EA043391B1 - METHODS FOR TREATING CANCER USING ANTIBODIES TO PD-1 - Google Patents

Description

Cross reference to related applications

This application claims benefit from U.S. Provisional Patent Application No. 62/444336, filed January 9, 2017, U.S. Provisional Patent Application No. 62/477423, filed March 27, 2017, U.S. Provisional Patent Application No. 62/491220, filed April 27, 2017, and U.S. Provisional Patent Application No. 62/556,386 filed September 9, 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 called TSR-006 SEQ LIST_ST25, which was created on January 8, 2018 and has a size of 14555 bits.

Prerequisites for creating the 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 American Cancer Society, Cancer Facts & Figures 2017 (https://www.cancer.org/research /cancer-factsstatistics/all-cancer-facts-figures/cancer-facts-figures-2017.html). Therefore, 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 inhibiting programmed cell death protein 1 (PD-1) antibody activity (eg, PD-1 binding agents) are useful for treating disorders such as cancer.

In embodiments, the PD-1 inhibitor is a PD-1 binding agent. In embodiments, the PD-1 binding agent is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. In embodiments, the PD-1 binding agent is an antibody-based agent (ie, an anti-PD-1 antibody-based agent).

In embodiments, the PD-1 binding agent is an anti-PD-1 antibody. In embodiments, the PD-1 binding agent comprises a heavy chain variable region with one or more CDR sequences characterized by at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96 %, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, 10, or 11. In embodiments, the PD-1 binding agent comprises a heavy chain variable region with two or three CDR sequences sharing at least about 80% , 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9, 10, or 11.

In embodiments, the PD-1 binding agent comprises a light chain variable region with one or more CDR sequences characterized by at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96 %, 97%, 98%, or 99% sequence identity to SEQ ID NOs: 12, 13, and 14. In embodiments, the PD-1 binding agent comprises a light chain variable region with two or three CDR sequences sharing at least about 80% , 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NOs: 12, 13 and 14.

In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with one or more CDR sequences selected from SEQ ID NOs: 9, 10 and 11, and/or a light chain variable region with one or more CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with two or more CDR sequences selected from SEQ ID NOs: 9, 10 and 11, and/or a light chain variable region with two or more CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with three CDRs that have the sequences of SEQ ID NOs: 9, 10 and 11, and/or a light chain variable region with three CDRs that have the sequences of SEQ ID NOs: 12, 13 and 14. In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with three CDRs that have the sequences of SEQ ID NOs: : 9, 10 and 11, and a light chain variable region with three CDRs, which have the sequences of SEQ ID NOs: 12, 13 and 14.

In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain variable domain comprising an amino acid sequence characterized by 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 some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain variable domain comprising an amino acid sequence characterized by at least approximately 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 1. In some embodiments, the binding PD -1 agent contains an immunoglobulin heavy chain variable domain containing an amino acid sequence characterized by at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,

- 1 043391

97%, 98%, or 99% sequence identity to SEQ ID NO: 7.

In some embodiments, the PD-1 binding agent comprises an immunoglobulin light chain variable domain comprising an amino acid sequence characterized by 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, the PD-1 binding agent comprises an immunoglobulin light chain variable domain comprising an amino acid sequence characterized by at least approximately 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 2. In some embodiments, the binding PD -1 agent contains an immunoglobulin light chain variable domain containing an amino acid sequence characterized by at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 % or 99% sequence identity to SEQ ID NO: 8.

In some embodiments, the PD-1 binding 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 PD-1 binding agent comprises an immunoglobulin heavy chain comprising an amino acid sequence characterized by at least 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 PD-1 binding agent comprises an immunoglobulin light chain comprising an amino acid sequence characterized by at least 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 PD-1 binding 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.

The PD-1 binding agents can be any PD-1 binding agent known in the art. In some embodiments, the PD-1 binding agent 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 anti-PD-1 antibodies disclosed in the WO 2014/179664.

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody agent) binds an epitope of PD-1, which blocks the binding of PD-1 to any one or more of its putative ligands. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody agent) binds an epitope of PD-1, which blocks the binding of PD-1 to two or more of its putative ligands. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody agent) binds an epitope of the PD-1 protein, which blocks the binding of PD-1 to PD-L1 and/or PD-L2. PD-1 binding agents (eg, anti-PD-1 antibody agents) of the present invention may comprise a heavy chain constant region (F _c ) of any suitable class. In some embodiments, the PD-1 binding agent (eg, an anti-PD-1 antibody agent) comprises a heavy chain constant region that is based on wild-type IgG1, IgG2, or IgG4 antibodies or variants thereof.

The present invention provides methods for treating a disorder in a subject, comprising administering a therapeutically effective dose of an agent that is capable of inhibiting programmed cell death protein 1 (PD-1) signaling. In embodiments, the therapeutically effective dose is approximately 1, 3, or 10 mg/kg. In embodiments, the therapeutically effective dose is a continuous dose of about 100-2000 mg (e.g., 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; constant dose approximately 600 mg; constant dose approximately 700 mg; constant dose approximately 800 mg; constant dose approximately 900 mg; constant dose approximately 1000 mg; constant dose approximately 1100 mg; constant dose approximately 1200 mg; constant dose approximately 1300 mg; constant dose approximately 1400 mg; continuous dose approximately 1500 mg; continuous dose approximately 1600 mg; continuous dose approximately 1700 mg; continuous dose approximately 1800 mg; continuous dose approximately 1900 mg or continuous dose approximately 2000 mg). In embodiments, the therapeutically effective dose is approximately 1 mg/kg. In embodiments, the therapeutically effective dose is approximately 3 mg/kg. In embodiments, the therapeutically effective dose is approximately 10 mg/kg. In embodiments, the therapeutically effective dose is

- 2 043391 is a constant dose of approximately 500 mg. In embodiments, the therapeutically effective dose is approximately 800 mg. In embodiments, the therapeutically effective dose is approximately 1000 mg. In embodiments, the PD-1 inhibitor is any PD-1 binding agent described herein (eg, any anti-PD-1 antibody described herein).

The present invention provides methods for increasing T cell activation or T cell effector function in a subject, the method comprising administering a therapeutically effective dose of an agent that is capable of inhibiting programmed cell death protein 1 (PD-1) signaling. In embodiments, the therapeutically effective dose is approximately 1, 3, or 10 mg/kg. In embodiments, the therapeutically effective dose is a continuous dose of about 100-2000 mg (e.g., 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; constant dose approximately 600 mg; constant dose approximately 700 mg; constant dose approximately 800 mg; constant dose approximately 900 mg; constant dose approximately 1000 mg; constant dose approximately 1100 mg; constant dose approximately 1200 mg; constant dose approximately 1300 mg; constant dose approximately 1400 mg; continuous dose approximately 1500 mg; continuous dose approximately 1600 mg; continuous dose approximately 1700 mg; continuous dose approximately 1800 mg; continuous dose approximately 1900 mg or continuous dose approximately 2000 mg). In embodiments, the therapeutically effective dose is approximately 1 mg/kg. In embodiments, the therapeutically effective dose is approximately 3 mg/kg. In embodiments, the therapeutically effective dose is approximately 10 mg/kg. In embodiments, the therapeutically effective dose is a constant dose of approximately 500 mg. In embodiments, the therapeutically effective dose is approximately 800 mg. In embodiments, the therapeutically effective dose is approximately 1000 mg. In embodiments, the PD-1 inhibitor is any PD-1 binding agent described herein (eg, any anti-PD-1 antibody described herein).

The present invention provides methods for reducing tumors or inhibiting the growth of tumor cells in a subject, the method comprising administering a therapeutically effective dose of an agent that is capable of inhibiting programmed cell death protein 1 (PD-1) signaling. In embodiments, the therapeutically effective dose is approximately 1, 3, or 10 mg/kg. In embodiments, the therapeutically effective dose is a continuous dose of about 100-2000 mg (e.g., 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; constant dose approximately 600 mg; constant dose approximately 700 mg; constant dose approximately 800 mg; constant dose approximately 900 mg; constant dose approximately 1000 mg; constant dose approximately 1100 mg; constant dose approximately 1200 mg; constant dose approximately 1300 mg; constant dose approximately 1400 mg; continuous dose approximately 1500 mg; continuous dose approximately 1600 mg; continuous dose approximately 1700 mg; continuous dose approximately 1800 mg; continuous dose approximately 1900 mg or continuous dose approximately 2000 mg). In embodiments, the therapeutically effective dose is approximately 1 mg/kg. In embodiments, the therapeutically effective dose is approximately 3 mg/kg. In embodiments, the therapeutically effective dose is approximately 10 mg/kg. In embodiments, the therapeutically effective dose is a constant dose of approximately 500 mg. In embodiments, the therapeutically effective dose is approximately 800 mg. In embodiments, the therapeutically effective dose is approximately 1000 mg. In embodiments, the PD-1 inhibitor is any PD-1 binding agent described herein (eg, any anti-PD-1 antibody described herein).

The present invention provides methods for inducing an immune response in a subject, the method comprising administering a therapeutically effective dose of an agent that is capable of inhibiting programmed cell death protein 1 (PD-1) signaling. In embodiments, the therapeutically effective dose is approximately 1, 3, or 10 mg/kg. In embodiments, the therapeutically effective dose is a continuous dose of about 100-2000 mg (e.g., 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; constant dose approximately 600 mg; constant dose approximately 700 mg; constant dose approximately 800 mg; constant dose approximately 900 mg; constant dose approximately 1000 mg; constant dose approximately 1100 mg; constant dose approximately 1200 mg; constant dose approximately 1300 mg; constant dose approximately 1400 mg; continuous dose approximately 1500 mg; continuous dose approximately 1600 mg; continuous dose approximately 1700 mg; continuous dose approximately 1800 mg; continuous dose approximately 1900 mg; or continuous dose approximately 2000 mg). In embodiments, the therapeutically effective dose is approximately 1 mg/kg. In embodiments, the therapeutically effective dose is approximately 3 mg/kg. In embodiments, the therapeutically effective dose is approximately 10 mg/kg. In embodiments, the therapeutically effective dose is a constant dose of approximately 500 mg. In embodiments, the therapeutically effective dose is approximately 800 mg. In embodiments, the therapeutically effective dose is approximately 1000 mg. In embodiments, the PD-1 inhibitor is any PD-1 binding agent described herein (eg, any anti-PD-1 antibody described herein).

The present invention provides methods for enhancing an immune response or increasing immune cell activity in a subject, the method comprising administering a therapeutically effective dose of an agent that is capable of inhibiting programmed cell death protein 1 (PD-1) 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 Cellular response. In embodiments, the therapeutically effective dose is approximately 1, 3, or 10 mg/kg. In embodiments, the therapeutically effective dose is a continuous dose of about 100-2000 mg (e.g., 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; constant dose approximately 600 mg; constant dose approximately 700 mg; constant dose approximately 800 mg; constant dose approximately 900 mg; constant dose approximately 1000 mg; constant dose approximately 1100 mg; constant dose approximately 1200 mg; constant dose approximately 1300 mg; constant dose approximately 1400 mg; continuous dose approximately 1500 mg; continuous dose approximately 1600 mg; continuous dose approximately 1700 mg; continuous dose approximately 1800 mg; continuous dose approximately 1900 mg or continuous dose approximately 2000 mg). In embodiments, the therapeutically effective dose is approximately 1 mg/kg. In embodiments, the therapeutically effective dose is approximately 3 mg/kg. In embodiments, the therapeutically effective dose is approximately 10 mg/kg. In embodiments, the therapeutically effective dose is a constant dose of approximately 500 mg. In embodiments, the therapeutically effective dose is approximately 800 mg. In embodiments, the therapeutically effective dose is approximately 1000 mg. In embodiments, the PD-1 inhibitor is any PD-1 binding agent described herein (eg, any anti-PD-1 antibody described herein).

The present invention provides methods for treating cancer that include administering compositions that provide delivery of specific PD-1 binding agents. In embodiments, the PD-1 binding agent is administered in an amount that is approximately 1, 3, or 10 mg/kg. In embodiments, the PD-1 binding agent is administered in an amount that is about 100-2000 mg (e.g., about 100 mg; about 200 mg; about 300 mg; about 400 mg; about 500 mg; about 600 mg; about 700 mg about 800 mg; approximately 900 mg; approximately 1000 mg; approximately 1100 mg; approximately 1200 mg; approximately 1300 mg; approximately 1400 mg; approximately 1500 mg; approximately 1600 mg; approximately 1700 mg; approximately 1800 mg; approximately 1900 mg or approximately 2000 mg ). In embodiments, the PD-1 binding agent is administered in an amount that is approximately 1 mg/kg. In embodiments, the PD-1 binding agent is administered in an amount that is approximately 3 mg/kg. In embodiments, the PD-1 binding agent is administered in an amount that is approximately 10 mg/kg. In embodiments, the PD-1 binding agent is administered in an amount that is approximately 500 mg. In embodiments, the therapeutically effective dose is approximately 800 mg. In embodiments, the PD-1 binding agent is administered in an amount that is approximately 1000 mg. In embodiments, the PD-1 inhibitor is any PD-1 binding agent described herein (eg, any anti-PD-1 antibody described herein).

The present invention provides methods for treating cancer comprising administering to a patient in need of treatment an anti-programmed cell death protein 1 (PD-1) antibody at a therapeutically effective dose at an interval of administration for a period sufficient to obtain clinical benefit. In embodiments, the anti-PD-1 antibody comprises a heavy chain variable region comprising the CDR sequences of SEQ ID NOs: 9, 10, and 11, and a light chain variable region comprising the CDR sequences of SEQ ID NOs: 12, 13, and 14. In embodiments An anti-PD-1 antibody contains an immunoglobulin heavy chain variable domain, the amino acid sequence of which contains SEQ ID NO:1 or SEQ ID NO:7, and/or an immunoglobulin light chain variable domain, the amino acid sequence of which contains SEQ ID NO:

- 4 043391 or SEQ ID NO: 8. In embodiments, the anti-PD-1 antibody comprises an immunoglobulin heavy chain polypeptide whose amino acid sequence contains SEQ ID NO: 3, and/or an immunoglobulin light chain polypeptide whose amino acid sequence contains SEQ ID NO: 3 4. In embodiments, the therapeutically effective dose is approximately 1, 3, or 10 mg/kg. In embodiments, the therapeutically effective dose is a continuous dose of about 100-2000 mg (e.g., 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; constant dose approximately 600 mg; constant dose approximately 700 mg; constant dose approximately 800 mg; constant dose approximately 900 mg; constant dose approximately 1000 mg; constant dose approximately 1100 mg; constant dose approximately 1200 mg; constant dose approximately 1300 mg; constant dose approximately 1400 mg; continuous dose approximately 1500 mg; continuous dose approximately 1600 mg; continuous dose approximately 1700 mg; continuous dose approximately 1800 mg; continuous dose approximately 1900 mg or continuous dose approximately 2000 mg). In embodiments, the therapeutically effective dose is approximately 1 mg/kg. In embodiments, the therapeutically effective dose is approximately 3 mg/kg. In embodiments, the therapeutically effective dose is approximately 10 mg/kg. In embodiments, the therapeutically effective dose is a constant dose of approximately 500 mg. In embodiments, the therapeutically effective dose is approximately 800 mg. In embodiments, the therapeutically effective dose is approximately 1000 mg.

The present invention provides methods for treating cancer comprising administering to a patient in need of treatment an anti-programmed cell death protein 1 (PD-1) antibody in a first dose at a first interval during a first period and administering an anti-PD-1 antibody to a patient in a second dose in a second period. interval during the second period. In embodiments, the anti-PD-1 antibody comprises a heavy chain variable region comprising the CDR sequences of SEQ ID NOs: 9, 10, and 11, and a light chain variable region comprising the CDR sequences of SEQ ID NOs: 12, 13, and 14. In embodiments embodiment, the anti-PD-1 antibody contains an immunoglobulin heavy chain variable domain, the amino acid sequence of which contains SEQ ID NO: 1 or SEQ ID NO: 7, and/or an immunoglobulin light chain variable domain, the amino acid sequence of which contains SEQ ID NO: 2 or SEQ ID NO: 8. In embodiments, the anti-PD-1 antibody comprises an immunoglobulin heavy chain polypeptide whose amino acid sequence contains SEQ ID NO: 3, and/or an immunoglobulin light chain polypeptide whose amino acid sequence contains SEQ ID NO: 4. In embodiments, the dose is approximately 1, 3 or 10 mg/kg. In embodiments, the dose is a constant dose of about 100-2000 mg (e.g., 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 approximately 600 mg; constant dose approximately 700 mg; constant dose approximately 800 mg; constant dose approximately 900 mg; constant dose approximately 1000 mg; constant dose approximately 1100 mg; constant dose approximately 1200 mg; constant dose approximately 1300 mg; constant dose approximately 1400 mg; constant dose of approximately 1500 mg; constant dose of approximately 1600 mg; constant dose of approximately 1700 mg; constant dose of approximately 1800 mg; constant dose of approximately 1900 mg or constant dose of approximately 2000 mg). In embodiments, the therapeutically effective dose is approximately 1 mg/kg. In embodiments, the dose is approximately 3 mg/kg. In embodiments, the dose is approximately 10 mg/kg. In embodiments, the therapeutically effective dose is a constant dose of approximately 500 mg. In embodiments, the therapeutically effective dose is a constant dose of approximately 800 mg. In embodiments, the therapeutically effective dose is approximately 1000 mg. In embodiments, the first dose and the second dose are different. In embodiments, the first dose is approximately 500 mg, and the second dose is approximately 1000 mg. In embodiments, the first interval and the second interval are different. In embodiments, the first interval is once every three weeks, and the second interval is once every six weeks. In embodiments, the anti-PD-1 antibody is administered in a first dose of 500 mg once every three weeks for a first period of 2-6 dosing cycles (e.g., the first 3, 4, or 5 dosing cycles) and in a second dose of 1000 mg once every six weeks until therapy is discontinued (eg, due to disease progression, an adverse event, or as determined by the physician). In embodiments, the anti-PD-1 antibody is administered in a first dose of 500 mg once every three weeks for the first three dosing cycles and in a second dose of 1000 mg once every six weeks or more until therapy is discontinued (eg , due to disease progression, adverse event, or as determined by the physician). In embodiments, the anti-PD-1 antibody is administered in a first dose of 500 mg once every three weeks for the first four dosing cycles and in a second dose of 1000 mg once every six weeks or more until therapy fails.

- 5 043391 will be discontinued (for example, due to disease progression, an adverse event, or as determined by the physician). In embodiments, the anti-PD-1 antibody is administered in a first dose of 500 mg once every three weeks for the first five dosing cycles and in a second dose of 1000 mg once every six weeks or more until therapy is discontinued (eg , due to disease progression, adverse event, or as determined by the physician). In embodiments, the dose is administered once every six weeks.

In any of the methods described herein, the therapeutically effective dose is approximately 1 mg/kg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 3 mg/kg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 10 mg/kg of the PD-1 binding agent. In embodiments, the PD1 binding agent is any anti-PD-1 antibody described herein.

In any of the methods described herein, the therapeutically effective dose is approximately 100 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 200 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 300 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 400 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 500 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 600 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 700 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 800 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 900 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 1000 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 1100 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 1200 mg of the PD1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 1300 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 1400 mg of the PD1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 1500 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 1600 mg of the PD1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 1700 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 1800 mg of the PD1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 1900 mg of the PD-1 binding agent. In any of the methods described herein, the therapeutically effective dose is approximately 2000 mg of the PD1 binding agent. In embodiments, the PD-1 binding agent is any anti-PD-1 antibody described herein.

In embodiments, the PD-1 binding agent is administered at a dosing 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 PD-1 binding agent is administered in a once-weekly (Q1W) dosing interval (or treatment cycle). In embodiments, the PD-1 binding agent is administered at a dosing interval (or treatment cycle) of once every 2 weeks (Q2W). In embodiments, the PD-1 binding agent is administered at a dosing interval (or treatment cycle) of once every three weeks (Q3W). In embodiments, the PD-1 binding agent is administered at a dosing interval (or treatment cycle) of once every 4 weeks (Q4W). In embodiments, the PD-1 binding agent is administered in a dosing interval (or treatment cycle) of once every 5 weeks (Q5W). In embodiments, the PD-1 binding agent is administered at a dosing interval (or treatment cycle) of once every 6 weeks (Q6W). In embodiments, the PD-1 binding agent 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 PD-1 binding agent is administered on the first day of the treatment cycle or on days 1, 2, or 3 of the first day of the treatment cycle. In embodiments, the PD-1 binding agent is any anti-PD-1 antibody described herein.

In embodiments, the PD-1 binding agent described herein is administered according to dosing regimens demonstrated to achieve clinical benefit in some

- 6 043391 patients (for example, according to the schedule determined by the physician, including modifications in dosage administration). In embodiments, the PD-1 binding agent described herein is administered until treatment is discontinued due to, for example, disease progression or an adverse reaction, or as determined by the physician. In embodiments, clinical benefit is stable disease (SD), partial response (PR), and/or complete response (CR). In embodiments, the clinical benefit is disease stability (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 is defined according to Response Evaluation Criteria in Solid Tumors (RECIST). In embodiments, the PD-1 binding agent is administered over a longer period to maintain clinical benefit. In embodiments, the PD-1 binding agent is any anti-PD-1 antibody described herein.

In embodiments, the PD-1 binding agent is administered to the subject periodically at a dose of about 500 mg or about 1000 mg. In embodiments, the PD-1 binding agent is administered to a subject periodically at a dose of approximately 500 mg (eg, once every three weeks (Q3W) and/or over 2, 3, 4, 5, 6 or more cycles). In embodiments, the PD-1 binding agent is administered to a subject periodically at a dose of approximately 1000 mg (eg, once every three weeks (Q3W) and/or over 2, 3, 4, 5, 6 or more cycles). In embodiments, the PD1 binding agent is administered to a subject at a dose of approximately 500 mg administered once every three weeks (Q3W) for 3 cycles. In embodiments, the PD-1 binding agent is administered to a subject at a dose of approximately 500 mg administered once every three weeks (Q3W) for 4 cycles. In embodiments, the PD-1 binding agent is administered to a subject at a dose of approximately 500 mg administered once every three weeks (Q3W) for 5 cycles. In embodiments, the PD-1 binding agent is administered to a subject at a dose of approximately 1000 mg administered once every six weeks or more (Q3W). In embodiments, the PD-1 binding agent is administered to a subject at a dose of approximately 1000 mg administered once every six weeks (Q3W). In embodiments, the PD-1 binding agent is administered at a first dose of approximately 500 mg once every 3 weeks for 3 cycles, followed by a second dose of approximately 1000 mg once every 6 weeks or more (e.g., until treatment is discontinued ). In embodiments, the PD-1 binding agent is administered at a first dose of approximately 500 mg once every 3 weeks for 4 cycles, followed by a second dose of approximately 1000 mg once every 6 weeks (eg, until treatment is discontinued). In embodiments, the PD-1 binding agent is administered at a first dose of approximately 500 mg once every 3 weeks for 5 cycles, followed by a second dose of approximately 1000 mg once every 6 weeks or more (e.g., until treatment is discontinued ). In embodiments, the second dose is approximately 1000 mg once every six weeks (eg, until treatment is discontinued). In embodiments, the PD-1 binding agent is any anti-PD-1 antibody described herein.

In embodiments, the subject has or will be further administered an additional therapeutic agent, whereby the subject receives a PD-1 binding agent and an additional therapeutic agent (eg, one, two, three, four or more additional therapeutic agents). In embodiments, the PD-1 binding agent is any anti-PD-1 antibody described herein.

In embodiments, the subject has been or will be further administered an immune checkpoint inhibitor, whereby the subject receives a PD-1 binding agent and an immune checkpoint inhibitor. Thus, a subject can be administered a PD-1 binding agent in combination with at least one immune checkpoint inhibitor. In embodiments, the PD-1 binding agent is any anti-PD-1 antibody described herein.

In embodiments, an immune checkpoint inhibitor is an agent capable of inhibiting any of the following: PD-1 (e.g., suppression by anti-PD-1, anti-PD-L1, or anti-PD-L2 therapies), CTLA-4, TIM-3, TIGIT, LAG (for example, LAG-3), SEASAM (for example, SEASAM-1, -3 and/or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80, CD86, B7-NZ ( CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (eg TGFR beta), B7-H1, B7-H4 (VTCN1 ), OX-40, CD137, CD40, IDO or CSF-1R. In embodiments, the checkpoint inhibitor is a small molecule, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or 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 T cell immunoglobulin and mucin domain containing protein 3 (TIM3), 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)

- 7 043391 or colony stimulating factor 1 receptor (CSF1R).

In embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is a small molecule, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, toxin, or binder. In embodiments, the TIM-3 inhibitor is a TIM-3 binding agent (eg, an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the TIM3 inhibitor is a TIM-3 inhibitor described in WO 2016/161270, which is incorporated herein by reference in its entirety. In embodiments, the TIM-3 inhibitor is TSR-022. For example, a TIM-3 inhibitor (e.g., TSR-022) can be administered at a dose of about 1, 3, or 10 mg/kg (e.g., about 1 mg/kg; about 3 mg/kg or about 10 mg/kg), or a constant dose of about 100 to 1500 mg (for example, 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 approximately 700 mg; constant dose approximately 800 mg; constant dose approximately 900 mg; constant dose approximately 1000 mg; constant dose approximately 1100 mg; constant dose approximately 1200 mg; constant dose approximately 1300 mg; constant dose approximately 1400 mg or constant dose approximately 1500 mg).

In embodiments, the immune checkpoint inhibitor is a CTLA4 inhibitor (eg, an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the CTLA-4 inhibitor is a small molecule, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or 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 (eg, an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the LAG-3 inhibitor is a small molecule, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or 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 links in their entirety.

In embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor (eg, an antibody, antibody conjugate, or antigen-binding fragment thereof). In embodiments, the TIGIT inhibitor is a small molecule, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or 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, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or 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, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or 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 subject has been or will be further administered an agent that inhibits poly(ADP-ribose) polymerase (PARP), whereby the subject is treated with a PD-1 binding agent and a PARP inhibitor.

In embodiments, the PARP inhibitor is a small molecule, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or toxin. In embodiments, the PARP inhibitor is selected from the group consisting of: ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983,

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CEP 9722, DR 2313, E7016, E7449, flusoparib, IMP 4297, INO1001, JPI 289, JPI 547, monoclonal antibody conjugate B3-LysPE40, MP 124, niraparib, NU 1025, NU 1064, NU 1076, NU10 85, 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[4,3- d]pyrimidin-4-ol and their salts or derivatives. In embodiments, the PARP inhibitor is nirapirib, olaparib, rucaparib, talazoparib, or veliparib. In embodiments, the PARP inhibitor is niraparib (eg, niraparib free base, niraparib tosylate, or niraparib tosylate monohydrate, or any combination thereof).

In embodiments, the subject is or will be further administered one or more immune checkpoint inhibitors (e.g., a TIM-3 inhibitor and/or a LAG-3 inhibitor), whereby the subject receives treatment with a PD-1 binding agent, a PARP inhibitor (e.g. , niraparib) and one or more immune checkpoint inhibitors. In embodiments, the subject is administered a PD-1 binding agent, a PARP inhibitor (eg, niraparib), and a TIM-3 inhibitor. In embodiments, the subject is administered a PD-1 binding agent, a PARP inhibitor (eg, niraparib), and a LAG-3 inhibitor. In embodiments, the subject is administered a PD-1 binding agent, a PARP inhibitor (eg, niraparib), a TIM-3 inhibitor, and a LAG-3 inhibitor.

In embodiments, a therapeutic agent (e.g., a PD-1 binding agent, an immune checkpoint inhibitor, or a PARP inhibitor) described herein is administered according to dosing regimens that have been demonstrated to achieve clinical benefit in some patients (e.g., according to a regimen determined by a physician, including modifications in dose administration).

In some embodiments, the clinical benefit is a complete response (CR), partial response (PR), or stable disease (SD). In some embodiments, the clinical benefit is at least SD. In some embodiments, the clinical benefit corresponds to at least a PR. In some embodiments, the clinical benefit corresponds to 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 CR. In some embodiments, at least 10% of patients achieve clinical benefit. In some embodiments, at least 10% of patients achieve SD. In some embodiments, at least 10% of patients achieve at least a PR. 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 (eg, SD, PR, and/or CR) is determined according to the Response Evaluation Criteria in Solid Tumors (RECIST). In some embodiments, clinical benefit (eg, SD, PR, and/or CR) is determined according to RECIST guidelines. In some embodiments, clinical benefit (eg, SD, PR, and/or CR) is determined according to RECIST guidelines (version 1.1). In some embodiments, clinical benefit (eg, SD, PR, and/or CR) is determined according to the immune system-related RECIST (irRECIST) guideline. 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. When used in this document, the term RECIST guidelines may refer to RECIST 1.0, RECIST 1.1, or irRECIST interchangeably.

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

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

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, cancer is associated with high TMB and MSI-L or MSS. In embodiments, cancer is associated with high TMB and MSI-L. In embodiments, 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 (eg, MSI-H or MSS/MSI-L endometrial cancer). In embodiments, the cancer is an MSI-H cancer harboring a mutation in POLE or POLD (eg, a non-endometrial MSI-H cancer harboring a mutation in POLE or POLD). In embodiments, the cancer is breast cancer (eg, triple negative breast cancer (TNBC)). In embodiments, the cancer is lung cancer (eg, 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 adenocarcinoma, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, testicular cancer, primary peritoneal cancer, colon cancer, colorectal cancer, stomach cancer, small intestinal cancer, anogenital squamous cell carcinoma areas (eg, squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), soft tissue sarcoma (eg, leiomyosarcoma), melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell carcinoma of the lung, stomach cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, head and neck squamous cell carcinoma, prostate cancer, pancreatic cancer, mesothelioma, Merkel cell carcinoma , sarcoma, glioblastoma, hematological cancer, multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma/primary mediastinal B-cell lymphoma, chronic myelogenous leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, neuroblastoma, CNS tumor, di diffuse brainstem glioma (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 a high TMB, has a high TMB and is MSS or MSIL, has a high TMB and is MSI-H, has a defective DNA mismatch repair system, has a defect in the 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, 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's lymphoma. In embodiments, the cancer is Hodgkin's lymphoma. In embodiments, the cancer is a neuroblastoma. In embodiments, the cancer is a CNS tumor. In embodiments, the cancer is a diffuse brainstem glioma (DIPG). In embodiments, the cancer is Ewing's sarcoma. In embodiments, the cancer is an embryonal rhabdomyosarcoma. In embodiments, the cancer is osteosarcoma. In embodiments, the cancer is a Wilms tumor. In embodiments, the cancer is a soft tissue sarcoma (eg, leiomyosarcoma).

In some embodiments, the patient has 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, appendix cancer, urothelial cell or squamous cell carcinoma carcinoma (eg, lung; anogenital area, including the anus, penis, cervix, vagina, or vulva; or esophagus). In some certain embodiments, the patient has anal cancer, fallopian tube cancer, ovarian cancer, or lung cancer. In some certain embodiments, the patient has anal cancer. In some certain embodiments, the patient has cancer of the fallopian tube(s). In some certain embodiments, the patient has ovarian cancer. In some certain embodiments, the patient has lung cancer.

In some embodiments, the patient has a cancer with microsatellite instability. In some embodiments, microsatellite instability is considered high when

- 10 043391 this instability is significantly higher than the instability observed in the control cell (eg, MSI-H status). In some embodiments, the microsatellite instability is MSI-Low. In some embodiments, the microsatellite instability is microsatellite stability (eg, MSS status). In some embodiments, the cancer with microsatellite instability 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, appendix cancer, urothelial cell carcinoma or squamous cell carcinoma (eg, lung; anogenital area, including the anus, penis, cervix, vagina, or vulva; or esophagus). In some certain embodiments, the cancer with microsatellite instability is anal cancer, fallopian tube cancer, ovarian cancer, or lung cancer. In some certain embodiments, the patient has endometrial cancer with microsatellite instability. In some embodiments, the patient has endometrial cancer that is microsatellite stable (MSS).

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 (eg, high expression of PD-1 and/or high expression of PD-L1). In a certain 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, cell carcinoma Merkel, 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, stomach cancer, colorectal cancer , appendix cancer, urothelial cell carcinoma, or squamous cell carcinoma (eg, lung; anogenital area, 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 embodiments, the cancer is an advanced stage 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, 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 POLEmutant 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 (eg, a non-endometrial solid tumor). In embodiments, the non-endometrial cancer is an advanced stage 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 (eg, MSS solid tumor, MSI-H solid tumor, POLD-mutant solid tumor, or POLE-mutant solid tumor). In embodiments, the non-endometrial cancer is a high TMB cancer. In embodiments, non-endometrial cancer is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is endometrial cancer (eg, a solid tumor). In embodiments, the endometrial cancer is an advanced stage cancer. In embodiments, the endometrial cancer is a metastatic cancer. In embodiments, the endometrial cancer is MSI-H endometrial cancer. In embodiments, the endometrial cancer is MSS endometrial cancer. In embodiments, the endometrial cancer is POLE-mutant endometrial cancer. In embodiments, endometrial cancer is

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POLD-mutant endometrial cancer. In embodiments, the endometrial cancer is a high TMB endometrial cancer. In embodiments, endometrial cancer is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is a lung cancer (eg, a solid tumor). In embodiments, the lung cancer is advanced stage 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 an ALK translocation lung cancer (eg, a lung cancer with a known ALK translocation). In embodiments, the lung cancer is an EGFR-mutant lung cancer (eg, a 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 a 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, lung cancer is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is colorectal (CRC) cancer (eg, 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 a POLE mutant colorectal cancer. In embodiments, the colorectal cancer is POLD mutant colorectal cancer. In embodiments, the colorectal cancer is high TMB colorectal cancer. In embodiments, colorectal cancer is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

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

In embodiments, the cancer is a squamous cell carcinoma of the anogenital region (eg, anus, penis, cervix, vagina, or vulva). In embodiments, squamous cell carcinoma of the anogenital region (eg, anus, penis, cervix, vagina, or vulva) is an advanced stage cancer. In embodiments, squamous cell carcinoma of the anogenital region (eg, anus, penis, cervix, vagina, or vulva) is a metastatic cancer. In embodiments, squamous cell carcinoma of the anogenital region (eg, anus, penis, cervix, vagina, or vulva) is MSI-H. In embodiments, squamous cell carcinoma of the anogenital region (eg, 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 (eg, 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 a POLE mutant ovarian cancer. In embodiments, the ovarian cancer is POLD mutant ovarian cancer. In embodiments, the ovarian cancer is a high TMB ovarian cancer. In embodiments, 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 stage 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 a POLE mutant fallopian tube cancer. In embodiments, the fallopian tube cancer is a POLD mutant fallopian tube cancer. In embodiments, the fallopian tube cancer is a high TMB fallopian tube cancer. In embodiments, 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 stage 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, 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 a clear cell primary peritoneal cancer.

In embodiments, the cancer is acute lymphoblastic leukemia (ALL). In embodiments, the acute lymphoblastic leukemia is an 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 a POLE mutant acute lymphoblastic leukemia. In embodiments, the acute lymphoblastic leukemia is a POLD mutant acute lymphoblastic leukemia. In embodiments, 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 an 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 a POLE mutant acute myeloid leukemia. In embodiments, the acute myeloid leukemia is POLD mutant acute myeloid leukemia. In embodiments, acute myeloid leukemia is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

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

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 a neuroblastoma (NB). In embodiments, the neuroblastoma is an advanced neuroblastoma. In embodiments, the neuroblastoma is a metastatic neuroblastoma. In embodiments, the neuroblastoma is an MSI-H neuroblastoma. In embodiments, the neuroblastoma is an MSS neuroblastoma. In embodiments, the neuroblastoma is a POLE mutant neuroblastoma. In embodiments, the neuroblastoma is a POLD mutant neuroblastoma. In embodiments, the neuroblastoma is a high TMB neuroblastoma. In embodiments, 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 at an advanced stage. In embodiments, the CNS tumor is a metastatic CNS tumor. In embodiments, the CNS tumor is an MSI-H CNS tumor. In embodiments, the CNS tumor is a CNS MSS tumor. In embodiments, the CNS tumor is a POLEmutant 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 a diffuse brainstem glioma (DIPG). In embodiments, the DIPG is a late stage DIPG. In embodiments, the DIPG is a metastatic DIPG. In embodiments, the DIPG is an MSI-H DIPG. In embodiments, the DIPG is a DIPG MSS. In embodiments, the DIPG is a POLE mutant DIPG. In embodiments, the DIPG is a POLD mutant DIPG. In embodiments, the DIPG is a high TMB DIPG. In embodiments, DIPG is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD).

In embodiments, the cancer is Ewing's sarcoma. In embodiments, the Ewing sarcoma is an advanced stage Ewing sarcoma. In embodiments, the Ewing sarcoma is metastatic Ewing sarcoma. In embodiments, the Ewing sarcoma is an MSI-H Ewing sarcoma. In embodiments, the Ewing sarcoma is an MSS Ewing sarcoma. In embodiments, the Ewing sarcoma is a POLE mutant Ewing sarcoma. In embodiments, the Ewing sarcoma is a POLD mutant Ewing sarcoma. In embodiments, the Ewing sarcoma is a high TMB Ewing sarcoma. In embodiments, Ewing's 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 an advanced embryonal rhabdomyosarcoma. In embodiments, the embryonal rhabdomyosarcoma is a metastatic embryonal rhabdomyosarcoma. In embodiments, the embryonal rhabdomyosarcoma is an MSI-H embryonal rhabdomyosarcoma. In embodiments, the embryonal rhabdomyosarcoma is an MSS embryonal rhabdomyosarcoma. In embodiments, the embryonal rhabdomyosarcoma is a POLE mutant embryonal rhabdomyosarcoma. In embodiments, the embryonal rhabdomyosarcoma is a POLD mutant embryonal rhabdomyosarcoma. In embodiments, the embryonal rhabdomyosarcoma is a high TMB embryonal rhabdomyosarcoma. In embodiments, 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 an advanced stage osteosarcoma. In embodiments, the osteosarcoma is metastatic osteosarcoma. In embodiments, the osteosarcoma is an MSI-H osteosarcoma. In embodiments, the osteosarcoma is an MSS osteosarcoma. In embodiments, the osteosarcoma is a POLE mutant osteosarcoma. In embodiments, the osteosarcoma is a POLD mutant osteosarcoma. In embodiments, the osteosarcoma is a high TMB osteosarcoma. In embodiments, 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

- 14 043391 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 a Wilms tumor. In embodiments, the Wilms tumor is an advanced stage 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, 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 (eg, one or more of surgery, radiation therapy, chemotherapy, or immunotherapy). In embodiments, the subject has previously been treated with one other cancer treatment (eg, one or more of surgery, radiation therapy, chemotherapy, or immunotherapy). In embodiments, the subject has previously been treated with two or more other cancer treatments (eg, one or more of surgery, radiation therapy, chemotherapy, or immunotherapy). In embodiments, the subject has previously received treatment with cytotoxic therapy. In embodiments, the subject has previously received treatment with chemotherapy. In embodiments, the subject has previously been treated with two other cancer treatments (eg, one or more of surgery, radiation therapy, chemotherapy, or immunotherapy). In embodiments, the subject has previously been treated with three other cancer treatments (eg, one or more of surgery, radiation therapy, chemotherapy, or immunotherapy).

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

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 a subject to treatment with an agent that inhibits PD-1.

In embodiments, the subject contains an exhausted immune cell (eg, an exhausted immune cell that is an exhausted T cell).

In embodiments of the methods described herein, the subject is an animal (eg, a mammal). In embodiments, the subject is a human. In embodiments, the subject is a non-human mammal (eg, mice, rats, rabbits, or non-human primates). Therefore, the methods described herein may be applicable in both human and veterinary medicine.

In embodiments, the PD-1 binding agent (eg, any anti-PD-1 antibody) is administered intravenously (eg, via intravenous infusion).

The present invention also provides, in some embodiments, methods for treating cancer that include administering to a patient in need of treatment an anti-programmed cell death protein 1 (PD-1) antibody at a therapeutically effective dose, spaced apart for a period sufficient to obtain clinical benefit. . In embodiments, the anti-PD-1 antibody comprises a heavy chain variable region comprising the CDR sequences of SEQ ID NOs: 9, 10, and 11, and a light chain variable region comprising the CDR sequences of SEQ ID NOs: 12, 13, and 14. In embodiments embodiments, the heavy chain variable region comprises SEQ ID NO: 1 and the light chain variable domain comprises SEQ ID NO: 2. In embodiments, the heavy chain variable region comprises SEQ ID NO: 7 and the light chain variable region comprises SEQ ID NO: 8. B In embodiments, the heavy chain variable region comprises SEQ ID NO: 3, and the light chain variable region comprises SEQ ID NO: 4.

- 15 043391

The present invention provides, in some embodiments, methods for treating cancer in a patient in need thereof, the method comprising administering a composition that delivers a PD-1 binding agent in a regimen that has been demonstrated to achieve a response rate in a relevant patient population, that disease progression was observed in no more than 50-80% of patients 2, 4, 6, 8, 10, 12, 14, 16, 18 or 20 weeks after the start of treatment. In some embodiments, disease progression is demonstrated in no more than 80% of patients at least 10 weeks after initiation of treatment.

In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9, 10 and 11, and/or a light chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 12, 13, and 14. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7, and a light chain variable domain an immunoglobulin whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain whose amino acid sequence contains SEQ ID NO: 4.

The present invention provides, in some embodiments, methods for treating cancer in a patient in need thereof, the method comprising administering a composition that provides delivery of a PD-1 binding agent sufficient to achieve an average PD-1 receptor occupancy of at least approximately 50% to approximately 90%, 1, 2, 3, 4 or 5 days after taking a single dose of the composition. In some embodiments, administration of a composition that delivers a PD-1 binding agent is sufficient to achieve an average PD-1 receptor occupancy of at least 85% 3 days after administration of a single dose of the composition. In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9, 10 and 11, and/or a light chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 12, 13, and 14. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7, and a light chain variable domain an immunoglobulin whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain whose amino acid sequence contains SEQ ID NO: 4.

The present invention provides, in some embodiments, methods for treating cancer in a patient in need thereof, the method comprising administering a composition that provides delivery of a PD-1 binding agent sufficient to achieve an average stimulation score of at least 1 in functional analysis of PD-1 receptor occupancy 3 days after administration of a single dose of a PD-1 binding agent. In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9, 10 and 11, and/or a light chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 12, 13, and 14. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7, and a light chain variable domain an immunoglobulin whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain whose amino acid sequence contains SEQ ID NO: 4.

The present invention provides, in some embodiments, methods for treating cancer in a patient in need thereof, the method comprising administering a composition that provides delivery of a PD-1 binding agent sufficient to achieve an average PD-1 receptor occupancy of at least 75 %, for the first period of time (eg, from about 15 days to about 60 days; in some embodiments, about 29 days) after administration of a single dose of the PD-1 binding agent. In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9, 10 and 11, and/or a light chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 12, 13, and 14. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7, and a light chain variable domain immunoglobulin 16 043391, the amino acid sequence of which contains SEQ ID NO: 2 or SEQ ID NO:

8. In some embodiments, the PD-1 binding 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.

The present invention provides, in some embodiments, methods for treating cancer in a patient in need thereof, the method comprising administering a composition that provides delivery of a PD-1 binding agent sufficient to achieve an average stimulation score of at least 1 in functional analyzing PD-1 receptor occupancy for a first period of time (eg, about 15 days to about 60 days; in some embodiments, about 29 days) after administration of a single dose of a PD-1 binding agent. In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9, 10 and 11, and/or a light chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 12, 13, and 14. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7, and a light chain variable domain an immunoglobulin whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain whose amino acid sequence contains SEQ ID NO: 4.

In some embodiments, the patient to be treated with the PD-1 binding agent delivery composition has a tumor. 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 a metastatic solid tumor.

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

In some embodiments, the patient has advanced cancer, including head and neck cancer, lung cancer (eg, 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, urothelial cell carcinoma or squamous cell carcinoma (eg, lung; anogenital area, including the anus, penis, cervix, vagina, or vulva; or esophagus) at an advanced stage. In some certain embodiments, the patient has anal cancer, fallopian tube cancer, ovarian cancer, breast cancer, endometrial cancer, or advanced lung cancer. In some embodiments, the patient has advanced cancer, such as endometrial cancer, triple-negative breast cancer, ovarian cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, or squamous cell carcinoma of the anogenital region (e.g., squamous cell carcinoma of the anus, penis, cervix , vagina or vulva) at a late stage.

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 generative mutation. In some embodiments, the POLE or POLD mutation is a sporadic mutation. In some embodiments, the method described herein further includes the step of initially identifying a patient having cancer with a POLE or POLD mutation. In some embodiments, the POLE or POLD mutation is identified using sequencing.

In some embodiments, the patient has a cancer with microsatellite instability (eg, MSI-H status). In some embodiments, the microsatellite instability is MSI-Low. In some embodiments, the microsatellite instability is microsatellite stability (eg, MSS status). In some embodiments, the patient has endometrial cancer. In some embodiments, the patient has endometrial cancer with microsatellite instability. In some embodiments, the patient has advanced cancer with microsatellite instability. In some embodiments, the advanced cancer with microsatellite instability is an endometrial cancer, triple negative breast cancer, ovarian cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, or squamous cell carcinoma of the anogenital region (e.g., squamous cell carcinoma of the anus, penis , cervix, vagina or vulva). In some embodiments, the patient has a solid tumor (eg, a solid tumor or an advanced metastatic solid tumor). In some embodiments, the patient has an MSI-H solid tumor.

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

In some embodiments, the patient has not previously received treatment 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 surgery, radiation therapy, chemotherapy, or immunotherapy. In some embodiments, the patient has previously been treated with surgery. In some embodiments, the patient has previously been treated with chemotherapy (eg, non-platinum-based chemotherapy). In some such embodiments, the platinum-based agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin. In some embodiments, the patient has cancer that has responded to induction therapy with platinum-based agents. In some embodiments, the cancer is sensitive to platinum-based agents at the time of initiation of treatment. In some embodiments, the cancer responded to the most recent platinum-based chemotherapy regimen prior to initiation of treatment. In some embodiments, the response to the most recent platinum-based chemotherapy regimen is a complete response. In some embodiments, the response to the most recent platinum-based chemotherapy regimen is a partial response.

In some embodiments, a composition that delivers a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered in an amount that delivers a dose of 1, 3, or 10 mg/kg of the PD-1 binding agent. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of 1, 3, or 10 mg/kg every two weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of 1, 3, or 10 mg/kg every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of 1, 3, or 10 mg/kg every four weeks.

In some embodiments, a composition that provides delivery of a PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered in an amount that provides a dose (e.g., a therapeutically effective dose) in the range of about 100 mg to about 2000 mg of binder PD-1 means. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered at a dose ranging from about 100 mg to about 1200 mg, such as a therapeutically effective dose that is about 100 mg, about 300 mg, approximately 500 mg or approximately 1000 mg. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered at a dose of about 400 mg, about 500 mg, about 800 mg, and/or about 1000 mg of the PD-1 binding agent. In some embodiments, a dose of a particular PD-1 binding agent is considered to be a dose of approximately [specified amount] if it achieves a corresponding biological or pharmacological effect that is comparable to the effect achieved using a dose of a specified amount of a specific reference PD-1 binding agent (e.g., a specific anti-PD-1 antibody, such as a specific anti-PD-1 monoclonal antibody or another anti-PD-1 antibody agent, including, for example, the anti-PD-1 antibody illustrated herein). In some embodiments, such a dose of a particular PD-1 binding agent may be described as a dose corresponding to a specified amount of a reference PD-1 binding agent.

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that includes multiple separate doses (eg, as noted above) separated from each other by a period of time. In some embodiments, the individual doses may be separated from each other by a time period of two weeks, three weeks, four weeks, five weeks, six weeks, or more. In embodiments, the anti-PD-1 antibody is administered

- 18 043391 with 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. In embodiments, the administration interval is once every 3 weeks. In embodiments, the administration interval is once every 6 weeks. In embodiments, the anti-PD-1 antibody is administered over a period of at least 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 weeks.

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered at a dose of 100 mg of the PD-1 binding agent. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 100 mg dose every two weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 100 mg dose every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 100 mg dose every four weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 100 mg dose every five weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered at a dose of 100 mg every six weeks.

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered at a dose of 300 mg of the PD-1 binding agent. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of 300 mg every two weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 300 mg dose every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 300 mg dose every four weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 300 mg dose every five weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered at a dose of 300 mg every six weeks.

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered at a dose of 400 mg of the PD-1 binding agent. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 400 mg dose every two weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 400 mg dose every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 400 mg dose every four weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 400 mg dose every five weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered at a dose of 400 mg every six weeks.

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered at a dose of 500 mg. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 500 mg dose every two weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 500 mg dose every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 500 mg dose every four weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 500 mg dose every five weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 500 mg dose every six weeks.

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered at a dose of 600 mg. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 600 mg dose every two weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 600 mg dose every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 600 mg dose every four weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 600 mg dose every five weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 600 mg dose every six weeks.

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered at a dose of 700 mg. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 700 mg dose every four weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 700 mg dose every five weeks. In some

- 19 043391 embodiments, the PD-1 binding agent (eg, anti-PD-1 antibody) is administered according to a schedule that delivers a 700 mg dose every six weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 700 mg dose every seven weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 700 mg dose every eight weeks.

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered at a dose of 800 mg. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers an 800 mg dose every four weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers an 800 mg dose every five weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers an 800 mg dose every six weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers an 800 mg dose every eight weeks.

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered at a dose of 900 mg. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 900 mg dose every four weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 900 mg dose every five weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 900 mg dose every six weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 900 mg dose every seven weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 900 mg dose every eight weeks.

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered at a dose of 1000 mg. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 1000 mg dose every four weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 1000 mg dose every five weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 1000 mg dose every six weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 1000 mg dose every seven weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a 1000 mg dose every eight weeks.

In some specific embodiments, a PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a regimen that comprises or consists of at least one single dose cycle (e.g., a 400 mg single dose or a 500 mg single dose) once every two weeks, a single dose once every three weeks, a single dose once every four weeks, a single dose once every five weeks, a single dose once every six weeks, etc. In some embodiments, a cycle includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more single doses. In some embodiments, the circuit provides multiple cycles. In some embodiments, the individual cycles may be separated from each other by a rest period (ie, no dosing).

In embodiments, a PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is administered in a first dose of approximately 500 mg once every 3 weeks for 3, 4, or 5 cycles, followed by a second dose of approximately 1000 mg once every 6 weeks or more (eg, a second dose of approximately 1000 mg every 6 weeks). In embodiments, a PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is administered in a first dose of approximately 500 mg once every 3 weeks for 3 cycles, followed by a second dose of approximately 1000 mg once every 6 weeks or more (eg, a second dose of approximately 1000 mg once every 6 weeks). In embodiments, a PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is administered in a first dose of approximately 500 mg once every 3 weeks for 4 cycles, followed by a second dose of approximately 1000 mg once every 6 weeks or more (eg, a second dose of approximately 1000 mg once every 6 weeks). In embodiments, a PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is administered in a first dose of approximately 500 mg once every 3 weeks for 5 cycles, followed by a second dose of approximately 1000 mg once every 6 weeks or more (eg, a second dose of approximately 1000 mg once every 6 weeks).

In some embodiments, dosing may be achieved by administering the composition in a unit unit dose (ie, one composition that contains and/or delivers the appropriate dose amount). In some embodiments, dosing may be achieved by administering multiple compositions in unit unit doses. In some embodiments, dosing may be achieved by administering a portion of the composition in a single unit dose.

In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a schedule that delivers the first dose of the PD-1 binding agent once every three weeks for the first 2 to 6 dosing cycles (e.g., the first 3, 4, or 5 dosing cycles) and then delivers a second dose of the PD-1 binder once every six weeks until disease progression is observed. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a schedule that delivers a first dose of the PD-1 binding agent once every three weeks for 3, 4, or 5 dosing cycles, and then delivers a second dose of the PD-1 binder once every six weeks or more until disease progression is observed. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a schedule that delivers a first dose of the PD-1 binding agent once every three weeks for 3, 4, or 5 dosing cycles, and then delivers a second dose of the PD-1 binder once every six weeks or more until disease progression is observed. In some embodiments, the first and/or second dose of the PD-1 binding agent (eg, anti-PD-1 antibody) is from about 100 to about 2000 mg. In some embodiments, the first dose and the second dose are the same. In some embodiments, the first dose and the second dose are different.

In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a schedule that includes a 500 mg dose every 3 weeks for 3, 4, or 5 doses followed by at least one 1000 mg dose every six weeks after the third, fourth or fifth dose of 500 mg. In some embodiments, a PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a schedule that includes a 500 mg dose every 3 weeks for 3 doses followed by at least one 1000 mg dose every six weeks or more after the third dose 500 mg. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a schedule that includes a 500 mg dose every 3 weeks for 4 doses followed by at least one 1000 mg dose every six weeks or more after the fourth dose 500 mg. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a schedule that includes a 500 mg dose every 3 weeks for 5 doses followed by at least one 1000 mg dose every six weeks or more after the fifth dose 500 mg. In some embodiments, additional 1000 mg doses are administered every six weeks or more after the first 1000 mg dose until no further clinical benefit is achieved. In some specific embodiments, the PD-1 binding agent (eg, anti-PD-1 antibody) is administered according to a dosing schedule that includes 500 mg over 4 cycles of Q3W followed by 1000 mg of Q6W.

In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a schedule that includes a 300 mg dose every 3 weeks for 3, 4, or 5 doses followed by at least one 800 or 1000 dose mg every six weeks after the third, fourth, or fifth dose of 300 mg. In some embodiments, additional doses of 800 or 1000 mg are administered every six weeks after the first dose of 800 or 1000 mg until no further clinical benefit is achieved. In some specific embodiments, the PD-1 binding agent (eg, anti-PD-1 antibody) is administered according to a dosing regimen that includes 300 mg over 4 cycles of Q3W followed by 800 or 1000 mg of Q6W.

In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a schedule that includes a 400 mg dose every 3 weeks for 3, 4, or 5 doses followed by at least one 800 or 1000 dose mg every six weeks after the third, fourth, or fifth dose of 400 mg. In some embodiments, additional doses of 800 or 1000 mg are administered every six weeks after the first dose of 800 or 1000 mg until no further clinical benefit is achieved. In some specific embodiments, the PD-1 binding agent (eg, anti-PD-1 antibody) is administered according to a dosing schedule that includes 400 mg over 4 cycles of Q3W followed by 800 mg or 1000 mg of Q6W.

In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a schedule that includes a 600 mg dose every 3 weeks for 3, 4, or 5 doses followed by at least one 800 or 1000 dose mg every six weeks after the third, fourth, or fifth dose of 600 mg. In some embodiments, additional doses of 800 or 1000 mg are administered every six weeks after the first dose of 800 or 1000 mg until no further clinical benefit is achieved. In some specific embodiments, the PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a dosing regimen that includes 600 mg over 4 cycles of Q3W followed by 800 mg or 1000 mg of Q6W.

In some embodiments, a PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a regimen that has been demonstrated to achieve an average PD-1 binding agent _Cmax in a patient population that is between 10 and 500 μg/mL . In some embodiments, the regimen has been demonstrated to achieve an average PD-1 binding agent _Cmax in a patient population that is about 20 μg/mL, about 65, or about 200 μg/mL. In some embodiments, the regimen has been demonstrated to achieve an average PD-1 binding agent C _max in a patient population that is approximately 140 μg/mL, approximately 180 μg/mL, approximately 200 μg/mL, approximately 230 μg/mL, approximately 290 mcg/ml. In embodiments, administration of the anti-PD-1 antibody results in the patient achieving an average Cmax of between 10 μg/mL and 500 μg/mL (e.g., an average Cmax of approximately 20 μg/mL, approximately 65 μg/mL, or approximately 200 mcg/ml in the patient's body).

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that has been demonstrated to achieve a mean AUC _{of o_3364} in a patient population. concentration-time curve in the case of a PD-1 binding agent, which ranges from 2500 hours * μg/ml to 50,000 hours * μg/ml. In some embodiments, the regimen has been demonstrated to achieve an average AUC _{of o_3364} in a patient population. concentration-time curve for a PD-1 binding agent, which is approximately 3400 ppm*μg/mL, approximately 11,000 ppm*μg/mL, or approximately 36,800 ppm*μg/mL. In embodiments, administration of the anti-PD-1 antibody results in the patient achieving an average AUC _o . ₃₃₆₄ _, ranging from 2500 ppm*μg/ml to 50,000 ppm*μg/ml (e.g., mean AUC _o . ₃₃₆₄ _, approximately 3400 ppm*μg/ml, approximately 11,000 ppm*μg/ml or approximately 36800 hours*µg/ml).

In some embodiments, the PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that has been demonstrated to achieve peak serum concentrations of the PD-1 binding agent within 0.5 to 3 hours after administration.

In some embodiments, the PD-1 binding agent has a terminal half-life of about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 days. In some embodiments, the PD-1 binding agent has a terminal half-life of approximately 12 days.

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered intravenously. In some embodiments, the PD-1 binding agent (eg, anti-PD-1 antibody) is administered via intravenous infusion.

In some embodiments, the PD-1 binding agent (eg, anti-PD1 antibody) is aseptically filled into a clear glass vial. In some embodiments, the glass vial is sealed with a fluoropolymer-laminated chlorobutyl elastomer stopper and sealed with an aluminum cap. In some embodiments, the PD-1 binding agent (eg, anti-PD-1 antibody) is stored at 2-8°C. In some embodiments, the PD-1 binding agent (eg, anti-PD-1 antibody) does not contain preservatives.

In some embodiments, the patient is or will be receiving an additional therapy in combination with a PD-1 binding agent. In some embodiments, the additional therapy is surgery, radiation therapy, chemotherapy, or immunotherapy. In some embodiments, the additional therapy comprises treatment with a composition that delivers a LAG-3 binding agent (e.g., any described in WO 2016/126858, WO 2017/019894, or WO 2015/138920, each of which is incorporated herein by reference in its entirety) and/or a TIM-3 binding agent (eg, any described in WO 2016/161270). In embodiments, the anti-TIM-3 antibody therapy (eg, anti-TIM-3 antibody) may be administered at a dose of about 1, 3, or 10 mg/kg; a constant dose of approximately 100 to 1500 mg; constant dose of approximately 100 mg; constant dose of approximately 200 mg; constant dose of approximately 300 mg; constant dose of approximately 400 mg; constant dose of approximately 500 mg; constant dose of approximately 600 mg; constant dose of approximately 700 mg; constant dose of approximately 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 of approximately 1300 mg; constant dose of approximately 1400 mg; constant dose of approximately 1500 mg; approximately 1 mg/kg; approximately 3 mg/kg or approximately 10 mg/kg. 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 present invention provides a method of administering

- 22 043391 PD-1 binding agent in combination with niraparib to a patient who has recurrent and/or platinum-sensitive cancer. In some embodiments, the recurrent and/or platinum-sensitive cancer is head and neck cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cancer cervical, 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, stomach cancer, colorectal cancer, appendix cancer , urothelial cell carcinoma or squamous cell carcinoma (eg, lung; anogenital area, including the anus, penis, cervix, vagina, or vulva; or esophagus). In certain embodiments, the recurrent and/or platinum-sensitive cancer is anal cancer, fallopian tube cancer, ovarian cancer, or lung cancer. In some certain embodiments, the recurrent and/or platinum-sensitive cancer is endometrial cancer, triple negative breast cancer, ovarian cancer, non-small cell lung cancer (NSCLC), squamous cell carcinoma of the lung, or squamous cell carcinoma of the anogenital region (e.g., squamous cell carcinoma anus, penis, cervix, vagina or vulva).

In some embodiments, niraparib is administered to a patient at a dose of 5 to 500 mg. In some embodiments, niraparib is administered according to a regimen that provides a dose of 50 to 500 mg of niraparib once daily. In some embodiments, the dose of niraparib is 100 to 300 mg once daily. In some embodiments, the dose of niraparib is 100, 20, or 300 mg once daily. In some embodiments, a once daily dose of niraparib is administered orally.

In some embodiments, the method further includes the step of decreasing the therapeutically effective dose of the anti-PD-1 antibody and/or extending the dosing interval after clinical benefit has been achieved.

The present invention provides, in some embodiments, methods for treating cancer, comprising administering to a patient in need of treatment an anti-programmed cell death protein 1 (PD-1) antibody at a first dose at a first interval during a first period; administering the anti-PD-1 antibody to the patient at a second dose at a second interval during a second period; wherein the anti-PD-1 antibody comprises a heavy chain variable region comprising the CDR sequences of SEQ ID NOs: 9, 10 and 11, and a light chain variable region comprising the CDR sequences of SEQ ID NOs: 12, 13 and 14. In some embodiments, the first dose and second dose are different. In some embodiments, the first dose is 500 mg and the second dose is 1000 mg. In embodiments, the first interval and the second interval are different. In embodiments, the first interval is once every three weeks, and the second interval is once every six weeks. In embodiments, the anti-PD-1 antibody is administered in a first dose once every three weeks during the first period of 2-6 dosing cycles (e.g., the first 3, 4, or 5 dosing cycles) and in a second dose once every six weeks until disease progression is observed.

The present invention provides, in some embodiments, compositions containing a PD-1 binding agent for use in the treatment of cancer in a selected population of patients who have cancer, wherein the composition is administered according to a schedule demonstrated to achieve clinical benefit. In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9, 10 and 11, and/or a light chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 12, 13, and 14. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7, and a light chain variable domain an immunoglobulin whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain whose amino acid sequence contains SEQ ID NO: 4.

In some embodiments, the clinical benefit is a complete response (CR), partial response (PR), or stable disease (SD). In some embodiments, the clinical benefit is at least SD. In some embodiments, the clinical benefit corresponds to at least a PR. In some embodiments, the clinical benefit corresponds to 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 in the patient population achieve clinical benefit. In some embodiments, at least 5% of patients in the patient population achieve SD. In some embodiments, at least 5% of patients in the patient population achieve at least a PR. In some embodiments, at least 5% of patients in the patient population achieve CR. In some embodiments, at least 20% of patients in the patient population achieve clinical benefit. In some embodiments, at least 20% of patients in the patient population achieve SD.

In some embodiments, clinical benefit (eg, SD, PR, and/or CR) is determined according to the Response Evaluation Criteria in Solid Tumors (RECIST). In some embodiments, clinical benefit (eg, SD, PR, and/or CR) is determined according to RECIST guidelines. In some embodiments, clinical benefit (eg, SD, PR, and/or CR) is determined according to RECIST guidelines (version 1.1). In some embodiments, clinical benefit (eg, SD, PR, and/or CR) is determined according to the immune system-related RECIST (irRECIST) guideline.

The present invention provides in some embodiments compositions containing a PD-1 binding agent for use in the treatment of cancer in a selected population of patients who have cancer, wherein the composition is administered according to a regimen demonstrated to achieve an average PD-1 receptor occupancy of at least 50 -85%, within 1-5 days of administration of a single dose of PD-1 binder. In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9, 10 and 11, and/or a light chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 12, 13, and 14. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7, and a light chain variable domain an immunoglobulin whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain whose amino acid sequence contains SEQ ID NO: 4.

The present invention provides in some embodiments compositions containing a PD-1 binding agent for use in the treatment of cancer in a selected population of patients who have cancer, wherein the composition is administered according to a regimen demonstrated to achieve an average PD-1 receptor occupancy of at least 75 %, over a first period of time (eg, from about 15 days to about 60 days; in some embodiments, about 29 days). In some embodiments, the PD-1 binding 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 PD-1 binding 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, each of the patients in the population of patients with cancer has a tumor. In some embodiments, each of the patients in the population of patients with cancer has a solid tumor. In some embodiments, at least some of the patients in the patient population with cancer have an advanced solid tumor. In some embodiments, at least some patients in a population of patients with 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 with cancer has a cancer such as head and neck cancer, lung cancer (eg, non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, cell carcinoma Merkel, 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, stomach cancer, colorectal cancer , appendiceal cancer, urothelial cell carcinoma, or squamous cell carcinoma (eg, lung; anogenital area, including the anus, penis, cervix, vagina, or vulva; or esophagus). In certain embodiments, each of the patients in the patient population having cancer has a cancer such as anal cancer, fallopian tube cancer, ovarian cancer, or lung cancer. In some embodiments, each of the patients in the population of patients with cancer has a cancer with microsatellite instability (eg, MSI-H status). In some embodiments, the microsatellite instability is MSI-Low. In some embodiments, the microsatellite instability is microsatellite stability (eg, MSS status). In some embodiments, each of the patients in the population of patients with cancer has endometrial cancer. In some embodiments, at least some of the patients in the population of patients having cancer have endometrial cancer with

- 24 043391 microsatellite instability or endometrial cancer that is microsatellite stable (MSS).

In some embodiments, each of the patients in the population of patients with cancer has hematologic cancer. In some embodiments, each of the patients in the cancer patient population has a hematologic cancer, such as diffuse large 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 with cancer has a hematologic cancer with microsatellite instability.

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

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

Brief description of graphic materials

The graphics, which consist of the following figures, are included herein for illustrative purposes only and not for limitation.

In fig. 1 is a graphical representation of the log-linear profile of mean concentration versus time following administration of a single dose of anti-PD-1 antibody. Dots indicate the 1 mg/kg dose, squares indicate the 3 mg/kg dose, and triangles indicate the 10 mg/kg dose. The x-axis shows the time since administration (in hours), and the y-axis shows the serum concentration of anti-PD-1 antibody in ng/mL. Error bars represent ± standard deviation.

In fig. 2A-2B depict a graphical representation of the log-linear mean concentration versus time profile following single dose administrations of anti-PD1 antibody at various dosages. (A) Dots indicate the 1 mg/kg dose, squares indicate the 3 mg/kg dose, and triangles indicate the 10 mg/kg dose. (B) Dots indicate the 500 mg dose, and squares indicate the 1000 mg dose. The x-axes show the time since administration (in hours) and the y-axes show the serum concentration of anti-PD-1 antibody in μg/mL. Error bars represent ± standard deviation.

In fig. 3 is a graphical representation of the relationship between dose and exposure of an exemplary anti-PD-1 antibody. AUC _o _ ₃₃₆₄ . (h*µg/ml) was used as an exposure model and was observed to increase linearly with increasing dosage of anti-PD-1 antibody.

In fig. 4 is a graphical representation of the relationship between clearance and body weight. Body weight was found to covariate significantly with anti-PD-1 antibody clearance.

In fig. 5A-5B depict the results of receptor occupancy assays for doses of 1, 3 and 10 mg/kg. Panel A depicts % PD-1 receptor occupancy in CD3+ cells. Panel B shows the IL-2 stimulation rate.

In fig. 6A-6D depict the results of receptor occupancy assays for doses of 500 mg Q3W and 1000 mg Q6W. Panels A and C depict % PD-1 receptor occupancy in CD3+ cells. Panels B and D show the IL-2 stimulation rate.

In fig. 7A-7B depict a summary of responses to anti-PD-1 antibody treatment. In panel A of FIG. 7 is a pool lane plot and panel B is a radar plot of responses to treatment with an exemplary PD-1 binding agent.

In fig. 8 depicts the percentage of PD-1 receptor occupancy by anti-PD-1 antibody measured on circulating CD3+ T cells by flow pitometry before the first and second 500 mg doses and again at the end of treatment.

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 referenced value. Generally, those skilled in the art familiar with the context will recognize that, in that context, the term approximates the appropriate degree of deviation. For example, in some embodiments, the term may approximately 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%,

- 25 043391

3%, 2%, 1% or less of the specified value.

Introduction

As used herein, the term administration generally refers to the administration of a composition to a subject or system to achieve delivery of the 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, under appropriate circumstances, be used for administration to a subject, such as a human. Example routes of administration include parenteral, eg, intravenous, intradermal, subcutaneous, oral (eg, inhalation), transdermal (ie, topical), transmucosal, and rectal. For example, in some embodiments, administration may be ophthalmic, oral, parenteral, topical, etc. In embodiments, administration is parenteral (eg, intravenous administration). In embodiments, the intravenous administration is an 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 dermal, intradermal, interdermal, transdermal, etc.) , enteral, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, intraspecific organ (for example, intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, local, tracheal (for example, by intratracheal instillation), vaginal, vitreal, 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, administration may involve dosing that is intermittent (eg, multiple doses separated by time) and/or intermittent (eg, individual doses separated by the same period of time) dosing. In some embodiments, administration may involve continuous dosing (eg, perfusion) for at least a selected period of time.

Solutions or suspensions used for parenteral, intradermal or subcutaneous use may include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, 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 tonicity adjusters such as sodium chloride or dextrose. The pH value can be adjusted using acids or bases such as hydrochloric acid or sodium hydroxide. The parenteral drug may be contained in ampoules, disposable syringes, or multi-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, for example, a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be accomplished by transmucosal or transdermal means. For transmucosal or transdermal administration, the composition uses penetration agents suitable for penetration through the barrier. Such penetration agents are generally known in the art and include, for example, transmucosal agents, surfactants, bile acids and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, balms, gels or creams typically known in the art.

The compounds may also be formulated as 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 various ways. In some embodiments, affinity is measured using a quantitative assay. In some such embodiments, the concentration of the binding partner may be fixed to be greater than the concentration of the ligand to mimic physiological conditions. Alternatively or in addition, in some embodiments, the concentration of the binding partner and/or the concentration of the ligand may be varied. In some such embodiments, the affinity may be compared to a reference under comparable conditions (eg, concentration).

Antibody

As used herein, the term antibody refers to a polypeptide that contains

- 26 043391 elements of the canonical immunoglobulin sequence sufficient to ensure specific binding to a particular target antigen. As is 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 with each other to form what is commonly called a Y-shaped structure. Each heavy chain consists of at least four domains (each approximately 110 amino acids long) - the amino-terminal variable (VH) domain (located at the ends of the Y structure), followed by three constant domains: CH1, CH2 and carboxy-terminal CH3 (located at the base stem Y). 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 the intact antibody. Each light chain consists of two domains, an amino-terminal variable (VL) domain followed by a carboxy-terminal constant (CL) domain, separated from each other by another switch. Those skilled in the art will be familiar with the structure and sequence elements of antibodies, recognize 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 sequence of an antibody chain may, for example , indicate such a boundary at a location that is offset by one or more residues from 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 a single disulfide bond; The other two disulfide bonds connect 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, usually at the CH2 domain. Each domain in a natural antibody has a structure characterized by an immunoglobulin fold formed from two beta sheets (eg, 3-, 4-, or 5-strand 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 combine in three dimensions, resulting in a single hypervariable antigen-binding site located at top of the Y-structure. The Fc region of naturally occurring antibodies binds to elements of the complement system as well as 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 through glycosylation or other modification. In some embodiments, the antibodies produced and/or used in accordance with the present invention include glycosylated Fc domains, including Fc domains modified or engineered by such glycosylation. For purposes of the present invention, in some embodiments, any polypeptide or complex of polypeptides that contains sufficient sequences of immunoglobulin domains that are found in naturally occurring antibodies may be referred to and/or used as an antibody, regardless of whether such polypeptide is naturally derived (e.g., produced organism responding to an antigen) or obtained 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 mouse, rabbit, primate, or human antibodies. In some embodiments, the antibody sequence elements are humanized, primatized, chimeric, etc., as known in the art. Moreover, the term antibody as used herein may refer in appropriate embodiments (unless otherwise stated or clear from the context) to any of the known or art-developed constructs or formats for exploiting 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 is in a format selected, without limitation, from intact IgA, IgG, IgE, or IgM antibodies; bi- or multispecific antibodies (eg 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 (eg, shark single-domain antibodies, such as IgNAR or fragments thereof); camel antibodies; masked antibodies (eg Probodies®); Small Modular ImmunoPharmaceuticals (SMIP™); single-chain or tandem diabodies (TandAb®); VHH; Anticalins®;

- 27 043391 minitel Nanobodies®; 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 the covalent modification (eg, glycan attachment) that it would have if it were produced naturally. In some embodiments, the antibody may contain a covalent modification (eg, glycan attachment, payload [eg, detection moiety, therapeutic moiety, catalytic moiety, etc.] or other pendant group [eg, polyethylene glycol, etc.]).

Antibodies include antibody fragments. Antibodies also include, but are not limited to, polyclonal, monoclonal, chimeric dAbs (domain antibodies), single chain, F _ab -, F _ab ' -, F(ab') ₂ fragment, scFv and F _ab expression libraries. The antibody may be a whole antibody, or an immunoglobulin, or an antibody fragment.

Antibody based product

As used herein, the term antibody agent refers to an agent that specifically binds to a particular antigen. In some embodiments, the term covers any polypeptide or polypeptide complex that contains immunoglobulin structural elements sufficient to provide specific binding. Exemplary antibody agents include, but are not limited to, monoclonal antibodies or polyclonal antibodies. In some embodiments, the antibody agent may contain one or more constant region sequences that are characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, the antibody agent may contain one or more sequence elements that are humanized, primatized, chimeric, etc., as known in the art. In many embodiments, the term antibody agent is used to refer to one or more prior art or developed constructs or formats for utilizing the structural and functional features of an antibody in an alternative presentation. For example, in embodiments, the antibody agent used in accordance with the present invention is in a format selected, without limitation, from intact IgA, IgG, IgE, or IgM antibodies; bi- or multispecific antibodies (eg 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 (eg, shark single-domain antibodies, such as IgNAR or fragments thereof); camel antibodies; masked antibodies (eg Probodies®); Small Modular ImmunoPharmaceuticals (SMIP™); single-chain or tandem diabodies (TandAb®); VHH; Anticalins®; minitel Nanobodies®; 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 the covalent modification (eg, glycan attachment) that it would have if it were produced naturally. In some embodiments, the antibody may contain a covalent modification (eg, glycan attachment, payload [eg, detection moiety, therapeutic moiety, catalytic moiety, etc.] or other pendant group [eg, polyethylene glycol, etc.]). In many embodiments, the antibody agent is or contains a polypeptide whose amino acid sequence contains one or more structural elements known to those skilled in the art as a complementarity determining region (CDR); in some embodiments, the antibody agent is or contains a polypeptide whose amino acid sequence contains 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 of , found in the reference antibody. In some embodiments, the included CDR is substantially identical to the reference CDR in that it is either identical in sequence to or contains 1 to 5 amino acid substitutions compared to the reference CDR. 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 to 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 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 deleted, added, or replaced from the reference CDR, but the included CDR has an amino acid sequence that is otherwise identical to that of 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 replaced from the reference CDR, one

- 28043391 kb 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 changed from the reference CDR, however, 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 replaced from the reference CDR, however, the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments, the antibody agent is or contains a polypeptide whose amino acid sequence contains 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 noted that the term binding as used herein generally refers to a non-covalent association between or within two or more particles. Direct binding involves physical contact between particles or fragments; indirect binding involves physical interaction through physical contact with one or more intermediate particles. Binding between two or more particles can typically 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., 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 higher affinity. The immunological binding properties of selected polypeptides can be quantified using methods well known in the art. One such method involves measuring the rates of formation and dissociation of an antigen-binding site/antigen complex, where these rates depend 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 (K _on ) and the dissociation rate constant (K _off ) can be determined by calculating the concentrations and actual rates of association and dissociation. (See Nature 361:186-87 (1993)). The ratio K _off /K _on allows you to cancel all parameters not related to affinity, and is equal to the dissociation constant K _d . (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, the 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. Typically, the binding agent may be or contain a particle from any chemical class (eg, polymer, non-polymer, small molecule, polypeptide, carbohydrate, lipid, nucleic acid, etc.). In some embodiments, the binding agent is a single chemical particle. In some embodiments, the binding agent is a complex of two or more individual chemical species 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., antibody or aptamers with a specific molecular target) that is associated with a partner of a common binding moiety. In some embodiments, such an approach may allow the modular assembly of multiple binders by linking different specific binding moieties to the same partner of a common binding moiety. In some embodiments, the binding agents are or contain polypeptides (including, for example, antibodies or antibody fragments). In some embodiments, the binding agents are or contain small molecules. In some embodiments, the binding agents are or contain nucleic acids. In some embodiments, the binding agents are aptamers. In some embodiments, the binding agents are polymers; in some embodiments, binding

- 29 043391 products are not polymers. In some embodiments, the binding agents are non-polymeric in that they do not have polymer moieties. In some embodiments, the binding agents are or contain carbohydrates. In some embodiments, the binding agents are or contain lectins. In some embodiments, the binding agents are or contain peptidomimetics. In some embodiments, the binding agents are or contain scaffold proteins. In some embodiments, the binding agents are or contain mimotopes. In some embodiments, the binding agents are or contain 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, such that they exhibit 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 (eg, benign), malignant, pre-metastatic, metastatic, and/or non-metastatic. The present invention specifically identifies certain forms of cancer for which its teachings may be particularly suitable. In some embodiments, the respective cancer may be a solid tumor (eg, a metastatic solid tumor or an advanced solid tumor). In some embodiments, the respective cancer may be characterized by a hematologic tumor. Generally, 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, forms of cancer of the genitourinary system such as prostate, cervical, bladder, uterine, endometrial cancer, and renal cell carcinomas, cancer bone, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, endocrine system cancer, thyroid cancer, parathyroid cancer, forms of head and neck cancer, breast cancer, forms of gastrointestinal cancer and forms of nervous system cancer, benign lesions , such as papillomas, etc.

Carrier

As used herein, refers to the diluent, adjuvant, adjuvant, or carrier medium with which the composition is administered. In some illustrative embodiments, carriers may 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 so on. In some embodiments, the carriers are or include one or more solid components. In some embodiments, the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (eg, glycerin, 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 a dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved using various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases it will be preferable to include in the composition isotonic agents, 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 provides delayed 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 (eg, two or more therapies). In some embodiments, two or more therapeutic regimens may be administered simultaneously. In some embodiments, two or more therapeutic regimens may be administered sequentially (eg, the first regimen is administered before any doses of the second regimen are administered). In some embodiments, two or more therapeutic regimens are administered with overlapping dosing schedules. In some embodiments, administration of the combination therapy may involve administering one or more therapies or methods to a subject receiving the other agent(s) or method. In some embodiments, the combination therapy does not necessarily require that the individual agents be administered together in the same composition (or even necessarily at the same time). In some embodiments, two or more therapies or combination therapies are administered to a subject separately, e.g., in separate compositions, via separate routes of administration (e.g., one agent orally and the other agent intravenously) and/or at different times. time. 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 moiety), through the same route of administration, and/or at the same time. .

Full answer

As used herein, the term complete response or CR is used to denote the disappearance of all or substantially all of the target lesions. In some embodiments, CR refers to a reduction in the sum of target lesion diameters (i.e., lesion elimination) of approximately 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98%, 99% or 100%, using the sum of the diameters at the baseline as reference. In some embodiments, the CR indicates that less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the total diameter of the lesion remains after treatment. Illustrative methods for assessing complete response are defined in the RECIST guidelines. See, for example, 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 can be used to refer to a physically discrete unit of an active agent (eg, a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, such amount is an amount of a dosage unit (or a whole fraction thereof) suitable for administration in accordance with a dosage regimen that has been determined to correlate with a desired or beneficial outcome when administered to the relevant population (i.e., a therapeutic regimen dose administration). Those of ordinary skill in the art will appreciate that the total amount of 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.

Dosage schedule 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, the therapeutic agent is characterized by a recommended dosage schedule, which may include one or more doses. In some embodiments, the dosing schedule includes multiple doses, each of which is separated in time from other doses. In some embodiments, the individual doses are separated from each other by a period of time of equal duration; in some embodiments, the dosing regimen includes multiple doses and at least two different time periods separating the individual doses. In some embodiments, all doses in a dosage regimen have the same number of unit doses. In some embodiments, different doses in a dosing regimen have different amounts. In some embodiments, the dosing regimen includes a first dose of a first dose amount, followed by one or more additional doses of a second dose amount different from the first dose amount. In some embodiments, the dosing regimen includes a first dose of a first dose amount, followed by one or more additional doses of a second dose amount similar to the first dose amount. In some embodiments, the dosing schedule correlates with a desired or beneficial outcome when administered to the appropriate population (ie, is a therapeutic dosing schedule). In some embodiments, the regimen includes at least one dose, where the dose comprises one unit dose of a therapeutic agent (eg, a PD-1 binding agent). In some embodiments, the regimen provides at least one dose, where the dose provides two or more unit doses of the therapeutic agent. For example, a 500 mg dose may be administered as one 500 mg unit dose or as two 250 mg unit doses. In some embodiments, the regimen correlates with or leads to a desired or beneficial outcome when administered to an appropriate population (ie, is a therapeutic regimen).

Risk share

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

- 31 043391 the risk share is constant over time.

Homology

As used herein, the term homology refers to the general relatedness between polymer molecules, for example, between nucleic acid molecules (eg, 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 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 (eg, 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 generally classified as similar to each other, as hydrophobic or hydrophilic amino acids, and/or as having polar or nonpolar side chains. Replacing one amino acid with another of the same type can often be considered a homologous substitution.

As those skilled in the art will appreciate, a variety of algorithms are available that allow sequences to be compared to determine their degree of homology, including by allowing gaps of a given length in one sequence relative to another by considering which residues match each other in different sequences. For example, calculating the percent homology between two nucleic acid sequences can be performed by aligning the two sequences for the purpose of optimal comparison (e.g., gaps can be introduced in one or both of the first and second nucleic acid sequences for optimal alignment, and non-matching sequences can be ignored for the purpose of comparisons). 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, then the molecules at this position are identical; when a position in the first sequence is occupied by a nucleotide similar to the corresponding position in the second sequence, then the molecules at this position are similar. The percentage of homology between two sequences is a function of the number of identical and similar positions shared by 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. Exemplary algorithms and computer programs useful for determining percent homology between two nucleotide sequences include, for example, the Meyers and Miller algorithm (CABIOS, 1989, 4: 11-17), which was included in the ALIGN program (version 2.0) using tables of residue weights of PAM120, gap length penalty of 12 and gap length penalty of 4. The percentage of 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 (eg, an antibody or a binding component thereof) from a complex with its partner (eg, an epitope to which the antibody or binding component thereof binds).

_Koff , as used herein, refers to the dissociation rate constant when a binding agent (eg, an antibody or its binding moiety) dissociates from a complex with its partner (eg, an epitope to which the antibody or its binding moiety binds).

K _on as used herein refers to the association rate constant when a binding agent (eg, an antibody or a binding component thereof) associates with its partner (eg, an epitope to which the antibody or binding component thereof binds).

Niraparib

As used herein, the term niraparib includes any of the free base form ((3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine), salt form, including pharmaceutically acceptable (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2yl}phenyl]piperidine salts (e.g. (3S)-3-[4-{7-(aminocarbonyl)-2H-indazole -2-yl}phenyl]piperidintosylate), or a solvated or hydrated form thereof (e.g., (3S)-3-[4-{7(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidintosylate monohydrate). In some embodiments, such forms may be separately referred to as niraparib free base, niraparib tosylate, and niraparib tosylate monohydrate, respectively. Unless otherwise specified, the term niraparib includes all forms of the compound (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2yl}phenyl]piperidine.

- 32 043391

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, for example, for experimental, diagnostic, prophylactic and/or therapeutic purposes. Illustrative subjects include animals. The term animal refers to any member of the animal kingdom. In some embodiments, the animal refers to humans at any stage of development. In some embodiments, the animal refers to non-human animals at any stage of development. In some embodiments, the non-human animal is a mammal (eg, rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cattle, primate, and/or pig). In some embodiments, animals include, but are not limited to, mammals, 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, for example, mammals such as mice, rats, rabbits, non-human primates and humans; insects; worms, etc. In some embodiments, the subject is a human. In some embodiments, the subject may suffer from or be susceptible to a disease, disorder and/or condition (eg, cancer). As used herein, the term patient population or subject population refers to a plurality of patients or subjects.

Partial answer

As used herein, the term partial response (PR) refers to a reduction in tumor progression in a subject, as indicated by a decrease 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 diameters or target lesions by at least 30%, using the sum of diameters at baseline as a reference. Illustrative methods for assessing partial response are defined in the RECIST guidelines. See, for example, 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).

Pharmaceutical composition

As used herein, the term pharmaceutical composition refers to a composition in which the active agent (eg, a PD-1 binding agent) is formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in an amount corresponding to a unit dose suitable for administration according to a therapeutic regimen that indicates a statistically significant likelihood of achieving a predetermined therapeutic effect when administered to the 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, e.g., oral liquid dosage forms (aqueous or non-aqueous solutions or suspensions), tablets, e.g. for buccal, sublingual and systemic absorption, large tablets, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection in the form of, for example, a sterile solution or suspension, or sustained release formulation; topical application, such as a cream, ointment, or controlled-release patch or aerosol applied to the skin, lungs, or mouth; intravaginally or intrarectally, for example, in the form of a pessary, cream or foam; sublingually; inside the eye; transdermally or nasally, inside the lungs and against other mucous surfaces. In some embodiments, the active agent (eg, a PD-1 binding agent) is formulated for parenteral administration.

Pharmaceutically acceptable

As used herein, the term pharmaceutically acceptable in relation 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 cause an adverse effect on the recipient thereof. .

Progression-free survival

As used herein, the term progression-free survival means the period of time during which a subject who has a disease (eg, cancer) survives without significant worsening of the disease. Progression-free survival can be assessed as a period of time during which there is no progression of tumor growth and/or in which the patient's disease status is not defined as disease progression. In some embodiments, progression-free survival in a subject who has cancer is assessed by assessing tumor size, number of tumors, and/or metastasis.

Progressive or progressive disease

The term tumor progression or disease progression (PD), as used herein in relation to cancer status, indicates an increase in the sum of the diameters of target lesions (tumors). In some embodiments, tumor growth progression refers to at least a 20% increase in the sum of target lesion diameters, using the smallest sum in the study as a reference (this includes the sum at baseline if it is the smallest in the study). In some embodiments, in addition to a relative increase of 20%, the sum of the target lesion diameters must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions may also be taken into account when determining tumor progression. Progression, in the context of defining progression-free survival, may also be defined 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) using additional diagnostic tests (eg, histology/cytology, ultrasound techniques, endoscopy, positron emission tomography) identify new lesions or identify existing lesions characteristic of overt disease progression AND progression in relation to CA-125 in accordance with the criteria of the International the Gynecologic Cancer Study Group (GCIG) (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] unrelieved pain associated with cancer; [ii] intestinal obstruction due to malignancy/worsening dysfunction; or [iii] overt symptomatic worsening of ascites or pleural effusion ) and progression towards CA-125 according to GCIG criteria.

Solid tumor

As used herein, the term solid tumor refers to an abnormal mass of tissue that typically does not contain cysts or areas of fluid. In some embodiments, a solid tumor may be benign; in some embodiments, the solid tumor may be malignant. Those skilled in the art will appreciate that the various types of solid tumors are generally named by the type of cells that form them. Examples of solid tumors are 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 gland, uterus, vagina and/or vulva.

Stabilization or stable disease

As used herein, the term stabilization of tumor growth or stable disease (SD) does not refer to either a sufficient reduction in tumor size to be defined as PR, nor a sufficient increase in size to be defined as 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 a reference. Exemplary methods for assessing stable tumor growth or stable disease are defined in the RECIST guidelines. See, for example, 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).

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 a 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 that amount that provides the particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. In some embodiments, a 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, 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, the therapeutically effective agent may be formulated and/or administered in multiple dosages, such as

- 34 043391 part of the dosage regimen.

Treatment

As used herein, the term treatment (also treat or administer a treatment) refers to any administration of a therapy that partially or completely attenuates, reduces the severity of, improves, suppresses, delays the onset of, reduces the severity of, and/or reduces the frequency of occurrence of one or more symptoms, signs and/or causes of a specific disease, disorder and/or condition. In some embodiments, such treatment may be for a subject who is not showing signs of the corresponding disease, disorder and/or condition, and/or for a subject who is showing only early signs of the disease, disorder and/or condition. Alternatively or additionally, such treatment may be provided to a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition. In some embodiments, the treatment may be directed to a subject who has been diagnosed as suffering from a corresponding disease, disorder and/or condition. In some embodiments, treatment may be directed to a subject known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the corresponding disease, disorder and/or condition.

Treatment options, including treatments for cancer

Described herein are methods of treating disorders in a subject (eg, disorders that would benefit from administration of an anti-PD-1 antibody therapy). For example, an anti-PD-1 antibody therapy described herein may be administered, for example, as a monotherapy or combination therapy, for a period sufficient to obtain clinical benefit, or according to a schedule determined by a physician (e.g., anti-PD-1 antibody therapies are administered in dosage amounts and number of treatment cycles as determined by the physician).

In embodiments, the methods described herein are useful for treating T-cell dysfunctional disorders (eg, cancer). In embodiments, the methods described herein are useful for reducing tumors or inhibiting the growth of tumor cells in a subject.

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 immune cell activity in a subject.

The methods of the present invention can be used to treat any type of infectious disease (ie, 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 can be any vaccine of any suitable type that specifically targets a particular virus (eg, live attenuated vaccines, subunit vaccines, recombinant vector vaccines) and small molecule antiviral therapeutics (eg, inhibitors of viral replication 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, for example, in 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 anti-TIM-3 antibody agent can be used in combination with an anti-inflammatory agent, including, for example, corticosteroids (eg, prednisone and fluticasone) and non-steroidal anti-inflammatory drugs (NSAIDs) (eg, aspirin, ibuprofen and naproxen).

PD-1 is expressed at abnormal levels in various forms of cancer (see, for example, Brown et al., J. Immunol., 170: 1257-1266 (2003) and Flies et. al., Yale Journal of Biology and Medicine, 84 : 409-421 (2011)), and PD-L1 expression in some patients with renal cell carcinoma correlates with tumor aggressiveness. 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, appendix cancer, B cell leukemia, B cell lymphoma, bladder cancer, brain cancer brain, breast cancer (eg, triple negative breast cancer (TNBC)), cancer of the fallopian tube(s), testicular cancer, cerebral cancer, cervical cancer, choriocarcinoma, chronic myelogenous leukemia, CNS tumor, colon adenocarcinoma colon, colon cancer, colorectal cancer, diffuse brainstem glioma (DIPG), diffuse large cell lymphoma (DLBCL), embryonal rhabdomyosarcoma (ERMS), endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, follicular lymphoma (FL), cancer gallbladder, stomach cancer, gastrointestinal cancer, glioma, head and neck cancer, hematological cancer, hepatocellular cancer, Hodgkin lymphoma/primary mediastinal B-cell lymphoma, kidney cancer, clear cell kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell carcinoma, mesothelioma, monocytic leukemia, multiple myeloma, myeloma, CNS neuroblastic tumor, non-Hodgkin's lymphoma (NHL), non-small cell lung cancer (NSCLC), oral cancer, osteosarcoma, ovarian cancer, ovarian carcinoma , pancreatic cancer, peritoneal cancer, primary peritoneal cancer, prostate cancer, relapsed or refractory classical Hodgkin lymphoma (cHL), renal cell carcinoma, rectal cancer, salivary gland cancer (eg, salivary gland tumor), sarcoma, skin cancer, small cell carcinoma lung, small intestine cancer, squamous cell carcinoma of the anogenital area (eg, squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), squamous cell carcinoma of the esophagus, squamous cell carcinoma of the head and neck (SCHNC), squamous cell carcinoma of the lung, stomach cancer, T- cell leukemia, T-cell lymphoma, thymic cancer, thymoma, thyroid cancer, uveal melanoma, urothelial cell carcinoma, uterine 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 (eg, non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma (see, for example, 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, tumor salivary gland, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendiceal cancer, urothelial cell carcinoma, or squamous cell carcinoma (eg, lung; anogenital area, including the anus, penis, cervix, vagina, or vulva; or In some embodiments, the cancer to be treated 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, stomach cancer, salivary gland cancer, prostate cancer, pancreatic cancer or Merkel cell carcinoma.

In some embodiments, the patient or population of patients has hematologic cancer. In some embodiments, the patient has a hematologic cancer, such as diffuse large B cell lymphoma (DLBCL), Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), follicular lymphoma (FL), acute myeloid leukemia (AML), acute lymphoblastic leukemia ( ALL) or multiple myeloma (MM). In embodiments, the cancer is a cancer originating from hematopoietic tissue, such as acute lymphoblastic leukemia (ALL), acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia (AML), acute promyelocytic leukemia (APL), acute monoblastic leukemia, acute erythroblastic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute non-lymphoblastic 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 leukemias.

In embodiments, the cancer is lymphoma, such as Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, Waldenström'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 head and neck squamous cell carcinoma (HNSCC).

In embodiments, the cancer is a squamous cell carcinoma of the anogenital region (eg, anus, penis, cervix, vagina, or vulva).

In embodiments, the cancer is bladder cancer, breast cancer

- 36 043391 (for example, triple negative breast cancer (TNBC)), cancer of the fallopian tube(s), cholangiocarcinoma, colon adenocarcinoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gastric cancer, clear cell kidney cancer, lung cancer (for example, adenocarcinoma of the lung or squamous cell carcinoma of the lung), mesothelioma, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, endometrial uterine cancer or uveal melanoma. In embodiments, the cancer is ovarian cancer, fallopian tube(s) cancer, or peritoneal cancer. In embodiments, the cancer is breast cancer (eg, TNBC). In embodiments, the cancer is lung cancer (eg, non-small cell lung cancer). In embodiments, the cancer is prostate cancer.

In embodiments, the cancer is a CNS or brain cancer, such as neuroblastoma (NB), glioma, diffuse intrinsic pontine glioma (DIPG), piloid 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 some embodiments, the patient or population of patients has a solid tumor. In embodiments, the cancer is a solid tumor such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, osteosarcoma , colon cancer, colorectal cancer , kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepetoma, 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 population of patients to be treated with the methods of the present invention has cancer, such as head and neck cancer, lung cancer (eg, 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 , stomach cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma or squamous cell carcinoma (eg, lung; anogenital area, including the anus, penis, cervix, vagina or vulva; or esophagus), or are susceptible to it. In some embodiments, the patient or patient population to be treated with the methods of the present invention has lung cancer (e.g., NSCLC), kidney cancer, melanoma, cervical cancer, colorectal cancer, or endometrial cancer (e.g., MSS endometrial cancer or endometrial cancer MSI-H) or susceptibility to them.

In some embodiments, the cancer is a gynecological 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, forms of cancer of the female reproductive system include, but are not limited to, ovarian cancer, fallopian tube(s) cancer, peritoneal cancer, and breast cancer.

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

In some embodiments, the ovarian cancer is an epithelial carcinoma. Epithelial carcinoma accounts for 85 to 90% of ovarian cancers. Although the disease was historically thought to develop on the surface of the ovary, new evidence suggests that at least some types of ovarian cancer originate from specific cells in a part of the fallopian tube. The fallopian tubes are small ducts that connect a woman's ovaries to her uterus and are part of a woman's reproductive system. The normal female reproductive system has two fallopian tubes, one on each hundred

- 37 043391 rona uteri. Cancer cells that originate in the fallopian tube can come to the surface of the ovary at an early stage. The term ovarian cancer is often used to describe forms of epithelial cancer that originate in the ovary, fallopian tube, and the lining of the abdomen 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 develops in the egg-producing cells of the ovaries. 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 may secrete estrogen, leading to unusual vaginal bleeding at the time of diagnosis. In some embodiments, gynecological cancer is associated with homologous recombination repair deficiency/homologous repair deficiency (HRD) and/or BRCA1/2 mutation(s). In some embodiments, the gynecological cancer is sensitive to platinum-based agents. In some embodiments, the gynecological cancer responded to a platinum-based therapy. In some embodiments, the gynecological cancer has become resistant to the platinum-based therapy. In some embodiments, the gynecologic cancer has once demonstrated a partial or complete response to a platinum-based therapy (eg, a partial or complete response to the last platinum-based therapy or to the penultimate platinum-based therapy). In some embodiments, the gynecologic cancer is currently resistant to the platinum-based therapy.

In embodiments, the cancer is breast cancer. Typically, breast cancer begins either in the cells of the mammary glands, known as lobules, or in the ducts. Less commonly, breast cancer may begin in stromal tissues. These include the fatty and fibrous connective tissue of the mammary gland. Over time, breast cancer cells can spread to nearby tissues, such as armpit lymph nodes or lungs, in a process known as metastasis. The stage of breast cancer, the size of the tumor and its growth rate are factors that determine the type of treatment offered. Treatment options include surgery to remove the tumor, drug treatments that include chemotherapy and hormone therapy, radiation therapy, and immunotherapy. Prognosis and survival rates vary widely; Five-year relative survival rates vary from 98 to 23% depending on the type of breast cancer that occurs. Breast cancer is the second most common cancer in the world, with approximately 1.7 million new cases reported in 2012, and it is the fifth leading cause of cancer death, with approximately 521,000 deaths. Of these cases, approximately 15% are triple negative, in which estrogen receptor, progesterone receptor (PR), or HER2 are not expressed. In some embodiments, triple negative breast cancer (TNBC) is characterized as breast cancer cells that are estrogen receptor negative (<1% of cells), progesterone receptor negative (<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, HER2-positive breast cancer, HER2-negative breast cancer, BRCA1/2-positive cancer breast, BRCA1/2-negative breast 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 an 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 to be treated with the methods of the present invention has or is susceptible to endometrial cancer (EC). Endometrial carcinoma is the most common form of female genital tract cancer, accounting for 10–20 cases per 100,000 person-years. The annual number of new cases of endometrial cancer (EC) is estimated at approximately 325 thousand 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 therapeutics for use in EC. There is a need for agents and regimens that provide improved survival in advanced EC and recurrent EC when administered 1L and 2L.

- 38 043391

An estimated 10,170 EU deaths are projected to occur in the US in 2016. The most common histological 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 less than 1%, and mixed approximately 10%.

From a pathogenetic point of view, EC is divided into two different types, the so-called types I and II. Type I tumors are low-grade and estrogen-associated endometrioid carcinomas (EEC), while type II tumors are non-endometrioid (NEEC) (mainly serous and clear cell) carcinomas. The World Health Organization recently updated the pathological classification of EC, recognizing nine different subtypes of EC, 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) contains tubular glands somewhat reminiscent of proliferative endometrium, with architectural complexity with glandular fusion and a cribriform character. High EEC shows a solid growth pattern. In contrast, SC occurs in postmenopausal patients in the absence of hyperestrogenism. Microscopically, SC demonstrates thick, fibrous or edematous papillae with marked 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. EEC grade 3 (EEC3) is an aggressive tumor with an increased incidence of lymph node metastasis. SC is very aggressive, not associated with estrogen stimulation, and mainly occurs in older women. EEC 3 and SC are considered high-grade tumors. SC and EEC3 were compared using data from the Surveillance, Epidemiology, and End Results (SEER) program from 1988 to 2001. They represented 10% and 15% of the EU, respectively, but accounted for 39% and 27% of cancer deaths, respectively.

Forms of endometrial cancer can also be classified into four molecular subgroups: (1) ultramutated/POLE-mutant; (2) hypermutated MSI+ (eg, 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 2L endometrial cancer from the mismatch repair deficiency subgroup.

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 ALK translocation lung cancer (eg, NSCLC with ALK translocation). In embodiments, the lung cancer is EGFR-mutant lung cancer (eg, EGFR-mutant NSCLC).

In embodiments, the cancer is colorectal (CRC) cancer (eg, 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 a POLE mutant colorectal cancer. In embodiments, the colorectal cancer is POLD mutant colorectal cancer. In embodiments, the colorectal cancer is high TMB colorectal cancer.

In embodiments, the cancer is melanoma. In embodiments, the melanoma is an 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 a 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 a metastatic cancer.

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

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

In some embodiments, the tumor being treated is characterized by microsatellite instability. In some embodiments, the tumor is characterized by microsatellite instability high (MSI-H) status. Microsatellite instability (MSI) is or involves a change in the DNA of certain cells (such as tumor cells) in which the number of microsatellite repeats (short repeating sequences of DNA) is different from the number of repeats that were contained in the DNA from which it originated. Approximately 15% of sporadic colorectal cancers (CRC) contain widespread changes in microsatellite (MS) sequence length, known as microsatellite instability (MSI) (Boland and Goel, 2010). Sporadic CRC MSI tumors exhibit unique clinicopathological features, including a near-diploid karyotype, a higher incidence in older populations and women, and a 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 gynecological malignancy (Duggan et al., 1994). The same Bethesda reference panel, originally developed for screening for the inherited genetic disorder (Lynch syndrome) (Umar et al., 2004), is currently used for MSI testing in CRC and EC. However, genes that are frequently targeted by MSI in CRC genomes rarely mediate 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 failure allows mismatch mutations to persist throughout the genome, but especially in regions of repeated DNA known as microsatellites, resulting in increased mutational load. It has been demonstrated that at least some tumors characterized by MSI-H 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 is characterized by microsatellite instability, which is high microsatellite instability (eg, MSI-H status). In some embodiments, the cancer has a microsatellite instability status of low microsatellite instability (eg, MSI-Low). In some embodiments, the cancer has a microsatellite instability status of microsatellite stable (eg, MSS status). In some embodiments, 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 IHC. In some embodiments, microsatellite instability is detected using PCR.

In embodiments, the patient has MSI-L cancer.

In embodiments, the patient has 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 endometrial cancer. In embodiments, the MSI-H cancer is a non-endometrial cancer. In embodiments, the MSI-H cancer is colorectal cancer.

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

In embodiments, the cancer is associated with a POLE (DNA polymerase epsilon) mutation (ie, 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 generative mutation. In embodiments, the POLE mutation is sporadic

- 40 043391 mutation. In embodiments, MSI cancer is also associated with a POLE mutation. In embodiments, 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 (ie, the cancer is a POLD mutant cancer). In embodiments, the POLD mutation is a mutation in the exonuclease domain. In embodiments, the POLD mutation is a somatic mutation. In embodiments, the POLD mutation is a generative mutation. In embodiments, POLD-mutant cancers are 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 a brain cancer.

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

In embodiments, the MMRd cancer is colorectal cancer.

Microsatellite instability may result from an inability to correct replication errors due to a defective DNA mismatch repair (MMR) system. This failure allows for the persistence of mismatch mutations throughout the genome, but especially in regions of repeated DNA known as microsatellites, resulting in an increased mutational load that could improve responses to certain anti-PD-1 drugs. Right there. 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 immunohistochemical (IHC) testing.

In embodiments, the cancer (eg, MMRd cancer) has a high tumor mutational load (ie, the cancer is a high TMB cancer). In some embodiments, cancer is associated with high TMB and MSI-H. In some embodiments, cancer is associated with high TMB and MSI-L or MSS. In some embodiments, the cancer is endometrial cancer associated with high TMB. In some related embodiments, endometrial cancer is associated with high TMB and MSI-H. In some related embodiments, endometrial cancer is associated with high TMB and MSI-L or MSS. In embodiments, the high TMB cancer is colorectal cancer. In embodiments, the high TMB cancer is a lung cancer (eg, small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), such as squamous cell NSCLC or non-squamous NSCLC). In embodiments, the TMB-high cancer is melanoma. In embodiments, the TMB-high cancer is a 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 a breast cancer (eg, triple negative breast cancer (TNBC) or HER2-positive breast cancer). In embodiments, the TIL-rich cancer is a metastatic cancer (eg, metastatic breast cancer).

In embodiments, immune-related gene expression signatures may be predictive of response to anti-PD-1 therapy in cancer, as described herein. For example, a gene panel that includes genes associated with IFN-γ signaling may be useful in identifying cancer patients who will benefit from 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 (eg, 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 a patient or patient population. In some embodiments, mutational load and baseline gene expression profiles in archival 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.

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

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

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

In some embodiments, at least some of the patients in the population of patients having cancer have previously been treated with chemotherapy (eg, platinum-based chemotherapy). For example, a patient who has received two lines of cancer treatment may be identified as a 2L patient having cancer (eg, a 2L patient having NSCLC). In embodiments, the patient has received two or more lines of cancer treatment (eg, 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 (eg, 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 (eg, 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 a subject to treatment with an agent that inhibits PD-1.

In embodiments, the subject contains an exhausted immune cell (eg, an exhausted immune cell that is an exhausted T cell).

In embodiments of the methods described herein, the subject is an animal (eg, a mammal). In embodiments, the subject is a human. In embodiments, the subject is a non-human mammal (eg, mice, rats, rabbits, or non-human primates). Therefore, the methods described herein may be applicable in both human and veterinary medicine.

In embodiments, the PD-1 inhibitor (eg, anti-PD-1 antibody) is administered intravenously (eg, via intravenous infusion).

Programmed death protein 1 (PD-1)

Programmed death protein 1 (PD-1) (also known as programmed cell death protein 1) is a 268 amino acid type I transmembrane protein originally identified by subtractive hybridization in a mouse T cell line undergoing apoptosis (Ishida et al., Embo J., 11: 3887-95 (1992)). PD-1 is a member of the CD28/CTLA-4 family of T cell regulators and is expressed on activated T cells, B cells, and myeloid lineage cells (Greenwald et al., Annu. Rev. Immunol, 23: 515-548 (2005 ) and Sharpe et al., Nat. Immunol., 8: 239-245 (2007)). PD-1 is an inhibitory member of the CD28 receptor family, which also includes CD28, CTLA-4, ICOS, and BTLA. PD-1 is expressed on activated B cells, T cells and myeloid cells (Agata et al., supra; Okazaki et al. (2002) Curr. Opin. Immunol 14:391779-82; Bennett et al. (2003) J Immunol., 170:711-8).

Two ligands for PD-1 have been identified, PD ligand-1 (PD-L1) and PD ligand-2 (PDL2), both belonging to the B7 protein superfamily (Greenwald et al., supra). PD-L1 is expressed in a variety of cell types, including lung, heart, thymus, spleen, and kidney cells (see, e.g., Freeman et al., J. Exp. Med., 192(7): 1027-1034 (2000) and Yamazaki et al., J. Immunol., 169(10): 5538-5545 (2002)).

PD-L1 expression is upregulated on macrophages and dendritic cells (DC) in response to treatment with lipopolysaccharide (LPS) and GM-CSF, as well as on T cells and B cells when signaling through T-cell and B-cell receptors . PD-L1 is also expressed in various murine tumor cell lines (see, for example, Iwai et al., Proc. Nat.l Acad. Sci. USA, 99(9): 12293-12297 (2002) and Blank et al., Cancer Res., 64(3): 1140-1145 (2004)). In contrast, PD-L2 exhibits a more restricted expression pattern and is expressed primarily by antigen-presenting cells (eg, dendritic cells and macrophages) and some tumor cell lines (see, e.g., Latchman et al., Nat. Immunol., 2 (3): 261-238 (2001)). High levels of PD-L1 expression in tumors, whether on the tumor cell, stroma, or other cells within the tumor microenvironment, correlate with poor clinical prognosis, presumably through inhibition of effector T cells and activation of regulatory T cells (Tregs) in the tumor.

PD-1 negatively regulates T cell activation, and this inhibitory function is associated with an immunoreceptor tyrosine switch motif (ITSM) in the cytoplasmic domain (see, e.g., Greenwald et al., supra and Parry et al., Mol. Cell. Biol., 25: 9543-9553 (2005)). PD-1 deficiency can lead to autoimmunity. For example, C57BL/6 mice with a knockout of the PD-1 gene have been shown to develop a lupus-like syndrome (see, for example, Nishimura et al., Immunity, 11: 1411151 (1999)). In humans, single nucleotide polymorphisms in the PD-1 gene are associated with a higher incidence of systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis, and progression of multiple sclerosis (see, for example, Nielsen et al., Tissue Antigens, 62(6): 492-497 (2003); Bertsias et al., Arthritis Rheum., 60(1): 207-218 (2009); Ni et al., Hum. Genet., 121(2): 223-232 (2007); Tahoori et al. , Clin. Exp. Rheumatol., 29(5): 763-767 (2011) and Kroner et al., Ann. Neurol., 58(1): 50-57 (2005)). Abnormal PD-1 expression has also been implicated in T cell dysfunction in several pathologies, such as immune tumor invasion and chronic viral infections (see, e.g., Barber et al., Nature, 439: 682687 (2006) and Sharpe et al., higher).

Recent studies demonstrate that PD-1-induced T cell suppression also plays a role in the suppression of antitumor immunity. For example, PD-L1 is expressed on a variety of human and mouse tumors, and binding of PD-1 to PD-L1 on tumors results in T cell suppression as well as tumor invasion and protection (Dong et al., Nat. Med., 8: 793-800 (2002)). Expression of PD-L1 by tumor cells is directly associated with their resistance to killing by antitumor T cells in vitro (Dong et al., supra and Blank et al., Cancer Res., 64: 1140-1145 (2004)). PD-1 knockout mice are resistant to the introduction of tumor cells (Iwai et al., Int. Immunol., 17: 133-144 (2005)), and T cells from PD-1 knockout mice are very effective in tumor rejection by adoptive transfer to tumor-bearing mice (Blank et al., supra). Blocking PD-1 inhibitory signals using a monoclonal antibody can stimulate host antitumor immunity in mice (Iwai et al., supra and Hirano et al., Cancer Res., 65: 1089-1096 (2005)), and high levels of PD-1 expression L1 in tumors are associated with poor prognosis for many types of human cancer (Hamanishi et al., Proc. Natl. Acad. Sci. USA, 104: 3360-335 (2007), Brown et al., J. Immunol., 170: 1257 -1266 (2003) and Flies et al., Yale Journal of Biology and Medicine, 84(4): 409-421 (2011)).

In view of the above, strategies to inhibit PD-1 activity, as well as immunopotentiation strategies (eg, for the treatment of infectious diseases) have been developed for the treatment of various types of cancer (see, for example, Ascierto et al., Clin. Cancer. Res., 19(5) : 1009-1020 (2013)). However, monoclonal antibodies targeting PD-1 have been developed for the treatment of cancer (see, for example, Weber, Semin. Oncol., 37(5): 430-4309 (2010) and Tang et al., Current Oncology Reports, 15 (2): 98-104 (2013)). For example, nivolumab (also known as BMS-936558) resulted in complete or partial responses in non-small cell lung cancer, melanoma, and renal cell cancer in a phase I clinical trial (see, e.g., Topalian, New England J. Med, 366: 2443-2454 (2012)), and is currently undergoing phase III clinical trials. MK-3575 is a humanized monoclonal antibody directed against PD-1 that has demonstrated evidence of antitumor activity in phase I clinical trials (see, e.g., Patnaik et al., 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, Abstract # 2512). In addition, recent evidence suggests that therapeutics targeting PD-1 may enhance immune responses against pathogens such as HIV (see, e.g., Porichis et al., Curr. HIV/AIDS Rep., 9( 1): 81-90 (2012)). However, despite these advances, the effectiveness of these potential therapeutics in humans may be limited.

PD-1 binding agents

The present invention provides methods for treating cancer that include administering compositions that deliver specific programmed cell death protein 1 (PD-1) binding agents in schedules that can achieve clinical benefit. The present invention describes, at least in part, PD-1 binding agents (eg, anti-PD-1 antibody agents) and various related compositions and methods. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody agent) binds an epitope of PD-1, which blocks the binding of PD-1 to any one or more of its putative ligands. In some embodiments, a PD-1 binding agent (e.g., an anti-PD-1 antibody agent) binds an epitope of PD-1, which blocks PD-1 from binding to two

- 43 043391 or more of its putative ligands. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody agent) binds an epitope of the PD-1 protein, which blocks the binding of PD-1 to PD-L1 and/or PD-L2. PD-1 binding agents (eg, anti-PD-1 antibody agents) of the present invention may comprise a heavy chain constant region (Fc) of any suitable class. In some embodiments, the PD-1 binding agent (eg, an anti-PD-1 antibody agent) comprises a heavy chain constant region that is based on wild-type IgG1, IgG2, or IgG4 antibodies or variants thereof. In some embodiments, the PD-1 binding agent is a monoclonal antibody.

In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with one or more CDR sequences selected from SEQ ID NOs: 9, 10 and 11, and/or a light chain variable region with one or more CDR sequences selected from SEQ ID NOs: 12, 13, and 14. In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with two or more CDR sequences selected from SEQ ID NOs: 9, 10, and 11, and/or a light chain variable region with two or more CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, the PD-1 binding agent comprises a heavy chain variable region with three CDRs that have the sequences of SEQ ID NOs: 9, 10 and 11, and/or a light chain variable region with three CDRs having the sequences of SEQ ID NOs: 12, 13 and 14.

SEQ ID NO: 9 (HCDR1) - SYDMS

SEQ ID NO: 10 (HCDR2) - TISGGGS YTYYQDSVKG

SEQ ID NO: 11 (HCDR3) - PYYAMDY

SEQ ID NO: 12 (LCDR1) - KASQDVGTAVA

SEQ ID NO: 13 (LCDR2) - WASTLHT

SEQ ID NO: 14 (LCDR3) - QHYSSYPWT

In some embodiments, the PD-1 binding 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

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEW VSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASP YYAMDYWGQGTTVTVSSA

SEQ ID NO: 7

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEW VSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASP YYAMDYWGQGTTVTVSS

In some embodiments, the PD-1 binding 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

DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLI YWASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQG TKLEIKR

SEQ ID NO: 8

DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLI YWASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQG TKLEIK

In some embodiments, the PD-1 binding 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 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 contains 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 with one or more mutations in 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 the exchange of half the molecule with other IgG4 molecules. In some embodiments, one or more mutations in the IgG4 hinge region

- 44 043391 may include a stabilizing mutation replacing serine with proline, which prevents the exchange of half the molecule with other IgG4 molecules. In some embodiments, one or more mutations in the IgG4 hinge region may include the S228P mutation. See, for example, 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: 3.

SEQ ID NO: 3. Anti-PD-1 Antibody Heavy Chain Polypeptide (CDR Sequences)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTIS GGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYA MDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDH kps ESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNHYTQKSLSLSLGK

In some embodiments, the PD-1 binding agent comprises an immunoglobulin light chain polypeptide whose amino acid sequence comprises SEQ ID NO: 4.

SEQ ID NO: 4. Anti-PD-1 Antibody Light Chain Polypeptide (CDR Sequences)

DIOLTOSPSFLSAYVGDRVTITCKASODVGTAVAWYOQKPGKAPKLLIYWA STLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGOGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYE KHKVYACEVTHQGLSSPVTKS FNRGEC

SEQ ID NOs: 3 and 4 describe an exemplary humanized anti-PD1 monoclonal antibody using 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 with a Ser to Pro substitution in the hinge region of the IgG4 heavy chain. This mutation is at the canonical position S228, corresponding to residue 224 of SEQ ID NO: 3. Without wishing to be bound by theory, this point mutation is believed to serve to stabilize the antibody heavy chain hinge.

The biophysical and biochemical characteristics of this exemplary humanized anti-PD-1 monoclonal antibody were consistent with the expected disulfide bond pattern for an IgG4 molecule. The residues involved in the expected inter- and intrachain disulfide bonds are listed in the table below (Tables 1 and 2).

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

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

Table 2. Expected Residues Involved in the Light Chain Disulfide Bonds of an Exemplary Anti-PD-1 Antibody Agent Having the Amino Acid Sequence Set forth in SEQ ID NO: 4

Cysteine residue ID according to Edelman ³ Residue LC mAb to PD-1 (position in SEQ ID NO: 4) I 23 II 88 III 134 IV 194 V 214

This exemplary anti-PD-1 antibody demonstrates an occupied N-glycosylation site at asparagine residue 293 in the CH2 domain of each heavy chain in the mature protein sequence (SEQ

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ID NO: 3). The resulting N-glycosylation at this site during expression is a mixture of oligosaccharide species typically seen on IgG expressed in mammalian cell culture, for example, the following shows the relative abundance of glycan species from a preparation of this exemplary anti-PD-1 antibody cultured in cells Chinese hamster ovary (CHO) (Table 3).

Table 3. Glycan analysis of anti-PD-1 antibody binder

View Representation (% of total oligosaccharides) Description of glycan G0 <0.1% Non-fucosylated oligosaccharide of the agalactosylated biantennary complex type G0F 19.5% Oligosaccharide type agalactosylated biantennary complex with core fucosylation G1 0.1% Non-fucosylated oligosaccharide of the monogalactosylated biantennary complex type GIF 45.6% Monogalactosylated biantennary complex-type oligosaccharide with core fucosylation G2F 27.4% Galactosylated biantennary complex-type oligosaccharide with core fucosylation M5 0.5% Oligomannosidated N-glycan, MansGlcNAci

In some embodiments, the present invention provides an anti-PD-1 antibody agent comprising at least one immunoglobulin heavy chain having the amino acid sequence set forth in SEQ ID NO: 3 and at least one immunoglobulin light chain having the amino acid sequence set forth under SEQ ID NO: 4. In some embodiments, the anti-PD-1 antibody agent comprises two immunoglobulin heavy chains, each having the amino acid sequence set forth under SEQ ID NO: 3. Alternatively or in addition, in In some embodiments, the anti-PD-1 antibody agent comprises two immunoglobulin light chains, each having the amino acid sequence set forth in SEQ ID NO: 4. In some embodiments, the anti-PD-1 antibody agent is in a canonical antibody format.

In some embodiments, the PD-1 binding agent is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, or any of the antibodies disclosed in WO 2014/179664.

Pembrolizumab is an anti-PD-1 monoclonal antibody (mAb) (also known as MK-3475, SCH 9000475, Keytruda). Pembrolizumab is a humanized mAb based on immunoglobulin C4/kappa isotype. The mechanism of action of pembrolizumab is that the mAb binds to the PD-1 receptor of lymphocytes, blocking the interaction of PD-1 with PD-L1 and PD-L2 ligands produced by other cells in the body, including tumor cells of some forms of cancer.

In a similar manner to pembrolizumab, nivolumab (also known as BMS-936558, Opdivo) was first approved by the FDA in 2014 for the treatment of melanoma that cannot be removed by surgery or has metastasized after treatment with ipilimumab and a BRAF inhibitor, where appropriate.

In some embodiments, the anti-PD-1 antibody agent is one disclosed in International Patent Application Publication WO 2014/179664, the entire contents of which are incorporated herein.

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, one or more disulfide bonds is or includes a disulfide bond at the expected position of an IgG4 immunoglobulin.

In some embodiments, the PD-1 binding agent is glycosylated at one or more sites. As used herein, glycan refers to the sugar polymer component (fragment) of a glycoprotein. The term glycan covers free glycans, including glycans that have been cleaved or otherwise released from the 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).

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

In some embodiments, the PD-1 binding agent binds with high affinity to human and cynomolgus PD-1. In some embodiments, the binding of a PD-1 binding agent can be characterized using surface plasmon resonance (SPR). In some embodiments, the SPR measurements may demonstrate or confirm binding of a PD-1 binding agent to the Fc domain fusion of human and/or cynomolgus PD-1. In some embodiments, the PD-1 binding agent binds human and cynomolgus PD-1 at a high association rate, low dissociation rate, and high affinity (Table 4). For example, when using an exemplary PD-1 binding agent, binding kinetics to human and cynomolgus PD-1 were similar, with less than a 2-fold difference in KD values. In addition, the binding of an exemplary PD-1 binding agent to human or cynomolgus PD-1 expressed on CHOK1 cells was assessed by flow cytometry. An exemplary PD-1 binding agent was found to bind to cell surface human and cynomolgus PD-1 with an _EC50 of 2.0 and 3.4 nM, respectively.

Table 4. Binding of PD-1 binding agent (containing SEQ ID NOs: 1 and 2) to PD-1, as determined by surface plasmon resonance and binding assay using CHO cells expressing PD-1_________

Kinetic parameters (SPR) CHO cells expressing PD-1 View Cassoc. (Ms) ¹ Kdissoc. (from 9 K _D (nM) EC ₅ o(nM) human PD-1 5.7 x 10 ⁵ 1.7 X 10- ⁴ 0.30 2.0 PD-1 cyno 4.3 x 10 ⁵ 2.3 x ΙΟ' ⁴ 0.53 3.4

CHO = Chinese hamster ovary;

cyno = cynomolgus macaque,

EC5 ₀ = half-maximal effective concentration;

K _assoc . = association rate constant; KD = dissociation constant;

K _gissoc . = dissociation rate constant;

-1 = programmed cell death protein 1;

SPR = surface plasmon resonance.

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

In some embodiments, the PD-1 binding agent can effectively neutralize the activity of PD-1 (eg, can inhibit the binding of PD-1 to PD-L1 and PD-L2). In some embodiments, the functional antagonistic activity of the PD-1 binding agent can be confirmed or determined by a mixed lymphocyte reaction (MLR) demonstrating increased interleukin (IL)-2 production 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 PD-1 binding agent is expressed from a vector containing one or more nucleic acid sequences. In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain polypeptide encoded by a nucleotide sequence that comprises SEQ ID NO: 5.

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SEQ ID NO: 5

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 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 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: 6.

SEQ ID NO: 6

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 ATS 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 PD-1 binding agent is expressed from a vector comprising one or more nucleic acid sequences encoding a PD-1 binding immunoglobulin heavy chain variable domain polypeptide and/or a PD-1 binding immunoglobulin light chain variable domain polypeptide. In some embodiments, the PD-1 binding agent is expressed from a vector containing one or more nucleic acid sequences encoding a PD-1 binding immunoglobulin heavy chain polypeptide and/or a PD-1 binding immunoglobulin light chain polypeptide. The vector may be, for example, a plasmid, episome, cosmid, viral vector (eg, retroviral or adenoviral) or phage. Suitable vectors and methods for their preparation are well known in the art (see, for example, 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 expression vector(s) for PD-1 binding agents further comprise expression control sequences, such as promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), and the like, which ensure expression of the coding sequence in the host cell. Exemplary expression regulation 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).

Vector(s) containing nucleic acid(s) encoding PD-1 binding agents in accordance with the present invention can be introduced into a host cell capable of expressing those encoded by the nucleic acid. polypeptides, including any suitable prokaryotic or eukaryotic cell. Some preferred qualities of host cells include easy and stable growth, fairly rapid growth rates, well-characterized expression systems, and/or easy/efficient transformation or transfection.

In some embodiments, mammalian cells are used. A number of suitable mammalian host cells are known in the art, and many are available from the American Type Culture Collection (ATCC, Manassas, VA). Examples of approaches

- 48 043391 mammalian living cells include, but are not limited to, Chinese hamster ovary (CHO) cells (ATCC 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 no. CRL1573) and 3T3 cells (ATCC no. CCL92). Other suitable mammalian cell lines are the monkey COS-1 cell line (ATCC No. CRL1650) and the COS-7 cell line (ATCC No. CRL1651), as well as the CV1 cell line (ATCC No. CCL70).

Additional exemplary mammalian 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, as well as primary explants. Other suitable mammalian cell lines include, but are not limited to, mouse neuroblastoma N2A cells, HeLa cells, mouse L929 cells, and BHK or HaK hamster cell lines, all of which are available from ATCC. Methods for selecting suitable mammalian 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 may be a human lymphoid cell line or a lymphoid cell-derived cell line, such as a pre-B lymphocyte-derived cell line. 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 cells (CCL-86) and their derivatives.

In some embodiments, the PD-1 binding 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. An anti-PD-1 antibody agent may be formulated alone or in combination with other drugs (eg, as an adjuvant). For example, a PD-1 binding agent may be administered in combination with other agents to treat or prevent diseases disclosed herein (eg, cancer).

Therapeutic compositions generally must be sterile and stable under the conditions of manufacture and storage. The composition may be formulated as a solution, microemulsion, liposome, or other ordered structure suitable for high drug concentrations. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (eg, glycerin, 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 a dispersion, and by the use of surfactants. In many cases it may be advisable 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 delayed absorption, for example, monostearate salts and gelatin.

Sterile injectable solutions can be prepared by introducing the active compound in the desired amount into an appropriate solvent with one or a combination of the ingredients listed above, if necessary, followed by sterilization microfiltration. Typically, dispersions are prepared by introducing the active compound into a sterile carrier medium that contains the basic dispersion medium and other necessary ingredients listed above. In the case of sterile powders for preparing sterile injectable solutions, such preparation methods may include vacuum drying and freeze drying (lyophilization) to obtain a powder of the active ingredient plus any additional required ingredient from a pre-sterile filtered solution thereof.

In some embodiments, the therapeutic composition is formulated as a sterile liquid. In some embodiments, the composition does not contain visible particles. In some embodiments, the composition is formulated in a buffer (eg, citrate buffer). In some embodiments, the composition contains a PD-1 binding agent and two or more of the following: citrate, arginine, sodium chloride, and polysorbate 80.

In some embodiments, the therapeutic composition of the present invention (eg, a PD-1 binding agent) is aseptically filled into a clear glass vial. In some embodiments, such a glass vial is sealed with a fluoropolymer-laminated chlorobutyl elastomer stopper and sealed with an aluminum cap.

In some embodiments, the PD-1 binding agent is stored at 2-8°C. In some embodiments, the drug product of the present invention does not contain preservatives.

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General protocol

As described herein, the present methods involve administering a PD-1 binding agent to a patient, subject, or population of subjects according to a schedule that achieves clinical benefit.

The provided methods may provide various advantages (eg, clinical benefit). In embodiments, the method described herein achieves clinical benefit. In embodiments, the clinical benefit is disease stability (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 provides clinical benefit for each therapy administered to the patient. For example, a combination therapy may enhance the clinical benefit obtained with a PD-1 inhibitor (eg, any anti-PD-1 antibody described herein).

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

In some embodiments, the regimen includes at least one parenteral dose of a PD-1 binding agent. In some embodiments, the regimen provides multiple parenteral doses.

In some embodiments, the parenteral dose is an amount of PD-1 binding agent that ranges from about 5 to about 5000 mg (e.g., about 5 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, approximately 400 mg, approximately 500 mg, approximately 600 mg, approximately 700 mg, approximately 800 mg, approximately 900 mg, approximately 1000 mg, approximately 1100 mg, approximately 1200 mg, approximately 1300 mg, approximately 1400 mg, approximately 1500 mg , about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, or a range defined by any two of the above values). In some embodiments, the parenteral dose of the PD-1 binding agent is 500 mg or 1000 mg.

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

In some embodiments, a composition that delivers a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered to a patient at a dose of about 1, 3, or 10 mg/kg. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 1, 3, or 10 mg/kg every two weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 1, 3, or 10 mg/kg every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 1, 3, or 10 mg/kg every four weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 1 mg/kg every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 3 mg/kg every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 10 mg/kg every three weeks.

In some embodiments, a composition that delivers a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered to a patient at a dose of approximately 400 mg. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 400 mg every two weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 400 mg every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 400 mg every four weeks.

In some embodiments, a composition that delivers a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered to a patient at a dose of approximately 500 mg. In some

- 50 043391 embodiments, the PD-1 binding agent (eg, anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 500 mg every two weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 500 mg every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 500 mg every four weeks.

In some embodiments, a composition that delivers a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered to a patient at a dose of approximately 800 mg. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 800 mg every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 800 mg every four weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 800 mg every six weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 800 mg every eight weeks.

In some embodiments, a composition that delivers a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered to a patient at a dose of approximately 1000 mg. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 1000 mg every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 1000 mg every four weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 1000 mg every five weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 1000 mg every six weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 1000 mg every seven weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 1000 mg every eight weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 1000 mg every nine weeks.

In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 500 mg every three weeks. In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that delivers a dose of approximately 1000 mg every six weeks.

In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a schedule that ensures that the first dose of the PD-1 binding agent is delivered over the first 2 to 6 dosing cycles (e.g., the first 3, 4, or 5 dosing cycles) and then delivers a second dose of the PD-1 binding agent over subsequent dosing cycles until therapy is discontinued (eg, due to disease progression or an adverse effect, or as directed by the physician). In some embodiments, the duration of the first group of 2-6 dosing cycles (eg, the first 3, 4, or 5 dosing cycles) is different from the duration of subsequent dosing cycles. In embodiments, the PD-1 binding agent (eg, anti-PD-1 antibody) is administered according to a schedule that delivers a first dose of the PD-1 binding agent once every three weeks for the first three dosing cycles and then delivers a second dose PD-1 binding agent once every six weeks or more for the remaining dosing cycles (eg, a second dose of the PD-1 binding agent once every six weeks for the remaining dosing cycles). In embodiments, the PD-1 binding agent (eg, anti-PD1 antibody) is administered according to a schedule that delivers a first dose of the PD-1 binding agent once every three weeks for the first four dosing cycles and then delivers a second dose of the PD binding agent. -1 agent once every six weeks or more for the remaining dosing cycles (eg, a second dose of the PD-1 binding agent once every six weeks for the remaining dosing cycles). In embodiments, the PD-1 binding agent (eg, anti-PD-1 antibody) is administered according to a schedule that delivers a first dose of the PD-1 binding agent once every three weeks for the first five dosing cycles and then delivers a second dose PD-1 binding agent once every six weeks or for the remaining dosing cycles (eg, a second dose of the PD-1 binding agent once every six weeks for the remaining dosing cycles). In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a schedule that delivers the first dose of the PD-1 binding agent once every three weeks for the first 2 weeks.

- 51 043391 dosing cycles (e.g., the first 3, 4, or 5 dosing cycles) and then deliver a second dose of PD-1 binder once every six weeks or until therapy is discontinued (e.g., cause of disease progression, or adverse effect, or as directed by a physician). In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a schedule that delivers a first dose of the PD-1 binding agent once every three weeks for 3, 4, or 5 dosing cycles (e.g., first 4 dosing cycles) and then delivers a second dose of the PD-1 binder once every six weeks or more until therapy is discontinued (eg, due to disease progression or an adverse effect, or as directed by the physician ). In embodiments, the method includes delivering a second dose of the PD-1 binding agent once every six weeks until therapy is discontinued.

In some embodiments, the first and/or second dose of a PD-1 binding agent (e.g., anti-PD-1 antibody) is from about 100 mg to about 2000 mg (e.g., about 100 mg, about 200 mg, about 300 mg, about 400 mg, approximately 500 mg, approximately 600 mg, approximately 700 mg, approximately 800 mg, approximately 900 mg, approximately 1000 mg, approximately 1100 mg, approximately 1200 mg, approximately 1300 mg, approximately 1400 mg, approximately 1500 mg, approximately 1600 mg, approximately 1700 mg, approximately 1800 mg, approximately 1900 or approximately 2000 mg). In some embodiments, the first dose and the second dose are the same. In some embodiments, the first dose and the second dose are different. In embodiments, the first dose is approximately 500 mg of a PD-1 binding agent (eg, anti-PD-1 antibody). In embodiments, the first dose is approximately 1000 mg of a PD-1 binding agent (eg, anti-PD-1 antibody).

In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a schedule that includes a dosage of approximately 500 mg every 3 weeks for four doses followed by at least one dose of approximately 1000 mg every six weeks after the fourth dose approximately 500 mg. In some embodiments, additional doses of approximately 1000 mg are administered every six weeks after the first dose of approximately 1000 mg until no further clinical benefit is achieved. In some specific embodiments, the PD-1 binding agent (eg, anti-PD1 antibody) is administered according to a dosing regimen that includes 500 mg over 4 cycles of Q3W followed by 1000 mg of Q6W.

In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a schedule that includes a 400 mg dose every 3 weeks for four doses followed by at least one 800 mg dose every six weeks after the fourth doses 400 mg. In some embodiments, additional 800 mg doses are administered every six weeks after the first 800 mg dose until no further clinical benefit is achieved. In some specific embodiments, the PD-1 binding agent (eg, anti-PD-1 antibody) is administered according to a dosing schedule that includes 400 mg over 4 cycles of Q3W followed by 800 mg of Q6W.

Therapeutic or prophylactic effectiveness can be monitored by periodic evaluation of treated patients. For repeated administrations over several days or more depending on the condition, treatment may be repeated until the desired suppression of disease symptoms is achieved. However, other dosage regimens may be applicable and are within the scope of the present invention.

The required dosage may be delivered by a single bolus of the composition, multiple bolus doses of the composition, or a continuous infusion of the composition.

In some embodiments, the PD-1 binding agent is administered to a patient or population of subjects who have demonstrated a response to prior therapy. In some embodiments, the patient or population of subjects has demonstrated a response to prior anticancer therapy.

In some embodiments, the PD-1 binding agent is administered to a patient or population of subjects who 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 anticancer therapy.

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 a subject to treatment with an agent that inhibits PD-1.

In embodiments, an anti-PD-1 therapy described herein is administered in combination with one or more additional therapies (eg, therapies described herein). Thus, the subject is treated with an anti-PD-1 therapy 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 an immunotherapy.

In some embodiments, the PD-1 binding 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 lymphocyte activation gene-3 (LAG-3) protein or T-cell immunoglobulin domain-mucin domain-containing protein-3 (TIM-3)) and/or a chemotherapeutic agent (eg, niraparib). In some embodiments, the PD-1 binding agent is administered before, during, or after administration of the additional therapeutic agent. In some embodiments, the PD-1 binding agent is administered before, during, or after administration of a chemotherapy agent (eg, niraparib).

An anti-PD-1 antibody agent may be administered alone or in combination with other drugs (eg, as an adjuvant). For example, a PD-1 binding agent may be administered in combination with other agents to treat or prevent diseases disclosed herein (eg, cancer). In this regard, the PD-1 binding agent can be used in combination with at least one other anticancer agent, including, for example, any chemotherapeutic agent known in the art; ionizing radiation; low molecular weight anticancer agents; cancer vaccines; biologic therapies (eg, other monoclonal antibodies, anticancer viruses, gene therapy, and T-cell adoptive transfer) and/or surgery.

Administration of a PD-1 binding agent simultaneously or sequentially with an additional therapeutic agent is referred to herein as a combination therapy. For combination therapy, the PD-1 binding agent may be administered before (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 or after (for example, after 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 ) administering an additional therapeutic agent to a subject in need thereof. In some embodiments, the PD-1 binding agent and the additional therapeutic agent are administered at an interval of 1 minute, at an interval of 10 minutes, at an interval of 30 minutes, at an interval of less than 1 hour, at an interval of 1 to 2 hours, at an interval of 2 to 3 h, at intervals from 3 to 4 hours, at intervals from 4 to 5 hours, at intervals from 5 to 6 hours, at intervals from 6 to 7 hours, at intervals from 7 to 8 hours, at intervals from 8 to 9 hours, at intervals from 9 to 10 hours, at intervals from 10 to 11 hours, at intervals from 11 to 12 hours, at intervals of no more than 24 hours, or at intervals of no more than 48 hours.

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, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or toxin. In related embodiments, the agent is ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, flusoparib (SHR 3162), IMP 4297, INO1001, JPI 289, JPI 547 , conjugate monoclonal antibody B3-LysPE40, MP 124, niraparib (ZEJULA) (MK-4827), NU 1025, NU 1064, NU 1076, NU1085, olaparib (AZD2281), ONO2231, PD 128763, R503, R554, rupapar ib (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-d]pyrimidin-4-ol and its salts or derivatives. 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, (3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine, is an orally available potent poly(adenosine diphosphate [ADP]ribose) polymerase (PARP) inhibitor. -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 links in their entirety. Niraparib may be

- 53 043391 obtained in accordance with scheme 1 of WO 2008/084261.

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

^CH 3 (1).

Niraparib is a potent and selective inhibitor of PARP-1 and PARP-2 with a concentration providing 50% inhibition from control (IC ₅₀ ) = 3.8 and 2.1 nM, respectively, and its selectivity is at least 100 times higher than with other members of the PARP family. Niraparib inhibits PARP activity stimulated by hydrogen peroxide-induced DNA damage in various cell lines with an _IC50 and 90% control concentration ( _IC90 ) of approximately 4 and 50 nM, respectively.

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

Checkpoint inhibitors

In embodiments, the additional therapy is an immunotherapy. In embodiments, the immunotherapy comprises the administration of one or more additional immune checkpoint inhibitors (eg, the administration of one, two, three, four or more additional immune checkpoint inhibitors).

Exemplary targets for immune checkpoint inhibition include PD-1 (eg, inhibition by anti-PD-1, anti-PD-L1, or anti-PD-L2 therapies), CTLA-4, TIM-3, TIGIT, LAG (for example, LAG-3), SEASAM (for example, SEASAM-1, -3 and/or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80, CD86, V7-NZ (CD276), V7-H4 ( VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (eg, TGFR beta), B7-H1, B7-H4 (VTCN1), OX-40, CD137 , CD40, IDO and CSF-1R. Therefore, agents that inhibit any of these molecules can be used in combination with an anti-PD-1 antibody therapy described herein.

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

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

In embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is a TIM-3 binding agent (eg, an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the TIM-3 inhibitor is a TIM-3 inhibitor described in WO 2016/161270, which is incorporated herein by reference in its entirety. In embodiments, the TIM-3 inhibitor is TSR-022. For example, a TIM-3 inhibitor (eg, TSR-022) can be administered at a dose of about 1, 3, or 10 mg/kg (eg, about 1 mg/kg; about 3 or about 10 mg/kg), or a constant dose from about 100 to 1500 mg (for example, a constant dose of approximately 100 mg; a constant dose of approximately 200 mg; a constant dose of approximately 300 mg; a constant dose of approximately 400 mg; a constant dose of approximately 500 mg; a constant dose of approximately 600 mg; a constant dose of approximately 700 mg ; constant dose of approximately 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 of approximately 1300 mg; constant dose of approximately 1400 mg or constant dose of approximately

1500 mg).

In embodiments, the immune checkpoint inhibitor is a CTLA4 inhibitor (eg, an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the CTLA-4 inhibitor is a small molecule, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or 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 (eg, an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the LAG-3 inhibitor is a small molecule, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or 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 links in their entirety.

In embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor (eg, an antibody, antibody conjugate, or antigen-binding fragment thereof). In embodiments, the TIGIT inhibitor is a small molecule, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or 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, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or 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, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or 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, a checkpoint inhibitor (e.g., a TIM-3 inhibitor such as TSR-022) can be administered at a dose of about 1, 3, or 10 mg/kg (e.g., about 1 mg/kg; about 3 mg/kg or approximately 10 mg/kg), or a constant dose of approximately 100 to 1500 mg (e.g., a constant dose of approximately 100 mg; a constant dose of approximately 200 mg; a constant dose of approximately 300 mg; a constant dose of approximately 400 mg; a constant dose of approximately 500 mg; constant a constant dose of approximately 600 mg; a constant dose of approximately 700 mg; a constant dose of approximately 800 mg; a constant dose of approximately 900 mg; a constant dose of approximately 1000 mg; a constant dose of approximately 1100 mg; a constant dose of approximately 1200 mg; a constant dose of approximately 1300 mg; a constant dose of approximately 1400 mg or a constant dose of approximately 1500 mg).

In embodiments, the anti-PD-1 agent is administered in combination with at least one additional immune checkpoint inhibitor, or at least two, or at least three additional immune checkpoint inhibitors. In embodiments, a PARP inhibitor is further administered.

In embodiments, the anti-PD-1 agent is administered in combination with a TIM-3 inhibitor and a LAG-3 inhibitor. In embodiments, the anti-PD-1 agent is administered in combination with a TIM-3 inhibitor, a LAG-3 inhibitor, and a CTLA-4 inhibitor.

In embodiments, the anti-PD-1 agent is administered in combination with a LAG-3 inhibitor and a PARP inhibitor (eg, niraparib). In embodiments, the anti-PD-1 agent is administered in combination with a TIM-3 inhibitor, a LAG-3 inhibitor, and a PARP inhibitor (eg, niraparib).

For patients of childbearing potential, it is preferred that the patient have a negative serum pregnancy test within 72 hours prior to the date of the first dose of the anti-PD-1 antibody binder. It is also preferable that female patients of childbearing potential and male patients agree to use 2 appropriate methods of contraception with their partner. In some embodiments, the patient agrees to use 2 appropriate methods of contraception beginning at a screening visit 150 days after the last dose of study therapy.

Measuring Tumor Response

In some embodiments, the clinical benefit is a complete response (CR), partial response (PR), or stable disease (SD). In some embodiments, the clinical benefit is at least SD. In some embodiments, the clinical benefit corresponds to at least a PR. In some embodiments, the clinical benefit corresponds to 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 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 (eg, SD, PR, and/or CR) is determined according to the Response Evaluation Criteria in Solid Tumors (RECIST). In some embodiments, clinical benefit (eg, SD, PR, and/or CR) is determined according to RECIST guidelines.

In some embodiments, tumor response can be measured, for example, using RECIST v 1.1 guidelines. Guidelines are provided in E.L. 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. In some embodiments, the RECIST guidelines may serve as the basis for all protocol guidelines related to the disease state. In some embodiments, RECIST guidelines are used to assess tumor response to treatment and/or date of disease progression.

RECIST guidelines require an initial estimate of total tumor burden at baseline, which is used as a reference 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 by the presence of at least one measurable lesion. In studies where the primary endpoint is tumor progression (either the time to progression or the proportion with progression over a fixed period of time), the protocol should specify whether admission is limited to patients with measurable disease or only patients with nonmeasurable disease are eligible. measuring the disease.

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

Target lesions should be selected based on their size (those with the largest diameter), should be representative of all affected organs, and should also be capable of reproducible, repeatable measurements.

Lymph nodes deserve special attention because they are normal anatomical structures that may be visible on imaging even if they are not affected by tumor. Pathological nodes that are determined to be measurable and can be identified as target lesions must satisfy the P15 mm short axis criterion on CT scanning. Only the short axis of these nodes will be taken into account in the total value at the initial level. The short axis of a nodule is the diameter commonly used by radiologists to judge whether a nodule is affected by a solid tumor. The size of a nodule is usually indicated in two dimensions in the plane in which the image is acquired (for CT scanning, this is almost always the axial plane; for MRI, the plane for object detection can be axial, sagittal, or coronal). The smaller of these measured values represents the short axis.

For example, an abdominal nodule that is recorded at 20x30 mm has a short axis of 20 mm and is considered a malignant measurable nodule. In this example 20 mm should

- 56 043391 be recorded as a node measurement. All other pathological nodes (short axis P10 mm but <15 mm) should be considered non-target lesions. Short-axis nodules <10 mm are considered non-pathological and should not be recorded or monitored.

The sum of the diameters (largest for non-nodal lesions, short axes for nodal lesions) for all target lesions will be calculated and recorded as the sum of the diameters at baseline. 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 diameters at baseline 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 pathological 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, in rare cases, clearly progressing. In addition, multiple nontarget lesions involving the same organ may be recorded as a single item on the individual record sheet (eg, 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 dimension with a minimum size of 10 mm (at the largest diameter on CT or MRI scan) for non-nodular lesions, and greater than or equal to 15 mm for nodular lesions, or at least 20 mm on a chest x-ray.

In some embodiments, immune system-related response criteria include CR (complete resolution of all lesions (measurable or not and no new lesions)); PR (reduction of tumor burden by 50% or more relative to the initial level); SD (failure to meet CR or PR criteria in the absence of PD) or PD (increase in tumor burden by 25% or more from the lowest level). 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 pharmacokinetic and pharmacodynamic parameters of drug metabolism in human subjects, the relevant components of the pharmacokinetic and pharmacodynamic profile describing a particular composition may vary. Typically, pharmacokinetic and pharmacodynamic profiles are based on the determination of mean parameter values across a group of subjects. A subject group includes any reasonable number of subjects suitable for determining a representative average, such as 5 subjects, 10 subjects, 16 subjects, 20 subjects, 25 subjects, 30 subjects, 35 subjects or more. The mean is determined by calculating the average of all measurements in a subject for each parameter measured.

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 embodiments, the cancer is head and neck cancer, lung cancer (eg, non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, cancer uterine, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma or squamous cell carcinoma (eg, lung; anogenital area, including the anus, penis, cervix, vagina or vulva; or esophagus). In some certain embodiments, the cancer is endometrial cancer, NSCLC, kidney cancer, melanoma, cervical cancer, squamous cell carcinoma (eg, lung), or colorectal cancer. In some embodiments, the patient population includes one or more subjects (eg, includes or consists of subjects) suffering from cancer. For example, in some embodiments, a population of patients suffering from cancer may have previously been treated with a therapy, such as radiation and/or chemotherapy.

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

- 57 043391

For example, in some embodiments, the C _max is approximately 1 μg/ml; approximately 5 µg/ml, approximately 10 µg/ml, approximately 15 µg/ml, approximately 20 µg/ml, approximately 25 µg/ml, approximately 30 µg/ml, approximately 35 µg/ml, approximately 40 µg/ml, approximately 45 µg/ml, approximately 50 µg/ml, approximately 55 µg/ml, approximately 60 µg/ml, approximately 65 µg/ml, approximately 70 µg/ml, approximately 75 µg/ml, approximately 80 µg/ml, approximately 85 µg/ ml, approximately 90 μg/ml, approximately 95 μg/ml, approximately 100 μg/ml, approximately 150 μg/ml, approximately 200 μg/ml, approximately 250 μg/ml, approximately 300 μg/ml or any other _Cmax value, suitable for describing the pharmacokinetic profile of a PD-1 binding agent.

In some embodiments, the T _max is, for example, no more than about 0.5 hour, no more than about 1.0 hour, no more than about 1.5 hour, no more than about 2.0 hour, no more than about 2.5 hours or no more than about 3.0 hours or any other Tmax value suitable to describe the pharmacokinetic profile of the PD-1 binding agent.

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

AUC( _{O_3364 .} ) may be, for example, about 500 μg*hour/ml, about 1000 μg*hour/ml, about 1500 μg*hour/ml, about 2000 μg*hour/ml, about 2500 µg*hr./ml, approximately 3000 µg*hr./ml, approximately 3500 µg*hr./ml, approximately 4000 µg*hr./ml, approximately 4500 µg*hr./ml, approximately 5000 µg*hr./ ml, approximately 7500 mcg*hour/ml, approximately 10000 mcg*hour/ml, approximately 15000 mcg*hour/ml, approximately 20000 mcg*hour/ml, approximately 25000 mcg*hour/ml, approximately 30000 mcg *h/ml, approximately 35,000 mcg*h/ml, approximately 40,000 mcg*h/ml, approximately 45,000 mcg*h/ml, approximately 50,000 mcg*h/ml, approximately 65,000 mcg*h/ml , approximately 75,000 mcg*hr/mL, approximately 90,000 mcg*hr/mL, or any other AUC value ( _{O. 3364_} ) suitable to describe the pharmacokinetic profile of the therapeutic agent (eg, PD-1 binding agent). _In some embodiments, a PD-1 binding agent (eg, an anti-PD-1 antibody) is administered according to a schedule that has been demonstrated to achieve a mean AUC _{O_3364} in a patient population. concentration-time curve in the case of a PD-1 binding agent, which ranges from 2500 hours * μg/ml to 50,000 hours * μg/ml. _In some embodiments, the regimen has been demonstrated to achieve an average AUC of _{O_3364} in a patient population. concentration-time curve for a PD-1 binding agent, which is approximately 3400 ppm*μg/mL, approximately 11,000 ppm*μg/mL, or approximately 36,800 ppm*μg/mL.

In some embodiments, the AUC from 0 hour 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 3 weeks. In some embodiments, the dosing period is six weeks.

In some embodiments, the PD-1 binding agent is administered according to a regimen that has been demonstrated to achieve a response rate in an appropriate patient population such that disease progression is observed in no more than 50-80% of patients after 2, 4, 6, 8. 10, 12, 14, 16, 18 or 20 weeks after starting treatment. In some embodiments, disease progression is demonstrated in no more than 80% of patients at least 10 weeks after initiation of treatment.

In some embodiments, the PD-1 binding agent is administered according to a schedule that is sufficient to achieve an average PD-1 receptor occupancy of at least 50-90% 1, 2, 3, 4, or 5 days after a single dose of the composition. In some embodiments, administration of a composition that delivers a PD-1 binding agent is sufficient to achieve an average PD-1 receptor occupancy of at least 85% 3 days after administration of a single dose of the composition.

In some embodiments, the PD-1 binding agent is administered in a schedule sufficient to achieve an average stimulation score of at least 1 in a PD-1 receptor occupancy assay 3 days after administration of a single dose of the PD-1 binding agent.

In some embodiments, the PD-1 binding agent is administered according to a schedule sufficient to ensure that an average PD-1 receptor occupancy of at least 75% is achieved over a first period of time, such as from about 14 days to

- 58 043391 approximately 60 days after taking a single dose of a PD-1 binding agent. In some embodiments, the PD-1 binding agent is administered at a schedule sufficient to achieve an average PD-1 receptor occupancy of at least 75% over a first period of time (e.g., from about 15 days to about 60 days; in in some embodiments, approximately 29 days) after administration of a single dose of the PD-1 binding agent.

In some embodiments, the PD-1 binding agent is administered according to a schedule sufficient to achieve an average stimulation score of at least 1 in the PD-1 receptor occupancy assay over a first period of time, e.g., from about 14 days to about 60 days after taking a single dose of a PD-1 binder. In some embodiments, the PD-1 binding agent is administered according to a schedule sufficient to achieve an average stimulation score of at least 1 in a PD-1 receptor occupancy functional assay over a first period of time (e.g., from about 15 days to about 60 days; in some embodiments, approximately 29 days) after administration of a single dose of the PD-1 binding agent.

Examples

The following examples are provided for purposes of illustration and not limitation of the claimed invention.

Example 1 Dosage Schedules for an Exemplary PD-1 Binding Agent

This example describes a multicenter, open-label, phase 1, first-in-human study evaluating a PD-1 binding agent (anti-PD-1 antibody) in patients with tumors. In particular, this example describes dosage effects of treatment with a specific PD-1 binding agent in patients, and in particular in patients with advanced solid tumors or metastatic solid tumors. The PD-1 binding agent described in the present study provides a humanized monoclonal antibody to PD-1. In particular, a particular PD-1 binding agent that comprises a heavy chain variable region comprising the CDR sequences of SEQ ID NOs: 9, 10 and 11, and a light chain variable region comprising the CDR sequences of SEQ ID NOs: 12, 13 and 14 This exemplary anti-PD-1 antibody uses 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 replacing Ser with Pro in the hinge region of the IgG4 heavy chain at the canonical position S228.

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

This study consists of 2 parts: dose escalation and cohort expansion. Part 1 of the study (dose escalation) is designed, inter alia, to evaluate the safety, PK and PDy profile, tolerability, and anticancer effect of the anti-PD-1 antibody. A modified 3+3 dose escalation regimen was used at 1, 3, and 10 mg/kg every 2 weeks (Q2W). Dose escalation was continued until a maximum administered dose of 10 mg/kg Q2W was reached and the MTD was not identified. No DLT was observed. Preliminary safety results indicate that the exemplary PD-1 binding agent is safe and well tolerated.

Part 2 of the study is designed, inter alia, to evaluate the safety and tolerability, PK and PDy profile of anti-PD-1 antibody at fixed doses of 400 or 500 mg given every 3 weeks (Q3W) and 800 or 1000 mg given every 6 weeks ( Q6W), using a modified 6+6 circuit. Part 2 of this study assessed the effects in patients who have specific tumor types, such as endometrial cancer in separate cohorts consisting of MSS tumors and MSI-H tumors, triple-negative breast cancer, ovarian cancer, NSCLC, and anogenital squamous cell carcinoma (eg, squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva).

The pharmacokinetic parameters of the PD-1 binding agent were determined in patients administered various doses. As described herein, the study enrolled at least 18 patients, with at least 12 subjects included in the dose-limiting toxicity (DLT) cohorts and at least 6 subjects in the PK/PDy cohorts. Clearance of the PD-1 binding agent was determined in patients after a single intravenous infusion. Administration was carried out via a 30-minute intravenous infusion. Each of the log-linear mean serum concentration versus time profiles following a single dose of anti-PD-1 antibody at concentrations of 1 mg/kg, 3 mg/kg, and 10 mg/kg is shown in FIG. 1 and panels A of FIG. 2.

This anti-PD-1 antibody treatment demonstrated PK dose proportionality in all dose groups tested (see Table 5). The average _Cmax was approximately 21, 66 and 224 µg/ml, and the average

- 59 043391 nyaya AUC _o _ ₃₃₆₄ . was approximately 3378, 10999 and 39303 ppm*µg/ml for dose levels of 1, 3 and 10 mg/kg, respectively. The time to maximum serum concentration was in the range of 0.5-3 hours for all three treatment groups with a median of 1.5 hours. Mean clearance values were 0.201, 0.117 and 0.152 ml/h/kg for dose groups 1, 3 and 10 mg/kg respectively. The terminal half-life ranged from about 201 to 438 hours. Moreover, as shown in FIG. 3, an exemplary anti-PD-1 antibody demonstrated an effect magnitude, assessed by C _max and AUC, that was linearly proportional to dose.

Table 5. Mean values of pharmacokinetic parameters for PD-1 binding agent treatment groups (with the heavy chain variable region containing the CDR sequences of SEQ ID NO: 9, 10 and 11, and the light chain variable region containing the CDR sequences of SEQ ID NO: 12, 13 and 14) after intravenous infusion to patients

Dose (mg/kg) Stach (mcg/ml) SzZbch. (µg/ml) tmax (h) tl/2 (h) AUCo-zzbch. (h*mcg/ml) Vss (ml/ct) CL (ml/h./kg) 1 mg/kg (n=6) 21.4 ±4.43 5.99 ±2.38 1.5 (0.53.0) 311±149 3378±1141 74.2 ± 23.7 0.201 ± 0.121 3 mg/kg (n=3) 66.4 ± 6.25 23.4 ± 1.52 1.5 (1.53.0) 438 ± 114 10999 ±841 71.7 ± 11.4 0.117 ± 0.010 10 mg/kg (n=11) 244 ± 52.7 76.6 ±25.1 1.5 (1.53.0) 317 ± 155 39303 ±10301 60.7 ± 16.6 0.152 ± 0.052

Abbreviations: AUC _o _ ₃₃₆₄ . = area under the concentration-time curve from time 0 to 336 hours;

From _336h . = concentration at time 336 h;

CL = clearance; C _max = maximum concentration; n = quantity;

PD-1 = programmed cell death protein 1;

SD = standard deviation;

t _1/2 = half-life;

t _max = time required to reach maximum concentration;

Vss = volume of distribution at steady state.

Note: Data are presented as mean ± SD for _Cmax , _C336h , t1 _/2 , AUC _o-3364 , Vss and _CL values and median (range) for tmax values.

Following repeated doses of the PD-1 binder over 2-week cycles (Q2W), the PK profiles of 2 patients in the 1 mg/kg dose group and 2 patients in the 3 mg/kg dose group reached steady state after 3 doses. The accumulation coefficient based on the concentration at the end of the dosing interval (Ctrough) ranged from 1.45 to 2.93.

To select fixed doses, a two-compartment model was used to describe the observed PK data and predict the appropriate dose and schedule. The effect of body weight on PD-1 binding agent clearance was also examined. Body weights above the range of 45 kg to 146 kg were found to not exhibit significant covariance with respect to clearance (see Fig. 4). Full receptor occupancy was achieved at a serum anti-PD-1 antibody concentration of 2.43 μg/ml or higher. Based on the model prediction results, the Ctrough value at steady state for 500 mg Q3W and 1000 mg Q6W was 51.1 and 29.2 μg/ml with 90% confidence intervals of (13.4, 111.1) and (4) respectively ,1, 78.5). The predicted mean and 90% lower limit of Ctrough at 500 mg Q3W and 1000 mg Q6W were approximately 21.0 and 12.0; 5.5 and 1.7 times higher than the level required to achieve full occupancy of peripheral blood cell receptors. Data evaluating dose and regimens at the onset of steady state are presented in Table. 6 below.

Table 6. Pharmacokinetic parameters for different treatment regimens with a PD-1 binding agent (with the heavy chain variable region containing the CDR sequences of SEQ ID NO: 9, 10 and 11, and the light chain variable region containing the CDR sequences of ______________________ SEQ ID NO : 12, 13 and 14)______________________

Dose and regimen Ctrough (µg/ml) 90% confidence interval Stach (mcg/ml) AUC (0Tai) (h*mcg/ml) 400 mg Q3W 40.9 (10.7, 88.9) 142.9 35864 500 mg Q3W 51D (13.4, 111.1) 181.7 45445 800 mg Q6W 23.4 (3.3, 62.8) 230.8 66469 1000 mg Q6W 29.2 (4,1,78,5) 291.8 90848

These data support the administration of constant doses, including 400, 500, 800 and/or 1000 mg.

The clearance of the PD-1 binding agent was determined after a single dose of 500 and 1000 mg.

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The log-linear profile of the mean serum concentration versus time following a single dose of 500 and 1000 mg anti-PD-1 antibody is shown in panel B of FIG. 2, and summary pharmacokinetic data for a single dose are presented in table. 7 below. The mean maximum concentrations were approximately 174 and 322 μg/mL for 500 mg Q3W and 1000 mg Q6W, respectively; The average area under the concentration-time curve from time 0 to 504 hours (AUC _o-5O44 ) and AUC _o-1OO84 were approximately 36.424 and 91.376 h*μg/ml, respectively. Time to peak serum concentration ranged from 0.5 to 3.0 hours for both treatment groups, with a median of 1.0 and 1.5 hours, respectively. Serum concentrations of an exemplary PD-1 binding agent observed 3 weeks after a 500 mg dose were comparable to those observed 6 weeks after a 1000 mg dose.

Table 7. Mean values of pharmacokinetic parameters for treatment groups receiving a fixed dose of PD-1 binding agent (with a heavy chain variable region containing the CDR sequences of SEQ ID NO: 9, 10 and 11, and a light chain variable region containing the CDR sequences of SEQ ID NO: 12, 13 and 14), after intravenous infusion to patients

Dose (mg/kg) Stach (mcg/ml) Clast (µg/ml) tmax (h) AUCo-last (parts*µg/ml) 500 mg (n=6) 174 ±35.2 40.2 ±9.31 1.0 (0.5-3.0) 36424 ±6674 1000 mg (n=7) 322±101 43.7±18.2 ^a 1.5 (0.5-3.0) 91376 ±26808

AUC _0-last = area under the concentration-time curve from time 0 to 504 hours (500 mg cohort) or with or without extrapolation to 1008 hours (1000 mg cohort); C _last = last measurable plasma concentration; C _max = maximum concentration; n = quantity; Q3W = every 2 weeks; Q6W = every 6 weeks; SD = standard deviation; t _max = time required to reach maximum concentration; data are presented as mean ± SD for C _max , C _last , AUC _{0-last values} , and median (range) for t _max values. C _max was measured at time 504 hours for the 500 mg Q3W group and 1008 hours for the 1000 mg Q6W group, ^and n=5

Example 2 Binding to a PD-1 Target of an Exemplary PD-1 Binding Agent

This example describes the ability of an exemplary PD-1 binding agent, which is a humanized anti-PD-1 monoclonal antibody, to bind to its target (eg, the PD-1 receptor). Specifically, an exemplary anti-PD-1 antibody that comprises a heavy chain variable region comprising the CDR sequences of SEQ ID NOs: 9, 10 and 11, and a light chain variable region comprising the CDR sequences of SEQ ID NOs: 12, 13 and 14 Target binding of the anti-PD-1 antibody was determined by measuring PD-1 receptor occupancy in peripheral blood from patients following administration of the first dose of the anti-PD-1 antibody. Two assays were used: the first assay, called a conventional receptor occupancy (cRO) assay, provides a measure of direct binding of an anti-PD-1 antibody to CD3+ cells, and the second assay, called a functional receptor occupancy (fRO) assay, provides a measure of IL- production 2 ex vivo stimulated T cells after administration of an anti-PD-1 antibody.

cRO analysis results

To measure direct binding in the cRO assay, PBMCs were isolated from patients at baseline and on days 3 and 15 after the first dose of the anti-PD-1 antibody. In addition, additional samples from some patients were collected on days 22 and 29 after the first dose. PD-1 receptor occupancy by an anti-PD-1 antibody agent was measured on circulating CD3+ T cells using flow cytometry.

Following a single dose of anti-PD-1 antibody at 1, 3, or 10 mg/kg, the average percent occupancy on day 3 at all dose levels was approximately 90%. Consistent with published data for nivolumab (Brahmer et al., 2010), a mean occupancy rate of approximately 80% was maintained during the first 29 days following a single 1 mg/kg dose (Table 8; data cutoff September 30, 2016 G.)

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Table 8. Mean percent PD-1 occupancy for anti-PD-1 antibody in CD3+ _____________ cells at dose levels of 1, 3, and 10 mg/kg______________

Dose PD-1 occupancy percentage, mean ± SD (N) Baseline Day 3 Day 15 Day 22 Day 29 1 mg/kg 3.23 ±3.12 (6) 95.6 ± 17.1 (6) 84.3 ± 4.27 (6) 82.8 ± 3.67 (3) 77.8 ± 0.514 (2) 3 mg/kg 5.75 ± 1.72 (3) 88.0 ± 5.42 (3) 85.9 ± 2.49 (3) n/a n/a 10 mg/kg 2.42 ± 0.898 (5) 86.9 ± 4.08 (5) 85.8 ± 7.45 (3) n/a n/a

Abbreviations: CD = cluster of differentiation; n = quantity;

n/a = no data;

PD-1 = programmed cell death protein 1;

SD = standard deviation.

Results for receptor occupancy assessed for administered doses at exemplary PD-1 binding agent dose levels of 1, 3, and 10 mg/kg are also shown in panel A of FIG. 5.

In addition, the PD-1 receptor occupancy rates assessed above were maintained at three and six weeks for fixed dose administration levels of 500 mg Q3W (n=6) and 1000 mg Q6W (n=7), respectively. Results for receptor occupancy by an exemplary PD-1 binding agent at 500 and 1000 mg dose levels are shown in panels A and C of FIG. 6 respectively.

fRO analysis results

To obtain functional readouts of receptor occupancy in the fRO assay, whole blood was collected at baseline and on days 3 and 15 after the first dose. In addition, additional samples were collected from some patients on days 22 and 29 after the first dose. PD-1 receptor occupancy by an anti-PD-1 antibody agent was measured on circulating T cells as a function of IL-2 production following ex vivo stimulation with the superantigen staphylococcal enterotoxin B (SEB) in the presence of saturating concentrations of the antibody agent to PD-1 or isotype control (Patnaik et al., 2015). In this assay, an IL-2 stimulation score of 1 reflects a stimulation level close to the maximum stimulation level and reflects maximum receptor occupancy.

Following a single dose of the anti-PD-1 antibody, a median IL-2 stimulation score of 1 was achieved on day 3 at all dose levels. A mean IL-2 stimulation score of approximately 1 was maintained for 29 days following a single dose of 1 mg/kg (Table 9).

Table 9. Mean IL-2 Stimulation Score in the fRO Assay at Anti-PD-1 Antibody Dose Levels of 1, 3, and 10 mg/kg_______

Dose PD-1 occupancy percentage, mean ± SD (n=) Baseline Day 3 Day 15 Day 22 Day 29 1 mg/kg 1.69 ± 0.241 (6) 1.01 ±0.073 (6) 1.00 ±0.0513 (6) 1.32 ± 0.276 (2) 1.08 ± 0.064 (2) 3 mg/kg 1.62 ± 0.236 (3) 0.927 ± 0.0473 (3) 0.977 ± 0.0702 (3) n/a n/a 10 mg/kg 1.86 ± 0.547 (4) 1.05 ± 0.0603 (3) 0.860 (1) n/a n/a

Results for IL-2 stimulation for dosing levels at 1, 3, and 10 mg/kg dose levels of an exemplary PD-1 binding agent are also shown in panel B of FIG. 5. In addition, IL-2 stimulation rates for an exemplary PD-1 binding agent at 500 mg Q3W (n=6) and 1000 mg Q6W (n=7) are shown in panels B and D of FIG. 6 respectively.

Receptor occupancy and IL-2 stimulation experiments demonstrated that the anti-PD-1 antibody agent fully bound PD-1 on peripheral T cells from treated patients at all dose levels tested. The lowest concentration of an anti-PD-1 antibody that resulted in full receptor occupancy was calculated to be 2.43 μg/mL. Moreover, the data demonstrate that PD-1 binding of the anti-PD-1 antibody agent was maintained for at least 29 days following a single 1 mg/kg dose. These

- 62 043391 results demonstrate the effectiveness and stability of a single dose of an anti-PD-1 antibody product.

Moreover, for the fixed dose regimens (500 mg Q3W and 1000 Q6W), the average Cmin at which full receptor occupancy was observed was -2 μg/ml. Receptor occupancy studies incorporating pharmacokinetic data demonstrate the benefit provided by a PD-1 binder dosing schedule of 500 mg Q3W followed by 1000 mg Q6W. One beneficial aspect of this dosing schedule is that it provides residual concentrations that are at least 20 times the lowest concentration at which full peripheral blood cell receptor occupancy is achieved (40.2 μg/mL) for 500 mg Q3W and 43.7 µg/ml for 1000 mg Q6W).

Receptor occupancy (RO) for this fixed dose regimen of 500 mg Q3W/1000 mg Q6W anti-PD-1 antibody was also studied in patients with MSS endometrial cancer, MSI-H endometrial cancer, and NSCLC.

To measure direct binding in the RO assay, PBMCs were isolated from patients at baseline (pre-dose day 1) as well as before the second dose (pre-dose day 22) according to a 500 mg Q3W schedule. Anti-PD-1 antibody occupancy of PD-1 receptors was measured on circulating CD3+ T cells by flow cytometry using a method similar to that previously described for nivolumab (Brahmer, JCO 2010). PBMCs from treated patients were preincubated ex vivo with a saturating concentration of either unlabeled human IgG4 (isotype control) or anti-PD-1 antibody. After washing and staining with anti-human CD3 and anti-human IgG4 antibodies, PD-1 occupancy by infused anti-PD-1 antibody was assessed as the ratio of CD3+ cells stained with anti-human IgG4 antibody after ex vivo saturation with isotype control antibody (indicating in vivo binding ) and those after saturation with anti-PD-1 antibody (indicates the total number of available binding sites).

The RO analysis data is shown in FIG. 8, with the number of patients indicated in parentheses. In this graph, the line in the center of the whisker box represents the median value, with the length of the box representing the 25th and 75th percentiles. The whiskers represent the minimum and maximum values and indicate that high receptor occupancy by anti-PD-1 antibody has been achieved.

Example 3 Treatment of Patients with an Exemplary PD-1 Binding Agent

This example describes the clinical effectiveness of an exemplary PD-1 binding agent in patients who have cancer, such as patients with advanced solid tumors. Administration of a PD-1 binding agent using a dosing schedule in accordance with the present invention has been found to provide clinical benefit to patients. An exemplary PD-1 binding agent described in the present study is a humanized anti-PD-1 monoclonal antibody. For example, a specific PD1 binding agent was evaluated with a heavy chain variable region containing the CDR sequences of SEQ ID NOs: 9, 10 and 11, and a light chain variable region containing the CDR sequences of SEQ ID NOs: 12, 13 and 14. In this antibody for PD-1, the human heavy chain gene IGHG4*01 and the human kappa light chain gene IGKC*01 are used as framework sequences. In addition, there is one point mutation replacing Ser with Pro in the hinge region of the IgG4 heavy chain at the canonical position S228.

Moreover, administration of the anti-PD-1 antibody composition following intravenous infusion was found to provide clinical benefit to patients at each dose tested. Tumor response in patients evaluated as of September 2016 is presented in Table. 10.

Table 10. Tumor response in patients treated with PD-1 binding agent at different dosing schedules

Tumor type Cohort Tumor response Dose escalation for individual patient, yes/no Adenocarcinoma of the breast 1 mg/kg P.D. Adenocarcinoma ovary 1 mg/kg P.D. Parotid salivary glands 1 mg/kg P.D. Yes Adenocarcinoma ovary 3 mg/kg PR No Prostate cancer glands 3 mg/kg P.D.

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Fallopian tube carcinoma 3 mg/kg SD Yes TNBC 1 mg/kg PK/PDy P.D. Adenocarcinoma ovary 1 mg/kg PK/PDy P.D. Anal cancer 1 mg/kg PK/PDy SD Yes Peritoneal carcinoma 10 mg/kg P.D. Adenocarcinoma of the breast 10 mg/kg P.D. Small cell lung cancer 10 mg/kg PR Colon cancer 10 mg/kg PK/PDy P.D. TNBC 10 mg/kg PK/PDy P.D. Adenocarcinoma ovary 10 mg/kg MTD P.D. Endometrioid ovarian cancer 10 mg/kg MTD P.D. Esophageal carcinoma 10 mg/kg MTD P.D. Pancreatic cancer glands 10 mg/kg PK/Pdy P.D. Adenocarcinoma ovary 10 mg/kg PK/Pdy n/a Adenocarcinoma ovary 10 mg/kg PK/Pdy SD Cervical cancer 10 mg/kg PK/Pdy n/a

PD = disease progression;

SD = stable disease;

PR = partial response;

n/a = not determined during assessment

A wide variety of tumor types have been tested, including to date tumors of the anus, rectum, parotid gland, ovary, breast, fallopian tube, endometrium, uterus, appendix, prostate, lung, cervix, esophagus, peritoneum, kidney, and colon. intestines. As of July 2017, 19 patients had follow-up scans in part 1, and 2 of 19 patients were classified as susceptible. Both of these 2 patients achieved PR: one patient with ovarian cancer had a duration of response of 26 weeks and completed treatment at week 36 without progression, and one patient with small cell lung cancer who remained on treatment had a duration of response of > 31 weeks. Five patients had stable disease, two of whom continued treatment (fallopian tube cancer, n=1; ovarian cancer, n=1). Treatment responses are summarized in FIG. 7. In panel A of FIG. 7 depicts a pool track plot and panel B shows a radar plot of responses to treatment with an exemplary PD-1 binding agent.

Patients may also receive 500 mg of anti-PD-1 antibody every three weeks (Q3W) for the first four cycles, followed by 1,000 mg every 6 weeks (Q6W) for all subsequent cycles. The effect of this anti-PD-1 antibody composition administered according to this regimen was studied in patients with MSS endometrial cancer (Table 11). Patients may also receive 500 mg of anti-PD-1 antibody every three weeks (Q3W) for the first three cycles and then 1,000 mg every 6 weeks (Q6W) for all subsequent cycles, or patients may receive 500 mg of anti-PD-1 antibody every three weeks (Q3W) for the first five cycles, then 1000 mg every 6 weeks (Q6W) for all subsequent cycles.

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Table 11. Tumor scores in cohort A2 with endometrial cancer MSS

Best overall answer according to irRECIST Cohort A2 (No. 25) [η (%)] irCR 0 irPR 6(24) irSD 7(28) irPD 11 (44) Cannot be assessed 0 Not produced 14)

Twenty-five patients with advanced MSS endometrial cancer/recurrent MSS endometrial cancer were treated with anti-PD-1 antibody and had at least one CT scan for tumor evaluation. These patients represent patients who have progressed during or after platinum doublet therapy and patients who have received no more than two lines of cancer therapy for recurrent or advanced disease. Of the six patients who achieved irPR, one response was confirmed. Five patients continued treatment and one patient discontinued treatment due to disease progression. These clinical outcomes with the anti-PD-1 antibody are unexpected, in contrast to previous results with agents such as atezolizumab and pembrolizumab.

A dosing regimen of 500 mg anti-PD-1 antibody every three weeks (Q3W) for the first four cycles, followed by 1000 mg every 6 weeks (Q6W) for all subsequent cycles may also be applicable for patients with non-small cell lung cancer (NSCLC) and patients with forms of MSI-H cancer (eg, MSI-H endometrial cancer). Other dosing schedules include 500 mg anti-PD-1 every three weeks (Q3W) for the first three cycles and then 1000 mg every 6 weeks (Q6W) for all subsequent cycles or 500 mg anti-PD-1 every three weeks (Q3W) for the first five cycles, then 1000 mg every 6 weeks (Q6W) for all subsequent cycles.

Therefore, this example shows that an exemplary PD-1 binding agent with a heavy chain variable region comprising the CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region containing the CDR sequences of SEQ ID NOs: 12, 13 and 14, demonstrates encouraging results regarding clinical benefit in patients with a variety of cancer types.

Example 4 Treatment of Ovarian Cancer with an Exemplary PD-1 Binding Agent in Combination with Niraparib

This case study describes a clinical trial of niraparib in combination with an anti-PD-1 antibody in the first-line maintenance treatment of patients with advanced ovarian cancer who have responded to induction therapy with platinum-based agents. An exemplary PD-1 binding agent may be a humanized anti-PD-1 monoclonal antibody. For example, a particular PD-1 binding agent may be evaluated with a heavy chain variable region comprising the CDR sequences of SEQ ID NOs: 9, 10 and 11, and a light chain variable region containing the CDR sequences of SEQ ID NOs: 12, 13 and 14 , described in example 1.

Patients with histologically or cytologically confirmed advanced (unresectable) gynecologic solid tumor or metastatic gynecologic solid tumor (eg, ovarian cancer) and who have demonstrated a response to platinum-based chemotherapy may be included.

Specifically, this study will evaluate the effectiveness of treating patients with advanced recurrent ovarian cancer with an exemplary PD-1 binding agent in combination with niraparib. When combined with niraparib, an exemplary PD-1 binding agent may comprise a heavy chain variable region having CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region having CDR sequences of SEQ ID NOs: 12, 13 and 14. Combination Treatment may include oral administration of 100-300 mg of niraparib once daily (eg, one to three capsules with a dose value of 100 mg may be taken at each dose). It is contemplated that the PD-1 binding agent may be administered at a dose of 200-1000 mg of the anti-PD-1 antibody agent (eg, via intravenous administration). An exemplary anti-PD-1 antibody may be administered in fixed doses, such as 400 or 500 mg administered every 3 weeks (Q3W), followed by 800 or 1000 mg administered every 6 weeks (Q6W). In some embodiments, the anti-PD-1 antibody agent is administered at a dose of 1, 3, and 10 mg/kg. E(treatment cycles can be 14-42 days, for example 21 days, 28 days, etc.

Tumor assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) using clinically validated imaging modalities can be performed at the end of every 1-3 cycles until progression.

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Patients will continue to receive their assigned treatment until disease progression, unacceptable toxicity, death, withdrawal of consent, and/or loss to follow-up.

Example 5 Treatment of Lung Cancer with Niraparib

This example describes a clinical trial of niraparib alone and/or in combination with an exemplary anti-PD-1 antibody agent for the treatment of lung cancer (eg, NSCLC and/or squamous cell carcinoma). An exemplary PD-1 binding agent may be a humanized anti-PD-1 monoclonal antibody. For example, a particular PD-1 binding agent may be evaluated with a heavy chain variable region comprising the CDR sequences of SEQ ID NOs: 9, 10 and 11, and a light chain variable region containing the CDR sequences of SEQ ID NOs: 12, 13 and 14 , described in example 1.

Patients with histologically or cytologically confirmed advanced (unresectable) lung cancer or metastatic solid lung cancer (eg, NSCLS and/or squamous cell carcinoma) may be included. In some embodiments, the patient will experience disease progression after treatment with available therapies that are known to provide clinical benefit, or who have not tolerated other known treatment(s).

This study will evaluate the effectiveness of treating patients with advanced lung cancer with niraparib and/or an exemplary PD-1 binding agent. Patients with advanced forms of lung cancer, such as squamous cell carcinoma or NSCLC, can be treated with niraparib alone and/or in combination with an exemplary PD-1 binding agent. Treatment with niraparib may involve oral administration of 100-300 mg of niraparib once daily (eg, one to three capsules with a dose value of 100 mg may be taken at each dose). It is contemplated that the PD-1 binding agent may be administered at a dose of 200-1000 mg of the anti-PD-1 antibody agent (eg, via intravenous administration). An exemplary anti-PD-1 antibody may be administered in fixed doses of 400 or 500 mg administered every 3 weeks (Q3W), followed by 800 or 1000 mg administered every 6 weeks (Q6W). In some embodiments, the anti-PD-1 antibody agent is administered at a dose of 1, 3, and 10 mg/kg. Treatment cycles can be 14-42 days, for example 21 days, 28 days, etc.

Tumor assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) using clinically validated imaging modalities can be performed at the end of every 1-3 cycles until progression.

Patients will continue to receive their assigned treatment until disease progression, unacceptable toxicity, death, withdrawal of consent, and/or loss to follow-up.

Example 6 Treatment of PD-1 Expressing Lung Cancer with an Exemplary PD-1 Binding Agent in Combination with Niraparib

This example describes a clinical trial of an exemplary anti-PD-1 antibody agent in combination with niraparib for the treatment of lung cancer (eg, NSCLS and/or squamous cell carcinoma) that is characterized by expression of PD-1 and/or PD-L1, including in subjects whose PD-1 or PDL-1 levels are considered high. An exemplary PD-1 binding agent may be a humanized anti-PD-1 monoclonal antibody. For example, a particular PD-1 binding agent may be evaluated with a heavy chain variable region comprising the CDR sequences of SEQ ID NOs: 9, 10 and 11, and a light chain variable region containing the CDR sequences of SEQ ID NOs: 12, 13 and 14 , described in example 1.

The effectiveness of combination treatment of PD-1/PD-L1-expressing lung cancer with an exemplary PD-1 binding agent in combination with niraparib can be compared with the effectiveness of treatment with a PD-1 binding agent alone.

Patients with histologically or cytologically confirmed advanced (unresectable) lung cancer or metastatic solid lung cancer (eg, NSCLS and/or squamous cell carcinoma) may be included. In some embodiments, the patient will experience disease progression after treatment with available therapies that are known to provide clinical benefit, or who have not tolerated other known treatment(s). In some embodiments, lung cancer is characterized by high levels of expression of PD-1 and/or PD-L1.

This study will evaluate the effectiveness of treatment of patients with advanced lung cancer with an exemplary PD-1 binding agent in combination with niraparib compared with treatment with a PD-1 binding agent alone for patients with PD-1/PD-L1- expressing lung cancer. Patients will include those with advanced forms of lung cancer, such as squamous cell carcinoma or NSCLC. It is contemplated that the PD-1 binding agent may be administered at a dose of 200-1000 mg of the anti-PD-1 antibody agent (eg, via intravenous administration). Treatment with niraparib may include oral administration.

Claims (2)

dosing 100 to 300 mg of niraparib once daily (for example, one to three capsules with a dose value of 100 mg may be taken at each dose). An exemplary anti-PD-1 antibody may be administered in fixed doses of 400 or 500 mg administered every 3 weeks (Q3W), followed by 800 or 1000 mg administered every 6 weeks (Q6W). In some embodiments, the anti-PD-1 antibody agent is administered at a dose of 1, 3, and 10 mg/kg. Treatment cycles can be 14-42 days, for example 21 days, 28 days, etc. Tumor assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) using clinically validated imaging modalities can be performed at the end of every 1-3 cycles until progression. Patients will continue to receive their assigned treatment until disease progression, unacceptable toxicity, death, withdrawal of consent, and/or loss to follow-up. Thus, having described at least some aspects and embodiments of the present invention, it will be understood that various changes, modifications and improvements will be apparent to those skilled in the art. Such changes, modifications and improvements are intended to form part of the present disclosure and are intended to be within the spirit and scope of the present invention. Accordingly, the above description and drawings are given by way of example only, and the present invention is described in more detail in the following claims. Equivalents As used herein, the singular number in the specification and claims, unless expressly stated to the contrary, should be understood to include references to the plural. A claim or description containing or between one or more members of a group shall be considered satisfied if one, more than one, or all members of the group are present in, used in, or otherwise related to the specified product or process, unless otherwise stated. or otherwise is not obvious from the context. The present invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise related to the specified product or method. The present invention also includes embodiments in which more than one or all members of a group are present in, used in, or otherwise related to the specified product or method. It is further understood that the present invention covers all variations, combinations and combinations in which one or more limitations, elements, conditions, descriptive terms, etc. of one or more of the listed claims are inserted into another claim dependent on the same independent claim (or any other claim, as applicable), unless otherwise indicated or if one of ordinary skill in the art technical field, it will not be obvious that a contradiction or inconsistency would arise. If elements are presented in list form (eg, a Markush group or similar format), it should be understood that each subgroup of elements is also disclosed, and any element(s) can be removed from the group. In general, it should be understood that if the present invention or aspects of the present invention are/are designated as containing/containing specific elements, features, etc., then certain embodiments of the present invention or aspects of the present invention consist or essentially consist of such elements, signs, etc. For purposes of simplicity, such embodiments have not in every case been specifically set forth herein in such detail. It should also be understood that any embodiment or aspect of the present invention may be expressly excluded from the claims, regardless of whether a specific exclusion is set forth in the specification. Publications, websites and other references incorporated herein by reference to describe the prior art of the present invention and to provide additional information regarding its practical implementation are incorporated herein by reference. CLAIM 1. A method for treating solid cancer characterized by microsatellite instability high (MSI-H) status in humans, the method comprising administering a humanized monoclonal antibody - immunoglobulin G4 (IgG4) to programmed cell death protein-1 (PD-1), wherein the antibody administered in a first dose of 500 mg once every three weeks (Q3W) for 4 cycles, followed by a second dose of 1000 mg once every 6 weeks (Q6W); wherein the heavy chain contains an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 3, and the light chain contains an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 4. 2. The method according to claim 1, where the antibody is administered intravenously. -