embodiments, the patient has a cancer characterized by expression of PD-1 and/or PD-L1. In some embodiments, the cancer is characterized by high expression of PD1 and/or PD-L1 (e.g., high expression of PD-1 and/or high expression of PD-L1). In a specific embodiment, the cancer characterized by expression of PD-1 and/or PD-L1 is head and neck cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendiceal cancer, urothelial cell carcinoma, or squamous cell carcinoma (e.g., of the lung; anogenital region, including the anus, penis, cervix, vagina, or vulva; or esophagus). In some embodiments, the cancer characterized by expression of PD-1 and/or PD-L1 is anal cancer, fallopian tube cancer, ovarian cancer, or lung cancer.

In some embodiments, the patient has head and neck cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendiceal cancer, urothelial cell carcinoma, or squamous cell carcinoma.

In embodiments, the cancer is an advanced cancer. In embodiments, the cancer is a metastatic cancer. In embodiments, the cancer is an MSI-H cancer. In embodiments, the cancer is an MSS cancer. In embodiments, the cancer is a POLE mutant cancer. In embodiments, the cancer is a POLD mutant cancer. In embodiments, the cancer is a high-TMB cancer. In embodiments, the cancer is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is a solid tumor. In embodiments, the solid tumor is at an advanced stage. In embodiments, the solid tumor is a metastatic solid tumor. In embodiments, the solid tumor is an MSI-H solid tumor. In embodiments, the solid tumor is an MSS solid tumor. In embodiments, the solid tumor is a POLE mutant solid tumor. In embodiments, the solid tumor is a POLD mutant solid tumor. In embodiments, the solid tumor is a high-TMB solid tumor. In embodiments, the solid tumor is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is a non-endometrial cancer (e.g., a non-endometrial solid tumor). In embodiments, the non-endometrial cancer is an advanced cancer. In embodiments, the non-endometrial cancer is a metastatic cancer. In embodiments, the non-endometrial cancer is an MSI-H cancer. In embodiments, the non-endometrial cancer is an MSS cancer. In embodiments, the non-endometrial cancer is a POLE mutant cancer. In embodiments, the non-endometrial cancer is a solid tumor (e.g., an MSS solid tumor, an MSI-H solid tumor, a POLD mutant solid tumor, or a POLE mutant solid tumor). In embodiments, the non-endometrial cancer is a high-MBM cancer. In embodiments, the non-endometrial cancer is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

- 9 050059

In embodiments, the cancer is endometrial cancer (e.g., a solid tumor). In embodiments, the endometrial cancer is an advanced cancer. In embodiments, the endometrial cancer is a metastatic cancer. In embodiments, the endometrial cancer is an MSI-H endometrial cancer. In embodiments, the endometrial cancer is an MSS endometrial cancer. In embodiments, the endometrial cancer is a POLE mutant endometrial cancer. In embodiments, the endometrial cancer is a POLD mutant endometrial cancer. In embodiments, the endometrial cancer is a high-TMB endometrial cancer. In embodiments, the endometrial cancer is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is lung cancer (e.g., a solid tumor). In embodiments, the lung cancer is advanced lung cancer. In embodiments, the lung cancer is metastatic lung cancer. In embodiments, the lung cancer is squamous cell carcinoma of the lung. In embodiments, the lung cancer is small cell lung cancer (SCLC). In embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In embodiments, the lung cancer is ALK translocation lung cancer (e.g., lung cancer with a known ALK translocation). In embodiments, the lung cancer is EGFR mutant lung cancer (e.g., lung cancer with a known EGFR mutation). In embodiments, the lung cancer is MSI-H lung cancer. In embodiments, the lung cancer is MSS lung cancer. In embodiments, the lung cancer is POLE mutant lung cancer. In embodiments, the lung cancer is POLD mutant lung cancer. In embodiments, the lung cancer is a high TMB lung cancer. In embodiments, the lung cancer is associated with homologous recombination repair deficiency/homologic repair deficiency (HRD).

In embodiments, the cancer is colorectal (CRC) cancer (e.g., a solid tumor). In embodiments, the colorectal cancer is advanced colorectal cancer. In embodiments, the colorectal cancer is metastatic colorectal cancer. In embodiments, the colorectal cancer is MSI-H colorectal cancer. In embodiments, the colorectal cancer is MSS colorectal cancer. In embodiments, the colorectal cancer is POLE mutant colorectal cancer. In embodiments, the colorectal cancer is POLD mutant colorectal cancer. In embodiments, the colorectal cancer is TMB-high colorectal cancer. In embodiments, the colorectal cancer is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is melanoma. In embodiments, the melanoma is advanced melanoma. In embodiments, the melanoma is metastatic melanoma. In embodiments, the melanoma is MSI-H melanoma. In embodiments, the melanoma is MSS melanoma. In embodiments, the melanoma is POLE mutant melanoma. In embodiments, the melanoma is POLD mutant melanoma. In embodiments, the melanoma is TMB-high melanoma. In embodiments, the melanoma is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is anogenital squamous cell carcinoma (e.g., anus, penis, cervix, vagina, or vulva). In embodiments, the anogenital squamous cell carcinoma (e.g., anus, penis, cervix, vagina, or vulva) is an advanced cancer. In embodiments, the anogenital squamous cell carcinoma (e.g., anus, penis, cervix, vagina, or vulva) is a metastatic cancer. In embodiments, the anogenital squamous cell carcinoma (e.g., anus, penis, cervix, vagina, or vulva) is MSI-H. In embodiments, the anogenital squamous cell carcinoma (e.g., anus, penis, cervix, vagina, or vulva) is MSS. In embodiments, the lung cancer is a POLE mutant cancer. In embodiments, squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva) is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is ovarian cancer. In embodiments, the ovarian cancer is advanced ovarian cancer. In embodiments, the ovarian cancer is metastatic ovarian cancer. In embodiments, the ovarian cancer is MSI-H ovarian cancer. In embodiments, the ovarian cancer is MSS ovarian cancer. In embodiments, the ovarian cancer is POLE mutant ovarian cancer. In embodiments, the ovarian cancer is POLD mutant ovarian cancer. In embodiments

- 10 050059 embodiments, the ovarian cancer is ovarian cancer with high TMB. In embodiments, the ovarian cancer is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD). In embodiments, the ovarian cancer is serous cell ovarian cancer. In embodiments, the ovarian cancer is clear cell ovarian cancer.

In embodiments, the cancer is fallopian tube cancer. In embodiments, the fallopian tube cancer is advanced fallopian tube cancer. In embodiments, the fallopian tube cancer is metastatic fallopian tube cancer. In embodiments, the fallopian tube cancer is MSI-H fallopian tube cancer. In embodiments, the fallopian tube cancer is MSS fallopian tube cancer. In embodiments, the fallopian tube cancer is POLE mutant fallopian tube cancer. In embodiments, the fallopian tube cancer is POLD mutant fallopian tube cancer. In embodiments, the fallopian tube cancer is high-TMB fallopian tube cancer. In embodiments, the fallopian tube cancer is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD). In embodiments, the fallopian tube cancer is serous cell fallopian tube cancer. In embodiments, the fallopian tube cancer is clear cell fallopian tube cancer.

In embodiments, the cancer is a primary peritoneal cancer. In embodiments, the primary peritoneal cancer is an advanced primary peritoneal cancer. In embodiments, the primary peritoneal cancer is a metastatic primary peritoneal cancer. In embodiments, the primary peritoneal cancer is an MSI-H primary peritoneal cancer. In embodiments, the primary peritoneal cancer is an MSS primary peritoneal cancer. In embodiments, the primary peritoneal cancer is a POLE mutant primary peritoneal cancer. In embodiments, the primary peritoneal cancer is a POLD mutant primary peritoneal cancer. In embodiments, the primary peritoneal cancer is a high-TMB primary peritoneal cancer. In embodiments, the primary peritoneal cancer is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD). In embodiments, the primary peritoneal cancer is a serous cell primary peritoneal cancer. In embodiments, the primary peritoneal cancer is clear cell primary peritoneal cancer.

In embodiments, the cancer is acute lymphoblastic leukemia (ALL). In embodiments, the acute lymphoblastic leukemia is advanced acute lymphoblastic leukemia. In embodiments, the acute lymphoblastic leukemia is metastatic acute lymphoblastic leukemia. In embodiments, the acute lymphoblastic leukemia is MSI-H acute lymphoblastic leukemia. In embodiments, the acute lymphoblastic leukemia is MSS acute lymphoblastic leukemia. In embodiments, the acute lymphoblastic leukemia is POLE mutant acute lymphoblastic leukemia. In embodiments, the acute lymphoblastic leukemia is POLD mutant acute lymphoblastic leukemia. In embodiments, the acute lymphoblastic leukemia is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is acute myeloid leukemia (AML). In embodiments, the acute myeloid leukemia is advanced acute myeloid leukemia. In embodiments, the acute myeloid leukemia is metastatic acute myeloid leukemia. In embodiments, the acute myeloid leukemia is MSI-H acute myeloid leukemia. In embodiments, the acute myeloid leukemia is MSS acute myeloid leukemia. In embodiments, the acute myeloid leukemia is POLE mutant acute myeloid leukemia. In embodiments, the acute myeloid leukemia is POLD mutant acute myeloid leukemia. In embodiments, the acute myeloid leukemia is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is non-Hodgkin lymphoma (NHL).

In embodiments, the non-Hodgkin lymphoma is an advanced non-Hodgkin lymphoma. In embodiments, the non-Hodgkin lymphoma is a metastatic non-Hodgkin lymphoma. In embodiments, the non-Hodgkin lymphoma is an MSI-H non-Hodgkin lymphoma. In embodiments, the non-Hodgkin lymphoma is an MSS non-Hodgkin lymphoma. In embodiments, the non-Hodgkin lymphoma is a POLE mutant non-Hodgkin lymphoma. In embodiments, the non-Hodgkin lymphoma is a POLD mutant non-Hodgkin lymphoma. In embodiments, the non-Hodgkin lymphoma is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

- 11 050059

In embodiments, the cancer is Hodgkin lymphoma (HL). In embodiments, the Hodgkin lymphoma is an advanced stage Hodgkin lymphoma. In embodiments, the Hodgkin lymphoma is metastatic Hodgkin lymphoma. In embodiments, the Hodgkin lymphoma is MSI-H Hodgkin lymphoma. In embodiments, the Hodgkin lymphoma is MSS Hodgkin lymphoma. In embodiments, the Hodgkin lymphoma is POLE mutant Hodgkin lymphoma. In embodiments, the Hodgkin lymphoma is POLD mutant Hodgkin lymphoma. In embodiments, Hodgkin lymphoma is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is neuroblastoma (NB). In embodiments, the neuroblastoma is advanced neuroblastoma. In embodiments, the neuroblastoma is metastatic neuroblastoma. In embodiments, the neuroblastoma is MSI-H neuroblastoma. In embodiments, the neuroblastoma is MSS neuroblastoma. In embodiments, the neuroblastoma is POLE mutant neuroblastoma. In embodiments, the neuroblastoma is POLD mutant neuroblastoma. In embodiments, the neuroblastoma is TMB-high neuroblastoma. In embodiments, the neuroblastoma is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is a CNS tumor. In embodiments, the CNS tumor is advanced. In embodiments, the CNS tumor is a metastatic CNS tumor. In embodiments, the CNS tumor is a CNS MSI-H tumor. In embodiments, the CNS tumor is a CNS MSS tumor. In embodiments, the CNS tumor is a POLE mutant CNS tumor. In embodiments, the CNS tumor is a POLD mutant CNS tumor. In embodiments, the CNS tumor is a high-TMB CNS tumor. In embodiments, the CNS tumor is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is diffuse intrinsic brainstem glioma (DIPG). In embodiments, the DIPG is advanced DIPG. In embodiments, the DIPG is metastatic DIPG. In embodiments, the DIPG is DIPG MSI-H. In embodiments, the DIPG is DIPG MSS. In embodiments, the DIPG is POLE mutant DIPG. In embodiments, the DIPG is POLD mutant DIPG. In embodiments, the DIPG is high-MB DIPG. In embodiments, the DIPG is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is Ewing sarcoma. In embodiments, the Ewing sarcoma is advanced Ewing sarcoma. In embodiments, the Ewing sarcoma is metastatic Ewing sarcoma. In embodiments, the Ewing sarcoma is MSI-H Ewing sarcoma. In embodiments, the Ewing sarcoma is MSS Ewing sarcoma. In embodiments, the Ewing sarcoma is POLE mutant Ewing sarcoma. In embodiments, the Ewing sarcoma is POLD mutant Ewing sarcoma. In embodiments, the Ewing sarcoma is TMB-high Ewing sarcoma. In embodiments, the Ewing sarcoma is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is embryonal rhabdomyosarcoma (ERS). In embodiments, the embryonal rhabdomyosarcoma is advanced embryonal rhabdomyosarcoma. In embodiments, the embryonal rhabdomyosarcoma is metastatic embryonal rhabdomyosarcoma. In embodiments, the embryonal rhabdomyosarcoma is MSI-H embryonal rhabdomyosarcoma. In embodiments, the embryonal rhabdomyosarcoma is MSS embryonal rhabdomyosarcoma. In embodiments, the embryonal rhabdomyosarcoma is POLE mutant embryonal rhabdomyosarcoma. In embodiments, the embryonal rhabdomyosarcoma is POLD mutant embryonal rhabdomyosarcoma. In embodiments, the embryonal rhabdomyosarcoma is TMB-high embryonal rhabdomyosarcoma. In embodiments, the embryonal rhabdomyosarcoma is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is osteosarcoma (OS). In embodiments, the osteosarcoma is advanced osteosarcoma. In embodiments, the osteosarcoma is metastatic osteosarcoma. In embodiments, the osteosarcoma is MSI-H osteosarcoma. In embodiments, the osteosarcoma is MSS osteosarcoma. In embodiments, the osteosarcoma is POLE mutant osteosarcoma. In embodiments, the osteosarcoma is POLD mutant osteosarcoma.

- 12 050059 coma. In embodiments, the osteosarcoma is a high-TMB osteosarcoma. In embodiments, the osteosarcoma is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is a soft tissue sarcoma. In embodiments, the soft tissue sarcoma is an advanced soft tissue sarcoma. In embodiments, the soft tissue sarcoma is a metastatic soft tissue sarcoma. In embodiments, the soft tissue sarcoma is an MSI-H soft tissue sarcoma. In embodiments, the soft tissue sarcoma is an MSS soft tissue sarcoma. In embodiments, the soft tissue sarcoma is a POLE mutant soft tissue sarcoma. In embodiments, the soft tissue sarcoma is a POLD mutant soft tissue sarcoma. In embodiments, the soft tissue sarcoma is a high-TMB soft tissue sarcoma. In embodiments, the soft tissue sarcoma is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD). In embodiments, the soft tissue sarcoma is a leiomyosarcoma.

In embodiments, the cancer is Wilms tumor. In embodiments, the Wilms tumor is an advanced Wilms tumor. In embodiments, the Wilms tumor is a metastatic Wilms tumor. In embodiments, the Wilms tumor is an MSI-H Wilms tumor. In embodiments, the Wilms tumor is an MSS Wilms tumor. In embodiments, the Wilms tumor is a POLE mutant Wilms tumor. In embodiments, the Wilms tumor is a POLD mutant Wilms tumor. In embodiments, the Wilms tumor is a high-TMB Wilms tumor. In embodiments, the Wilms tumor is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the subject has previously been treated with one or more different cancer treatments (e.g., one or more of surgery, radiation therapy, chemotherapy, or immunotherapy).

In embodiments, the subject has been previously treated with one other cancer treatment (e.g., one or more of surgery, radiation, chemotherapy, or immunotherapy). In embodiments, the subject has been previously treated with two or more other cancer treatments (e.g., one or more of surgery, radiation, chemotherapy, or immunotherapy). In embodiments, the subject has been previously treated with cytotoxic therapy. In embodiments, the subject has been previously treated with chemotherapy. In embodiments, the subject has been previously treated with two other cancer treatments (e.g., one or more of surgery, radiation, chemotherapy, or immunotherapy). In embodiments, the subject has been previously treated with three other cancer treatments (e.g., one or more of surgery, radiation, chemotherapy, or immunotherapy).

In embodiments of the methods described herein, the method further comprises administering one or more of surgery, radiotherapy, chemotherapy or immunotherapy, an anti-angiogenic agent or an anti-inflammatory agent. In embodiments, the method further comprises administering chemotherapy.

In some embodiments, at least some patients in the population of patients having cancer have been previously treated with chemotherapy (e.g., platinum-based chemotherapy). For example, a patient who has received two lines of cancer treatment may be identified as a 2L patient having cancer (e.g., a 2L patient having NSCLC). In embodiments, the patient has received two or more lines of cancer treatment (e.g., a 2L+ patient having cancer, such as a 2L+ patient having endometrial cancer). In embodiments, the patient has been previously treated with an anti-PD-1 therapy. In embodiments, the patient has previously received at least one line of cancer treatment (e.g., the patient has previously received at least one line or at least two lines of cancer treatment). In embodiments, the patient has previously received at least one line of metastatic cancer treatment (e.g., the patient has previously received one or two lines of metastatic cancer treatment).

In embodiments, the subject is refractory to treatment with an agent that suppresses PD-1.

In embodiments, the subject is difficult to treat with an agent that suppresses PD-1.

In embodiments, the method described herein increases the sensitivity of a subject to treatment with an agent that suppresses PD-1.

In embodiments, the subject comprises an exhausted immune cell (e.g., an exhausted immune cell that is an exhausted T cell).

In embodiments of the methods described herein, the subject is a living

- 13 050059 veterinary (e.g., a mammal). In embodiments, the subject is a human. In embodiments, the subject is a non-human mammal (e.g., mice, rats, rabbits, or non-human primates). Therefore, the methods described herein may be applicable to both human and veterinary medicine.

In embodiments, the TIM-3 inhibitor is administered intravenously (e.g., via intravenous infusion).

In some embodiments, the present invention provides methods of treating cancer in a patient in need thereof, the method comprising administering a composition that delivers an anti-TIM-3 antibody agent.

In some embodiments, the patient has not previously been treated with a cancer treatment method.

In some embodiments, the patient has previously been treated with one or more different cancer treatments. In some embodiments, the patient has previously been treated with one or more of radiotherapy, chemotherapy, or immunotherapy. In some embodiments, the patient has previously been treated with chemotherapy (e.g., non-platinum-based chemotherapy).

In some embodiments, a composition that delivers a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is administered at a dose of 1, 3, or 10 mg/kg. In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered according to a schedule that provides a dose of 1, 3, or 10 mg/kg every two weeks. In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered according to a schedule that provides a dose of 1, 3, or 10 mg/kg every three weeks. In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered according to a schedule that provides a dose of 1, 3, or 10 mg/kg every four weeks.

In some embodiments, a composition that delivers an anti-TIM-3 antibody agent at a fixed dose in the range of about 100 to about 1500 mg (e.g., about 100 to 1500 mg). In some embodiments, a composition that delivers an anti-TIM-3 antibody agent at a fixed dose in the range of about 100 to about 300 mg, about 300 to about 1000 mg, or about 1000 to about 1200 mg. In embodiments, the fixed dose is about 100 mg. In embodiments, the fixed dose is about 300 mg. In embodiments, the fixed dose is about 500 mg. In embodiments, the fixed dose is about 900 mg. In embodiments, the fixed dose is about 1200 mg. In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered according to a schedule that provides a fixed dose every two weeks (Q2W). In some embodiments, a composition that delivers an anti-TM-3 antibody agent is administered according to a schedule that provides a fixed dose every three weeks (Q3W). In some embodiments, a composition that delivers an anti-TM-3 antibody agent is administered according to a schedule that provides a fixed dose every four weeks (Q4W). In embodiments, the anti-TIM-3 antibody is administered at an administration interval of once a week (Q1W), once every 2 weeks (Q2W), once every 3 weeks (S3W), once every 4 weeks (Q4W), once every 5 weeks (Q5W), or once every 6 weeks (Q6W). In embodiments, the anti-TIM-3 antibody is administered for a period of at least 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 weeks. In embodiments, the dose is administered as a monotherapy (e.g., a therapeutically effective amount of 1200 mg of the anti-TIM-3 antibody administered by Q2W or Q3W), or the dose is administered in combination with one or more other therapies. For example, 100 mg, 300 mg, 500 mg, or 900 mg (e.g., 100 mg or 300 mg) of an anti-TIM-3 antibody can be administered in combination with an anti-PD-1 antibody according to the regimens described herein (e.g., 500 mg of an anti-PD-1 antibody administered Q3W for four treatment cycles followed by 1000 mg of an anti-PD-1 antibody Q6W until treatment is discontinued (e.g., due to disease progression)).

In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered by intravenous infusion.

In some embodiments, the clinical benefit is a complete response (CR), a partial response (PR), or stable disease (SD). In some embodiments, the clinical benefit is at least an SD. In some embodiments, the clinical benefit is at least a PR. In some embodiments, the clinical benefit is a CR. In some embodiments, at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of patients achieve clinical benefit. In some embodiments, at least 5% of patients achieve clinical benefit. In some embodiments, at least 5% of patients achieve SD. In some embodiments, at least 5% of patients achieve at least a PR. In some embodiments, at least 5%

- 14,050,059 patients achieve CR. In some embodiments, at least 20% of patients achieve clinical benefit. In some embodiments, at least 20% of patients achieve SD.

In some embodiments, clinical benefit (e.g., SD, PR, and/or CR) is determined according to the Response Evaluation Criteria in Solid Tumors (RECIST). In some embodiments, clinical benefit (e.g., SD, PR, and/or CR) is determined according to RECIST guidelines. In some embodiments, clinical benefit (e.g., SD, PR, and/or CR) is determined according to RECIST guidelines (version 1.1). In some embodiments, clinical benefit (e.g., SD, PR, and/or CR) is determined according to the immune-related RECIST (irRECIST) guidelines. In some embodiments, tumor response can be assessed by either irRECIST or RECIST version 1.1. In some embodiments, tumor response can be assessed by both irRECIST and RECIST version 1.1. When used in this document, the term RECIST guidelines may refer to RECIST 1.0, RECIST 1.1, or irRECIST interchangeably.

In some embodiments, the patient receives or will receive an additional therapy in combination with an anti-TIM-3 antibody agent. In some embodiments, the additional therapy is radiotherapy, chemotherapy, or immunotherapy. In some embodiments, the additional therapy comprises treatment with a composition that delivers a PD-1 inhibitor (e.g., a PD-1 binding agent) and/or a LAG-3 binding agent. In some embodiments, the additional PD-1 inhibitor is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ63723283, MGA012, BI-754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGBA333, AMP-514 (MEDI-0680), AGEN-2034, CS1001, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ-053, CK-301, AK 104, GLS-010, PD-1VR or PD-1FL, or any of the PD-1 antibodies disclosed in WO2014/179664. In some embodiments, the additional therapy is a PARP inhibitor. In some embodiments, the PARP inhibitor is niraparib, olaparib, rucaparib, talazoparib and veliparib. In some embodiments, the PARP inhibitor is niraparib.

In some embodiments, the present invention provides methods of treating cancer in a patient in need thereof, wherein the method comprises administering one or more compositions that deliver an anti-TIM-3 antibody-based agent in combination with a PD-1 binding agent. In some embodiments, the patient or patient population receives a combination therapy that comprises administering an anti-TIM-3 antibody-based agent and a PD-1 binding agent (e.g., an anti-PD-1 antibody).

In some embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7, and an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain whose amino acid sequence comprises SEQ ID NO: 3, and an immunoglobulin light chain whose amino acid sequence comprises SEQ ID NO: 4.

In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO: 11 or SEQ ID NO: 17 and an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO: 12 or SEQ ID NO: 18 (PD-1VR). In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain having an amino acid sequence comprising SEQ ID NO: 13 and an immunoglobulin light chain having an amino acid sequence comprising SEQ ID NO: 14 (PD1-FL).

In some embodiments, an anti-TIM-3 antibody agent (e.g., an anti-TIM-3 antibody) is administered at a dose of about 1, 3, or 10 mg/kg. In some embodiments, the anti-TIM-3 antibody agent is administered on a schedule that provides a dose of 1, 3, or 10 mg/kg every two weeks. In some embodiments, the anti-TIM-3 antibody agent is administered on a schedule that provides a dose of about 1, 3, or 10 mg/kg every three weeks. In some embodiments, the anti-TIM-3 antibody agent is administered on a schedule that provides a dose of 1, 3, or 10 mg/kg every four weeks. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose in the range of about 100 mg to 1500 mg. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose of about 300 to 1000 mg, about 100 to about 500 mg, about 100 to about 1200 mg, or about 1000 to about 1500 mg. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose of about 100, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900

- 15,050,059 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose of about 100 mg. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose of about 300 mg. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose of about 500 mg. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose of about 900 mg. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose of about 1200 mg. In some embodiments, the anti-TIM-3 antibody agent is administered according to a schedule that provides a fixed dose every two weeks (Q2W). In some embodiments, the anti-TIM-3 antibody agent is administered according to a schedule that provides a fixed dose every three weeks (Q3W). In some embodiments, the anti-TIM-3 antibody agent is administered according to a schedule that provides a fixed dose every four weeks (Q4W).

In some embodiments, the therapeutically effective dose is a dose of the TIM-3 antibody of about 100 mg to about 1500 mg, such as a dose that is about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200 mg, 1300 mg, 1400 mg, or 1500 mg. In embodiments, the therapeutically effective dose is about 100 mg (e.g., administered by Q2W or Q3W). In embodiments, the therapeutically effective dose is about 300 mg (e.g., administered by Q2W or Q3W). In embodiments, the therapeutically effective dose is about 500 mg (e.g., administered by Q2W or Q3W). In embodiments, the therapeutically effective dose is about 900 mg (e.g., administered by Q2W or Q3W). In embodiments, the therapeutically effective dose is about 1200 mg (e.g., administered by Q2W or Q3W). In embodiments, the anti-TIM-3 antibody is administered at an administration interval of once a week (Q1W), once every 2 weeks (Q2W), once every 3 weeks (S3W), once every 4 weeks (Q4W), once every 5 weeks (Q5W), or once every 6 weeks (Q6W). In embodiments, the anti-TIM-3 antibody is administered for a period of at least 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 weeks.

In embodiments, the therapeutically effective dose is about 100 mg, and the agent is administered at an administration interval of once every 2 weeks. In embodiments, the therapeutically effective dose is about 100 mg, and the agent is administered at an administration interval of once every 3 weeks.

In embodiments, the therapeutically effective dose is about 300 mg, and the agent is administered at an administration interval of once every 2 weeks. In embodiments, the therapeutically effective dose is about 300 mg, and the agent is administered at an administration interval of once every 3 weeks.

In embodiments, the therapeutically effective dose is about 500 mg, and the agent is administered at an administration interval of once every 2 weeks. In embodiments, the therapeutically effective dose is about 500 mg, and the agent is administered at an administration interval of once every 3 weeks.

In embodiments, the therapeutically effective dose is about 900 mg, and the agent is administered at an administration interval of once every 2 weeks. In embodiments, the therapeutically effective dose is about 900 mg, and the agent is administered at an administration interval of once every 3 weeks.

In embodiments, the therapeutically effective dose is about 1200 mg, and the agent is administered at an administration interval of once every 2 weeks. In embodiments, the therapeutically effective dose is about 1200 mg, and the agent is administered at an administration interval of once every 3 weeks.

In embodiments, the dose is administered as a monotherapy (e.g., a therapeutically effective amount of 1200 mg of an anti-TIM-3 antibody administered by Q2W or Q3W), or the dose is administered in combination with one or more other therapies. For example, 100 mg or 300 mg of an anti-TIM-3 antibody can be administered in combination with an anti-PD-1 antibody according to the regimens described herein (e.g., 500 mg of an anti-PD-1 antibody administered by Q3W for four treatment cycles followed by 1000 mg of an anti-PD-1 antibody by Q6W until treatment is discontinued (e.g., due to disease progression)).

In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered at a dose of 0.1, 1, 3, 10, or 20 mg/kg. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered on a schedule that provides a dose of 1, 3, or 10 mg/kg every two weeks. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered on a schedule that provides a dose of 1, 3, or 10 mg/kg every three weeks. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered on a schedule that provides a dose of 1, 3, or 10 mg/kg every four weeks. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered at a dose of 500 mg.

- 16 050059 In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a regimen that provides a dose of 500 mg every two weeks. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a regimen that provides a dose of 500 mg every three weeks. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a regimen that provides a dose of 500 mg every four weeks. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a regimen that provides a dose of 500 mg every three weeks for at least one treatment cycle (e.g., for at least one, two, three, or four treatment cycles), followed by administration. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a regimen that provides a dose of 1000 mg every three weeks. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a regimen that provides a dose of 1000 mg every four weeks. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a regimen that provides a dose of 1000 mg every five weeks. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a regimen that provides a dose of 1000 mg every six weeks. In embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a regimen that provides a dose of 500 mg every three weeks for four treatment cycles, followed by a dose of 1000 mg every six weeks until treatment is discontinued (e.g., due to disease progression). In embodiments, the anti-TIM-3 antibody agent is administered to Q2W or Q3W at a dose that is about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200 mg, or at a dose that is about 1-10 mg/kg (such as at a dose that is about 1, about 3, or about 10 mg/kg). In embodiments, the anti-TIM-3 antibody agent is administered to Q2W or Q3W at a dose that is about 100 mg. In embodiments, the anti-TIM-3 antibody agent is administered to Q2W or Q3W at a dose that is about 300 mg.

In embodiments, a PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is administered at a first dose of about 500 mg once every 3 weeks for 3, 4, or 5 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more (e.g., a second dose of about 1000 mg once every 6 weeks). In embodiments, the therapeutically effective dose of the agent (e.g., the anti-TIM-3 antibody) is a constant dose of about 100 mg. In embodiments, the therapeutically effective dose of the agent (e.g., the anti-TIM-3 antibody) is a constant dose of about 300 mg. In embodiments, the therapeutically effective dose of the agent (e.g., the anti-TIM-3 antibody) is a constant dose of about 500 mg. In embodiments, the therapeutically effective dose of the agent (e.g., the anti-TIM-3 antibody) is a constant dose of about 900 mg. In embodiments, a therapeutically effective dose of the agent (e.g., an antibody to TIM-3) is administered once every three weeks.

In embodiments, a PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is administered at a first dose of about 500 mg once every 3 weeks for 3 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more (e.g., a second dose of about 1000 mg once every 6 weeks). In embodiments, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a constant dose of about 100 mg. In embodiments, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a constant dose of about 300 mg. In embodiments, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a constant dose of about 500 mg. In embodiments, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a constant dose of about 900 mg. In embodiments, a therapeutically effective dose of the agent (e.g., an antibody to TIM-3) is administered once every three weeks.

In embodiments, a PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is administered at a first dose of about 500 mg once every 3 weeks for 4 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more (e.g., a second dose of about 1000 mg once every 6 weeks). In embodiments, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a constant dose of about 100 mg. In embodiments, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a constant dose of about 300 mg. In embodiments, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a constant dose of about 500 mg. In embodiments, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a constant dose of about 900 mg. In embodiments, a therapeutically effective dose of the agent (e.g., an antibody to TIM-3) is administered once every three weeks.

- 17 050059

In embodiments, a PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is administered at a first dose of about 500 mg once every 3 weeks for 5 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more (e.g., a second dose of about 1000 mg once every 6 weeks). In embodiments, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a constant dose of about 100 mg. In embodiments, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a constant dose of about 300 mg. In embodiments, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a constant dose of about 500 mg. In embodiments, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a constant dose of about 900 mg. In embodiments, a therapeutically effective dose of the agent (e.g., an antibody to TIM-3) is administered once every three weeks.

In some embodiments, the present invention provides compositions comprising an anti-TIM-3 antibody agent for use in treating cancer in a selected patient population having cancer. In some embodiments, the anti-TIM-3 antibody agent comprises a heavy chain comprising three CDRs that have the sequences of SEQ ID NO: 21, 22, or 23. In some embodiments, the anti-TIM-3 antibody agent comprises a light chain comprising three CDRs that have the sequences of SEQ ID NO: 24, 25, or 26. In some embodiments, the anti-TIM-3 antibody agent comprises a heavy chain comprising three CDRs that have the sequences of SEQ ID NO: 21, 22, or 23; and a light chain comprising three CDRs that have the sequences of SED ID NO: 24, 25, or 26. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO: 1 or SEQ ID NO: 7 and an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain having an amino acid sequence comprising SEQ ID NO: 3. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin light chain having an amino acid sequence comprising SEQ ID NO: 4. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain having an amino acid sequence comprising SEQ ID NO: 3, and an immunoglobulin light chain, the amino acid sequence of which comprises SEQ ID NO: 4.

In some embodiments, each of the patients in the population of patients having cancer has a tumor. In some embodiments, each of the patients in the population of patients having cancer has a solid tumor. In some embodiments, at least some of the patients in the population of patients having cancer have an advanced solid tumor. In some embodiments, at least some of the patients in the population of patients having cancer have a metastatic solid tumor. In some embodiments, the patient has an MSI-H solid tumor. In some embodiments, each of the patients in the population of patients having cancer has a cancer such as non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cancer, melanoma, cervical cancer, colorectal cancer, anogenital squamous cell carcinoma (e.g., squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), head and neck cancer, triple-negative breast cancer, ovarian cancer, or endometrial cancer.

In embodiments, the patient has lung cancer (e.g., non-small cell lung cancer (NSCLC). In embodiments, the patient has melanoma.

In some embodiments, the patient has a cancer associated with a POLE (DNA polymerase epsilon) or POLD (DNA polymerase delta) mutation. In some embodiments, the POLE or POLD mutation is in the exonuclease domain. In some embodiments, the POLE or POLD mutation is a germline mutation. In some embodiments, the POLE or POLD mutation is a sporadic mutation. In some embodiments, the method described herein further comprises the step of initially identifying a patient having a cancer with a POLE or POLD mutation. In some embodiments, the POLE or POLD mutation is identified using sequencing.

In some embodiments, each of the patients in the population of patients having cancer has a cancer with microsatellite instability. In some embodiments, the microsatellite instability is considered high, wherein the instability is significantly higher than the instability observed in a control cell (e.g., MSI-H status). In some embodiments,

- 18 050059 the microsatellite instability is MSI low (MSI-L). In some embodiments, the microsatellite instability is microsatellite stability (e.g., MSS status). In some embodiments, the patient has a late-stage solid tumor with microsatellite instability.

In some embodiments, each of the patients in the population of patients having cancer has a hematological cancer. In some embodiments, each of the patients in the population of patients having cancer has a hematological cancer, such as diffuse large B cell lymphoma (DLBCL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), follicular lymphoma (FL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM). In some embodiments, each of the patients in the population of patients having cancer has a hematological cancer with microsatellite instability.

In some embodiments, at least some patients in the patient population having cancer have been previously treated with one or more different cancer treatments. In some embodiments, at least some patients in the patient population having cancer have been previously treated with one or more of radiotherapy, chemotherapy, or immunotherapy. In some embodiments, at least some patients in the patient population having cancer have been previously treated with chemotherapy (e.g., platinum-based chemotherapy).

In some embodiments, at least some patients in the population of patients having cancer have not previously been treated with one or more different cancer treatments.

In some embodiments, the present invention provides a combination therapy for use in the treatment of cancer in a population of selected patients having cancer, wherein the combination therapy comprises administering an anti-TIM-3 antibody agent and a PD-1 binding agent.

Brief description of graphic materials

Fig. 1 is a schematic illustration, not drawn to scale, of the enhancement of immune cell activation by anti-TIM-3 antibody and anti-PD1 antibody.

Figures 2A-2B depict results obtained using an exemplary T cell exhaustion model. (A) Targeted expression of PD-1 and TIM-3 in responsive (pre-stimulation) and exhausted (post-stimulation) cells. (B) Quantification of IFNy production in post-stimulation exhausted cells treated with a combination of anti-PD-1 antibody-based agent and anti-TIM-3 antibody-based agent, anti-PD-1 antibody-based agent, anti-TIM-3 antibody-based agent, and isotype control.

Figure 3 depicts the results of an in vivo study of the efficacy of a combination of antibodies comprising an exemplary anti-PD-1 antibody (TSR-042) and an exemplary anti-TIM-3 antibody (TSR-022). In this study, huNOG-EXL mice that had been neonatally transplanted with CD34+ hematopoietic stem cells were implanted with A549 NSCLC cells and treated with either anti-PD-1 or anti-TIM-3 antibodies alone or in combination.

Fig. 4A relates to a dose escalation study of an illustrative anti-TIM-3 antibody (TSR-022) as monotherapy or in combination with an anti-PD-1 antibody.

Fig. 4B represents an expansion cohort to evaluate the antitumor activity of an exemplary anti-TIM-3 antibody (TSR-022) as monotherapy and in combination with an anti-PD-1 antibody in patients with certain tumor types.

Figure 5 describes patient demographics and baseline characteristics of the dose-escalation study participants.

Fig. 6A depicts the mean PK profiles of an illustrative anti-TIM-3 antibody (TSR-022) following the first dose.

Fig. 6B shows the degree of TIM-3 occupancy in circulating monocytes measured by flow cytometry in whole blood samples collected from patients treated with an exemplary TIM-3 antibody (TSR-022).

Figures 7A-7C depict the occupancy rate of TIM-3 receptors for an exemplary TIM-3 antibody (TSR-022) at doses of 1 mg/kg (Figure 7A), 3 mg/kg (Figure 7B), and 10 mg/kg (Figure 7C) administered once every two weeks (Q2W).

Fig. 8 depicts the effects of treatment with an exemplary TIM-3 antibody (TSR-022). Treatment durations associated with specific doses are shown, and partial responses are indicated by black squares and stable disease is indicated by black triangles.

Fig. 9 shows a brain scan of a patient with leiomyosarcoma with metastases to the lung and kidney, and who received three doses of an illustrative TIM-3 antibody (TSR-022) at 10 mg/kg prior to imaging for cancer restaging.

Fig. 10 depicts a study of receptor occupancy at a constant dose of 100 mg of an exemplary TIM-3 antibody (TSR-022) administered once every three weeks (Q3W).

- 19 050059

Fig. 11 depicts a receptor occupancy study at a constant dose of 300 mg of an exemplary anti-TIM-3 antibody (TSR-022) administered in combination with a constant dose of 500 mg of an exemplary anti-PD-1 antibody (TSR-042). A second dose of TSR-022 was administered on day 22, with the RO sample collected prior to the second dose.

Figure 12 shows a collection of mean receptor occupancy data for 1 mg/kg, 3 mg/kg, 10 mg/kg, and constant doses of 100 mg, 300 mg, and 1200 mg of an exemplary TIM-3 antibody (TSR-022). The figure shows the occupancy ratio (free TIM-3:total TIM-3) measured over several days.

Detailed Description of Certain Embodiments Definitions

Approximately: The term "approximately" when used herein in relation to a value refers to a value that is similar in the context of the stated value. Generally, those skilled in the art familiar with the context will understand that in this context, the term "approximately" covers a corresponding degree of deviation. For example, in some embodiments, the term "approximately" may cover a range of values that are within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction of the stated value.

Administration: As used herein, the term administration generally refers to the introduction of a composition into a subject or into a system to achieve delivery of an agent that is or is contained in the composition. Those of ordinary skill in the art are aware of a variety of routes that may be used to administer to a subject, such as a human, under appropriate circumstances. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In embodiments, administration is parenteral (e.g., intravenous administration). In embodiments, intravenous administration is intravenous infusion. In some specific embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or include, for example, one or more of topical administration to the dermis, intradermal, interdermal, transdermal, etc.), enteral, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, intra-organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreous, etc. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve the use of a fixed number of doses. In some embodiments, the administration may involve administration of doses that are intermittent (e.g., multiple doses separated in time) and/or periodic (e.g., individual doses separated by the same period of time) administration of doses. In some embodiments, the administration may involve continuous administration of doses (e.g., perfusion) for at least a selected period of time.

Solutions or suspensions used for parenteral, intradermal, or subcutaneous use may contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethyleneglycols, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH may be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. The parenteral preparation may be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser that contains a suitable propellant, e.g. a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be carried out by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrating agents suitable for penetration through the barrier are used in the formulation. Such penetrating agents are generally known in the art and include, for example, agents for transmucosal administration, surfactants, bile acids and fusidic acid derivatives. Transmucosal administration can be carried out by using nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, balms, gels or creams, generally known in the art.

- 20 050059

The compounds may also be prepared in the form of suppositories (eg, using traditional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

Affinity: As is known in the art, affinity is a measure of the strength with which a particular ligand binds to its partner. Affinity values can be measured in a variety of ways. In some embodiments, affinity is measured using a quantitative assay. In some such embodiments, the concentration of the binding partner can be fixed to be greater than the concentration of the ligand in order to mimic physiological conditions. Alternatively or in addition, in some embodiments, the concentration of the binding partner and/or the concentration of the ligand can be varied. In some such embodiments, affinity can be compared to a reference under comparable conditions (e.g., concentration).

Antibody: As used herein, the term "antibody" refers to a polypeptide that contains sufficient canonical immunoglobulin sequence elements to provide specific binding to a particular target antigen. As known in the art, intact antibodies produced in nature are tetrameric agents of approximately 150 kDa in size, consisting of two identical heavy chain polypeptides (approximately 50 kDa each) and two identical light chain polypeptides (approximately 25 kDa each) that are linked together to form what is commonly referred to as a Y-shaped structure. Each heavy chain is composed of at least four domains (each approximately 110 amino acids in length) - an amino-terminal variable (VH) domain (located at the ends of the Y structure), followed by three constant domains: CH1, CH2, and a carboxy-terminal CH3 (located at the base of the Y stem). A short region known as a switch connects the variable and constant regions of the heavy chains. The hinge connects the CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy chain polypeptides to each other in an intact antibody. Each light chain is composed of two domains, an amino-terminal variable (VL) domain followed by a carboxyl-terminal constant (CL) domain, separated from each other by another switch. Those skilled in the art are familiar with the structure and sequence elements of antibodies, recognize the variable and constant regions in the provided sequences, and understand that there may be some flexibility in defining the boundary between such domains, such that different representations of the same antibody chain sequence may, for example, specify such a boundary at a location that is offset by one or more residues relative to another representation of the same antibody chain sequence. Intact antibody tetramers consist of two heavy chain-light chain dimers in which the heavy and light chains are linked to each other by one disulfide bond; two other disulfide bonds link the hinge regions of the heavy chains to each other, causing the dimers to join together to form a tetramer. Naturally produced antibodies are also glycosylated, typically at the CH2 domain. Each domain in a natural antibody has a structure characterized by an immunoglobulin fold formed from two beta sheets (e.g., 3-, 4-, or 5-stranded sheets) packed against each other in a compressed antiparallel beta barrel. Each variable domain contains three hypervariable loops, known as complementarity-determining regions (CDR1, CDR2, and CDR3), and four somewhat invariant framework regions (FR1, FR2, FR3, and FR4). When natural antibodies fold, the FR regions form beta sheets that provide a structural framework for the domains, and the CDR loop regions from both the heavy and light chains are combined in three-dimensional space to create a single hypervariable antigen-binding site located at the apex of the Y structure. The Fc region of naturally occurring antibodies binds to elements of the complement system, as well as to receptors on effector cells, including, for example, effector cells that mediate cytotoxicity. As is known in the art, the affinity and/or other binding characteristics of Fc regions for Fc receptors can be modulated by glycosylation or other modification. In some embodiments, antibodies produced and/or used in accordance with the present invention include glycosylated Fc domains, including Fc domains that have been modified or engineered by such glycosylation. For purposes of the present invention, in some embodiments, any polypeptide or complex of polypeptides that contains sufficient immunoglobulin domain sequences found in naturally occurring antibodies may be referred to and/or used as an antibody, regardless of whether such polypeptide is naturally occurring (e.g., produced by an organism responding to an antigen) or produced by recombinant engineering, chemical synthesis, or other artificial system or technique. In some embodiments, the antibody is polyclonal; in some embodiments, the antibody is monoclonal. In some embodiments, the antibody has constant region sequences that are characteristic of antibodies from a mouse, a rabbit, a primate, or a human. In some embodiments, the sequence elements of the antibody are huma

- 21 050059 primatized, chimeric, etc., as known in the art. Moreover, the term antibody as used herein may refer in appropriate embodiments (unless otherwise indicated or clear from the context) to any of the known or developed in the art constructs or formats for utilizing the structural and functional features of an antibody in an alternative presentation. For example, in embodiments, the antibody used in accordance with the present invention has a format selected from, but not limited to, intact IgA, IgG, IgE, or IgM antibodies; bi- or multispecific antibodies (e.g., Zybodies®, etc.); antibody fragments such as Fab fragments, Fab' fragments, F(ab') ₂ fragments, Fd' fragments, Fd fragments, and isolated CDRs or sets thereof; single-chain Fv; Polypeptide-Fc fusions; single-domain antibodies (e.g., shark single-domain antibodies such as IgNAR or fragments thereof); camel antibodies; masked antibodies (e.g., Probodies®); Small Modular ImmunoPharmaceuticals (SMIP™); single-chain or tandem diabodies (TandAb®); VHH; Anticalins®; Nanobodies® minibodies; BiTE®; ankyrin repeat proteins or DARPINs®; Avimers®; DART; TCR-like antibodies; Adnectins®; Affilins®; Trans-bodies®; Affibodies®; TrimerX®; MicroProteins; Fynomers®, Centyrins®, and KALBITOR®. In some embodiments, the antibody may lack a covalent modification (e.g., a glycan attachment) that it would have if it were naturally produced. In some embodiments, the antibody may comprise a covalent modification (e.g., a glycan attachment, a payload [e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc.], or another side group [e.g., polyethylene glycol, etc.]).

Antibodies include antibody fragments. Antibodies also include, but are not limited to, polyclonal, monoclonal, chimeric dAb (domain antibodies), single chain, _Fab- , _Fab- , E1/2B-fragments, scFv, and _Fab expression libraries. An antibody may be a whole antibody or immunoglobulin or an antibody fragment.

Antibody-Based Agent: As used herein, the term antibody-based agent refers to an agent that specifically binds to a particular antigen. In some embodiments, the term encompasses any polypeptide or polypeptide complex that contains immunoglobulin structural elements sufficient to provide specific binding. Exemplary antibody-based agents include, but are not limited to, monoclonal antibodies or polyclonal antibodies. In some embodiments, an antibody-based agent may comprise one or more constant region sequences that are characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, an antibody-based agent may comprise one or more sequence elements that are humanized, primatized, chimeric, etc., as known in the art. In many embodiments, the term antibody-based agent is used to refer to one or more art-known or developed constructs or formats for utilizing the structural and functional features of an antibody in an alternative presentation. For example, in embodiments, an antibody agent used in accordance with the present invention has a format selected from, but is not limited to, intact IgA, IgG, IgE, or IgM antibodies; bi- or multispecific antibodies (e.g., Zybodies®, etc.); antibody fragments such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or sets thereof; single-chain Fv; polypeptide-Fc fusions; single-domain antibodies (e.g., shark single-domain antibodies such as IgNAR or fragments thereof); camelid antibodies; masked antibodies (e.g., Probodies®); Small Modular ImmunoPharmaceuticals (SMIP™); single-chain or tandem diabodies (TandAb®); VHH; Anticalins®; Nanobodies® minibodies; BiTE®; ankyrin repeat proteins or DARPINs®; Avimers®; DART; TCR-like antibodies; Adnectins®; Affilins®; Transbodies®; Affibodies®; TrimerX®; MicroProteins; Fynomers®, Centyrins®, and KALBITOR®. In some embodiments, an antibody may lack a covalent modification (e.g., a glycan attachment) that it would have if it were naturally produced. In some embodiments, an antibody may comprise a covalent modification (e.g., a glycan attachment, a payload [e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc.], or another side group [e.g., a polyethyleneglycol, etc.]). In many embodiments, the antibody agent is or comprises a polypeptide whose amino acid sequence comprises one or more structural elements known to those skilled in the art, such as a complementarity determining region (CDR); in some embodiments, the antibody agent is or comprises a polypeptide whose amino acid sequence comprises at least one CDR (e.g., at least one heavy chain CDR and/or at least one light chain CDR) that is substantially identical to that found in a reference antibody. In some embodiments, the included CDR is substantially identical to a reference CDR, in that it is either identical in sequence to or comprises 1 to 5 amino acid substitutions compared to the reference CDR.

- 22 050059 In some embodiments, the included CDR is substantially identical to the reference CDR in that it exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR in that it exhibits at least 96%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR in that at least one amino acid within the included CDR is deleted, added, or substituted compared to the reference CDR, but the included CDR has an amino acid sequence that is otherwise identical to that of the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR in that 1-5 amino acids within the included CDR are deleted, added, or substituted compared to the reference CDR, but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR in that at least one amino acid within the included CDR is substituted compared to the reference CDR, but the included CDR has an amino acid sequence that is otherwise identical to that of the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR in that 15 amino acids within the included CDR are deleted, added, or substituted compared to the reference CDR, but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments, the antibody agent is or comprises a polypeptide whose amino acid sequence comprises structural elements known to those skilled in the art as an immunoglobulin variable domain. In some embodiments, the antibody agent is a polypeptide protein with a binding domain that is homologous or substantially homologous to an immunoglobulin binding domain.

Binding: It should be appreciated that the term binding, as used herein, generally refers to a non-covalent association between or in two or more particles. Direct binding involves physical contact between the particles or moieties; indirect binding involves physical interaction through physical contact with one or more intermediate particles. Binding between two or more particles can generally be assessed in any of a number of contexts, including where the interacting particles or moieties are studied in isolation or in the context of more complex systems (e.g., in covalent or other association with a carrier particle and/or in a biological system or cell). In some embodiments, binding refers to non-covalent interactions of the type that occur between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific. The strength or affinity of immunological binding interactions can be expressed in terms of the dissociation constant (Kd) of the interaction, where a lower Kd represents a greater affinity. The immunological binding properties of selected polypeptides can be determined quantitatively using methods well known in the art. One such method involves measuring the rates of formation and dissociation of the antigen-binding site/antigen complex, these rates being dependent on the concentrations of the complex partners, the affinity of the interaction, and geometric parameters that affect the rate equally in both directions. Thus, both the association rate constant (Kon) and the dissociation rate constant (Koff) can be determined by calculating the concentrations and actual rates of association and dissociation. (See Nature 361:186-87 (1993)). The Koff/Kon ratio cancels out all parameters unrelated to affinity and is equal to the dissociation constant Kd. (See generally Davies et al. (1990) Annual Rev Biochem 59:439-473.)

Binding agent: Generally, the term binding agent is used herein to refer to any particle that binds to a target of interest, as described herein. In many embodiments, a binding agent of interest is one that specifically binds to its target, in that it distinguishes its target from other potential binding partners in a particular interaction context. Generally, a binding agent can be or comprise a particle from any chemical class (e.g., a polymer, a non-polymer, a small molecule, a polypeptide, a carbohydrate, a lipid, a nucleic acid, etc.). In some embodiments, a binding agent is a single chemical entity. In some embodiments, a binding agent is a complex of two or more separate chemical entities bound to each other under appropriate conditions through non-covalent interactions. For example, those skilled in the art will appreciate that in some embodiments, the binding agent may comprise a general binding moiety (e.g., one of biotin/avidin/streptavidin and/or a class-specific antibody) and a specific binding moiety (e.g., an antibody or aptamers with a specific molecular target) that is linked to

- 23 050059 a common binding moiety partner. In some embodiments, such an approach may allow modular assembly of multiple binding agents by binding different specific binding moieties to the same common binding moiety partner. In some embodiments, the binding agents are or comprise polypeptides (including, for example, antibodies or antibody fragments). In some embodiments, the binding agents are or comprise small molecules. In some embodiments, the binding agents are or comprise nucleic acids. In some embodiments, the binding agents are aptamers. In some embodiments, the binding agents are polymers; in some embodiments, the binding agents are not polymers. In some embodiments, the binding agents are non-polymeric in that they do not have polymeric moieties. In some embodiments, the binding agents are or comprise carbohydrates. In some embodiments, the binding agents are or comprise lectins. In some embodiments, the binding agents are or comprise peptidomimetics. In some embodiments, the binding agents are or comprise scaffold proteins. In some embodiments, the binding agents are or comprise mimotopes. In some embodiments, the binding agents are or comprise nucleic acids, such as DNA or RNA.

Cancer: The terms cancer, malignancy, neoplasm, tumor and carcinoma are used herein to refer to cells that exhibit relatively abnormal, uncontrolled and/or autonomous growth, resulting in an aberrant growth phenotype characterized by a significant loss of control of cellular proliferation. In some embodiments, a tumor may be or contain cells that are precancerous (e.g., benign), malignant, pre-metastatic, metastatic and/or non-metastatic. The present invention specifically identifies certain types of cancer for which its teachings may be particularly suitable. In some embodiments, the corresponding cancer may be characterized by a solid tumor. In some embodiments, the corresponding cancer may be characterized by a hematological tumor. Typically, examples of various types of cancers known in the art include, for example, hematopoietic cancers, including leukemias, lymphomas (Hodgkin's and non-Hodgkin's), myelomas and myeloproliferative disorders; sarcomas, melanomas, adenomas, hard tissue carcinomas, squamous cell carcinomas of the mouth, throat, larynx and lung, liver cancer, genitourinary cancers such as prostate, cervical, bladder, uterine, endometrial and renal cell carcinomas, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, endocrine cancer, thyroid cancer, parathyroid cancer, head and neck cancers, breast cancer, gastrointestinal cancers and nervous system cancers, benign lesions such as papillomas, etc.

Carrier: As used herein, refers to a diluent, adjuvant, auxiliary, or vehicle with which the composition is administered. In some exemplary embodiments, carriers can include sterile liquids such as, for example, water and oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. In some embodiments, carriers are or include one or more solid components. In some embodiments, the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the desired particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it will be preferable to include isotonic agents in the composition, for example, sugars, polyhydric alcohols such as mannitol, sorbitol, sodium chloride. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that ensures a delay in absorption, for example, aluminum monostearate and gelatin.

Combination Therapy: As used herein, the term combination therapy refers to a clinical intervention in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapies). In some embodiments, the two or more therapeutic regimens may be administered simultaneously. In some embodiments, the two or more therapeutic regimens may be administered sequentially (e.g., the first regimen is administered before any doses from the second regimen are administered). In some embodiments, the two or more therapeutic regimens are administered with overlapping regimens.

- 24 050059 dosing. In some embodiments, administering a combination therapy may involve administering one or more therapies or methods to a subject receiving the other(s) or method. In some embodiments, a combination therapy does not necessarily require that the individual agents be administered together in a single composition (or even necessarily at the same time). In some embodiments, two or more therapies or methods of a combination therapy are administered to the subject separately, such as in separate compositions, via separate routes of administration (e.g., one agent orally and the other agent intravenously), and/or at different times. In some embodiments, two or more therapies may be administered together in a combination composition or even in a combination compound (e.g., as part of a single chemical complex or covalent entity), via the same route of administration, and/or at the same time.

Complete Response: As used herein, the term complete response or CR is used to refer to the disappearance of all or substantially all target lesions. In some embodiments, CR refers to a reduction in the sum of the diameters of the target lesions (i.e., lesion clearance) by about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, using the sum of the diameters at baseline as a reference. In some embodiments, CR indicates that less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the total lesion diameter remains after treatment. Exemplary methods for assessing a complete response are defined in the RECIST guidelines. See, e.g., E.A. Eisenhauer, et al., New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.), Eur. J. of Cancer, 45: 228-247 (2009).

Dosage form or unit dosage form: Those skilled in the art will appreciate that the term dosage form may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of the active agent. In some embodiments, such quantity is a unit dosage amount (or an integral fraction thereof) suitable for administration in accordance with a dosage regimen that has been determined to correlate with a desired or beneficial result when administered to the appropriate population (i.e., a therapeutic dosage regimen). Those of ordinary skill in the art will appreciate that the total quantity of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

Dose regimen or regimen: Those skilled in the art will appreciate that the term regimen can be used to refer to a set of unit doses (typically more than one) that are administered to an individual subject, typically separated by periods of time. In some embodiments, a given therapeutic agent is characterized by a recommended dosage regimen, which may provide for one or more doses. In some embodiments, the dosage regimen provides a plurality of doses, each of which is separated in time from the other doses. In some embodiments, the individual doses are separated from each other by a period of time of the same duration; in some embodiments, the dosage regimen provides a plurality of doses and at least two different periods of time separating the individual doses. In some embodiments, all doses in the dosage regimen have the same number of unit doses. In some embodiments, the different doses in the dosage regimen have different amounts. In some embodiments, the dosage regimen includes a first dose in an amount of the first dose, followed by one or more additional doses in an amount of a second dose different from the amount of the first dose. In some embodiments, the dosing regimen comprises a first dose in an amount of the first dose, followed by one or more additional doses in an amount of the second dose similar to the amount of the first dose. In some embodiments, the dosing regimen correlates with a desired or beneficial outcome when administered to the appropriate population (i.e., is a therapeutic dosing regimen). In some embodiments, the regimen comprises at least one dose, wherein the dose provides one unit dose of the therapeutic agent (e.g., an anti-TIM-3 antibody agent). In some embodiments, the regimen provides at least one dose, wherein the dose provides two or more unit doses of the therapeutic agent. For example, a dose of 500 mg can be administered as a single unit dose of 500 mg or as two unit doses of 250 mg. In some embodiments, the regimen correlates with or results in a desired or beneficial outcome when administered to the appropriate population (i.e., is a therapeutic regimen).

Hazard ratio: As used herein, the term hazard ratio is an expression of the risk or probability of events occurring in a treatment group relative to events occurring in a control group. Hazard ratios can be estimated using the Cox model, a regression technique for survival data that provides an estimate of the hazard ratio and its confidence interval. The hazard ratio is an estimate of the ratio of the level of risk in the treatment group compared to the control group. The hazard ratio is the probability that

- 25 050059 if the event in question has not yet occurred, it will occur in the next time interval, divided by the length of that interval. The assumption of proportional hazards regression is that the proportion of risks is constant over time.

Homology: As used herein, the term homology refers to the overall relatedness between polymer molecules, such as between nucleic acid molecules (e.g., DNA molecules and/or RNA molecules) and/or between polypeptide molecules. In some embodiments, polymer molecules are considered homologous to each other if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical. In some embodiments, polymer molecules are considered to be homologous to each other if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% similar (e.g., contain residues with related chemical properties at corresponding positions). For example, as is well known to those of ordinary skill in the art, certain amino acids are typically classified as similar to each other, as hydrophobic or hydrophilic amino acids, and/or as having polar or non-polar side chains. Substitution of one amino acid for another of the same type can often be considered a homologous substitution.

As will be understood by those skilled in the art, a variety of algorithms are available that compare sequences to determine their degree of homology, including by allowing gaps of a given length in one sequence relative to another when considering which residues correspond to each other in different sequences. For example, calculating the percent homology between two nucleic acid sequences can be accomplished by aligning the two sequences for optimal comparison (e.g., gaps can be introduced into one or both of the first and second nucleic acid sequences for optimal alignment, and non-corresponding sequences can be ignored for comparison purposes). In some embodiments, the length of the sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or substantially 100% of the length of the reference sequence. The nucleotides at the corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, the molecules are identical at that position; when a position in the first sequence is occupied by a nucleotide similar to the corresponding position in the second sequence, the molecules are similar at that position. The percentage homology between two sequences is a function of the number of identical and similar positions common to the sequences, taking into account the number of gaps and the length of each gap that must be introduced to optimally align the two sequences. Illustrative algorithms and computer programs useful for determining the percent homology between two nucleotide sequences include, for example, the Meyers and Miller algorithm (CABIOS, 1989, 4: 11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 residue weight table, a gap length penalty of 12, and a gap penalty of 4. The percent homology between two nucleotide sequences can alternatively be determined, for example, using the GAP program in the GCG software package using the NWSgapdna.CMP matrix.

K _D , as used herein, refers to the dissociation constant of a binding agent (e.g., an antibody or its binding component) from a complex with its partner (e.g., an epitope to which the antibody or its binding component binds).

Koff, as used herein, refers to the dissociation rate constant for the dissociation of a binding agent (e.g., an antibody or its binding component) from a complex with its partner (e.g., an epitope to which the antibody or its binding component binds).

Ko _n , as used herein, refers to the association rate constant for the association of a binding agent (e.g., an antibody or its binding component) with its partner (e.g., an epitope to which the antibody or its binding component binds).

Patient or Subject: As used herein, the term patient or subject refers to any organism to which the provided compound or compounds described herein are administered in accordance with the present invention, such as for experimental, diagnostic, prophylactic and/or therapeutic purposes. Exemplary subjects include animals. The term animal refers to any member of the animal kingdom. In some embodiments, an animal refers to humans at any stage of development. In some embodiments, an animal refers to non-human animals at any stage of development. In some embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cattle, primate and/or pig). In some embodiments, animals include, but are not limited to, mammals,

- 26 050059 birds, reptiles, amphibians, fish, insects and/or worms. In some embodiments, the animal may be a transgenic animal, a genetically engineered animal and/or a clone. In embodiments, the animals are mammals such as mice, rats, rabbits, non-human primates and humans; insects; worms, etc. In a preferred embodiment, the subject is a human. In some embodiments, the subject may suffer from or be susceptible to a disease, disorder and/or condition (e.g., cancer). As used herein, the term patient population or subject population refers to a plurality of patients or subjects.

Partial Response: As used herein, the term partial response (PR) refers to a reduction in tumor progression in a subject, as indicated by a reduction in the sum of the diameters of the target lesions, using the sum of the diameters at baseline as a reference. In some embodiments, PR refers to a reduction in the sum of the diameters or target lesions of at least 30%, using the sum of the diameters at baseline as a reference. Exemplary methods for assessing a partial response are defined in the RECIST guidelines. See, e.g., E. A. Eisenhauer, et al., New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.), Eur. J. of Cancer, 45: 228247 (2009).

Pharmaceutical Composition: As used herein, the term "pharmaceutical composition" refers to a composition in which an active agent (e.g., an anti-TIM-3 antibody agent and/or a PD-1 binding agent) is formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose amount suitable for administration according to a therapeutic regimen that exhibits a statistically significant likelihood of achieving a predetermined therapeutic effect when administered to an appropriate population. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those adapted for the following: oral administration, such as oral liquid dosage forms (aqueous or non-aqueous solutions or suspensions), tablets, such as those intended for buccal, sublingual and systemic absorption, tablet sizes, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension or a sustained release formulation; topical application, such as a cream, ointment or patch with controlled release or an aerosol applied to the skin, lungs or mouth; intravaginally or intrarectally, such as a pessary, cream or foam; sublingually; intraocularly; transdermally or nasally, intrapulmonary and to other mucosal surfaces. In some preferred embodiments, the active agent (e.g., an anti-TIM-3 antibody agent and/or a PD-1 binding agent) is formulated for parenteral administration.

Pharmaceutically acceptable: As used herein, the term pharmaceutically acceptable with respect to a carrier, diluent, or excipient used to formulate a composition disclosed herein means that the carrier, diluent, or excipient must be compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

Progression-Free Survival: As used herein, the term progression-free survival means the period of time during which a subject having a disease (e.g., cancer) survives without significant worsening of the disease. Progression-free survival can be assessed as the period of time during which there is no progression of tumor growth and/or in which the patient's disease state is not determined to be disease progression. In some embodiments, progression-free survival in a subject having cancer is assessed by assessing the size of the tumor (lesion), the number of tumors (lesions), and/or metastasis.

Progression or Progressive Disease: The term tumor growth progression or disease progression (PD), as used herein in relation to cancer status, refers to an increase in the sum of the diameters of the target lesions (tumors). In some embodiments, tumor growth progression refers to at least a 20% increase in the sum of the diameters of the target lesions, using the lowest sum in the study as a reference (this includes the sum at baseline if that is the lowest sum in the study). In some embodiments, in addition to a relative increase of 20%, the sum of the diameters of the target lesions must also demonstrate an absolute increase of at least 5 mm. The development of one or more new lesions may also be taken into account in determining tumor growth progression. Progression in the context of determining progression-free survival may also be determined if at least one of the following criteria is met: 1) tumor evaluation by CT/MRI clearly indicates disease progression according to RECIST 1.1 or irRECIST criteria; or 2) additional diagnostic tests (e.g., histology/cytology,

- 27 050059 ultrasound techniques, endoscopy, positron emission tomography) identify new lesions or define existing lesions characteristic of overt disease progression AND CA-125 progression according to the Gynecologic Cancer Study Group (GCIG) criteria (see Rustin et al., Int J Gynecol Cancer 2011; 21: 419-423, which is incorporated herein in its entirety); 3) definitive clinical signs and symptoms of PD not due to non-malignant or iatrogenic causes ([i] intractable cancer-related pain; [ii] malignancy-related bowel obstruction/worsening dysfunction; or [iii] overt symptomatic worsening of ascites or pleural effusion) AND CA-125 progression according to GCIG criteria.

Solid Tumor: As used herein, the term solid tumor refers to an abnormal mass of tissue that does not typically contain cysts or areas of fluid. In some embodiments, a solid tumor may be benign; in some embodiments, a solid tumor may be malignant. Those skilled in the art will appreciate that the various types of solid tumors are generally referred to by the type of cells that form them. Examples of solid tumors include carcinomas, lymphomas, and sarcomas. In some embodiments, solid tumors may be or include tumors of the adrenal gland, bile duct, bladder, bone, brain, breast, cervix, colon, endometrium, esophagus, eye, gallbladder, gastrointestinal tract, kidney, larynx, liver, lung, nasal cavity, nasopharynx, oral cavity, ovary, penis, pituitary gland, prostate, retina, salivary gland, skin, small intestine, stomach, testicle, thymus, thyroid, uterus, vagina and/or vulva.

Stabilization or stable disease: As used herein, the term tumor growth stabilization or stable disease (SD) does not refer to a sufficient decrease in tumor size to be defined as a PR nor does it refer to a sufficient increase to be defined as a PD. In some embodiments, stabilization refers to a change (increase or decrease) in the sum of the diameters of the target lesions by less than 30%, 25%, 20%, 15%, 10%, or 5%, using the sum of the diameters at baseline as the reference. Exemplary methods for assessing tumor growth stabilization or stable disease are defined in the RECIST guidelines. See, e.g., Eisenhauer, E. A., et al., New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.), Eur. J. of Cancer, 45: 228-247 (2009).

Therapeutically effective amount: As used herein, refers to an amount that provides the desired effect for which it is administered. In some embodiments, the term refers to an amount that is sufficient when administered to a population suffering from or susceptible to a disease, disorder and/or condition, in accordance with a therapeutic dosage regimen for treating the disease, disorder and/or condition. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and/or severity of one or more symptoms of the disease, disorder and/or condition and/or delays the onset thereof. Those of ordinary skill in the art will appreciate that the term therapeutically effective amount does not actually require achieving successful treatment in a particular individual. Rather, a therapeutically effective amount may be one that provides a specific desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. In some embodiments, reference to a therapeutically effective amount may be a reference to an amount measured in one or more specific tissues (e.g., tissue affected by a disease, disorder, or condition) or fluids (e.g., blood, saliva, blood serum, sweat, tears, urine, etc.). Those of ordinary skill in the art will appreciate that in some embodiments, a therapeutically effective amount of a particular agent or therapy may be formulated and/or administered in a single dose. In some embodiments, a therapeutically effective agent may be formulated and/or administered in multiple doses, such as as part of a dosing regimen.

Treatment: As used herein, the term treatment (also treating or treating) refers to any administration of a therapeutic agent that partially or completely alleviates, reduces the intensity of, ameliorates, suppresses, delays the onset of, reduces the severity, and/or reduces the incidence of one or more symptoms, signs, and/or causes of a particular disease, disorder, and/or condition. In some embodiments, such treatment may be for a subject that does not exhibit signs of the relevant disease, disorder, and/or condition, and/or for a subject that exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be for a subject that exhibits one or more established signs of the relevant disease, disorder, and/or condition. In some embodiments, the treatment may be for a subject that has been diagnosed as suffering from the relevant disease, disorder, and/or condition. In some embodiments, the treatment may be for a subject that is known to have one or more factors of

- 28 050059 susceptibility factors that are statistically correlated with an increased risk of developing the relevant disease, disorder and/or condition.

Treatments, including cancer treatments

Described herein are methods for treating disorders in a subject (e.g., disorders that benefit from administration of an anti-TIM-3 antibody therapy). For example, an anti-TIM-3 antibody therapy described herein can be administered, for example, as a monotherapy or combination therapy, for a period sufficient to provide clinical benefit, or according to a schedule determined by a physician (e.g., the anti-TIM-3 antibody therapy is administered in dosage amounts and for a number of treatment cycles determined by a physician).

In embodiments, the methods described herein are useful for enhancing T cell activation or T cell effector function in a subject.

In embodiments, the methods described herein are useful for inducing an immune response in a subject.

In embodiments, the methods described herein are useful for enhancing an immune response or increasing the activity of an immune cell in a subject.

The methods of the present invention can be used to treat any type of infectious disease (i.e., a disease or disorder caused by a bacterium, virus, fungus, or parasite). Examples of infectious diseases that can be treated by the method of the present invention include, but are not limited to, diseases caused by human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), influenza virus, dengue virus, hepatitis B virus (HBV), or hepatitis C virus (HCV). If the method of the present invention is used to treat an infectious disease, the anti-TIM-3 antibody agent can be administered in combination with at least one antibacterial agent or at least one antiviral agent. In this case, the antibacterial agent can be any suitable antibiotic known in the art. An antiviral agent may be any vaccine of any suitable type that specifically targets a particular virus (e.g., live attenuated vaccines, subunit vaccines, recombinant vector vaccines) and small molecule antiviral therapeutics (e.g., viral replication inhibitors and nucleoside analogues).

The methods of the present invention can be used to treat any type of autoimmune disease (i.e., a disease or disorder caused by an overactive immune system in which the body attacks and damages its own tissues), such as those described in, for example, MacKay I.R. and Rose N.R., eds., The Autoimmune Diseases, Fifth Edition, Academic Press, Waltham, MA (2014). Examples of autoimmune diseases that can be treated by the method of the present invention include, but are not limited to, multiple sclerosis, type 1 diabetes mellitus, rheumatoid arthritis, scleroderma, Crohn's disease, psoriasis, systemic lupus erythematosus (SLE), and ulcerative colitis. When the method of the present invention is used to treat an autoimmune disease, the TIM-3 antibody agent can be used in combination with an anti-inflammatory agent, including, for example, corticosteroids (e.g., prednisone and fluticasone) and non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, and naproxen).

In embodiments, the methods described herein are useful for treating T cell dysfunctional disorders (e.g., cancer).

In embodiments, the methods described herein are useful for reducing tumors or suppressing the growth of tumor cells in a subject.

The methods of the present invention can be used to treat any type of cancer known in the art.

In embodiments, the cancer is adenocarcinoma, lung adenocarcinoma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), adrenocortical carcinoma, anal cancer, appendiceal cancer, B-cell leukemia, B-cell lymphoma, bladder cancer, brain cancer, breast cancer (e.g., triple-negative breast cancer (TNBC)), fallopian tube(s) cancer, testicular cancer, cerebral cancer, cervical cancer, choriocarcinoma, chronic myelogenous leukemia, CNS tumor, colon adenocarcinoma, colon cancer, colorectal cancer, diffuse intrinsic brainstem glioma (DIPG), diffuse large B cell lymphoma (DLBCL), embryonal rhabdomyosarcoma (ERMS), endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, follicular lymphoma (FL), gallbladder cancer, gastric cancer, gastrointestinal cancer, glioma, head and neck cancer, hematological cancer, hepatocellular carcinoma, Hodgkin's lymphoma (HL)/primary mediastinal B-cell lymphoma, kidney cancer, clear cell renal cell carcinoma, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell carcinoma, mesothelioma, monocytic leukemia, multiple myeloma, myeloma, CNS neuroblastic tumor (e.g., neuroblastoma (NB)), non-Hodgkin's lymphoma (NHL), non-small cell lung cancer (NSCLC), oral cancer, osteosarcoma, ovarian cancer, carcinoma

- 29 050059 Ovarian cancer, Pancreatic cancer, Peritoneal cancer, Primary peritoneal cancer, Prostate cancer, Relapsed or refractory classical Hodgkin's lymphoma (CHL), Renal cell carcinoma, Rectal cancer, Salivary gland cancer (eg, Salivary gland tumor), Sarcoma, Skin cancer, Small cell lung cancer, Small bowel cancer, Anogenital squamous cell carcinoma (eg, Squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), Esophageal squamous cell carcinoma, Head and neck squamous cell carcinoma (SCHNC), Lung squamous cell carcinoma, Gastric cancer, T-cell leukemia, T-cell lymphoma, Thymus cancer, Thymoma, Thyroid cancer, Uveal melanoma, Urothelial cell carcinoma, Uterine cancer, Cancer uterine endometrial cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Wilms' tumor.

In other embodiments, the cancer is head and neck cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), renal cell cancer, bladder cancer, melanoma, Merkel cell carcinoma (see, e.g., Bhatia et al., Curr. Oncol. Rep., 13(6):488-497 (2011), cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendiceal cancer, urothelial cell carcinoma, or squamous cell carcinoma (e.g., of the lung; anogenital region, including the anus, penis, cervix, vagina, or vulva; or esophagus). In some embodiments, the cancer for treatment in the context of the present invention is melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gallbladder cancer, laryngeal cancer, liver cancer, thyroid cancer, gastric cancer, salivary gland cancer, prostate cancer, pancreatic cancer or Merkel cell carcinoma.

In embodiments, the cancer is a lymphoma, such as Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and polycythemia vera.

In embodiments, the cancer is squamous cell carcinoma. In embodiments, the cancer is squamous cell carcinoma of the lung. In embodiments, the cancer is squamous cell carcinoma of the esophagus. In embodiments, the cancer is squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva). In embodiments, the cancer is squamous cell carcinoma of the head and neck (HNSCC).

In embodiments, the cancer is bladder cancer, breast cancer (e.g., triple negative breast cancer (TNBC)), fallopian tube(s) cancer, cholangiocarcinoma, colon adenocarcinoma, endometrial cancer, esophageal cancer, Ewing sarcoma, gastric cancer, clear cell renal cell carcinoma, lung cancer (e.g., lung adenocarcinoma or squamous cell lung cancer), mesothelioma, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, uterine endometrial cancer, or uveal melanoma. In embodiments, the cancer is ovarian cancer, fallopian tube(s), or peritoneal cancer. In embodiments, the cancer is breast cancer (e.g., TNBC). In embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer). In embodiments, the cancer is prostate cancer.

In embodiments, the cancer is a CNS or brain cancer, such as a neuroblastoma (NB), glioma, diffuse intrinsic pontine glioma (DIPG), pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic schwannoma, oligodendroglioma, meningioma, vestibular schwannoma, adenoma, metastatic brain tumor, meningioma, spinal cord tumor, or medulloblastoma. In embodiments, the cancer is a CNS tumor.

In other embodiments, the cancer is melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gallbladder cancer, laryngeal cancer, liver cancer, thyroid cancer, gastric cancer, salivary gland cancer, prostate cancer, pancreatic cancer, or Merkel cell carcinoma (see, e.g., Bhatia et al., Curr. Oncol. Rep., 13(6): 488-497 (2011)).

In some embodiments, the patient or patient population has a hematological cancer. In some embodiments, the patient has a hematological cancer such as diffuse large B cell lymphoma (DLBCL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), follicular lymphoma (FL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM). In embodiments, the cancer is a hematopoietic cancer such as acute lymphoblastic leukemia (ALL), acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia

- 30 050059 (APL), acute monoblastic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphoblastic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia and multiple myeloma; acute and chronic leukemias such as lymphoblastic, myelogenous, lymphocytic and myelocytic leukemia.

In some embodiments, the patient or patient population has a solid tumor. In embodiments, the cancer is a solid tumor such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, gastric cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, uterine cancer, testicular cancer, non-small cell lung cancer (NSCLC), small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, skin cancer, melanoma, neuroblastoma (NB), or retinoblastoma. In some embodiments, the tumor is an advanced solid tumor. In some embodiments, the tumor is a metastatic solid tumor. In some embodiments, the patient has an MSI-H solid tumor.

In some embodiments, the patient or patient population to be treated with the methods of the present invention has a cancer, such as head and neck cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendiceal cancer, urothelial cell carcinoma, or squamous cell carcinoma (e.g., of the lung; anogenital region, including the anus, penis, cervix, vagina, or vulva; or esophagus), or is susceptible thereto. In some embodiments, a patient or patient population to be treated with the methods of the present invention has or is susceptible to lung cancer (e.g., NSCLC), kidney cancer, melanoma, cervical cancer, colorectal cancer, or endometrial cancer (e.g., MSS endometrial cancer or MSI-H endometrial cancer).

In some embodiments, the patient or patient population to be treated with the methods of the present invention has or is susceptible to non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cell cancer, melanoma, cervical cancer, colorectal cancer, anogenital squamous cell carcinoma (e.g., squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), head and neck cancer, triple-negative breast cancer, ovarian cancer, or endometrial cancer. In some embodiments, the patient has an advanced solid tumor such as non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cell carcinoma, melanoma, cervical cancer, colorectal cancer, anogenital squamous cell carcinoma (e.g., squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), head and neck cancer, triple-negative breast cancer, ovarian cancer, or endometrial cancer. In some embodiments, the patient has an advanced solid tumor with microsatellite instability.

In some embodiments, the cancer is a gynecologic cancer (i.e., a cancer of the female reproductive system, such as ovarian cancer, fallopian tube cancer, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, or primary peritoneal cancer, or breast cancer). In some embodiments, female reproductive system cancers include, but are not limited to, ovarian cancer, fallopian tube(s), peritoneal cancer, and breast cancer.

In embodiments, the cancer is ovarian cancer (e.g., serous or clear cell ovarian cancer). In embodiments, the cancer is fallopian tube cancer (e.g., serous or clear cell fallopian tube cancer). In embodiments, the cancer is primary peritoneal cancer (e.g., serous or clear cell primary peritoneal cancer).

In some embodiments, the ovarian cancer is epithelial carcinoma. Epithelial carcinoma accounts for 85 to 90% of ovarian cancers. Although historically the disease has been thought to develop on the surface of the ovary, new evidence suggests that at least some ovarian cancers begin in specific cells in a portion of the fallopian tube. The fallopian tubes are small tubes that connect a woman's ovaries to her uterus and are part of a woman's reproductive system. In

- 31 050059 In a normal female reproductive system, there are two fallopian tubes, one on each side of the uterus. Cancer cells that originate in the fallopian tube can come to the surface of the ovary early on. The term ovarian cancer is often used to describe types of epithelial cancer that originate in the ovary, the fallopian tube, and the lining of the abdominal cavity called the peritoneum. In some embodiments, the cancer is or contains a germ cell tumor. Germ cell tumors are a type of ovarian cancer that develop in the cells of the ovaries that produce eggs. In some embodiments, the cancer is or contains a stromal tumor. Stromal tumors develop in the connective tissue cells that hold the ovaries together, which is sometimes the tissue that produces female hormones called estrogens. In some embodiments, the cancer is or contains a granulosa cell tumor. Granulosa cell tumors can secrete estrogen, resulting in unusual vaginal bleeding at the time of diagnosis. In some embodiments, the gynecologic cancer is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD) and/or BRCA1/2 mutation(s). In some embodiments, the gynecologic cancer is sensitive to platinum-based agents. In some embodiments, the gynecologic cancer has responded to a platinum-based agent. In some embodiments, the gynecologic cancer has become resistant to a platinum-based agent. In some embodiments, the gynecologic cancer has once demonstrated a partial or complete response to a platinum-based agent (e.g., a partial or complete response to the last platinum-based agent or to the penultimate platinum-based agent). In some embodiments, the gynecologic cancer is currently resistant to a platinum-based agent.

In embodiments, the cancer is breast cancer. Breast cancer typically begins in either the cells of the milk glands known as lobules or ducts. Less commonly, breast cancer may begin in the stromal tissues. These include the fatty and fibrous connective tissues of the breast. Over time, breast cancer cells can invade nearby tissues, such as the axillary lymph nodes or lungs, in a process known as metastasis. The stage of the breast cancer, the size of the tumor, and the rate at which it grows are factors that determine the type of treatment offered. Treatment options include surgery to remove the tumor, drug therapy, which includes chemotherapy and hormonal therapy, radiation therapy, and immunotherapy. Prognosis and survival rates vary greatly; five-year relative survival rates range from 98 to 23% depending on the type of breast cancer that occurs. Breast cancer is the second most common cancer worldwide, with approximately 1.7 million new cases in 2012, and is the fifth leading cause of cancer death, with approximately 521,000 deaths. Of these cases, approximately 15% are triple-negative, which does not express estrogen receptor, progesterone receptor (PR), or HER2. In some embodiments, triple-negative breast cancer (TNBC) is characterized as breast cancer cells that are negative for estrogen receptor expression (<1% of cells), negative for progesterone receptor expression (<1% of cells), and HER2-negative.

In embodiments, the cancer is ER-positive breast cancer, ER-negative breast cancer, PR-positive breast cancer, PR-negative breast cancer, HE2-positive breast cancer, HER2-negative breast cancer, BRCA1/2-positive breast cancer, BRCA1/2-negative cancer, or triple-negative breast cancer (TNBC). In embodiments, the cancer is triple-negative breast cancer (TNBC). In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is advanced breast cancer. In some embodiments, the cancer is stage II, stage III, or stage IV breast cancer. In some embodiments, the cancer is stage IV breast cancer. In some embodiments, the breast cancer is triple-negative breast cancer.

In some embodiments, the patient or patient population treated with the methods of the present invention has or is susceptible to endometrial cancer (EC). Endometrial carcinoma is the most common form of cancer of the female reproductive tract, accounting for 10-20 cases per 100,000 person-years. The annual incidence of new cases of endometrial cancer (EC) is estimated to be approximately 325,000 worldwide. In addition, EC is the most common cancer in postmenopausal women. Approximately 53% of endometrial cancer cases occur in developed countries. In 2015, approximately 55,000 cases of EC were diagnosed in the United States, and there are currently no approved targeted therapies for use in EC. There is a need for agents and regimens that provide

- 32 050059 Improved survival in advanced EC and recurrent EC with 1L and 2L. An estimated 10,170 people will die from EC in the United States in 2016. The most common histologic form is endometrioid adenocarcinoma, accounting for approximately 75-80% of diagnosed cases. Other histologic forms include uterine papillary serous (less than 10%), clear cell 4%, mucinous 1%, squamous cell less than 1%, and mixed approximately 10%.

Pathogenetically, EC is divided into two distinct types, the so-called types I and II. Type I tumors are low-grade and estrogen-related endometrioid carcinomas (EEC), while type II tumors are non-endometrioid (NEEC) (mostly serous and clear cell) carcinomas. The World Health Organization recently updated the pathological classification of EC, recognizing nine distinct EC subtypes, but EEC and serous carcinoma (SC) account for the vast majority of cases. EEC are estrogen-related carcinomas that occur in perimenopausal patients and are preceded by precancerous lesions (endometrial hyperplasia/endometrioid intraepithelial neoplasia). Microscopically, low-grade EEC (EEC 1-2) contain tubular glands somewhat resembling proliferative endometrium, with architectural complexity with fusion of glands and a cribriform pattern. High-grade EEC exhibits a solid growth pattern. In contrast, SC occurs in postmenopausal patients in the absence of hyperestrogenism. Microscopically, SC exhibits thick, fibrous or edematous papillae with prominent tumor cell stratification, cell budding, and anaplastic cells with large eosinophilic cytoplasms. The vast majority of EECs are low-grade tumors (grades 1 and 2) and are associated with a good prognosis when confined to the uterus. Grade 3 EEC (EEC3) is an aggressive tumor with an increased rate of lymph node metastasis. SC are very aggressive, are not associated with estrogen stimulation, and occur primarily in older women. EEC 3 and SC are considered high-grade tumors. SC and EEC3 were compared using Surveillance, Epidemiology, and End Results (SEER) program data from 1988 to 2001. They represented 10 and 15% of the EU, respectively, but accounted for 39 and 27% of cancer deaths, respectively. Endometrial cancers can also be classified into four molecular subgroups: (1) ultramutated/POLEmutant; (2) hypermutated MSI+ (e.g., MSI-H or MSI-L); (3) low copy number/microsatellite stable (MSS); and (4) high copy number/serosa-like. Approximately 28% of cases are characterized by high MSI. (Murali, Lancet Oncol. (2014). In some embodiments, the patient has mismatch repair deficient subgroup 2L endometrial cancer. In embodiments, the endometrial cancer is metastatic endometrial cancer. In embodiments, the patient has MSS endometrial cancer. In embodiments, the patient has MSI-H endometrial cancer.

In embodiments, the cancer is lung cancer. In embodiments, the lung cancer is squamous cell carcinoma of the lung. In embodiments, the lung cancer is small cell lung cancer (SCLC). In embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as squamous cell NSCLC. In embodiments, the lung cancer is lung cancer with an ALK translocation (e.g., NSCLC with an ALK translocation). In embodiments, the cancer is NSCLC with an identified ALK translocation. In embodiments, the lung cancer is EGFR mutant lung cancer (e.g., EGFR mutant NSCLC). In embodiments, the cancer is NSCLC with an identified EGFR mutation.

In embodiments, the cancer is colorectal (CRC) cancer (e.g., a solid tumor). In embodiments, the colorectal cancer is advanced colorectal cancer. In embodiments, the colorectal cancer is metastatic colorectal cancer. In embodiments, the colorectal cancer is MSI-H colorectal cancer. In embodiments, the colorectal cancer is MSS colorectal cancer. In embodiments, the colorectal cancer is POLE mutant colorectal cancer. In embodiments, the colorectal cancer is POLD mutant colorectal cancer. In embodiments, the colorectal cancer is TMB-high colorectal cancer.

In embodiments, the cancer is melanoma. In embodiments, the melanoma is late-stage melanoma. In embodiments, the melanoma is metastatic melanoma. In embodiments, the melanoma is MSI-H melanoma. In embodiments, the melanoma is MSS melanoma. In embodiments, the melanoma is POLE mutant melanoma. In embodiments, the melanoma is POLD mutant melanoma. In embodiments, the melanoma is TMB-high melanoma.

In embodiments, the cancer is an advanced stage cancer.

In embodiments, the cancer is metastatic cancer.

- 33 050059

In embodiments, the cancer is a recurrent cancer (e.g., a recurrent gynecologic cancer such as recurrent epithelial ovarian cancer, recurrent fallopian tube cancer, recurrent primary peritoneal cancer, or recurrent endometrial cancer).

Cancers that can be treated using the methods described herein include cancers associated with a high tumor mutational burden (TMB), cancers that are microsatellite stable (MSS), cancers that are characterized by microsatellite instability, cancers that have a microsatellite instability-high (MSI-H) status, cancers that have a microsatellite instability-low (MSI-L) status, cancers associated with high TMB and MSI-H (e.g., cancers associated with high TMB and MSI-L or MSS), cancers characterized by a DNA mismatch repair system deficiency, cancers that have a defect in a DNA mismatch repair gene, hypermutated cancers, cancers that have a homologous recombination repair deficiency/homologic recombination deficiency, cancers that have a high mutational burden (MDB), ... repair (HRD), cancers containing a mutation in polymerase delta (POLD), and cancers containing a mutation in polymerase epsilon (POLE).

In some embodiments, the tumor to be treated is characterized by microsatellite instability. In some embodiments, the tumor is characterized by a microsatellite instability-high (MSI-H) status. Microsatellite instability (MSI) is or involves an alteration in the DNA of certain cells (such as tumor cells) in which the number of microsatellite repeats (short repetitive DNA sequences) differs from the number of repeats that were contained in the DNA from which it originated. Approximately 15% of sporadic colorectal cancers (CRCs) contain widespread changes in the length of microsatellite (MS) sequences, known as microsatellite instability (MSI) (Boland and Goel, 2010). Sporadic MSI CRC tumors exhibit unique clinicopathologic features, including a near-diploid karyotype, higher frequency in older populations and in women, and better prognosis (de la Chapelle and Hampel, 2010; Popat et al., 2005). MSI is also present in other tumors such as endometrial cancer (EC) of the uterus, the most common gynecologic malignancy (Duggan et al., 1994). The same Bethesda reference panel, originally developed for screening an inherited genetic disorder (Lynch syndrome) (Umar et al., 2004), is now used to test for MSI in CRC and EC. However, genes that are frequently targeted by MSI in CRC genomes rarely involve DNA slippage events in EC genomes (Gurin et al., 1999).

Microsatellite instability results from the inability to correct replication errors due to a defective DNA mismatch repair (MMR) system.

This inability allows for the persistence of mismatch mutations throughout the genome, but particularly in regions of repetitive DNA known as microsatellites, resulting in increased mutational burden. At least some tumors characterized by MSI-H have been shown to exhibit improved responses to certain anti-PD-1 agents (Le et al., (2015) N. Engl. J. Med. 372(26):2509-2520; Westdorp et al., (2016) Cancer Immunol. Immunother. 65(10):1249-1259). In some embodiments, the cancer has a microsatellite instability status that is microsatellite instability high (e.g., MSI-H status). In some embodiments, the cancer has a microsatellite instability status that is microsatellite instability low (e.g., MSI-Low). In some embodiments, the cancer has a microsatellite instability status of microsatellite stable (e.g., MSS status). In some embodiments, the microsatellite instability status is assessed using a next generation sequencing (NGS)-based assay, an immunohistochemistry (IHC)-based assay, and/or a PCR-based assay. In some embodiments, microsatellite instability is detected using NGS. In some embodiments, microsatellite instability is detected using IHCC. In some embodiments, microsatellite instability is detected using PCR.

In embodiments, the patient has MSI-L cancer.

In embodiments, the patient has an MSI-H cancer. In some embodiments, the patient has an MSI-H solid tumor. In embodiments, the MSI-H cancer is an MSI-H endometrial cancer. In embodiments, the MSI-H cancer is a solid tumor. In embodiments, the MSI-H cancer is a metastatic tumor. In embodiments, the MSI-H cancer is an endometrial cancer. In embodiments, the MSI-H cancer is a non-endometrial cancer. In embodiments, the MSI-H cancer is a colorectal cancer.

In embodiments, the patient has MSS cancer. In embodiments, the MSS cancer is MSS endometrial cancer.

In embodiments, the cancer is associated with a POLE (DNA polymerase epsilon) mutation (i.e.

- 34 050059 the cancer is a POLE mutant cancer). In embodiments, the POLE mutation is a mutation in the exonuclease domain. In embodiments, the POLE mutation is a germline mutation. In embodiments, the POLE mutation is a sporadic mutation. In embodiments, the MSI cancer is also associated with a POLE mutation. In embodiments, the MSS cancer is also associated with a POLE mutation. In embodiments, the POLE mutation is identified using sequencing. In embodiments, the POLE mutant cancer is endometrial cancer. In embodiments, the POLE mutant cancer is colon cancer. In embodiments, the POLE mutant cancer is pancreatic cancer, ovarian cancer, or small intestinal cancer.

In embodiments, the cancer is associated with a POLD (DNA polymerase delta) mutation (i.e., the cancer is a POLD mutant cancer). In embodiments, the POLD mutation is an exonuclease domain mutation. In embodiments, the POLD mutation is a somatic mutation. In embodiments, the POLD mutation is a germline mutation. In embodiments, the POLD mutant cancer is identified using sequencing. In embodiments, the POLD mutant cancer is endometrial cancer. In embodiments, the POLD mutant cancer is colorectal cancer. In embodiments, the POLD mutant cancer is brain cancer.

In some embodiments, the patient has a cancer with a mismatch repair deficiency.

In embodiments, the MMRd cancer is colorectal cancer.

Microsatellite instability may result from a failure to repair replication-related errors due to a defective DNA mismatch repair (MMR) system. This failure allows mismatch mutations to persist throughout the genome, but particularly in regions of repetitive DNA known as microsatellites, resulting in increased mutational burden that may improve responses to certain anti-PD-1 agents. Ibid. In some embodiments, MSI-H status is assessed using an NGS-based assay and/or a PCR-based MSI assay. In some embodiments, microsatellite instability is detected using next-generation sequencing. In embodiments, microsatellite instability is detected using immunohistochemistry (IHC) testing.

In embodiments, the cancer (e.g., an MMRd cancer) has a high mutational burden of the tumor (i.e., the cancer is a high-MBC cancer). In some embodiments, the cancer is associated with a high-MBC and MSI-H. In some embodiments, the cancer is associated with a high-MBC and MSI-L or MSS. In some embodiments, the cancer is an endometrial cancer associated with a high-MBC. In some related embodiments, the endometrial cancer is associated with a high-MBC and MSI-H. In some related embodiments, the endometrial cancer is associated with a high-MBC and MSI-L or MSS. In embodiments, the high-MBC cancer is colorectal cancer. In embodiments, the high-MBC cancer is lung cancer (e.g., small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), such as squamous cell NSCLC or non-squamous NSCLC). In embodiments, the high-MBC cancer is melanoma. In embodiments, the high TMV cancer is urothelial cancer.

In embodiments, the patient has a cancer with increased expression of tumor infiltrating lymphocytes (TILs), i.e., the patient has a TIL-rich cancer. In embodiments, the TIL-rich cancer is breast cancer (e.g., triple-negative breast cancer (TNBC) or HER2-positive breast cancer). In embodiments, the TIL-rich cancer is metastatic cancer (e.g., metastatic breast cancer).

In embodiments, immune-related gene expression signatures can be predictors of response to an anti-PD-1 therapy in a cancer as described herein. For example, a gene panel that includes genes associated with IFN-γ signaling can be useful in identifying patients with cancer who would benefit from an anti-PD-1 therapy. Exemplary gene panels are described in Ayers et al., J. Clin. Invest., 127(8):2930-2940, 2017. In embodiments, the patient having cancer is characterized by a cancer that is breast cancer (e.g., TNBC) or ovarian cancer. In embodiments, the patient having cancer is characterized by a cancer that is bladder cancer, gastric cancer, bile duct cancer, esophageal cancer, or head and neck squamous cell carcinoma (HNSCC). In embodiments, the patient having cancer is characterized by cancer that is anal cancer or colorectal cancer.

In some embodiments, the patient has a tumor that expresses PD-L1. In some embodiments, the PD-L1 status is elevated in the patient or patient population. In some embodiments, the mutational burden and baseline expression profiles

- 35 050059 genes in archived or fresh pre-treatment biopsies are assessed before, during, and/or after treatment with an anti-PD-1 antibody agent. In some embodiments, patients are assessed for TIM-3 and/or LAG-3 status and/or expression.

In some embodiments, the patient has been previously treated with one or more different cancer therapies. In some embodiments, at least some of the patients in the population of patients having cancer have been previously treated with one or more of surgery, radiation therapy, chemotherapy, or immunotherapy. In some embodiments, at least some of the patients in the population of patients having cancer have been previously treated with chemotherapy (e.g., platinum-based chemotherapy). For example, a patient who has received two lines of cancer treatment may be identified as a 2L patient having cancer (e.g., a 2L patient having NSCLC). In embodiments, the patient has received two or more lines of cancer treatment (e.g., a 2L+ patient having cancer, such as a 2L+ patient having endometrial cancer). In embodiments, the patient has been previously treated with an anti-PD-1 therapy. In embodiments, the patient has previously received at least one line of cancer treatment (e.g., the patient has previously received at least one line or at least two lines of cancer treatment). In embodiments, the patient has previously received at least one line of treatment for metastatic cancer (e.g., the patient has previously received one or two lines of treatment for metastatic cancer). In embodiments, the subject is refractory to treatment with an agent that inhibits PD-1. In embodiments, the subject is difficult to treat with an agent that inhibits PD-1. In embodiments, the method described herein sensitizes the subject to treatment with an agent that inhibits PD-1.

T-cell immunoglobulin and mucin domain 3 (TIM-3)

T-cell immunoglobulin and mucin domain protein 3 (TIM-3), also known as hepatitis A virus cellular receptor 2 (HAVCR2), is a Th1-specific cell surface protein that regulates macrophage activation and increases the severity of experimental autoimmune encephalomyelitis in mice. TIM-3 is highly expressed on the surface of many immune cell types, including, for example, Th1 IFN-γ+ cells, IgII cells, natural killer (NK) cells, monocytes, and tumor-associated dendritic cells (DCs) (see, for example, Clayton et al., J. Immunol, 192(2): 782–791 (2014); Jones et al., J. Exp. Med., 205: 2763–2779 (2008); Monney et al., Nature, 415: 536–541 (2002); Hastings et al., Eur. J. Immunol, 39: 2492–2501 (2009); Seki et al., Clin. Immunol., 127: 78–88 (2008); Ju et al., B. J. Hepatol., 52: 322–329 (2010); Anderson et al., Science, 318: 1141–1143 (2007); Baitsch et al., PLoS ONE, 7: e30852 (2012); Ndhlovu et al., Blood, 119: 3734–3743 (2012). TIM-3 is also highly expressed on exhausted or attenuated CD8+ T cells in various chronic viral infections (e.g., HIV, HCV, and HBV) and in some types of cancer (see, e.g., McMahan et al., J. Clin. Invest., 120(12): 4546–4557 (2010); Jin et al., Proc Natl Acad Sci USA, 107(33): 14733–14738 (2010); Golden-Mason et al., J. Virol, 83(18): 9122-9130 (2009); Jones et al., supra; Fourcade et al., J. Exp. Med., 207(10): 2175-2186 (2010); Sakuishi et al., J. Exp. Med., 207(10):2187-2194 (2010); Zhou et al., Blood, 117(17): 4501-4510 (2011); Ngiow et al., Cancer Res., 77(10): 3540-3551 (2011)).

Putative ligands of TIM-3 include phosphatidylserine (Nakayama et al., Blood, 113: 38213830 (2009)), galectin-9 (Zhu et al., Nat. Immunol, 6: 1245–1252 (2005)), high-mobility group protein 1 (HMGB1) (Chiba et al., Nature Immunology, 13: 832–842 (2012)) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (Huang et al., Nature, 577(7534): 386–90 (2015)).

TIM-3 functions to regulate various aspects of the immune response.

The interaction of TIM-3 and galectin-9 (Gal-9) induces cell death, and blocking this interaction in vivo enhances autoimmunity and suppresses tolerance in experimental models, suggesting that TIM-3 is a negative regulatory molecule. In contrast to the effect on T cells, the interaction of TIM-3 and Gal-9 exerts antimicrobial effects by stimulating the clearance of intracellular pathogens from macrophages (see, e.g., Sakuishi et al., Trends in Immunology, 32(8): 345–349 (2011)). In vivo, suppression of TIM-3 has been shown to increase the pathological severity of experimental autoimmune encephalomyelitis (Monney et al., supra; and Anderson, A. C. and Anderson, D. E., Curr. Opin. Immunol, 18: 665–669 (2006)). Studies also suggest that dysregulation of the TIM-3–galectin-9 pathway may play a role in the development of chronic autoimmune diseases such as multiple sclerosis (Anderson and Anderson, supra). TIM-3 stimulates the clearance of apoptotic cells by binding phosphatidylserine through its unique binding cleft (see, e.g., DeKruyffet et al., J. Immunol, 184(4):1918–1930 (2010)).

Inhibition of TIM-3 activity, for example by the use of monoclonal antibodies, is currently being investigated as a tumor immunotherapy based on the results of preclinical trials (see, for example, Ngiow et al., Cancer Res., 77(21): 1–5 (2011); Guo et al., Journal of Translational Medicine, 11: 215 (2013); and Ngiow et al., Cancer Res., 77(21): 6567–6571 (2011)).

- 36 050059

The present invention relates to specific antibody-based agents and related methods for treating cancer.

Anti-TIM-3 antibody-based products

The present invention relates to methods of treating cancer that include administering compositions that deliver specific anti-TIM-3 antibody-based agents according to regimens that can achieve clinical benefit. The present invention describes, at least in part, anti-TIM-3 antibody-based agents and various related compositions and methods.

In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7.

SEQ ID NO:1

EVQLLESGGGLVQPGGSLRLSCAAASGFTFSSYDMSWVRQAPGKGLDWVSTISGGGTYTYYQDSVKG

RFTISRDNSKNTLYLQMNSLRAEDTAVYYCASMDYWGQGTTVTVSSA

SEQ ID NO:7

EVQLLESGGGLVQPGGSLRLSCAAASGFTFSSYDMSWVRQAPGKGLDWVSTISGGGTYTYYQDSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCASMDYWGQGTTVTVSS

In some embodiments, the TIM-3 antibody-based agent comprises an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8.

SEQ ID NO:2

DIQMTQSPSSLSSASVGDRVTITCRASQSIRRYLNWYHQKPGKAPKLLIYGASTLQSGVPSRFSGSGSGT

DFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTKVEIKR

SEQ ID NO:8

DIQMTQSPSSLSSASVGDRVTITCRASQSIRRYLNWYHQKPGKAPKLLIYGASTLQSGVPSRFSGSGSGT

DFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTKVEIK

In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7 and/or an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8.

In some embodiments, the anti-TIM-3 antibody agent comprises a variable heavy chain complementarity determining region 1, 2, and/or 3 (VH-CDR) comprising the amino acid sequences GFTFSSYDMS (SEQ ID NO: 21), TISGGGTYTYYQDSVK (SEQ ID NO: 22), and/or MDY (SEQ ID NO: 23), respectively. In some embodiments, the anti-TIM-3 antibody agent comprises a variable light chain complementarity determining region 1, 2, and/or 3 (VL-CDR) comprising the amino acid sequences RASQSIRRYLN (SEQ ID NO: 24), GASTLQS (SEQ ID NO: 25), and/or QQSHSAPLT (SEQ ID NO: 26), respectively. In some embodiments, the anti-TIM-3 antibody comprises the VH-CDR sequences of SEQ ID NOs: 21, 22, and 23, as well as the VL-CDR sequences of SEQ ID NOs: 24, 25, and 26 (see Table 1).

Table 1. Amino acid sequences of the complementarity determining regions (CDRs) of the heavy and light chains

Antibody Variable region CDR1 CDR2 CDR3 Antibody to TIM3 VH GFTFSSYDMS (SEQ ID NO: 21) TISGGGTYTYYQDSVK (SEQ ID NO: 22) MDY (SEQ ID NO: 23) Antibody to TIM3 VL RASQSIRRYLN (SEQ ID NO: 24) GASTLQS (SEQ ID NO: 25) QQSHSAPLT (SEQ ID NO: 26)

In some embodiments, the TIM-3 antibody agent is a monoclonal antibody. Specific antibodies of the present invention bind to TIM-3 with high affinity and effectively neutralize the activity of TIM-3. Specific sequences of the heavy chain polypeptide (SEQ ID NO: 3) and the light chain polypeptide (SEQ ID NO: 4) of the antibody are explicitly provided.

- 37 050059

Anti-TIM-3 antibody heavy chain polypeptide (SEQ ID NO: 3)

EVQLLESGGGLVQPGGSLRLSCAAASGFTFSSYDMSWVRQAPGKGLDWVSTISGGGTYTYYQDSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCASMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQ KSLSLSLGK

Anti-TIM-3 antibody light chain polypeptide (SEQ ID NO: 4)

DIQMTQSPSSLSASVGDRVTITCRASQSIRRYLNWYHQKPGKAPKLLIYGASTLQSGVPSRFSGSGSGT DFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

The present invention provides an isolated immunoglobulin heavy chain polypeptide having an amino acid sequence set forth in SEQ ID NO: 3. Further provided by the present invention is an isolated immunoglobulin heavy chain polypeptide having an amino acid sequence that is at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to the sequence set forth in SEQ ID NO: 3. In some embodiments, the sequence differences relative to the sequence set forth in SEQ ID NO: 3 are not within the CDRs. In some embodiments, the isolated immunoglobulin heavy chain polypeptide comprises all three CDRs of SEQ ID NO: 3. In some embodiments, the immunoglobulin heavy chain polypeptide comprises a signal peptide. In some embodiments, the immunoglobulin heavy chain polypeptide that comprises the signal peptide has the amino acid sequence set forth in SEQ ID NO: 5.

Anti-TIM-3 antibody heavy chain polypeptide with signal sequence (SEQ ID NO: 5) MEFGLSWLFLVAILKGVOCEVOLLESGGGLVOPGGSLRLSCAAASGFTFSSYDMSWVRQAPGKGLD

WVSTISGGGTYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASMDYWGQGTTVTVSSASTKG PSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKT YTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQ FNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK

In some embodiments, the provided immunoglobulin heavy chain polypeptide is or comprises an IgG4 polypeptide. In some embodiments, the provided immunoglobulin heavy chain polypeptide comprises a human IGHG4*01 polypeptide. In some embodiments, the provided immunoglobulin heavy chain polypeptide comprises one or more mutations within a region of the IgG heavy chain. In some embodiments, the provided immunoglobulin heavy chain polypeptide comprises an IgG4 heavy chain constant region with one or more mutations in the heavy chain constant region. In some embodiments, the provided immunoglobulin heavy chain polypeptide comprises an IgG4 heavy chain constant region with one or more mutations in the hinge region. It is contemplated that in some embodiments, a mutation in the hinge region of IgG4 may prevent half-molecule exchange with other IgG4 molecules. In some embodiments, the one or more mutations in the hinge region of IgG4 may provide for a serine-to-proline stabilizing mutation that prevents half-molecule exchange with other IgG4 molecules. In some embodiments, one or more mutations in the IgG4 hinge region may include the S228P mutation (See, e.g., J. Biol. Chem. 2015; 290(9):5462-5469).

The present invention provides an isolated immunoglobulin light chain polypeptide having an amino acid sequence set forth in SEQ ID NO:4. Further provided by the present invention is an isolated immunoglobulin light chain polypeptide having an amino acid sequence that has at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to the sequence set forth in SEQ ID NO:4. In some embodiments, the sequence differences relative to the sequence set forth in SEQ ID NO:4 are not within the CDRs. In some embodiments, the isolated immunoglobulin light chain polypeptide comprises all three CDRs of SEQ ID NO:4. In some embodiments, the provided immunoglobulin light chain polypeptide is a kappa light chain. In some embodiments, the provided immunoglobulin light chain polypeptide comprises a human IGKC*01 polypeptide. In some embodiments, the provided immunoglobulin light chain polypeptide comprises a sig

- 38 050059 signal peptide. In some embodiments, the immunoglobulin light chain polypeptide that comprises a signal peptide has the amino acid sequence set forth under SEQ ID NO: 6.

Anti-TIM-3 antibody light chain polypeptide with signal sequence (SEQ ID NO: 6)

MDMRVPAOLLGLLLLWLRGARCDIOMTOSPPSSLSASVGDRVTITCRASOSIRRYLNWYHQKPGKAPK LLIYGASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTKVEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA CEVTHQGLSSPVTKSFNRGEC

In some embodiments, the present invention provides an anti-TIM-3 antibody agent comprising at least one immunoglobulin heavy chain having an amino acid sequence set forth in SEQ ID NO: 3 and at least one immunoglobulin light chain having an amino acid sequence set forth in SEQ ID NO: 4. In some embodiments, the anti-TIM-3 antibody agent comprises two immunoglobulin heavy chains, each of which has the amino acid sequence set forth in SEQ ID NO: 3. Alternatively or in addition, in some embodiments, the anti-TIM-3 antibody agent comprises two immunoglobulin light chains, each of which has the amino acid sequence set forth in SEQ ID NO: 4. In some embodiments, the anti-TIM-3 antibody agent has a canonical antibody format.

In some embodiments, the provided heavy chain, light chain, and/or antibody agent is glycosylated at one or more sites. In some embodiments, the glycan is linked to the Fc region via an N atom. In some embodiments, the antibody agent is glycosylated at Asn297 (Kabat numbering). In some embodiments, the present invention provides a composition comprising one or more glycoforms of a heavy chain, light chain, and/or antibody agent described herein. In some embodiments, the provided composition comprises more than one such glycoform present in the specified absolute and/or relative amounts. In some embodiments, the present invention provides compositions that may be substantially free of one or more particular glycoforms of a heavy chain, light chain, and/or antibody agent described herein.

In embodiments, the TIM-3 binding agent is an anti-TIM-3 antibody that is TSR-022, which is a humanized anti-TIM-3 monoclonal antibody comprising a heavy chain having an amino acid sequence comprising SEQ ID NO: 3 and a light chain having an amino acid sequence comprising SEQ ID NO: 4. The anti-TIM3 antibody utilizes the human IGHG4*01 heavy chain gene and the human IGKC*01 kappa light chain gene as framework sequences. In addition, there is a single point mutation from Ser to Pro in the hinge region of the IgG4 heavy chain at canonical position S228, which corresponds to residue 240 of SEQ ID NO: 5, which contains the signal sequence. Without wishing to be bound by any theory, it is believed that this point mutation serves to stabilize the hinge region of the heavy chain of the antibody.

Additional biophysical and biochemical characterization of this exemplary humanized anti-TIM-3 monoclonal antibody is presented with respect to the observed disulfide bonds and glycosylation. Lys-C and trypsin digested peptides were carefully separated and detected by real-time LC-MS analysis. Linkages representing disulfide species were confirmed by comparing total ion chromatograms under non-reducing (NR) and reducing conditions. The disulfide bonds were consistent with the expected disulfide bond pattern in the IgG4 molecule. The residues involved in the expected inter- and intrachain disulfide bonds are tabulated below (Tables 2, 3, and 4).

- 39 050059

Table 2. Expected residues involved in disulfide bonds of the heavy chain of an exemplary anti-TIM-3 antibody agent having the amino acid sequence set forth under SEQ ID NO: 1 _______________________________________

ID of cysteine residue Residue of HC mAb to TIM-3 (position in SEQ ID NO: 1) I 22 II 96 III 127 IV 140 V 196 VI 219 VII 222 VIII 254 IX 314 X 360 XI 418

Table 3. Expected residues involved in disulfide bonds of the light chain of an exemplary anti-TIM-3 antibody agent having the amino acid sequence set forth under SEQ ID NO: 2 _____________________________________

ID of cysteine residue Residue LC of mAb to TIM-3 (position in SEQ ID NO: 2) I 23 II 88 III 134 IV 194 V 214

Table 4. Illustrative disulfide bond arrangements in the case of an antibody to TIM-3

No. of disulfide bond Peptides containing disulfide bonds NS Communication Site (position in SEQIDNO:1) Link site in LC (position in SEQ ID NO:2) DS1 VTITCR=FSGSGSGTDFTLTISSLQPEDF AVYYCQQSHSAPLTFGGGTK 23 88 DS2 SGTASVVCLLNNFYPR=VYACEVTHQGLSSPVTK 134 194 DS3 SFNRGEC=GPSVFPLAPCSR GEC=GPSVFPLAPCSR 127 214 DS4 LSCAAASGFTFSSYDMSWVR=AEDTA VYYCASMDYWGQGTTVTVSSASTK 22 97 DS5 STSSESTAALGCLVK=TYTCNVDHK STSESTAALGCLVK=TYTCNVDHKPSNTK 140 196 DS6 YGPPPCPPCPAPEFLGGPSVFLFPPK=YGPPCPPCPAP EFLGGPSVFLFPPK YGPPPCPPCPAPEFLGGPSVFLFPPK=YGPPCPPCPAP EFLGGPSVFLFPPKPK 219 222 DS7 TPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK =CK 254 314 DS8 NQVSLTCLVK=WQEGNVFSCSVMHEALHNHYTQ K 360 418

LC: light chain;

HC: heavy chain

This exemplary anti-TIM-3 antibody exhibits an occupied N-glycosylation site at asparagine 290 in the CH2 domain of each heavy chain in the mature protein sequence (SEQ ID NO: 1). The resulting N-glycosylation at this site upon expression is a mixture of oligosaccharide species typically seen on IgG expressed in mammalian cell culture, for example, the relative abundance of glycan species from a preparation of this exemplary anti-TIM-3 antibody cultured in Chinese hamster ovary (CHO) cells is shown below (Table 5).

- 40 050059

Table 5. Glycan analysis of the anti-TIM-3 antibody-based binder

View Presence (% of total oligosaccharides) Glycan description G0F 20.1% Oligosaccharide of the agalactosylated biantennary complex type with core fucosylation GIF 41.9% Oligosaccharide of the monogalactosylated biantennary complex type with core fucosylation G2F 29.0% Oligosaccharide of the galactosylated biantennary complex type with core fucosylation G2FS1 3.2% Oligosaccharide of the monosialylated galactosylated biantennary complex type with core fucosylation G2FS2 1.2% Oligosaccharide of the disialylated galactosylated biantennary complex type with core fucosylation M5 0.4% Oligomannose N-linked oligosaccharide, Man ₅ GlcNAc2

PD-1 binders

The present invention provides methods of treating cancer that further comprise administering compositions that deliver specific programmed death protein 1 (PD-1) binding agents according to regimens that can achieve clinical benefit. The present invention describes, at least in part, PD-1 binding agents (e.g., anti-PD-1 antibody agents) and various related compositions and methods. In some embodiments, the PD-1 binding agent is a monoclonal antibody.

In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 11 or SEQ ID NO: 17.

SEQ ID NO: 11

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYYQDSVKGR

FTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSA

SEQ ID NO:17

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYYQDSVKGR FTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSS

In some embodiments, the PD-1 binding agent comprises an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 12 or SEQ ID NO: 18.

SEQ ID NO:12

DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPSRFSGSGSG TEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKR

SEQ ID NO:18

DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPSRFSGSGSG TEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIK

In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO: 11 or SEQ ID NO: 17 and/or an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO: 12 or SEQ ID NO: 18. In some embodiments, the PD-1 binding agent is or comprises a humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb). In some embodiments, the PD-1 binding agent comprises a human IGHG4*01 polypeptide. In some embodiments, the PD-1 binding agent comprises one or more mutations within the IgG heavy chain region. In some embodiments, the PD-1 binding agent comprises an IgG4 heavy chain constant region having one or more mutations within the heavy chain constant region. In some embodiments, the PD-1 binding agent comprises an IgG4 heavy chain constant region with one or more mutations in the hinge region. It is contemplated that in some embodiments, a mutation in the hinge region of IgG4 may prevent half-molecule exchange with other IgG4 molecules. In some embodiments, the one or more mutations in the hinge region of IgG4 may provide for a serine-to-proline stabilizing mutation that prevents

- 41 050059 rotates the exchange of a half molecule with other IgG4 molecules. In some embodiments, one or more mutations in the hinge region of IgG4 may provide for the S228P mutation (See, e.g., J. Biol. Chem. 2015; 290(9):5462-5469).

In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain polypeptide whose amino acid sequence comprises SEQ ID NO: 13.

SEQ ID NO: 13. Anti-PD-1 antibody heavy chain polypeptide (CDR sequences)

EVOLLESGGGLVOPGGSLRLSCAASGFFSSYDMSWVROAPGKGLEWVSTISGGGSYTYYQDSVKGR

FTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH

YTQKSLSLSLGK

In some embodiments, the PD-1 binding agent comprises an immunoglobulin light chain polypeptide whose amino acid sequence comprises SEQ ID NO: 14.

SEQ ID NO: 14. Anti-PD-1 antibody light chain polypeptide (CDR sequences)

DIOLTOSPSFLSAYVGDRVTITCKASODVGTAVAWYOOKPGKAPKLLIYWASTLHTGVPSRFSGSGSG

TEFTLTISSLOPEDFATYYCOHYSSYPWTFGOGTKLEIKRTVAAPSVFIFPPSDEOLKSGTASVVCLLNNFYPRE

AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

The present invention provides an isolated immunoglobulin heavy chain polypeptide having an amino acid sequence set forth in SEQ ID NO: 13. Further provided by the present invention is an isolated immunoglobulin heavy chain polypeptide having an amino acid sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to the sequence set forth in SEQ ID NO: 13. In some embodiments, the sequence differences relative to the sequence set forth in SEQ ID NO: 13 are not within the CDRs. In some embodiments, the isolated immunoglobulin heavy chain polypeptide comprises all three CDRs of SEQ ID NO: 13. In some embodiments, the immunoglobulin heavy chain polypeptide comprises a signal peptide. In some embodiments, the immunoglobulin heavy chain polypeptide that comprises the signal peptide has the amino acid sequence set forth in SEQ ID NO: 15.

Anti-PD-1 antibody heavy chain polypeptide with signal sequence (SEQ ID NO: 15)

MEFGLSWLFLVAILKGVOCEVOLLESGGGLVOPGGSLRLSCAASGFFSSYDMSWVROAPGKGLEWV

STISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTK GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTK TYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEV QFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNHYTQKSLSLSLGK

The present invention provides an isolated immunoglobulin light chain polypeptide having an amino acid sequence set forth in SEQ ID NO: 14. Further provided by the present invention is an isolated immunoglobulin light chain polypeptide having an amino acid sequence that has at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to the sequence set forth in SEQ ID NO: 14. In some embodiments, the sequence differences relative to the sequence set forth in SEQ ID NO: 14 are not within the CDRs. In some embodiments, the isolated immunoglobulin light chain polypeptide comprises all three CDRs of SEQ ID NO: 14. In some embodiments, the provided immunoglobulin light chain polypeptide is a kappa light chain. In some embodiments, the provided immunoglobulin light chain polypeptide comprises a human IGKC*01 polypeptide. In some embodiments, the immunoglobulin light chain polypeptide comprises a signal peptide.

In some embodiments, the immunoglobulin light chain polypeptide that comprises the signal peptide has the amino acid sequence set forth in SEQ ID NO: 16.

- 42 050059

Anti-PD-1 antibody light chain polypeptide with signal sequence (SEQ ID NO: 16)

MDMRVPAOLLGLLLLWLPGARCDIOLTOSPSFLSAYVGDRVTITCKASODVGTAVAWYOQKPGKAP

KLLIYWASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLS SPVTKSFNRGEC

SEQ ID NOS: 13 and 14 describe an exemplary humanized monoclonal antibody to PD-1 (TSR-042) that utilizes the human IGHG4*01 heavy chain gene and the human IGKC*01 kappa light chain gene as framework sequences. There is a single point mutation from Ser to Pro in the hinge region of the IgG4 heavy chain. This mutation is located at canonical position S228. Without wishing to be bound by any theory, it is believed that this point mutation serves to stabilize the hinge region of the antibody heavy chain.

This document provides additional biophysical and biochemical characteristics of this illustrative humanized anti-PD-1 monoclonal antibody that are consistent with the expected disulfide bond pattern of an IgG4 molecule. The residues involved in the expected inter- and intrachain disulfide bonds are listed in the table below (Tables 6 and 7).

Table 6. Expected residues involved in disulfide bonds of the heavy chain of an exemplary anti-PD-1 antibody agent having the amino acid sequence set forth in SEQ ID NO: 13 ______________________________________

cysteine residue according to Edelman ³ Residue HC samAb to PD-1 (position in SEQ ID NO: 13) I 22 II 96 III 130 IV 143 V 199 VI 222 VII 225 VIII 257 IX 317 X 363 XI 421

Table 7. Expected residues involved in disulfide bonds of the light chain of an exemplary anti-PD-1 antibody agent having the amino acid sequence set forth in SEQ ID NO: 14

Cysteine residue ID according to Edelman ³ Residue LC of mAb to PD-1 (position in SEQ ID NO: 14) I 23 II 88 III 134 IV 194 V 214

This exemplary anti-PD-1 antibody exhibits an occupied N-glycosylation site at asparagine residue 293 in the CH2 domain of each heavy chain in the mature protein sequence (SEQ ID NO: 13). The resulting N-glycosylation at this site upon expression is a mixture of oligosaccharide species typically seen on IgG expressed in mammalian cell culture, for example, the relative abundance of glycan species from a preparation of this exemplary anti-PD-1 antibody cultured in Chinese hamster ovary (CHO) cells is shown below (Table 8).

- 43 050059

Table 8. Glycan analysis of anti-PD-1 antibody-based binder

View Representation (% of total oligosaccharides) Glycan description G0 <0.1% Non-fucosylated oligosaccharide of the agalactosylated biantennary complex type G0F 19.5% Oligosaccharide of the agalactosylated biantennary complex type with core fucosylation G1 0.1% Non-fucosylated oligosaccharide of the monogalactosylated biantennary complex type GIF 45.6% Oligosaccharide of the monogalactosylated biantennary complex type with core fucosylation G2F 27.4% Oligosaccharide of the galactosylated biantennary complex type with core fucosylation M5 0.5% Oligomannosidated N-glycan, Man ₅ GlcNAc2

In some embodiments, the present invention provides an anti-PD-1 antibody agent comprising at least one immunoglobulin heavy chain having an amino acid sequence set forth in SEQ ID NO: 13 and at least one immunoglobulin light chain having an amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the anti-PD-1 antibody agent comprises two immunoglobulin heavy chains, each of which has the amino acid sequence set forth in SEQ ID NO: 13. Alternatively or in addition, in some embodiments, the anti-PD-1 antibody agent comprises two immunoglobulin light chains, each of which has the amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the anti-PD-1 antibody agent has a canonical antibody format.

In some embodiments, the provided heavy chain, light chain and/or antibody agent has a structure that includes one or more disulfide bonds. In some embodiments, the one or more disulfide bonds are or include a disulfide bond at an expected position of the IgG4 immunoglobulin.

In some embodiments, the PD-1 binding agent is glycosylated at one or more sites. As used herein, glycan means a component of a glycoprotein that is a sugar polymer (moiety). The term glycan encompasses free glycans, including glycans that have been cleaved or otherwise released from a glycoprotein. In some embodiments, the present invention provides a composition comprising one or more glycoforms of a heavy chain, light chain, and/or antibody agent described herein. In some embodiments, the glycan is linked to the Fc region via an N atom. In some embodiments, the PD-1 binding agent is glycosylated at Asn297 (Kabat numbering).

As used herein, the term "glycoform" refers to a specific form of a glycoprotein. That is, if a glycoprotein comprises a specific polypeptide that can potentially bind to different glycans or sets of glycans, then each distinct version of the glycoprotein (i.e., when the polypeptide is bound to a specific glycan or set of glycans) is referred to as a glycoform. In some embodiments, the provided composition comprises multiple glycoforms of one or more heavy chain, light chain, and/or antibody agents described herein.

In some embodiments, the antagonist activity of a PD-1 binding agent in blocking PD-1/PD-L1 or PD-L2 interaction can be confirmed or determined using a flow cytometry-based assay that measures the binding of labeled PD-L1 and PD-L2 expressed as murine IgG1 Fc fusion proteins (PD-L1 mFc or PD-L2 mFc) to PD-1-expressing cells. In some embodiments, the PD-1 binding agent can effectively block PD-1/PD-L1 and PD-1/PD-L2 binding compared to an IgG4 isotype control.

In some embodiments, the PD-1 binding agent can effectively neutralize the activity of PD-1 (e.g., can inhibit the binding of PD-1 to PD-L1 and PD-L2). In some embodiments, the functional antagonist activity of the PD-1 binding agent can be confirmed or determined by a mixed lymphocyte reaction (MLR) demonstrating enhanced production of interleukin (IL)-2 upon addition of the PD-1 binding agent. In some embodiments, the MLR assay can be performed using primary human CD4+ T cells as responders and human dendritic cells as stimulators.

Expression and composition

In some embodiments, the TIM-3 antibody-based agent and/or the binding

- 44 050059

The PD-1 agent is expressed from a vector containing one or more nucleic acid sequences.

In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain polypeptide encoded by a nucleotide sequence that comprises SEQ ID NO: 9.

Nucleotide sequence encoding the heavy chain polypeptide of the antibody to TIM-3 (SEQ ID NO: 9)

GAG GTG CAG CTG TTG GAG TCT GGG GGA GGC TTG GTA CAG CCT GGG GGG TCC CTG AGA CTC TCC TGT GCA GCA GCC TCT GGA TTC ACT TTC AGT AGC TAT GAC ATG TCT TGG GTC CGC CAG GCT CCA GGG AAG GGG CTG GAC TGG GTC TCA ACC ATT AGT GGT GGT GGT ACT TAC ACC TAC TAT CAA GAC AGT GTG AAG GGG CGG TTC ACC ATC TCC AGA GAC AAT TCC AAG AAC ACG CTG TAT CTG CAA ATG AAC AGC CTG AGA GCC GAG GAC ACG GCC GTA TAT TAC TGT GCG TCC ATG GAC TAC TGG GGG CAA GGG ACC ACG GTC ACC GTC TCC TCA GCA TCC ACC AAG GGC CCA TCG GTC TTC CCG STA GCA CCC TGC TCC AGG AGC ACC TCC GAG AGC ACA GCC GCC CTG GGC TGC CTG GTC AAG GAC TAC TTC CCC GAA CCA GTG ACG GTG TCG TGG AAC TCA GGC GCC CTG ACC AGC GGC GTG CAC ACC TTC CCG GCT GTC STA CAG TCC TCA GGA CTC TAC TCC CTC AGC AGC GTG GTG ACC GTG CCC TCC AGC AGC TTG GGC ACG AAG ACC TAC ACC TGC AAC GTA GAT CAC AAG CCC AGC AAC ACC AAG GTG GAC AAG AGA GTT GAG TCC AAA TAT GGT CCC CCA TGC CCA CCA TGC CCA GCA CCT GAG TTC CTG GGG GGA CCA TCA GTC TTC CTG TTC CCC CCA AAA CCC AAG GAC ACT CTC ATG ATC TCC CGG ACC CCT GAG GTC ACG TGC GTG GTG GTG GAC GTG AGC CAG GAA GAC CCC GAG GTC CAG TTC AAC TGG TAC GTG GAT GGC GTG GAG GTG CAT AAT GCC AAG ACA AAG CCG CGG GAG GAG CAG TTC AAC AGC ACG TAC CGT GTG GTC AGC GTC CTC ACC GTC CTG CAC CAG GAC TGG CTG AAC GGC AAG GAG TAC AAG TGC AAG GTC TCC AAC AAA GGC CTC CCG TCC TCC ATC GAG AAA ACC ATC TCC AAA GCC AAA GGG CAG CCC CGA GAG CCA CAG GTG TAC ACC CTG CCC CCA TCC CAG GAG GAG ATG ACC AAG AAC CAG GTC AGC CTG ACC TGC CTG GTC AAA GGC TTC TAC CCC AGC GAC ATC GCC GTG GAG TGG GAG AGC AAT GGG CAG CCG GAG AAC AAC TAC AAG ACC ACG CCT CCC GTG CTG GAC TCC GAC GGC TCC TTC TTC CTC TAC AGC AGG STA ACC GTG GAC AAG AGC AGG TGG CAG GAG GGG AAT GTC TTC TCA TGC TCC GTG ATG CAT GAG GCT CTG CAC AAC CAC TAC ACA CAG AAG AGC CTC TCC CTG TCT CTG GGT AAA

In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin light chain polypeptide encoded by a nucleotide sequence that comprises SEQ ID NO: 10.

Nucleotide sequence encoding a light chain polypeptide of an antibody to TIM-3 (SEQ ID NO: 10)

GAC PBX CAG ATG ACC CAG TCT CCA TCC TCC CTG TCT GCA TCT GTA GGA GAC AGA GTC ACC PBX ACT TGC CGG GCA AGT CAG AGC ATT AGG AGG TAT TTA AAT TGG TAT CAC CAG AAA CCA GGG AAA GCC CCT AAG CTC CTG PBX TAT GGT GCA TCC ACC TTG CAA AGT GGG GTC CCA TCA AGG TTC AGT GGT AGT GGA TCT GGG ACA GAT TTC ACT CTC ACC ATC AGC AGT CTG CAA CCT GAA GAT TTT GCA GTG TAT TAC TGT CAA CAG AGT CAC AGT GCC CCC CTC ACT TTC GGC GGA GGG ACC AAG GTG GAG ATC AAA CGA ACT GTG GCT GCA CCA TCT GTC TTC ATC TTC CCG CCA TCT GAT GAG CAA TTG AAA TCT GGA ACT GCC TCT GTT GTG TGC CTG CTG AAT AAC TTC TAT CCC AGA GAG GCC AAA GTA CAG TGG AAG GTG GAT AAC GCC CTC CAA TCG GGT AAC TCC CAG GAG AGT GTC ACA GAG CAG GAC AGC AAG GAC AGC ACC TAC AGC CTC AGC AGC ACC CTG ACG CTG AGC AAA GCA GAC TAC GAG AAA CAC AAA GTC TAC GCC TGC GAA GTC ACC CAT CAG GGC CTC AGC TCG CCC GTC ACA AAG AGC TTC AAC AGG GGA GAG TGT

In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain polypeptide encoded by a nucleotide sequence that comprises SEQ ID NO: 19.

SEQ ID NO: 19 - Nucleotide sequence encoding a PD-1 binding agent immunoglobulin heavy chain polypeptide

- 45 050059

GAG GTG CAG CTG TTG GAG TCT GGG GGA GGC TTG GTA CAG CCT GGG GGG TCC CTG AGA CTC TCC TGT GCA GCC TCT GGA TTC ACT TTC AGT AGC TAT GAC ATG TCT TGG GTC CGC CAG GCT CCA GGG AAG GGG CTG GAG TGG GTC TCA ACC ATT AGT GGT GGT GGT AGT TAC ACC TAC TAT CAA GAC AGT GTG AAG GGG CGG TTC ACC ATC TCC AGA GAC AAT TCC AAG AAC ACG CTG TAT CTG CAA ATG AAC AGC CTG AGA GCC GAG GAC ACG GCC GTA TAT TAC TGT GCG TCC CCT TAC TAT GCT ATG GAC TAC TGG GGG CAA GGG ACC ACG GTC ACC GTC TCC TCA GCA TCC ACC AAG GGC CCA TCG GTC TTC CCG CTA GCA CCC TGC TCC AGG AGC ACC TCC GAG AGC ACA GCC GCC CTG GGC TGC CTG GTC AAG GAC TAC TTC CCC GAA CCA GTG ACG GTG TCG TGG AAC TCA GGC GCC CTG ACC AGC GGC GTG CAC ACC TTC CCG GCT GTC CTA CAG TCC TCA GGA CTC TAC TCC CTC AGC AGC GTG GTG ACC GTG CCC TCC AGC AGC TTG GGC ACG AAG ACC TAC ACC TGC AAC GTA GAT CAC AAG CCC AGC AAC ACC AAG GTG GAC AAG AGA GTT GAG TCC AAA TAT GGT CCC CCA TGC CCA CCA TGC CCA GCA CCT GAG TTC CTG GGG GGA CCA TCA GTC TTC CTG TTC CCC CCA AAA CCC AAG GAC ACT CTC ATG ATC TCC CGG ACC CCT GAG GTC ACG TGC GTG GTG GTG GAC GTG AGC CAG GAA GAC CCC GAG GTC CAG TTC AAC TGG TAC GTG GAT GGC GTG GAG GTG CAT AAT GCC AAG ACA AAG CCG CGG GAG GAG CAG TTC AAC AGC ACG TAC CGT GTG GTC AGC GTC CTC ACC GTC CTG CAC CAG GAC TGG CTG AAC GGC AAG GAG TAC AAG TGC AAG GTC TCC AAC AAA GGC CTC CCG TCC TCC ATC GAG AAA ACC ATC TCC AAA GCC AAA GGG CAG CCC CGA GAG CCA CAG GTG TAC ACC CTG CCC CCA TCC CAG GAG GAG ATG ACC AAG AAC CAG GTC AGC CTG ACC TGC CTG GTC AAA GGC TTC TAC CCC AGC GAC ATC GCC GTG GAG TGG GAG AGC AAT GGG CAG CCG GAG AAC AAC TAC AAG ACC ACG CCT CCC GTG CTG GAC TCC GAC GGC TCC TTC TTC CTC TAC AGC AGG CTA ACC GTG GAC AAG AGC AGG TGG CAG GAG GGG AAT GTC TTC TCA TGC TCC GTG ATG CAT GAG GCT CTG CAC AAC CAC TAC ACA CAG AAG AGC CTC TCC CTG TCT CTG GGT AAA

In some embodiments, the PD-1 binding agent comprises an immunoglobulin light chain polypeptide encoded by a nucleotide sequence that comprises SEQ ID NO: 20.

SEQ ID NO: 20 - Nucleotide sequence encoding a PD-1 binding agent immunoglobulin light chain polypeptide

GAC ATS CAG TTG ACC CAG TCT CCA TCC TTC CTG TCT GCA TAT GTA GGA GAC AGA GTC ACC ATS ACT TGC AAG GCC AGT CAG GAT GTG GGT ACT GCT GTA GCC TGG TAT CAG CAA AAA CCA GGG AAA GCC CCT AAG CTC CTG ATS TAT TGG GCA TCC ACC CTG CAC ACT GGG GTC CCA TCA AGG TTC AGC GGC AGT GGA TCT GGG ACA GAA TTC ACT CTC ACA ATC AGC AGC CTG CAG CCT GAA GAT TTT GCA ACT TAT TAC TGT CAG CAT TAT AGC AGC TAT CCG TGG ACG TTT GGC CAG GGG ACC AAG CTG GAG ATC AAA CGG ACT GTG GCT GCA CCA TCT GTC TTC ATS TTC CCG CCA TCT GAT GAG CAA TTG AAA TCT GGA ACT GCC TCT GTT GTG TGC CTG CTG AAT AAC TTC TAT CCC AGA GAG GCC AAA GTA CAG TGG AAG GTG GAT AAC GCC CTC CAA TCG GGT AAC TCC CAG GAG AGT GTC ACA GAG CAG GAC AGC AAG GAC AGC ACC TAC AGC CTC AGC AGC ACC CTG ACG CTG AGC AAA GCA GAC TAC GAG AAA CAC AAA GTC TAC GCC TGC GAA GTC ACC CAT CAG GGC CTC AGC TCG CCC GTC ACA AAG AGC TTC AAC AGG GGA GAG TGT

In some embodiments, the anti-TIM-3 antibody agent and/or the PD-1 binding agent is expressed from a vector comprising one or more nucleic acid sequences encoding an immunoglobulin heavy chain variable domain polypeptide and/or an immunoglobulin light chain variable domain polypeptide. In some embodiments, the anti-TIM-3 antibody agent and/or the PD-1 binding agent is expressed from a vector comprising one or more nucleic acid sequences encoding an immunoglobulin heavy chain polypeptide and/or an immunoglobulin light chain polypeptide. The vector can be, for example, a plasmid, an episome, a cosmid, a viral vector (e.g., a retroviral or adenoviral vector), or a phage. Suitable vectors and methods for their preparation are well known in the art (see, e.g., Sambrook et al., Molecular Cloning, a Laboratory Manual, 3rd edition, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2001), and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, N.Y. (1994)).

In some embodiments, the vector(s) for expressing the anti-TIM-3 antibody agent and/or PD-1 binding agent further comprises expression control sequences, such as promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), etc., that provide for expression of the coding sequence in a host cell. Exemplary expression control sequences are known in the art and are described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology, Vol. 185, Academic Press, San Diego, Calif. (1990).

- 46 050059

Vector(s) comprising nucleic acid(s) encoding the anti-TIM-3 antibody agent and/or PD-1 binding agent of the present invention may be introduced into a host cell capable of expressing the polypeptides encoded by the nucleic acid, including any suitable prokaryotic or eukaryotic cell. Some preferred qualities of host cells include easy and stable growth, sufficiently rapid growth rate, well-characterized expression systems, and/or easy/efficient transformation or transfection.

In some embodiments, mammalian cells are used. A number of suitable mammalian cell host cells are known in the art, and many are available from the American Type Culture Collection (ATCC, Manassas, Va.). Examples of suitable mammalian cells include, but are not limited to, Chinese hamster ovary (CHO) cells (ATCC Accession No. CCL61), CHO DHFR cells (Urlaub et al., Proc. Natl. Acad. Sci. USA, 97: 4216-4220 (1980)), human embryonic kidney (HEK) 293 cells or 293T cells (ATCC Accession No. CRL1573), and 3T3 cells (ATCC Accession No. CCL92). Other suitable mammalian cell lines include the monkey COS-1 (ATCC Accession No. CRL1650) and COS-7 (ATCC Accession No. CRL1651) cell lines, and the CV1 (ATCC Accession No. CCL70) cell line.

Additional exemplary mammalian cell host cells include primate cell lines and rodent cell lines, including transformed cell lines. Also suitable are normal diploid cells, cell strains derived from in vitro culture of primary tissue, and primary explants. Other suitable mammalian cell lines include, but are not limited to, mouse neuroblastoma N2A cells, HeLa cells, mouse L929 cells, and hamster BHK or HaK cell lines, all of which are available from the ATCC. Methods for selecting suitable mammalian cell host cells and methods for transforming, culturing, amplifying, screening, and purifying cells are known in the art.

In some embodiments, the mammalian cell is a human cell. For example, the mammalian cell can be a human lymphoid cell line or a cell line derived from lymphoid cells, such as a cell line derived from pre-B lymphocytes. Examples of human lymphoid cell lines include, but are not limited to, RAMOS (CRL-1596), Daudi (CCL-213), EB-3 (CCL-85), DT40 (CRL-2111), 18-81 (Jack et al., Proc. Natl. Acad. Sci. USA, 85: 15811585 (1988)), Raji (CCL-86) cells, and derivatives thereof.

In some embodiments, the anti-TIM-3 antibody agent is formulated as a pharmaceutical composition comprising one or a combination of monoclonal antibodies or antigen-binding portion(s) thereof formulated with a pharmaceutically acceptable carrier. The anti-TIM-3 antibody agent may be formulated alone or in combination with other drugs (e.g., as an adjuvant). For example, the anti-TIM-3 antibody agent may be administered in combination with other agents for the treatment or prevention of the diseases disclosed herein (e.g., cancer).

Therapeutic compositions generally must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome or other ordered structure suitable for high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be advantageous to include isotonic agents in the composition, for example, sugars, polyhydric alcohols such as mannitol, sorbitol or sodium chloride. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that provides a delay in absorption, for example, monostearate salts and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, if necessary, followed by sterilizing microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile carrier medium which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization), which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

In some embodiments, the therapeutic composition is formulated as a sterile liquid. In some embodiments, the composition is free of visible particles. In some embodiments, the composition is formulated in a buffer. In some embodiments, the anti-TIM-3 antibody agent is stored at 2-8°C. In some embodiments, the le

- 47 050059 The carbohydrate product according to the present invention does not contain preservatives.

General Protocol

As described herein, the present methods comprise administering an anti-TIM-3 antibody agent to a patient, subject, or population of subjects (e.g., according to a schedule that achieves clinical benefit).

The provided methods may provide various advantages (e.g., clinical benefit). In embodiments, the method described herein provides for achieving a clinical benefit. In embodiments, the clinical benefit is disease stabilization (SD). In embodiments, the clinical benefit is a partial response (PR). In embodiments, the clinical benefit is a complete response (CR).

In embodiments, the combination therapy achieves a clinical benefit for each therapy administered to the patient. For example, the subject may be refractory to treatment with an agent that suppresses PD-1, or the subject may be difficult to treat with an agent that suppresses PD-1. In embodiments, the method described herein sensitizes the subject to treatment with an agent that suppresses PD-1. Thus, in embodiments, an advantage of a combination therapy comprising administering a TIM-3 inhibitor (e.g., any anti-TIM-3 antibody described herein) and a PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is the achievement of a clinical benefit with the PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) or an improvement in clinical benefit.

In embodiments, the patient or subject is an animal. In embodiments, the patient or subject is a human.

In embodiments, the administration of the TIM-3 antibody agent is parenteral administration. In embodiments, the parenteral administration is intravenous administration. In embodiments, the intravenous administration is intravenous infusion.

In some embodiments, the regimen provides at least one parenteral dose of the TIM-3 antibody agent. In some embodiments, the regimen provides multiple parenteral doses.

In some embodiments, the parenteral dose is an amount of the anti-TIM-3 antibody agent that is in the range of about 5 to about 5000 mg (e.g., about 5 mg, about 10 mg, about 50 mg, about 100 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, or a range defined by any two of the foregoing). In some embodiments, the parenteral dose of the anti-TIM-3 antibody agent is 500 or 1000 mg. In some embodiments, the parenteral dose of the anti-TIM-3 antibody agent is about 100 mg, about 300 mg, or about 1200 mg.

In some embodiments, the dose is an amount relative to body weight. In some embodiments, the parenteral dose of the anti-TIM-3 antibody agent is in the range of about 0.01 to 100 mg/kg of animal or human body weight; however, doses above or below this illustrative range are within the scope of the present invention. The dose (e.g., daily parenteral dose) can be from about 0.01 to about 50 mg/kg of total body weight (e.g., about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg, about 15 mg/kg, about 20 mg/kg, or a range defined by any two of the foregoing).

In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered to a patient at a dose of 0.1, 1, 3, or 10 mg/kg. In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered according to a schedule that provides a dose of 0.1, 1, 3, or 10 mg/kg every two weeks. In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered according to a schedule that provides a dose of 0.1, 1, 3, or 10 mg/kg every three weeks. In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered according to a schedule that provides a dose of 0.1, 1, 3, or 10 mg/kg every four weeks.

In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered to a patient at a dose of about 100 to about 500 mg (e.g., 200 to 500 mg). ...

- 48 050059 delivery of an anti-TIM-3 antibody-based agent is administered according to a regimen that provides a dose of from about 100 to about 500 mg (e.g., 200 mg, 300 mg, 400 mg, 500 mg) every two weeks. In some embodiments, a composition that delivers an anti-TIM-3 antibody-based agent is administered according to a regimen that provides a dose of from about 100 to about 500 mg (e.g., 200 mg, 300 mg, 400 mg, 500 mg) every three weeks. In some embodiments, a composition that delivers an anti-TIM-3 antibody-based agent is administered according to a regimen that provides a dose of from about 100 to about 500 mg (e.g., 200 mg, 300 mg, 400 mg, 500 mg) mg every four weeks.

In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered to a patient at a dose of about 800 to about 1500 mg (e.g., 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg). In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that provides a dose of about 800 to about 1500 mg (e.g., 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg) mg every four weeks. In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that provides a dose of about 800 to about 1500 mg (e.g., 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg) every six weeks. In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that provides a dose of about 800 to about 1500 mg (e.g., 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg) every eight weeks.

In embodiments, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 1 mg/kg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, the administration of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent) is intravenous. In embodiments, the administration of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the anti-TIM-3 antibody agent is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO:4.

In embodiments, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 3 mg/kg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, the administration of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent) is intravenous. In embodiments, the administration of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent) is by intravenous infusion. In embodiments, the administration of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent) is for

- 49 050059 for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO: 4.

In embodiments, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 10 mg/kg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, the administration of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent) is intravenous. In embodiments, the administration of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO:4.

In embodiments, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 100-1500 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once a week (Q1W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO: 4.

In embodiments, the dose (e.g., a therapeutically effective dose, a dose administered at

- 50 050059 by means of a composition that provides for delivery of an anti-TIM-3 antibody agent, or a parenteral dose) is about 100 mg of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, the administration of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent) is intravenous. In embodiments, the administration of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 200 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO: , and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO: , 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 300 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (e.g., a

- 51 050059 antibodies to TIM-3) is intravenous. In embodiments, the administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody-based agent) is by intravenous infusion. In embodiments, the administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody-based agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 400 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO: 4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 500 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%,

- 52 050059

95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence characterized by at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 600 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor, e.g., an anti-PD-1 antibody, such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 700 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO: 3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO: 3, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 800 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous in

- 53 050059 fusion) is performed once every three weeks (Q3W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is performed once every four weeks (Q4W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is performed once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is performed once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO: 3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO: 3, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO: 4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 900 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO: 3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO: 3, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO: 4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 1000 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is by intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy.

- 54 050059 an anti-TIM-3 antibody) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO: 3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO: 4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 1100 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO: 4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 1200 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO: 4.

In any of the methods described herein, the dose (e.g., therapeutically effective)

- 55 050059 the effective dose, the dose administered via the composition that delivers the anti-TIM-3 antibody agent, or the parenteral dose) is about 1300 mg of the TIM-3 inhibitor (e.g., the anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 1400 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO: 3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO: 3, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO: 4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered via a composition that delivers an anti-TIM-3 antibody agent, or a parenteral dose) is about 1500 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In embodiments, the dosing (e.g., intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In embodiments, dosing (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (e.g., a

- 56 050059 antibodies to TIM-3) is intravenous. In embodiments, the administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody-based agent) is by intravenous infusion. In embodiments, the administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody-based agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is for a combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO: 3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO: 3, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% overall identity to SEQ ID NO: 4.

Therapeutic or prophylactic efficacy can be monitored by periodic assessment of treated patients. In the case of repeated administrations over several days or more, depending on the condition, treatment can be repeated until the desired suppression of disease symptoms occurs. However, other dosage regimens may be applicable and are within the scope of the present invention. The desired dosage can be delivered by a single bolus administration of the composition, multiple bolus administrations of the composition, or continuous infusion of the composition.

In some embodiments, the TIM-3 antibody agent is administered to a patient or population of subjects that has demonstrated a response to a previous therapy. In some embodiments, the patient or population of subjects has demonstrated a response to a previous cancer therapy.

In some embodiments, the TIM-3 antibody agent is administered to a patient or population of subjects that have demonstrated a lack of response to prior therapy. In some embodiments, the patient or population of subjects has not received or demonstrated a response to prior cancer therapy.

In embodiments, the subject is refractory to treatment with an agent that suppresses PD-1. In embodiments, the subject is difficult to treat with an agent that suppresses PD-1. In embodiments, the method described herein sensitizes the subject to treatment with an agent that suppresses PD-1.

In embodiments, the anti-TIM-3 antibody agent described herein is administered in combination with one or more additional therapies (e.g., therapies described herein). Thus, the subject is treated with the anti-TIM-3 antibody agent and one or more additional therapies are administered to the subject, whereby the subject receives each therapy.

In embodiments, the additional therapy is surgery. In embodiments, the additional therapy is radiotherapy. In embodiments, the additional therapy is chemotherapy. In embodiments, the additional therapy is immunotherapy.

In some embodiments, the anti-TIM-3 antibody agent is administered as monotherapy.

In some embodiments, the anti-TIM-3 antibody agent is administered in a combination therapy. In embodiments, the anti-TIM-3 antibody agent is administered in combination with another treatment method (e.g., one or more of surgery, radiation therapy, chemotherapy, or immunotherapy). In embodiments, the anti-TIM-3 antibody agent is administered in combination with surgery. In embodiments, the anti-TIM-3 antibody agent is administered in combination with radiation therapy. In embodiments, the anti-TIM-3 antibody agent is administered in combination with chemotherapy. In embodiments, the anti-TIM-3 antibody agent is administered in combination with immunotherapy.

In some embodiments, the anti-TIM-3 antibody agent is administered simultaneously or sequentially with an additional therapeutic agent, such as, for example, another antibody agent (e.g., an antibody agent that binds to PD-1) and/or a chemotherapeutic agent (e.g., niraparib). In some embodiments, the anti-TIM-3 antibody agent is administered before, during, or after administration of the additional therapeutic agent. In some embodiments, the anti-TIM-3 antibody agent is administered before, during, or after administration of the chemotherapeutic agent (e.g., niraparib).

The TIM-3 antibody may be administered alone or in combination with other

- 57 050059 medicinal products (e.g., as an adjuvant). For example, an anti-TIM-3 antibody-based product may be administered in combination with other products for the treatment or prevention of the diseases disclosed herein (e.g., cancer). In this regard, an anti-TIM-3 antibody-based product may be used in combination with at least one other anti-cancer product, including, for example, any chemotherapeutic product known in the art; ionizing radiation; small molecule anti-cancer products; anti-cancer vaccines; biological therapies (e.g., other monoclonal antibodies, anti-cancer viruses, gene therapy, and adoptive T-cell transfer) and/or surgery.

The administration of an anti-TIM-3 antibody agent simultaneously or sequentially with an additional therapeutic agent is referred to herein as a combination therapy. In the case of a combination therapy, the TIM-3 antibody agent may be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks), simultaneously with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks) the administration of an additional therapeutic agent to a subject in need thereof. In some embodiments, the anti-TIM-3 antibody agent and the additional therapeutic agent are administered at 1 minute intervals, at 10 minute intervals, at 30 minute intervals, at less than 1 hour intervals, at 1 to 2 hours intervals, at 2 to 3 hours intervals, at 3 to 4 hours intervals, at 4 to 5 hours intervals, at 5 to 6 hours intervals, at 6 to 7 hours intervals, at 7 to 8 hours intervals, at 8 to 9 hours intervals, at 9 to 10 hours intervals, at 10 to 11 hours intervals, at 11 to 12 hours intervals, at no more than 24 hours intervals, or at no more than 48 hours intervals.

PARP inhibitors

In embodiments, the additional therapy is a poly(ADP-ribose) polymerase (PARP) inhibitor.

In embodiments, the PARP inhibitor inhibits PARP-1 and/or PARP-2. In some embodiments, the agent is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In related embodiments, the agent is ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib (SHR 3162), IMP 4297, INO1001, JPI 289, JPI 547, B3-lyubPE40 monoclonal antibody conjugate, MP 124, niraparib (ZEJULA) (MK-4827), NU 1025, NU 1064, NU 1076, NU1085, olaparib (AZD2281), ONO2231, PD 128763, R 503, R554, rucaparib (RUBRACA) (AG-014699, PF01367338), SBP 101, SC 101914, simmiparib, talazoparib (BMN-673), veliparib (ABT-888), WW 46, 2(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3^]pyrimidin-4-ol, and salts or derivatives thereof. In some related embodiments, the agent is niraparib, olaparib, rucaparib, talazoparib, veliparib, or salts or derivatives thereof. In certain embodiments, the agent is niraparib or a salt or derivative thereof. In some embodiments, the agent is olaparib or a salt or derivative thereof. In some embodiments, the agent is rucaparib or a salt or derivative thereof. In some embodiments, the agent is talazoparib or a salt or derivative thereof. In some embodiments, the agent is veliparib or a salt or derivative thereof.

Niraparib, ((^)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine, is an orally available, potent inhibitor of poly(adenosine diphosphate [ADP]ribose) polymerase (PARP)-1 and -2. See WO 2008/084261 (published July 17, 2008), WO 2009/087381 (published July 16, 2009), and PCT/US17/40039 (filed June 29, 2017), each of which is incorporated herein by reference in its entirety. Niraparib can be prepared according to Scheme 1 of WO 2008/084261.

In some embodiments, niraparib may be prepared as a pharmaceutically acceptable salt. One skilled in the art will appreciate that such salt forms may exist as solvated or hydrated polymorphic forms. In some embodiments, niraparib is prepared as a hydrate.

In certain embodiments, niraparib is provided in the form of a tosylate salt. In some embodiments, niraparib is provided in the form of a tosylate monohydrate. The molecular structure of niraparib tosylate monohydrate salt is shown below:

Niraparib is a potent and selective inhibitor of PARP-1 and PARP-2 with a 50% inhibition concentration (IC ₅₀ ) of 3.8 and 2.1 nM, respectively, and its selectivity

- 58 050059 is at least 100-fold higher than other members of the PARP family. Niraparib inhibits hydrogen peroxide-induced DNA damage-induced PARP activity in a variety of cell lines with an IC ₅₀ and 90% inhibition concentration (IC ₉₀ ) of approximately 4 and 50 nM, respectively.

In embodiments, niraparib is administered at a dose equivalent to about 100 mg of niraparib free base (e.g., a pharmaceutically acceptable salt of niraparib, such as niraparib tosylate monohydrate, is administered at a dose equivalent to about 100 mg of niraparib free base). In embodiments, niraparib is administered at a dose equivalent to about 200 mg of niraparib free base (e.g., a pharmaceutically acceptable salt of niraparib, such as niraparib tosylate monohydrate, is administered at a dose equivalent to about 200 mg of niraparib free base). In embodiments, niraparib is administered at a dose equivalent to about 300 mg of niraparib free base (e.g., a pharmaceutically acceptable salt of niraparib, such as niraparib tosylate monohydrate, is administered at a dose equivalent to about 300 mg of niraparib free base).

Checkpoint inhibitors

In embodiments, the additional therapy is immunotherapy. In embodiments, the immunotherapy comprises administering one or more additional immune checkpoint inhibitors (e.g., administering one, two, three, four, or more additional immune checkpoint inhibitors).

Illustrative targets for immune checkpoint inhibition include: PD-1 (e.g., inhibition by anti-PD-1, anti-PD-L1, or anti-PD-L2 therapies), CTLA-4, TIM-3, TIGIT, LAG (e.g., LAG-3), CEACAM (e.g., CEACAM-1, -3, and/or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (e.g., TGFR beta), B7-H1, B7-H4 (VTCN1), OX-40, CD137, CD40, IDO, and CSF1R. Therefore, agents that inhibit either of these molecules may be used in combination with the TIM-3 antibody-based therapy described herein.

In embodiments, the immune checkpoint inhibitor is an agent that inhibits PD-1, CTLA-4, LAG-3, TIGIT, IDO, or CSF1R.

In embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. In embodiments, the PD-1 inhibitor is a PD-1 binding agent (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the PD-1 inhibitor is a PD-L1 or PD-L2 binding agent (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the PD-1 inhibitor is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN-2034, CS1001, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ-053, CK-301, AK 104, or GLS-010, or any of the PD-1 antibodies disclosed in WO2014/179664. In embodiments, the PD-1 inhibitor is TSR-042. In some embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered according to a regimen that comprises administering a dose of about 500 mg every 3 weeks for four doses, followed by at least one dose of about 1000 mg every six weeks after the fourth dose of about 500 mg. In some embodiments, additional doses of about 1000 mg are administered every six weeks after the first dose of about 1000 mg until no further clinical benefit is achieved. In some specific embodiments, the PD-1 inhibitor (eg, TSR-042) is administered according to a dosing schedule that provides 500 mg for 4 cycles Q3W followed by 1000 mg Q6W.

In embodiments, the immune checkpoint inhibitor is a CTLA4 inhibitor (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the CTLA-4 inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the CTLA4 inhibitor is a small molecule. In embodiments, the CTLA-4 inhibitor is a CTLA-4 binding agent. In embodiments, the CTLA-4 inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. In embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy), AGEN1884, or tremelimumab.

In embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the LAG-3 inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the LAG-3 inhibitor is a small molecule. In embodiments, the LAG-3 inhibitor is a LAG-3 binder. In embodiments, the LAG-3 inhibitor is an antibody,

- 59 050059 an antibody conjugate or an antigen-binding fragment thereof. In embodiments, the LAG-3 inhibitor is IMP321, BMS-986016, GSK2831781, Novartis LAG525, or a LAG-3 inhibitor described in WO 2016/126858, WO 2017/019894, or WO 2015/138920, each of which is incorporated herein by reference in its entirety.

In embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the TIGIT inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the TIGIT inhibitor is a small molecule. In embodiments, the TIGIT inhibitor is a TIGIT binding agent. In embodiments, the TIGIT inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. In embodiments, the TIGIT inhibitor is MTIG7192A, BMS-986207, or OMP-31M32.

In embodiments, the immune checkpoint inhibitor is an IDO inhibitor. In embodiments, the IDO inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the IDO inhibitor is a small molecule. In embodiments, the IDO inhibitor is an IDO binding agent. In embodiments, the IDO inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.

In embodiments, the immune checkpoint inhibitor is a CSF1R inhibitor. In embodiments, the CSF1R inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the CSF1R inhibitor is a small molecule. In embodiments, the CSF1R inhibitor is a CSF1R binding agent. In embodiments, the CSF1R inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.

In embodiments, the method comprises administering a TIM-3 inhibitor with at least two immune checkpoint inhibitors. In embodiments, the method comprises administering a third checkpoint inhibitor. In embodiments, the method comprises administering a TIM-3 inhibitor with a PD-1 inhibitor and a LAG-3 inhibitor, such that the subject receives all three. In embodiments, the method comprises administering a TIM-3 inhibitor with a PD-1 inhibitor, a LAG-3 inhibitor, and a CTLA-4 inhibitor, such that the subject receives all four.

In embodiments, the subject has additionally been or will be administered an agent that inhibits poly(ADP-ribose) polymerase (PARP), resulting in the subject receiving treatment with a TIM-3 inhibitor and a PARP inhibitor.

In embodiments, the subject is further administered or will be administered one or more immune checkpoint inhibitors (e.g., a PD-1 inhibitor and/or a LAG-3 inhibitor), whereby the subject is treated with a TIM-3 inhibitor, a PARP inhibitor (e.g., niraparib), and one or more immune checkpoint inhibitors. In embodiments, the subject is administered a TIM-3 inhibitor, a PD-1 inhibitor (e.g., TSR-042), and a PARP inhibitor (e.g., niraparib). In embodiments, the subject is administered a TIM-3 inhibitor, a PD-1 inhibitor (e.g., TSR042), a LAG-3 inhibitor, and a PARP inhibitor (e.g., niraparib).

For female patients of childbearing potential, it is preferred that the patient has a negative pregnancy test using serum within 72 hours prior to the date of administration of the first dose of the anti-TIM-3 antibody agent. It is also preferred that female patients of childbearing potential and male patients agree to use 2 suitable methods of contraception with their partner. In some embodiments, the patient agrees to use 2 suitable methods of contraception beginning with a screening visit 150 days after administration of the last dose of the study therapy.

In some embodiments, the present invention provides methods of treating cancer in a patient in need thereof, the method comprising administering one or more compositions that deliver an anti-TIM-3 antibody agent in combination with a PD-1 inhibitor (e.g., a PD-1 binding agent, such as an anti-PD-1 antibody). Fig. 1 is an exemplary diagram of a combination of anti-TIM-3 and anti-PD-1 antibodies to enhance anti-tumor efficacy. In some embodiments, the patient or patient population receives a combination therapy that comprises administering an anti-TIM-3 antibody agent and a PD-1 binding agent. In some embodiments, the PD-1 binding agent is nivolumab or pembrolizumab. In embodiments, the PD-1 inhibitor is a PD-1 binding agent (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the PD-1 binding agent is nivolumab, pembrolizumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ63723283, MGA012, BI-754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, AMP514/MEDI-0680, AGEN-2034, CS1001, TSR-042, Sym-021, PF-06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), AK 104, or GLS-010 or derivatives thereof. In embodiments, the inhibitor

- 60 050059 PD-1 inhibitor is a PD-L1 or PD-L2 binding agent (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the PD-1 inhibitor is a PD-L1 or PD-L2 binding agent such as durvalumab, atezolizumab, avelumab, BGB-A333, SHR-1316, FAZ-053, CK-301, or a PD-L1 millimolecule or derivatives thereof.

In some embodiments, the patient or patient population receives a combination therapy that comprises administering an anti-TIM-3 antibody agent comprising an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO: 1 or SEQ ID NO: 7 and an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain having an amino acid sequence comprising SEQ ID NO: 3 and an immunoglobulin light chain having an amino acid sequence comprising SEQ ID NO: 4.

In some embodiments, the patient or patient population receives a combination therapy that comprises administering a PD-1 binding agent comprising an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO: 11 or SEQ ID NO: 17 and an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO: 12 or SEQ ID NO: 18. In some embodiments providing for combinations, the PD-1 binding agent comprises an immunoglobulin heavy chain having an amino acid sequence comprising SEQ ID NO: 13 and an immunoglobulin light chain having an amino acid sequence comprising SEQ ID NO: 14.

In some embodiments, an anti-TIM-3 antibody agent (e.g., an anti-TIM-3 antibody) is administered at a dose of 0.1, 1, 3, or 10 mg/kg. In some embodiments, the anti-TIM-3 antibody agent is administered according to a schedule that provides a dose of 0.1, 1, 3, or 10 mg/kg every two weeks. In some embodiments, the anti-TIM-3 antibody agent is administered according to a schedule that provides a dose of 1, 3, or 10 mg/kg every three weeks.

In some embodiments, the anti-TIM-3 antibody agent is administered according to a regimen that provides a dose of 1, 3, or 10 mg/kg every four weeks. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose in the range of 200 to 1500 mg. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose in the range of 300 to 1000 mg. In some embodiments, the anti-TIM-3 antibody agent is administered according to a regimen that provides a fixed dose every two weeks. In some embodiments, the anti-TIM-3 antibody agent is administered according to a regimen that provides a fixed dose every three weeks. In some embodiments, the anti-TIM-3 antibody agent is administered according to a regimen that provides a fixed dose every four weeks.

In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered at a dose of about 1, 3, or 10 mg/kg. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered according to a regimen that provides a dose of about 1, 3, or 10 mg/kg every two weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered according to a regimen that provides a dose of about 1, 3, or 10 mg/kg every three weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a regimen that provides a dose of about 1, 3, or 10 mg/kg every four weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody, such as TSR-042) is administered at a dose of about 500 mg. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody, such as TSR-042) is administered on a schedule that provides a dose of about 500 mg every two weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody, such as TSR-042) is administered on a schedule that provides a dose of about 500 mg every three weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody, such as TSR-042) is administered on a schedule that provides a dose of about 500 mg every four weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody, such as TSR-042) is administered on a schedule that provides a dose of about 1000 mg every six weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered according to a regimen that provides a first dose of about 500 mg every three weeks (Q3W) for the first 2-6 (e.g., the first 2, 3, 4, 5, or 6) dosing cycles and a second dose of about 1000 mg every six weeks (Q6W) until treatment is discontinued (e.g., due to disease progression, adverse effects, or as determined by the physician). In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered according to a regimen that provides a first dose of about 500 mg every three weeks (Q3W) for the first four dosing cycles and a second dose of about 1000 mg every six weeks (Q6W) until treatment is discontinued (e.g.,

- 61 050059 due to disease progression, adverse effects, or as determined by the physician). In embodiments, the PD-1 binding agent is an antibody to PD-1. In embodiments, the PD-1 binding agent is TSR-042.

In some methods, the anti-TIM-3 antibody agent may be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks), simultaneously with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks) administration of a PD-1 binding agent to a subject in need thereof.

Measuring tumor response

In some embodiments, the clinical benefit is a complete response (CR), a partial response (PR), or stable disease (SD). In some embodiments, the clinical benefit is at least an SD. In some embodiments, the clinical benefit is at least a PR. In some embodiments, the clinical benefit is a CR. In some embodiments, at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of patients achieve clinical benefit. In some embodiments, at least 5% of patients achieve clinical benefit. In some embodiments, at least 5% of patients achieve SD. In some embodiments, at least 5% of patients achieve at least a PR. In some embodiments, at least 5% of patients achieve a CR. In some embodiments, at least 20% of patients achieve clinical benefit. In some embodiments, at least 20% of patients achieve an SD.

In some embodiments, clinical benefit (e.g., SD, PR, and/or CR) is determined according to Response Evaluation Criteria in Solid Tumors (RECIST). In some embodiments, clinical benefit (e.g., SD, PR, and/or CR) is determined according to RECIST guidelines.

In some embodiments, tumor response can be measured, for example, using the RECIST v 1.1 guidelines. The guidelines are provided in E. A. Eisenhauer, et al., New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.), Eur. J. of Cancer, 45: 228-247 (2009), which is incorporated by reference in its entirety. The guidelines require an initial assessment of total tumor burden at baseline, which is used as a comparator for subsequent measurements. Tumors can be measured using any imaging system known in the art, such as CT scanning or radiography. Measurable disease is defined as the presence of at least one measurable lesion. In studies where the primary endpoint is tumour progression (either time to progression or proportion with progression over a fixed period of time), the protocol should state whether enrolment is restricted to patients with measurable disease or whether only patients with non-measurable disease are eligible.

If more than one measurable lesion is present at baseline, all lesions up to a maximum of five lesions in total (and a maximum of two lesions per organ), representing all affected organs, should be identified as target lesions and will be recorded and measured at baseline (this means that in cases where patients have only one or two affected organ sites, a maximum of two and four lesions respectively can be recorded).

Target lesions should be selected based on their size (lesions with the largest diameter), they should be representative of all affected organs, but they should also be reproducible and measurable repeatedly.

Lymph nodes deserve special attention because they are normal anatomical structures that may be visible on imaging even when they are not involved with tumor. Pathological nodes that are defined as measurable and can be identified as target lesions must meet the short axis criterion of P15 mm on CT scanning. Only the short axis of these nodes will be included in the baseline summary value. The short axis of a node is the diameter commonly used by radiologists to judge whether a node is involved with a solid tumor. Node size is usually reported as two dimensions in the plane in which the image was acquired (for CT scanning, this is almost always the axial plane; for MRI, the plane of target detection may be axial, sagittal, or coronal). The smaller of these measurements is the short axis.

For example, an abdominal nodule that is recorded as 20 x 30 mm has a short axis of 20 mm and is considered a malignant measurable nodule. In this example, 20 mm should be recorded as the nodule measurement. All other pathological nodules (with a short axis of P10 mm but <15 mm)

- 62 050059 should be considered non-target lesions. Nodes with a short axis <10 mm are considered non-pathological and should not be recorded or monitored.

The sum of the diameters (largest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and recorded as the sum of the baseline diameters. If lymph nodes are to be included in the sum, then as noted above, only the short axis is added to the sum. The sum of the baseline diameters will be used as a reference to further characterize any objective tumor regression in measurable disease parameters.

All other lesions (or sites of disease), including abnormal lymph nodes, should be identified as non-target lesions and also recorded at baseline. No measurements are required and these lesions are described as present, absent, or, rarely, overt progression. Additionally, multiple non-target lesions involving the same organ may be recorded as a single entry on the case report form (e.g., multiple enlarged pelvic lymph nodes or multiple liver metastases).

In some embodiments, tumor response can be measured using, for example, immune-related RECIST (irRECIST) guidelines, which include immune-related response criteria (irRC). The irRC measures measurable lesions that are characterized by at least one measurement with a minimum size of 10 mm (at the largest diameter on a CT or MRI scan) for non-nodal lesions, and greater than or equal to 15 mm for nodal lesions, or at least 20 mm on a chest radiograph.

In some embodiments, immune-related response criteria include CR (complete disappearance of all lesions (measurable or not and no new lesions)); PR (decrease in tumor burden by 50% or more from baseline); SD (failure to meet CR or PR criteria in the absence of PD), or PD (increase in tumor burden by 25% or more from nadir). A detailed description of irRECIST can be found in Bohnsack et al., (2014) ESMO, ABSTRACT 4958, and Nishino et al., (2013) Clin. Cancer Res. 19(14): 3936-43.

In some embodiments, tumor response may be assessed using either irRECIST or RECIST version 1.1. In some embodiments, tumor response may be assessed using both irRECIST and RECIST version 1.1.

Pharmacokinetics

Pharmacokinetic data can be obtained using techniques known in the art. Due to the inevitable variation in the pharmacokinetic and pharmacodynamic parameters of drug metabolism in human subjects, the corresponding components of the pharmacokinetic and pharmacodynamic profile describing a particular composition may vary. Typically, pharmacokinetic and pharmacodynamic profiles are based on determining the average values of the parameters in a group of subjects. A group of subjects includes any reasonable number of subjects suitable for determining a representative average value, such as 5 subjects, 10 subjects, 16 subjects, 20 subjects, 25 subjects, 30 subjects, 35 subjects, or more. The average value is determined by calculating the average value of all measurements in a subject for each measured parameter.

In some embodiments, the patient population includes one or more subjects (subject population) suffering from metastatic disease.

In some embodiments, the patient population includes one or more subjects who have or are susceptible to cancer. In some such embodiments, the cancer is non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cell cancer, melanoma, cervical cancer, colorectal cancer, anogenital squamous cell carcinoma (e.g., squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), head and neck cancer, triple-negative breast cancer, ovarian cancer, or endometrial cancer. In embodiments, the cancer is a solid tumor (e.g., an advanced solid tumor, a metastatic solid tumor, an MSS solid tumor, an MSI-H solid tumor, or a POLE-mutant solid tumor). In embodiments, the cancer is melanoma (e.g., advanced melanoma, metastatic melanoma, MSS melanoma, MSI-H melanoma, or POLE mutant melanoma). In embodiments, the cancer is lung cancer, such as NSCLC (e.g., advanced NSCLC, metastatic NSCLC, MSI-H NSCLC, MSS NSCLC, POLE mutant NSCLC, EGFR mutant NSCLC, or ALK translocation NSCLC). In embodiments, the cancer is colorectal cancer (e.g., advanced colorectal cancer, metastatic colorectal cancer, MSS colorectal cancer, MSI-H colorectal cancer, or POLE mutant colorectal cancer). In some embodiments, the patient population includes (e.g., includes or consists of) one or more subjects suffering from cancer. For example, in some embodiments, a population of patients suffering from cancer may have previously been treated with a therapeutic agent, such as radiation and/or chemotherapy.

- 63 050059 therapy.

In some embodiments, the pharmacokinetic parameter(s) may be any parameter suitable for describing the composition of the present invention.

In some embodiments, the pharmacokinetic parameter(s) may be any parameter suitable for describing the composition of the present invention. For example, in some embodiments, the C _max is about 1 μg/mL; about 5 mcg/ml, about 10 mcg/ml, about 15 mcg/ml, about 20 mcg/ml, about 25 mcg/ml, about 30 mcg/ml, about 35 mcg/ml, about 40 mcg/ml, about 45 mcg/ml, about 50 mcg/ml, about 55 mcg/ml, about 60 mcg/ml, about 65 mcg/ml, about 70 mcg/ml, about 75 mcg/ml, about 80 mcg/ml, about 85 mcg/ml, about 90 mcg/ml, about 95 mcg/ml, about 100 mcg/ml, about 150 mcg/ml, about 200 mcg/mL, approximately 250 mcg/mL, approximately 300 mcg/mL, or any other C _max value suitable to describe the pharmacokinetic profile of the anti-TIM-3 antibody.

In some embodiments, T _max is, for example, no more than about 0.5 h, no more than about 1.0 h, no more than about 1.5 h, no more than about 2.0 h, no more than about 2.5 h, or no more than about 3.0 h, or any other T _max value suitable for describing the pharmacokinetic profile of the TIM-3 antibody.

Typically, the AUC described herein is a measure of the area under the curve that corresponds to the concentration of the analyte over a selected period of time after administration of a dose of the therapeutic agent. In some embodiments, such a time period begins at the time of dosing (i.e., 0 hours after dosing) and lasts about 2, about 6, about 12, about 36, about 48, about 72, about 168, about 336, about 514, about 682, or more hours after dosing. In some embodiments, the AUC is that obtained from time 0 hours to time 336 hours after administration of the dose described herein.

AUC( _0-336h ) can be, for example, about 500 mcg-hr/mL, about 1000 mcg-hr/mL, about 1500 mcg-hr/mL, about 2000 mcg-hr/mL, about 2500 mcg-hr/mL, about 3000 mcg-hr/mL, about 3500 mcg-hr/mL, about 4000 mcg-hr/mL, about 4500 mcg-hr/mL, about 5000 mcg-hr/mL, about 7500 mcg-hr/mL, about 10000 mcg-hr/mL, about 15000 mcg-hr/mL, about 20000 mcg-hr/mL, about 25,000 mcg-hr/mL, approximately 30,000 mcg-hr/mL, approximately 35,000 mcg-hr/mL, approximately 40,000 mcg-hr/mL, approximately 45,000 mcg-hr/mL, approximately 50,000 mcg-hr/mL, approximately 65,000 mcg-hr/mL, approximately 75,000 mcg-hr/mL, approximately 90,000 mcg-hr/mL or any other AUC value ( _{0-3 36h} ) suitable for describing the pharmacokinetic profile of the therapeutic agent (e.g., anti-TIM-3 antibody). In some embodiments, the anti-TIM-3 antibody is administered according to a regimen that has been demonstrated to achieve, in a patient population, a mean AUC^a concentration-time curve for the anti-TIM-3 antibody that is between 2,500 h*μg/mL and 50,000 h*μg/mL.

In some embodiments, the AUC from 0 hours to the end of the dosing period (AUC(0-Tau)) is determined. In some embodiments, the dosing period is one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, or ten weeks. In some embodiments, the dosing period is 2 weeks. In some embodiments, the dosing period is 3 weeks.

In some embodiments, the anti-TIM-3 antibody is administered according to a schedule that has been demonstrated to achieve a response rate in the relevant patient population such that disease progression is shown in no more than 50-80% of patients at 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 weeks after initiation of treatment. In some embodiments, disease progression is shown in no more than 80% of patients at least 10 weeks after initiation of treatment.

In some embodiments, the anti-TIM-3 antibody is administered according to a schedule that is sufficient to achieve an average TIM-3 receptor occupancy of at least 50-90% at 1, 2, 3, 4, or 5 days after a single dose of the composition. In some embodiments, administration of a composition that delivers an anti-TIM-3 antibody is sufficient to achieve an average TIM-3 receptor occupancy of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% at 3 days after a single dose of the composition.

In some embodiments, the TIM-3 antibody is administered according to a schedule that is sufficient to achieve a mean stimulation score of at least 1 in a functional TIM-3 receptor occupancy assay 3 days after a single dose of the binding

- 64 050059 go TIM-3 funds.

In some embodiments, the anti-TIM-3 antibody is administered according to a schedule that is sufficient to achieve an average TIM-3 receptor occupancy of at least 75% over a first period of time, such as from about 14 days to about 60 days after a single dose of the anti-TIM-3 antibody. In some embodiments, the anti-TIM-3 antibody is administered according to a schedule that is sufficient to achieve an average TIM-3 receptor occupancy of at least 75% over a first period of time (such as from about 15 days to about 60 days; in some embodiments, about 29 days) after a single dose of the anti-TIM-3 antibody.

In some embodiments, the anti-TIM-3 antibody is administered according to a schedule that is sufficient to achieve an average stimulation score of at least 1 in a functional TIM-3 receptor occupancy assay over a first period of time, such as from about 14 days to about 60 days after a single dose of the anti-TIM-3 antibody. In some embodiments, the anti-TIM-3 antibody is administered according to a schedule that is sufficient to achieve an average stimulation score of at least 1 in a functional TIM-3 receptor occupancy assay over a first period of time (such as from about 15 days to about 60 days; in some embodiments, about 29 days) after a single dose of the anti-TIM-3 antibody.

Examples

The following examples are provided for illustrative purposes and not to limit the claimed invention.

Example 1. Combined Blockade of TIM-3 and PD-1 in Murine Model Systems The effect of TIM-3 and PD-1 downregulation was examined in a murine T cell depletion assay (Burkhart et al. Int Immunol. 1999; 11:1625-1634). In this system, in vitro stimulation of CD4+ T cell receptor transgenic mouse T cells with a peptide-altered superagonist ligand resulted in an exhausted phenotype characterized by increased PD-1 and TIM-3 expression (Figure 2A). As shown in Figure 2B, the combination of anti-PD-1 and anti-TIM-3 antibodies was more effective than either agent alone in enhancing IFNy production in this system.

Example 2. Study of the efficacy of the combination of TSR-042 and TSR-022 in vivo

In addition to assessing the combined effect of targeting PD-1 and TIM-3 in vitro, the combination was tested in an animal model of lung cancer. A humanized mouse tumor model consisting of human A549 lung cancer cells (5x106 cells per mouse) implanted in huNOG-EXL mice was used. Neonatal-derived CD34+ hematopoietic stem cells were transplanted into the mice and the animals were treated with monoclonal blocking antibodies targeting PD-1 (TSR-042) and TIM-3 (TSR-022). In this example, we demonstrated that the combination of agents targeting PD-1 and TIM-3 exhibited a beneficial antitumor effect compared to either agent alone (Fig. 3).

Example 3: Dosage regimens for an illustrative TIM-3 binder

This example describes a multicenter, open-label, first-in-human, Phase 1 study evaluating a TIM-3 binder (anti-TIM-3 antibody) in patients with tumors. Specifically, a dose-response analysis is performed in patients with advanced solid tumors treated with a specific TIM-3 binder. The TIM-3 binder (TSR-022) described in this study was evaluated, which is a humanized monoclonal anti-TIM-3 antibody comprising a heavy chain having an amino acid sequence comprising SEQ ID NO: 3 and a light chain having an amino acid sequence comprising SEQ ID NO: 4. This anti-TIM-3 antibody utilizes the human IGHG4*01 heavy chain gene and the human IGKC*01 kappa light chain gene as framework sequences. In addition, there is one point mutation with a Ser to Pro substitution in the hinge region of the IgG4 heavy chain at the canonical position S228.

Patients with histologically or cytologically confirmed advanced-stage (unresectable) or metastatic solid tumor were included and who had disease progression after treatment with available therapies known to provide clinical benefit or who were intolerant to other known treatment(s).

The study consists of several parts: dose escalation and cohort expansion.

Part 1a of the study (dose escalation) is designed, inter alia, to evaluate the safety, PK and PDy profile, tolerability, and anticancer effect of the anti-TIM-3 antibody. A modified 3+3 dose escalation schedule was used at 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 3 mg/kg, and 10 mg/kg or more every 2 weeks (Q2W), with the anti-TIM-3 antibody dose not exceeding 20 mg/kg. Dose escalation was continued to 1.0 mg/kg Q2W and the MTD has not yet been identified. Part 1a could also include testing a constant dose or a specific fixed number of milligrams of the antibody.

- 65 050059 (as opposed to mg/kg weight-based dosing). Constant doses could range from 200 mg to 1500 mg of anti-TIM-3 antibody. Part 1b of the study (combination dose escalation cohorts with anti-PD-1 antibody) is designed, inter alia, to evaluate the safety, PK and PDy profile, tolerability, and anticancer effect of anti-TIM-3 antibody in combination with anti-PD-1 antibody, where anti-TIM-3 antibody was administered at dose escalation. Dosing will include anti-TIM-3 antibody at 1.0 mg/kg, 3 mg/kg, and 10 mg/kg or more every 2 weeks (Q2W) or every 3 weeks (Q3W), with the dose of anti-TIM-3 antibody not exceeding the MTD determined in Part 1a of the study, each dose in combination with an anti-PD-1 antibody (an illustrative anti-PD-1 antibody is a humanized monoclonal antibody to PD-1 comprising a heavy chain having an amino acid sequence comprising SEQ ID NO: 13 and a light chain having an amino acid sequence comprising SEQ ID NO: 14, nivolumab, or pembrolizumab). The anti-PD-1 antibody may be administered at the dose and schedule approved for the marketed agent and on a weight-based basis at 3 or 10 mg/kg Q2W or Q3W or at a constant dose of 500 mg Q2W or Q3W antibody using a modified 3+3 schedule.

Primary endpoints include determination of the safety and tolerability of TSR-022 according to the Common Terminology Criteria for Adverse Events (CTCAE v4) and determination of the recommended phase 2 dose (RP2D) and schedule for monotherapy and combination with an anti-PD-1 antibody. Secondary endpoints include pharmacokinetics (PK), overall response rate, duration of response, disease control rate, progression-free survival, overall survival, and immunogenicity. Exploratory endpoints include pharmacodynamic parameters.

Figure 4A shows the doses used in the Part 1a dose escalation study with TSR-022 monotherapy. The dose escalation study enrolled 38 patients with advanced cancer as of October 27. Patients were given doses of 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg.

Adult patients with advanced or metastatic solid tumors who had disease progression or intolerance after treatment with available therapies and who had appropriate organ function and ECOG [Eastern Cooperative Oncology Group] performance status were treated. Prior treatment with immune checkpoint inhibitors was allowed. A summary of patient demographics is shown in Fig. 5 for the 38 enrolled patients. There were 21 male and 17 female patients in Part 1a. The mean age was 60.1 years (SD=13.5) with a median of 61.0 years (min=25; max=85). The mean number of prior lines of treatment was 3.2 (SD=2.3) with a median of 2.0 (min=1; max=10). Ten patients had an ECOG performance status of 0 and 28 had an ECOG performance status of 1. Tumor sites included colon, skin, ovary, breast, brain, head and neck, testicle, pleura, lung, rectum, thyroid, liver, or esophagus.

Following the first dose of TSR-022 administered to patients at different levels (0.03-10 mg/kg), serum TSR-022 concentrations were monitored for two weeks and the pharmacokinetic (PK) characteristics were described. Figure 6A shows the serum concentration versus time profiles for all treatment groups in Part 1. TSR-022 demonstrated a linear PK pattern for the studied doses of 0.03-10 mg/kg.

Figure 6B shows TIM-3 occupancy on circulating monocytes measured by flow cytometry in whole blood samples collected from patients treated with anti-TIM-3 antibody. Receptor occupancy on peripheral monocytes is shown to correlate with TSR-022 exposure.

TIM-3 receptor occupancy (RO) by TSR-022 on circulating CD14+ monocytes was measured by flow cytometry. Briefly, whole blood samples from patients treated with TSR-022 were stained with anti-CD14 antibody, non-competing anti-TIM-3 antibody (indicating total TIM-3), and competing anti-TIM-3 antibody (indicating unbound or free TIM-3). TIM-3 occupancy by infused TSR-022 was assessed as the ratio of free TIM-3 on CD14+ cells to total TIM-3 on CD14+ cells. A decrease in the ratio indicates an increase in the amount of TIM-3 receptor bound by TSR-022. To measure binding in the RO assay, whole blood was collected from patients at the baseline visit (day 1 pre-dose), 48 hours after the first dose (day 3), and prior to the second dose (day 15 pre-dose) for the Q2W schedule. Additional samples were collected on day 22 and day 29 post-first dose for the subset of patients who did not receive a second dose. Samples to measure occupancy for the Q3W schedule were collected as follows:

Day 1 pre-dose, day 5, day 15, and day 22. Ex vivo TSR-022-saturated healthy donor samples (sat) and controls lacking detection antibodies (Bkgd) were included as controls.

Figures 7A-7C respectively show receptor occupancy studies with anti-TIM-3 antibody (TSR-022) administered at doses of 1 mg/kg (Figure 7A), 3 mg/kg (Figure 7B), and 10 mg/kg (Figure 7C) every other

- 66 050059 del (Q2W). All samples were collected pre-dose, with occupancy measured after a single dose on Day 1. The occupancy ratio (free TIM-3:total TIM-3) was determined at multiple time points (e.g., time points could include Day 1, Day 3, Day 15, Day 22, and Day 29). Receptor occupancy was highest on Day 3 for all doses of TSR-022. At 3 mg/kg, maximum occupancy was maintained through Day 29, and comparable results were observed for the 10 mg/kg dose across the days of available data.

Fig. 8 provides a brief description of the dosages administered to patients (0.03-10 mg/kg) and the duration of treatment during the Part 1a studies.

Observed best response was also assessed in patients who were evaluable for efficacy (eg, patients who received at least two doses and either had at least one post-baseline assessment or discontinued treatment due to clinical progression before post-baseline tumor assessment). Stable disease (5/25 patients) and partial response (1/25 patients at 10 mg/kg) were observed as best response in patients with colorectal, thyroid, neuroendocrine, or head and neck cancers or soft tissue sarcoma.

Figure 9 shows a brain scan of a patient with a partial response at 10 mg/kg. The patient is 42 years old and has leiomyosarcoma that has metastasized to the lung and kidney (leiomyosarcoma confirmed by kidney biopsy: PTEN splice site, MY C amplification, ATRX mutation, CD36 mutation, RB loss, p53 loss; low mutational burden). The patient received 3 doses of TSR-022 at 10 mg/kg before imaging for re-staging of the cancer. In addition, the patient received gemcitabine and docetaxel for 5 months with evidence of progression before study entry. Pending confirmatory imaging, there appears to be a 32% tumor shrinkage at the 10 mg/kg dose level and treatment is ongoing.

Studies have shown that monotherapy with TSR-022 is well tolerated at several dose levels.

Part 2 of the study is designed, inter alia, to evaluate the safety and tolerability, PK and PDy profile, and anticancer effect of (i) anti-TIM-3 antibody at fixed doses of Q2W or Q3W or (ii) anti-TIM-3 antibody at fixed doses of Q2W or Q3W in combination with anti-PD-1 antibody at weight-based or constant doses as described above. Anti-PD-1 antibody may be administered as a 500 mg regimen every three weeks (Q3W) for the initial treatment cycles (e.g. 500 mg administered Q3W for four treatment cycles) followed by 1000 mg administered every six weeks (Q6W) until treatment is discontinued (e.g. due to disease progression).

Continuous doses of about 100 to 1500 mg of an anti-TIM-3 antibody may be administered as monotherapy or in combination therapy. For example, a dose of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg of an anti-TIM-3 antibody may be administered Q1W, Q2W, Q3W, Q4W, Q5W, or Q6W as monotherapy or in combination with an anti-PD-1 antibody, which is administered at 500 mg Q3W for four treatment cycles, then 1000 mg Q6W until treatment is discontinued (e.g., due to disease progression). In embodiments, a dose of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg of an anti-TIM-3 antibody may be administered as Q2W or Q3W as monotherapy or in combination with an anti-PD-1 antibody, which is administered at 500 mg Q3W for four treatment cycles, then 1000 mg Q6W until treatment is discontinued (e.g., due to disease progression). A dose of 100 mg, 200 mg, 300 mg, 500 mg, 800 mg, 1000 mg, or 1200 mg of anti-TIM-3 antibody may be administered as monotherapy once weekly (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), or once every three weeks (Q6W). A dose of 100 mg, 200 mg, 300 mg, 500 mg, 800 mg, 1000 mg, or 1200 mg of anti-TIM-3 antibody may be administered as monotherapy once every two weeks (Q2W) or once every three weeks (Q3W).

Receptor occupancy studies were performed using a constant dose of 100 mg of TIM-3 antibody administered every three weeks (Q3W). All samples were collected pre-dose, with occupancy measured after a single dose on day 1. As shown in Fig. 10, peripheral target coverage was achieved at 100 mg throughout the dosing interval. In addition, receptor occupancy at 100 mg Q3W was comparable to 3 mg/kg Q2W (Fig. 7B).

Receptor occupancy studies were also performed following administration of a constant dose of 300 mg of an exemplary anti-TIM-3 antibody (TSR-022) administered in combination with a constant dose of 500 mg of an exemplary anti-PD-1 antibody (TSR-042) according to the methods described herein, and the data are shown in Fig. 11. A second dose of TSR-022 was administered on day 22, with the RO sample collected prior to the second dose. Using a constant dose of 300 mg of TSR-022, a high RO can be maintained over the measured time period.

Fig. 12 shows a set of mean receptor occupancy data for 1 mg/kg, 3 mg/kg, 10 mg/kg, and constant doses of an exemplary TIM-3 antibody (TSR-022).

-

Claims (7)

doses of 100 mg, 300 mg, and 1200 mg. Figure 4B shows that high occupancy ratios (free TIM-3:total TIM-3) can be achieved with different doses of TSR-022, as measured over multiple days. These monotherapy or combination regimens will be tested in specific tumor types, which may include anti-PD1/L1–treated melanoma, anti-PD1/L1–treated NSCLC, colorectal cancer, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, and/or breast cancer. Figure 4B provides an overview of the Part 2 expansion cohort study. Equivalents As used herein, the singular forms """ and """ in the specification and claims, unless clearly indicated to the contrary, are to be understood as including plural references. A claim or description that contains or is contained between one or more representatives of a group is considered satisfied if one, more than one, or all of the representatives of the group are present in, used in, or otherwise related to the stated product or method, unless otherwise stated or otherwise obvious from the context. The present invention includes embodiments in which exactly one representative of the group is present in, used in, or otherwise related to the stated product or method. The present invention also includes embodiments in which more than one or all of the representatives of the group are present in, used in, or otherwise related to the stated product or method. Furthermore, it should be understood that the present invention covers all variations, combinations, and permutations in which one or more of the limitations, elements, conditions, descriptive terms, etc. of one or more listed claims are introduced into another claim dependent on the same independent claim (or any other claim, as applicable), unless otherwise indicated or unless it would be obvious to one of ordinary skill in the art that a contradiction or inconsistency would arise. Where elements are presented in list form (e.g., in Markush group or similar format), it should be understood that each subgroup of elements is also disclosed, and any element(s) may be deleted from the group. In general, it should be understood that where the present invention or aspects of the present invention are referred to as comprising/comprising particular elements, features, etc., then particular embodiments of the present invention or aspects of the present invention consist of or consist essentially of such elements, features, etc. For purposes of simplicity, such embodiments have not in every instance been specifically set forth in such detail herein. It is also to be understood that any embodiment or aspect of the present invention may be expressly excluded from the claims, regardless of whether the specific exclusion is set forth in the description. Publications, websites and other references cited herein by reference to describe the state of the art of the present invention and to provide additional information regarding its practical implementation are incorporated herein by reference. CLAIM 1) a heavy chain comprising three CDRs that have the sequences of SEQ ID NO: 21, 22 or 23; and a light chain comprising three CDRs that have the sequences of SED ID NO: 24, 25 or 26; or 1. A method of treating cancer, comprising administering to a patient in need of treatment an antibody to a T-cell immunoglobulin and mucin domain 3 (TIM-3) in a therapeutically effective dose at an administration interval of once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks, for a period of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks, until a clinical benefit is obtained, wherein the antibody to TIM-3 is administered in combination with an additional therapy that comprises a therapy with an antibody to PD-1 that comprises a heavy chain comprising SEQ ID NO: 13 and a light chain comprising SEQ ID NO: NO: 14; wherein the antibody to TIM-3 comprises: 2. The method of claim 1, wherein the clinical benefit is stable disease (SD), partial response (PR) and/or complete response (CR); and/or wherein PR or CR is determined according to the Response Evaluation Criteria in Solid Tumors (RECIST); - 68 050059 and/or where the patient has cancer associated with a POLE (DNA polymerase epsilon) or POLD (DNA polymerase delta) mutation; preferably, wherein the POLE or POLD mutation is in the exonuclease domain; and/or wherein the POLE or POLD mutation is a germline mutation; and/or wherein the POLE or POLD mutation is a sporadic mutation; and/or wherein the method further comprises the step of first identifying a patient having a cancer with a POLE or POLD mutation; preferably, where the POLE or POLD mutation is identified using sequencing; and/or where the patient has a cancer with microsatellite instability; preferably where the patient has MSI-H cancer; more preferably, wherein the cancer is an MSI-H cancer involving a mutation in POLE or POLD, optionally a non-endometrial MSI-H cancer involving a mutation in POLE or POLD; or wherein the patient has an MSI-L cancer; or wherein the patient has a microsatellite stable (MSS) cancer; preferably, wherein the patient has a hematological cancer, more preferably, wherein the hematological cancer is DLBCL, HL, NHL, FL, AML, ALL or MM; and/or wherein the patient has a solid tumor; preferably, wherein the patient has an advanced solid tumor; or wherein the patient has a metastatic solid tumor; and/or wherein the cancer is characterized by homologous recombination repair deficiency/homologous repair deficiency (HRD); and/or where the patient has a cancer selected from head and neck cancer, lung cancer, renal cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, bulbar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendiceal cancer, urothelial cell carcinoma, squamous cell carcinoma, soft tissue sarcoma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, Hodgkin's lymphoma, neuroblastoma, CNS tumor, diffuse intrinsic glioma (DIPG), Ewing's sarcoma, embryonal rhabdomyosarcoma (ERS), osteosarcoma or Wilms' tumor; or where the patient has endometrial cancer; preferably where the patient has endometrial cancer with microsatellite instability; more preferably, where the patient has MSI-H endometrial cancer; or where the patient has MSS/MSI-L endometrial cancer; or where the patient has breast cancer; preferably, where the patient has triple-negative breast cancer (TNBC); or where the patient has ovarian cancer; preferably, wherein the ovarian cancer is epithelial ovarian cancer; or wherein the patient has lung cancer; preferably, wherein the lung cancer is non-small cell lung cancer (NSCLC); or wherein the patient has melanoma; or wherein the patient has colorectal cancer; or wherein the patient has squamous cell carcinoma; preferably, where the squamous cell carcinoma is squamous cell carcinoma of the anus, squamous cell carcinoma of the penis, squamous cell carcinoma of the cervix, squamous cell carcinoma of the vagina, or squamous cell carcinoma of the vulva; or where the patient has a soft tissue sarcoma; preferably, wherein the patient has leiomyosarcoma; and/or wherein the patient has not been previously treated with a cancer treatment method; or wherein the patient has been previously treated with one or more different cancer treatment methods; preferably, wherein the one or more different cancer treatment methods comprise surgery, radiotherapy, chemotherapy, or immunotherapy; and/or wherein the therapeutically effective dose is about 1, 3, or 10 mg/kg; or wherein the therapeutically effective dose is a constant dose of about 100 to 1500 mg; and/or wherein the anti-TIM-3 antibody is administered at an administration interval of once every 2 weeks; or wherein the anti-TIM-3 antibody is administered at an administration interval of once every 3 weeks; more preferably, wherein about 100 mg of the anti-TIM-3 antibody is administered; or wherein about 300 mg of the anti- - 69 050059 TIM-3; or wherein about 500 mg of an anti-TIM-3 antibody is administered; or wherein about 900 mg of an anti-TIM-3 antibody is administered; and/or wherein the anti-TIM-3 antibody is administered intravenously; preferably, wherein the anti-TIM-3 antibody is administered by intravenous infusion; and/or wherein the anti-PD-1 antibody is administered to the patient periodically at a dose of about 100 to 1000 mg; preferably, wherein the anti-PD-1 antibody is administered to the patient periodically at a dose of approximately 500 mg; preferably wherein the anti-PD-1 antibody is administered to the patient once every 3 weeks; and/or wherein the anti-PD-1 antibody is administered for 2-6 cycles; preferably, wherein the anti-PD-1 antibody is administered for 3 cycles; or wherein the anti-PD-1 antibody is administered for 4 cycles; or wherein the anti-PD-1 antibody is administered for 5 cycles; or wherein the anti-PD-1 antibody is periodically administered to the patient at a dose of about 1000 mg; preferably, wherein the anti-PD-1 antibody is administered to the patient once every 6 weeks or more; or wherein the anti-PD-1 antibody is administered in a first dose of about 500 mg once every 3 weeks for 3, 4 or 5 cycles followed by a second dose of about 1000 mg once every 6 weeks or more; preferably: wherein the anti-PD-1 antibody is administered at a first dose of about 500 mg once every 3 weeks for 3 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more; or wherein the anti-PD-1 antibody is administered at a first dose of about 500 mg once every 3 weeks for 4 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more; or wherein the anti-PD-1 antibody is administered at a first dose of about 500 mg once every 3 weeks for 5 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more; and/or wherein the second dose of 1000 mg is administered once every 6 weeks; and/or wherein the therapeutically effective dose of the anti-TIM-3 antibody is a constant dose of about 100 mg; or wherein the therapeutically effective dose of the TIM-3 antibody is a constant dose of about 300 mg; or wherein the therapeutically effective dose of the TIM-3 antibody is a constant dose of about 500 mg; or wherein the therapeutically effective dose of the TIM-3 antibody is a constant dose of about 900 mg; or wherein the TIM-3 antibody is administered once every three weeks. 2) an immunoglobulin heavy chain variable domain comprising SEQ ID NO: 1 or SEQ ID NO: 7 and an immunoglobulin light chain variable domain comprising SEQ ID NO: 2 or SEQ ID NO: 8; or 3. The method according to claim 1 or 2, wherein the antibody to TIM-3 comprises a variable domain of an immunoglobulin heavy chain comprising SEQ ID NO: 1 and a variable domain of an immunoglobulin light chain comprising SEQ ID NO: . 3) a heavy chain polypeptide comprising SEQ ID NO: 3 and a light chain polypeptide comprising SEQ ID NO: 4. 4. The method according to any of the preceding paragraphs, wherein the antibody to TIM-3 is administered at a constant dose of 300 mg once every 3 weeks. 5. The method according to any of the preceding paragraphs, wherein the k-PD-1 antibody is administered at a dose of 500 mg once every 3 weeks. 6. The method according to any one of the preceding paragraphs, wherein the cancer is lung cancer. 7. The method according to claim 1, wherein the cancer is non-small cell lung cancer, wherein the antibody to TIM-3 comprises an immunoglobulin heavy chain variable domain comprising SEQ ID NO: 1 and an immunoglobulin heavy chain variable domain comprising SEQ ID NO: 2, and is administered intravenously at a constant dose of 300 mg once every 3 weeks, and wherein the antibody to PD-1 comprises a heavy chain comprising SEQ ID NO: 13 and a light chain comprising SEQ ID NO: 14, and is administered intravenously at a constant dose of 500 mg once every 3 weeks. -