CANCER TREATMENT METHODS WITH ANTI-TIM-3 ANTIBODIES

专利摘要:
the present invention provides methods of administering certain tim-3 binding agents to cancer patients. dosage regimens for compositions comprising a tim-3 binding agent are also explicitly provided.
公开号:BR112019014169A2
申请号:R112019014169-3
申请日:2018-01-09
公开日:2020-02-11
发明作者:Bobilev Dmitri；R. Ferguson Andrew；Anne Mceachern Kristen；Wang Jing
申请人:Tesaro, Inc.；
IPC主号:

专利说明:

Descriptive report of the invention patent for “METHODS OF
CANCER TREATMENT WITH ANTI-TIM-3 ANTIBODIES ”CROSS-REFERENCE TO RELATED ORDERS [0001] This application claims the benefit of U.S. Provisional Application no. 62 / 444,354, filed on January 9, 2017, and U.S. Provisional Application no. 62 / 582,272, filed on November 6, 2017, each of which is incorporated by reference in its entirety.
SEQUENCE LISTING [0002] The present specification refers to a Sequence Listing provided in electronic format as an ASCII.txt file called “TSR-002 SEQ LIST_ST25” that was generated on January 8, 2018 and is 39,647 bytes in size .
BACKGROUND OF THE INVENTION [0003] Cancer is a serious public health problem, with about 600,920 people in the United States of America, who are expected to die of cancer in 2017 alone, according to the American Cancer Society, Cancer Facts & Figures 2017 (https: //www.cancer.org/research/cancer-facts-statistics/all-cancer-factsfigures/cancer-facts-figures-2017.html). Accordingly, there remains a need for effective therapies to treat cancer patients.
SUMMARY [0004] The present invention encompasses an acknowledgment that certain dose regimens for agents that are capable of inhibiting T-cell Immunoglobulin and Mucin Domain-3 (TIM-3) signaling (for example, anti-TIM antibody agents -3) are useful for treating disorders, such as cancer.
[0005] In some embodiments, the present disclosure provides methods for treating disorders, such as cancer, which includes administering compositions that deliver TIM-3 inhibitors in particular (e.g., anti-TIM-3 antibody agents), according to the dosing regimens that
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2/172 can achieve clinical benefit in at least some patients.
[0006] In the embodiments, a TIM-3 inhibitor is a TIM-3 binding agent. In one embodiment, a TIM-3 binding agent is an antibody, an antibody conjugate, or an antigen binding fragment thereof. In some embodiments, a TIM-3 binding agent is an antibody agent (i.e., an anti-TIM-3 antibody agent).
[0007] In the embodiments, an anti-TIM-3 antibody agent comprises a heavy chain variable region with one or more CDR sequences selected from SEQ ID NOs: 21, 22 and 23 and / or a light chain variable region with one or more CDR sequences selected from SEQ ID NOs: 24, 25 and 26. In the embodiments, an anti-TIM-3 antibody agent comprises a heavy chain variable region with two or three CDR sequences selected from SEQ ID NOs: 21,22 and 23 and / or light chain variable region with two or three CDR sequences selected from SEQ ID NOs: 24, 25 and 26. In the embodiments, an anti-TIM-3 antibody agent comprises a variable chain region weighed with three CDR sequences selected from SEQ ID NOs: 21, 22 and 23 and / or a light chain variable region with three CDR sequences from SEQ ID NOs: 24, 25 and 26. In the embodiments, an anti-antibody agent -TIM-3 comprises a heavy chain variable region with three sequences CDR copies selected from SEQ ID NOs: 21, 22 and 23 and a light chain variable region comprising three CDR sequences from SEQ ID NOs: 24, 25 and 26.
[0008] In the embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence is 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 the embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin light chain variable domain whose
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3/172 amino acid sequence has at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity sequence to SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain, the amino acid sequence of which comprises SEQ ID NO: 1 or SEQ ID NO: 7 and / or an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain, whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7 and an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8.
[0009] In some embodiments, a TIM-3 binding antibody agent comprises an immunoglobulin heavy chain polypeptide comprising an amino acid sequence having 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 TIM-3 binding antibody agent comprises an immunoglobulin light chain polypeptide comprising an amino acid sequence having 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, an anti-TIM-3 antibody agent comprises two immunoglobulin heavy chains, each having an amino acid sequence as set out in SEQ ID NO: 3 and / or an immunoglobulin light chain whose amino acid sequence comprises SEQ ID NO: 4. In some embodiments, an anti-TIM-3 antibody agent comprises two immunoglobulin heavy chains, each having an amino acid sequence as set out in SEQ ID NO: 3 and an immunoglobulin light chain whose amino acid sequence comprises SEQ ID NO: 4.
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4/172 [0010] The present disclosure provides, in some embodiments, methods of treating a disorder in a subject that responds to inhibition of T cell immunoglobulin and mucin protein 3 (TIM-3), comprising administering a therapeutically effective dose of an agent capable of inhibiting TIM-3 signaling. In the embodiments, a therapeutically effective dose is about 1.3 or 10 mg / kg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is about 100 - 1500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; or a fixed dose of about 1500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is about 1 mg / kg. In the embodiments, a therapeutically effective dose is about 3 mg / kg. In the embodiments, a therapeutically effective dose is about 10 mg / kg. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 300 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 1200 mg of a TIM-3 inhibitor. In the embodiments, a TIM-3 inhibitor is any anti-TIM-3 antibody agent described in this document.
[0011] The present disclosure provides, in some embodiments, methods to increase T cell activation or T cell effector function in a subject that responds to inhibition of T cell immunoglobulin and mucin protein 3 (TIM-3), comprising administering a dose
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5/172 a therapeutically effective agent capable of inhibiting TIM-3 signaling. In the embodiments, a therapeutically effective dose is about 1, 3 or 10 mg / kg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is about 100 - 1500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; or a fixed dose of about 1500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is about 1 mg / kg. In the embodiments, a therapeutically effective dose is about 3 mg / kg. In the embodiments, a therapeutically effective dose is about 10 mg / kg. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 300 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 900 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 1200 mg of a TIM-3 inhibitor. In the embodiments, a TIM-3 inhibitor is any anti-TIM-3 antibody agent described in this document.
[0012] The present disclosure provides, in some embodiments, methods to reduce tumors or inhibit the growth of tumor cells in a subject that is responsive to the inhibition of T Cell Immunoglobulin and Mucine Protein 3 (TIM-3) comprising administering a dose therapeutically effective effect of an agent that is able to inhibit TIM-3 signaling. In the modalities,
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6/172 a therapeutically effective dose is about 1.3 or 10 mg / kg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is about 100 - 1500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; or a fixed dose of about 1500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is about 1 mg / kg. In the embodiments, a therapeutically effective dose is about 3 mg / kg. In the embodiments, a therapeutically effective dose is about 10 mg / kg. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 mg of an inhibitor of
TIM-3. In the embodiments, a therapeutically effective dose is a fixed dose of about 300 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 900 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 1200 mg of a TIM-3 inhibitor. In the embodiments, a TIM-3 inhibitor is any anti-TIM-3 antibody agent described in this document.
[0013] The present disclosure provides, in some embodiments, methods to induce an immune response in a subject that responds to inhibition of T cell immunoglobulin and mucin protein 3 (TIM-3), comprising administering a therapeutically effective dose of an agent capable of inhibiting TIM-3 signaling. In the embodiments, a therapeutically effective dose is about 1.3 or 10 mg / kg of a TIM-3 inhibitor.
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In the embodiments, a therapeutically effective dose is about 100 - 1500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; or a fixed dose of about 1500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is about 1 mg / kg. In the embodiments, a therapeutically effective dose is about 3 mg / kg. In the embodiments, a therapeutically effective dose is about 10 mg / kg. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 300 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 900 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 1200 mg of a TIM-3 inhibitor. In the embodiments, a TIM-3 inhibitor is any anti-TIM-3 antibody agent described in this document.
[0014] The present disclosure provides, in some modalities, methods to enhance an immune response or increase the activity of an immune cell in a subject that responds to inhibition of T cell immunoglobulin and mucin protein 3 (TIM-3), comprising administering a therapeutically effective dose of an agent capable of inhibiting TIM-3 signaling. In the modalities, an immune response is a humoral or cell-mediated immune response. In modalities, an immune response is a response from
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8/172 CD4 or CD8 T cells. In the modalities, an immune response is a B cell response. In the modalities, a therapeutically effective dose is about 1, 3 or 10 mg / kg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is about 100 - 1500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; or a fixed dose of about 1500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is about 1 mg / kg. In the embodiments, a therapeutically effective dose is about 3 mg / kg. In the embodiments, a therapeutically effective dose is about 10 mg / kg. In the modalities, a therapeutically effective dose is a fixed dose of about
100 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 300 mg of a TIM-3 inhibitor. In the modalities, a therapeutically effective dose is a fixed dose of about
500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 900 mg of a TIM-3 inhibitor. In the modalities, a therapeutically effective dose is a fixed dose of about
1200 mg of a TIM-3 inhibitor. In the embodiments, a TIM-3 inhibitor is any anti-TIM-3 antibody agent described in this document.
[0015] The present disclosure provides, in some embodiments, methods for treating cancer that comprise administering to a patient in need of treatment a T-cell immunoglobulin and Mucin Domain-3 (TIM-3) at a therapeutically effective dose. In the embodiments, a therapeutically effective dose is about 1, 3 or 10 mg / kg of an inhibitor of
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TIM-3. In the embodiments, a therapeutically effective dose is about 100 1500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; or a fixed dose of about 1500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is about 1 mg / kg. In the embodiments, a therapeutically effective dose is about 3 mg / kg. In the embodiments, a therapeutically effective dose is about 10 mg / kg. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 300 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 900 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 1200 mg of a TIM-3 inhibitor. In the embodiments, a TIM-3 inhibitor is any anti-TIM-3 antibody agent described in this document.
[0016] The present disclosure provides, in some embodiments, methods for treating cancer that comprise administering, to a patient in need of treatment, an anti-mucin-domain-3 antibody and T-cell immunoglobulin (TIM-3) in one dose therapeutically effective over an administration interval long enough to achieve clinical benefit. In the embodiments, an anti-TIM-3 antibody comprises a heavy chain comprising three CDRs that have the sequences of SEQ ID NOs: 21,
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10/172 or 23; and / or a light chain comprising three CDRs that have SED ID NOs sequences: 24, 25 or 26. In the embodiments, an anti-TIM-3 antibody comprises an immunoglobulin heavy chain variable domain comprising SEQ ID NO: 1 or SEQ ID NO: 7 and an immunoglobulin light chain variable domain comprising SEQ ID NO: 2 or SEQ ID NO: 8. In the embodiments, an anti-TIM-3 antibody comprises a heavy chain polypeptide comprising SEQ ID NO: 3 and a light chain polypeptide comprising SEQ ID NO: 4. In the embodiments, a therapeutically effective dose is about 1, 3 or 10 mg / kg of an anti-TIM-3 antibody. In the embodiments, a therapeutically effective dose is about 100 - 1500 mg of an anti-TIM-3 antibody. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; or a fixed dose of about 1500 mg of an anti-TIM-3 antibody. In the embodiments, a therapeutically effective dose is about 1 mg / kg of an anti-TIM-3 antibody. In the embodiments, a therapeutically effective dose is about 3 mg / kg of an anti-TIM-3 antibody. In the embodiments, a therapeutically effective dose is about 10 mg / kg of an anti-TIM-3 antibody. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 mg of an anti-TIM-3 antibody. In the embodiments, a therapeutically effective dose is a fixed dose of about 300 mg of an anti-TIM-3 antibody. In the embodiments, a therapeutically effective dose is a fixed dose of about 500 mg of a TIM-3 inhibitor. In the embodiments, a therapeutically effective dose is a fixed dose of about 900 mg of a TIM-3 inhibitor. In modalities, a dose
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11/172 therapeutically effective is a fixed dose of about 1200 mg of an anti-TIM-3 antibody.
[0017] In any of the methods described in this document, a therapeutically effective dose is about 1 mg / kg of a TIM-3 inhibitor. In any of the methods described in this document, a therapeutically effective dose is about 3 mg / kg of a TIM-3 inhibitor. In any of the methods described in this document, a therapeutically effective dose is about 5 mg / kg of a TIM-3 inhibitor. In the embodiments, a TIM-3 inhibitor is any anti-TIM-3 antibody agent described in this document.
[0018] In any of the methods described in this document, a therapeutically effective dose is about 100 mg of a TIM-3 inhibitor. In any of the methods described in this therapeutically effective is about 200 mg of any of the methods described in this therapeutically effective is about 300 mg of any of the methods described in this therapeutically effective is about 400 mg of any of the methods described in this therapeutically effective is about 500 mg of any of the methods described in this therapeutically effective is about 600 mg of any of the methods described in this therapeutically effective is about 700 mg of any of the methods described in this therapeutically effective is about 800 mg of any of the methods described in this therapeutically effective is about 900 mg of any of the methods described in this document, a dose an TIM-3 inhibitor. In document, a dose is a TIM-3 inhibitor. In document, a dose is a TIM-3 inhibitor. In document, a dose is a TIM-3 inhibitor. In document, a dose is a TIM-3 inhibitor. In document, a dose is a TIM-3 inhibitor. In document, a dose is a TIM-3 inhibitor. In document, a dose is a TIM-3 inhibitor. In document, a dose
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12/172 therapeutically effective is about 1000 mg of any of the methods described in this therapeutically effective is about 1100 mg of any of the methods described in this therapeutically effective is about 1200 mg of any of the methods described in this therapeutically effective is about 1300 mg of any of the methods described in this therapeutically effective is about 1400 mg of any of the methods described in this therapeutically effective is about 1500 mg of modalities, a TIM-3 inhibitor is any antibody agent anti-TIM-3 described in this document.
a TIM-3 inhibitor. In document, a dose is a TIM-3 inhibitor. In document, a dose is a TIM-3 inhibitor. In document, a dose is a TIM-3 inhibitor. In document, a dose is a TIM-3 inhibitor. In document, a dose is a TIM-3 inhibitor. In [0019] In the modalities, a TIM-3 inhibitor is administered at an administration interval (or treatment cycle) once a 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 the embodiments, a TIM-3 inhibitor is administered for 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 the modalities, a TIM-3 inhibitor is administered at an administration interval (or treatment cycle) once a week (Q1W). In the modalities, a TIM-3 inhibitor is administered at an interval of administration (or treatment cycle) once every 2 weeks (Q2W). In the modalities, a TIM-3 inhibitor is administered at an interval of administration (or treatment cycle) once every three weeks (Q3W). In the modalities, a TIM-3 inhibitor is administered at an interval of administration (or treatment cycle) once every 4 weeks (Q4W). In the modalities, a TIM-3 inhibitor is administered in an administration interval (or treatment cycle) of one
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13/172 times every 5 weeks (Q5W). In the modalities, a TIM-3 inhibitor is administered at an interval of administration (or treatment cycle) once every 6 weeks (Q6W).
[0020] In the modalities, a TIM-3 inhibitor (for example, a therapeutically effective dose of about 100 mg, 300 mg, 500 mg or 900 mg) is administered within one administration interval (or treatment cycle) of one once every 3 weeks. In the embodiments, a therapeutically effective dose of about 100 mg is administered at an interval of administration (or treatment cycle) once every 3 weeks. In the embodiments, a therapeutically effective dose of about 300 mg is administered at an interval of administration (or treatment cycle) once every 3 weeks. In the embodiments, a therapeutically effective dose of about 500 mg is administered at an interval of administration (or treatment cycle) once every 3 weeks. In the embodiments, a therapeutically effective dose of about 900 mg is administered at an interval of administration (or treatment cycle) once every 3 weeks.
[0021] In the modalities, a TIM-3 inhibitor is administered on the first day of a treatment cycle or within 1, 2 or 3 days of the first day of a treatment cycle. In the embodiments, a TIM-3 inhibitor is any anti-TIM-3 antibody agent described in this document.
[0022] In the modalities, a TIM-3 inhibitor described in this document is administered according to the dosage at the dosage regimens demonstrated to achieve a clinical benefit in some patients (for example, according to a regimen, as determined by a doctor , including dosage modifications). In the embodiments, a TIM-3 inhibitor described in this document is administered until treatment is discontinued due to, for example, disease progression or an adverse reaction or as determined by a physician. In the modalities, a clinical benefit is a stable disease (DS), a partial response (PR) and / or
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14/172 a complete answer (CR). In the modalities, a clinical benefit is a stable disease (DS). In the modalities, a clinical benefit is a partial response (PR). In the modalities, a clinical benefit is a complete response (CR). In modalities, PR or CR is determined according to the Response Assessment Criteria in Solid Tumors (RECIST). In the modalities, a TIM-3 inhibitor is administered for a longer period to maintain the clinical benefit. In the embodiments, a TIM-3 inhibitor is any anti-TIM-3 antibody agent described in this document.
[0023] In the embodiments, a TIM-3 inhibitor is administered periodically to a subject at a dose of about 100 mg, about 300 mg or about 1200 mg. In the embodiments, a TIM-3 inhibitor is administered periodically to a subject at a dose of about 100 mg (for example, once every three weeks (Q3W) and / or for 2, 3, 4, 5, 6 or more cycles). In the embodiments, a TIM-3 inhibitor is administered periodically to a subject at a dose of about 300 mg (for example, once every three weeks (Q3W) and / or for 2, 3, 4, 5, 6 or more cycles). In the embodiments, a TIM-3 inhibitor is administered periodically to a subject at a dose of about 1200 mg (for example, once every three weeks (Q3W) and / or for 2, 3, 4, 5, 6 or more cycles). In the embodiments, a TIM-3 inhibitor is any anti-TIM-3 antibody agent described in this document.
[0024] In the embodiments, a therapeutic agent has been additionally administered or will be additionally administered to a subject, such that the subject receives a TIM-3 inhibitor (for example, any anti-TIM-3 antibody agent described in this document) n and an additional therapeutic agent (for example, one, two, three, four or more additional therapeutic agents).
[0025] In the modalities, an immune checkpoint inhibitor has been additionally administered or will be additionally administered to a subject, such that the subject receives a TIM-3 inhibitor (for example, any
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15/172 anti-TIM-3 antibody agent described in this document) and an immune checkpoint inhibitor. That is, a TIM-3 inhibitor in combination with at least one immune checkpoint inhibitor can be administered to a subject.
[0026] In the modalities, a checkpoint inhibitor is an agent capable of inhibiting any of the following: PD-1 (for example, inhibition via anti-PD-1, anti-PD-L1 or anti-PD-L2 therapies), CTLA-4, TIM-3, TIGIT, LAGs (e.g., LAG-3), CEACAM (e.g., CEACAM-1, -3 and / or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (e.g. beta TGFR), B7-H1, B7-H4 (VTCN1), OX-40, CD137, CD40, IDO or CSF-1R. In the embodiments, a checkpoint inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal or a toxin. In the embodiments, a checkpoint inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof.
[0027] In the modalities, an immunological checkpoint inhibitor is an agent that inhibits the signaling of programmed death protein-1 (PD-1), protein 4 associated with cytotoxic T lymphocytes (CTLA-4), lymphocyte activation gene 3 ( LAG-3), T cell immunoglobulin and ITIM domain (TIGIT), indoleamine 2,3-dioxigenase (IDO), or colony stimulating factor 1 receptor (CSF1R).
[0028] In the modalities, an immune checkpoint inhibitor is a PD-1 inhibitor. In the embodiments, a PD-1 inhibitor is a PD-1 binding agent (for example, an antibody, antibody conjugate or antigen binding fragment thereof). In embodiments, a PD-1 binding agent is nivolumab, pembrolizumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, AMP-514 / MEDI0680, AGEN-2034, CS1001, TSR-042, Sym-021, PF-06801591, LZM009, KNPetição 870190077286, of 09/09/2019, p. 18/193
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035, AB122, genolimzumab (CBT-501), AK 104, or GLS-010, or derivatives thereof. In the embodiments, a PD-1 inhibitor is a PD-L1 or PD-L2 binding agent (for example, an antibody, an antibody conjugate or an antigen-binding fragment thereof). In embodiments, a PD-1 inhibitor is a PD-L1 or PD-L2 binding agent that is durvalumab, atezolizumab, avelumab, BGB-A333, SHR-1316, FAZ-053, CK-301, or PD millamolecule -L1, or derivatives thereof. In the embodiments, the PD-1 inhibitor (e.g., TSR042) is administered to the subject periodically at a dose of about 500 mg or 1000 mg. In the embodiments, a PD-1 inhibitor (e.g., TSR-042) is administered to the subject periodically at a dose of about 500 mg or 1000 mg. In the embodiments, a PD-1 inhibitor (e.g., TSR-042) is administered to the subject periodically at a dose of about 500 mg. In the embodiments, a PD-1 inhibitor (for example, TSR-042) is administered to the subject once every 3 weeks. In the embodiments, a PD-1 inhibitor (for example, TSR-042) is administered for 2, 3, 4, 5, 6 or more cycles. In the embodiments, a PD-1 inhibitor (for example, TSR-042) is administered for 4 cycles. In the embodiments, a PD-1 inhibitor (e.g., TSR-042) is administered to the subject periodically at a dose of about 1000 mg. In the embodiments, a PD-1 inhibitor (for example, TSR-042) is administered to the subject once every 6 weeks. In the modalities, a PD-1 inhibitor (for example, TSR-042) is administered in a first dose of about 500 mg once every 3 weeks for 4 cycles, followed by a second dose of about 1000 mg every 6 weeks (for example, until treatment is stopped).
[0029] In embodiments, an immunological checkpoint inhibitor is a CTLA-4 inhibitor (for example, an antibody, antibody conjugate or antigen-binding fragment thereof). In embodiments, a CTLA-4 inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal,
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17/172 or a toxin. In embodiments, a CTLA-4 inhibitor is a small molecule. In embodiments, a CTLA-4 inhibitor is a CTLA-4 binding agent. In embodiments, a CTLA-4 inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof. In embodiments, a CTLA-4 inhibitor is ipilimunab (Yervoy), AGEN1884 or tremelimumab.
[0030] In modalities, an immunological checkpoint inhibitor is an LAG-3 inhibitor (for example, an antibody, an antibody conjugate or an antigen-binding fragment thereof). In some embodiments, a LAG-3 inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, a LAG-3 inhibitor is a small molecule. In embodiments, a LAG-3 inhibitor is a LAG-3 binding agent. In embodiments, a LAG-3 inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof. In embodiments, a LAG-3 inhibitor is an IMP321, BMS-986016, GSK2831781, Novartis LAG525 or an LAG-3 inhibitor described in WO 2016/126858, WO 2017/019894 or WO 2015/138920, each of which is incorporated in this document by reference in its entirety.
[0031] In modalities, an immunological checkpoint inhibitor is a TIGIT inhibitor (for example, an antibody, an antibody conjugate or an antigen-binding fragment thereof). In embodiments, a TIGIT inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, or a toxin. In modalities, a TIGIT inhibitor is a small molecule. In embodiments, a TIGIT inhibitor is a TIGIT binding agent. In embodiments, a TIGIT inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof. In embodiments, a TIGIT inhibitor is MTIG7192A, BMS-986207 or OMP-31M32.
[0032] In modalities, an immunological checkpoint inhibitor is a
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18/172 IDO inhibitor. In embodiments, an IDO inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, an IDO inhibitor is a small molecule. In embodiments, an IDO inhibitor is an IDO binding agent. In embodiments, an IDO inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof.
[0033] In modalities, an immunological checkpoint inhibitor is a CSF1R inhibitor. In embodiments, a CSF1R inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal or a toxin. In embodiments, a CSF1R inhibitor is a small molecule. In embodiments, a CSF1R inhibitor is a CSF1R binding agent. In embodiments, a CSF1R inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof.
[0034] In the embodiments, a method comprises administering a TIM-3 inhibitor (for example, any anti-TIM-3 antibody agent described herein) with at least two of the immunological checkpoint inhibitors. In modalities, one method comprises administering a third checkpoint inhibitor. In embodiments, one method comprises administering a TIM-3 inhibitor with a PD-1 inhibitor and a LAG-3 inhibitor, so that the subject receives all three. In embodiments, one method comprises administering a TIM-3 inhibitor with a PD-1 inhibitor, a LAG-3 inhibitor and a CTLA-4 inhibitor, so that the subject receives all four.
[0035] In embodiments, an agent that inhibits poly polymerase (ADPribose) (PARP) has been additionally administered or will be administered to a subject, so that the subject receives treatment with a TIM-3 inhibitor and a PARP inhibitor.
[0036] In the embodiments, a PARP inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a
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19/172 carbohydrate, a lipid, a metal, or a toxin. In the modalities, a PARP inhibitor is selected from the group consisting of: ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib, IMP 4297, INO1001, JPI 289, JPI 547, monoclonal antibody B3-LysPE40 conjugate, MP 124, niraparib, NU 1025, NU 1064, NU 1076, NU1085, olaparib, ONO2231, PD 128763, R 503, R554, rucaparib, SBP 101, SC 101914, simmiparib, talazoparib, veliparib, WW 46, 2- (4- (trifluoromethyl) phenyl) -7,8-dihydro5H-thiopyran [4,3-d] pyrimidin-4-ol, and salts or derivatives thereof. In the embodiments, a PARP inhibitor is niraparib, olaparib, rucaparib, talazoparib or veliparib. In the embodiments, a PARP inhibitor is niraparib (for example, niraparib free base, niraparib tosylate or niraparib tosylate monohydrate or any combination thereof).
[0037] In modalities, one or more immunological checkpoint inhibitors (for example, a PD-1 inhibitor and / or an LAG-3 inhibitor) are additionally administered or will be administered to a subject, so that the subject receives treatment with a TIM-3 inhibitor, a PARP inhibitor (eg, niraparib) and one or more immunological checkpoint inhibitors. In embodiments, a TIM-3 inhibitor, a PD-1 inhibitor (for example, TSR-042) and a PARP inhibitor (for example, niraparib) are administered to a subject. In embodiments, a TIM-3 inhibitor, a PD-1 inhibitor (for example, TSR042), a LAG-3 inhibitor and a PARP inhibitor (for example, niraparib) are administered to a subject.
[0038] In the modalities, a patient has a disorder that is a dysfunctional T-cell disorder.
[0039] In the modalities, a patient has a disorder that is cancer.
[0040] In the modalities, a cancer is associated with a high tumor mutation load (BMR).
[0041] In the modalities, a cancer is from stable microsatellites (MSS).
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20/172 [0042] In the modalities, a cancer is characterized by microsatellite instability.
[0043] In modalities, a cancer has a high instability microsatellite instability status (MSI-H).
[0044] In modalities, a cancer has a low instability microsatellite instability status (MSI-L).
[0045] In the modalities, a cancer is associated with high BMR and MSI-H.
[0046] In the modalities, a cancer is associated with high BMR and MSI-L or MSS. In the modalities, a cancer is associated with high BMR and MSIH. In the modalities, a cancer is associated with high BMR and MSI-L or MSS.
[0047] In the modalities, a cancer that has a defective DNA incompatibility repair system.
[0048] In the modalities, a cancer has a defect in the DNA incompatibility repair gene.
[0049] In the modalities, a cancer is a hypermutated cancer.
[0050] In the modalities, a cancer has homologous recombination repair deficiency / homologous repair deficiency (HRD).
[0051] In the modalities, a cancer comprises a mutation in the delta polymerase (POLD).
[0052] In the modalities, a cancer comprises a mutation in the epsilon polymerase (POLE).
[0053] In the modalities, a 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, cancer small intestine, squamous cell carcinoma of the anogenital region (for example, squamous cell carcinoma of the anus, penis, cervix, vagina or vulva), soft tissue sarcoma (for example, leiomyosarcoma), melanoma, carcinoma of
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21/172 kidney cells, 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, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, a hematological cancer , multiple myeloma, B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma (HL) / primary mediastinal B cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, nonHodgkin's lymphoma, neuroblastoma, a CNS tumor, diffuse intrinsic pontine glioma (DIPG), Ewing's sarcoma, embryonic rhabdomyosarcoma, osteosarcoma, or Wilms' tumor. In the modalities, a cancer is MSS or MSI-L, it is characterized by microsatellite instability, it is MSI-H, it has high TMB, it has high TMB and it is MSS or MSI-L, it has high TMB and it is MSI-H, it has a defective DNA incompatibility repair system, has a defect in a DNA incompatibility repair gene, is a hypermutated cancer, is a cancer with HRD, comprises a mutation in the delta polymerase (POLD), or comprises a mutation in the epsilon polymerase (POLE).
[0054] In the modalities, a cancer is a cancer of the endometrium (for example, cancer of the MSI-H or MSS / MSI-L endometrium). In the embodiments, a cancer is an MSI-H cancer comprising a mutation in POLE or POLD (for example, a non-endometrial cancer MSI-H comprising a mutation in POLE and POLD). In the modalities, a cancer is breast cancer (triple-negative breast cancer (TNBC)). In the modalities, a cancer is a lung cancer (for example, non-small cell lung cancer). In the modalities, a cancer is melanoma. In the modalities, a cancer is a colorectal cancer. In the modalities, a cancer is squamous cell carcinoma of the anus, squamous cell carcinoma of the penis, cell carcinoma
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22/172 squamous cells of the cervix, squamous cell carcinoma of the vagina, or squamous cell carcinoma of the vulva.
[0055] In the modalities, a cancer has homologous recombination repair deficiency / homologous repair deficiency (HRD). In the modalities, a cancer is acute myeloid leukemia. In the modalities, a cancer is acute lymphoblastic leukemia. In the modalities, a cancer is non-Hodgkin's lymphoma. In the modalities, a cancer is Hodgkin's lymphoma. In the modalities, a cancer is neuroblastoma. In the modalities, a cancer is a CNS tumor. In the modalities, a cancer is diffuse intrinsic pontine glioma (DIPG). In the modalities, a cancer is Ewing's sarcoma. In the modalities, a cancer is embryonic rhabdomyosarcoma. In the modalities, a cancer is osteosarcoma. In the modalities, a cancer is Wilms' tumor. In the modalities, a cancer is soft tissue sarcoma [0056] In some modalities, a patient has cancer, such as: a non-small cell lung cancer (NSCLC), a hepatocellular cancer, a kidney cancer, a melanoma, a cancer cervical, colorectal cancer, squamous cell carcinoma of the anogenital region, head and neck cancer, triple-negative breast cancer, ovarian cancer or endometrial cancer. In some modalities, a patient has cancer with microsatellite instability. In some modalities, microsatellite instability is considered high, where instability is significantly higher than that observed in a control cell (for example, MSI-H status). In some embodiments, the patient has a solid tumor. In some modalities, the patient has a solid, advanced stage tumor. In some modalities, a patient has a solid advanced stage tumor, such as: non-small cell lung cancer (NSCLC), hepatocellular cancer, kidney cancer, melanoma, cervical cancer, colorectal cancer, carcinoma of squamous cells of the anogenital region, a head and neck cancer, a triple breast cancer
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23/172 negative, an ovarian cancer or an endometrial cancer. In some modalities, a patient has an advanced solid stage tumor with microsatellite instability.
[0057] In some modalities, the patient has hematological cancer. In some modalities, the patient has hematological 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 some modalities, a patient has hematological cancer with microsatellite instability.
[0058] In some modalities, a patient has a cancer characterized by the expression of PD-1 and / or PD-L1. In some modalities, a cancer has high expression of PD-1 and / or PD-L1 (for example, by high expression of PD-1 and / or high expression of PD-L1). In some embodiments, a cancer characterized by the expression of PD-1 and / or PD-L1 is head and neck cancer, lung cancer (for example, non-small cell lung cancer (NSCLC)), cancer kidney, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, uterine tube cancer, breast cancer, a prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma or squamous cell carcinoma (for example , the lung, the anogenital region, including anus, penis, cervix, vagina or vulva; or the esophagus). In some modalities, a cancer characterized by the expression of PD-1 and / or PD-L1 is an anal cancer, a cancer of the fallopian tubes, an ovarian cancer or a lung cancer.
[0059] In some modalities, the patient has a head cancer
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24/172 and neck, lung cancer (for example, non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, cancer vaginal, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, cancer esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma or squamous cell carcinoma.
[0060] In modalities, a cancer is an advanced cancer. In the modalities, a cancer is a metastatic cancer. In the modalities, a cancer is an MSI-H cancer. In the modalities, a cancer is an MSS cancer. In the modalities, a cancer is a cancer mutant to POLE. In the modalities, a cancer is a mutant cancer for POLD. In the modalities, a cancer is a cancer of high BMR. In the modalities, a cancer is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD).
[0061] In the modalities, a cancer is a solid tumor. In the modalities, a solid tumor is advanced. In the embodiments, a solid tumor is a solid metastatic tumor. In the embodiments, a solid tumor is a solid MSI-H tumor. In the embodiments, a solid tumor is a solid MSS tumor. In the embodiments, a solid tumor is a solid tumor mutated for POLE. In the embodiments, a solid tumor is a solid tumor mutated for POLD. In the modalities, a solid tumor is a solid tumor of high BMR. In the modalities, a solid tumor is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD).
[0062] In the modalities, a cancer is a non-endometrial cancer (for example, solid non-endometrial tumor). In the modalities, a non-endometrial cancer is an advanced cancer. In the modalities, a non-endometrial cancer is a metastatic cancer. In the modalities, a non-endometrial cancer is an MSI-H cancer. In the modalities, a non-endometrial cancer is
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25/172 an MSS cancer. In the modalities, a non-endometrial cancer is a cancer mutant for POLE. In the embodiments, a non-endometrial cancer is a solid tumor (for example, a solid MSS tumor, a solid MSI-H tumor, a solid POLD mutant tumor or a solid POLE mutant tumor). In the modalities, a non-endometrial cancer is a cancer of high BMR. In modalities, non-endometrial cancer is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD).
[0063] In the modalities, a cancer is a non-endometrial cancer (for example, a solid tumor). In the modalities, an endometrial cancer is an advanced cancer. In the modalities, an endometrial cancer is a metastatic cancer. In the modalities, an endometrial cancer is an MSI-H endometrial cancer. In the modalities, an endometrial cancer is an MSS endometrial cancer. In the modalities, an endometrial cancer is a POLE mutant endometrial cancer. In the modalities, an endometrial cancer is a POLD mutant endometrial cancer. In the modalities, an endometrial cancer is an endometrial cancer of high BMR. In the modalities, an endometrial cancer is associated with homologous recombination repair deficiency / homologous repair deficiency (HDR).
[0064] In the modalities, a cancer is a lung cancer (for example, a solid tumor). In the modalities, a lung cancer is an advanced lung cancer. In the modalities, a lung cancer is a metastatic lung cancer. In the modalities, a lung cancer is squamous cell carcinoma of the lung. In the modalities, a lung cancer is small cell lung cancer (SCLC). In the modalities, a lung cancer is a non-small cell lung cancer (NSCLC). In the modalities, lung cancer is lung cancer translocated by ALK (for example, lung cancer with a known ALK translocation). In the embodiments, a lung cancer is an EGFR mutant lung cancer (for example, a lung cancer with a known EGFR mutation).
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In the modalities, a lung cancer is an MSI-H lung cancer. In the modalities, a lung cancer is an MSS lung cancer. In the modalities, a lung cancer is a lung cancer mutated to POLE. In the modalities, a lung cancer is a lung cancer mutated to POLD. In the modalities, a lung cancer is a high BMR lung cancer. In the modalities, lung cancer is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD).
[0065] In the modalities, a cancer is a colorectal cancer (CRC) (for example, a solid tumor). In the modalities, a colorectal cancer is an advanced colorectal cancer. In the modalities, a colorectal cancer is a metastatic colorectal cancer. In the modalities, a colorectal cancer is an MSI-H colorectal cancer. In the modalities, a colorectal cancer is an MSS colorectal cancer. In the modalities, a colorectal cancer is a POLE mutant colorectal cancer. In the modalities, a colorectal cancer is a colorectal cancer mutated to POLD. In the modalities, a colorectal cancer is a colorectal cancer of high BMR. In the modalities, a colorectal cancer is associated with homologous recombination repair deficiency / homologous repair deficiency (HDR).
[0066] In the modalities, a cancer is a melanoma. In modalities, a melanoma is an advanced melanoma. In modalities, a melanoma is a metastatic melanoma. In the modalities, a melanoma is an MSI-H melanoma. In the modalities, a melanoma is an MSS melanoma. In the modalities, a melanoma is a mutant melanoma for POLE. In the modalities, a melanoma is a mutant melanoma for POLD. In modalities, a melanoma is a high BMR melanoma. In the modalities, a melanoma is associated with homologous recombination repair deficiency / homologous repair deficiency (HDR).
[0067] In the modalities, a cancer is the squamous cell carcinoma of the anogenital region (for example, the anus, penis, cervix,
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27/172 vagina or vulva). In the modalities, a squamous cell carcinoma of the anogenital region (for example, of the anus, penis, cervix, vagina or vulva) is an advanced cancer. In the modalities, a squamous cell carcinoma of the anogenital region (for example, of the anus, penis, cervix, vagina or vulva) is a metastatic cancer. In the modalities, a squamous cell carcinoma of the anogenital region (for example, of the anus, penis, cervix, vagina or vulva) is MSI-H. In the modalities, a squamous cell carcinoma of the anogenital region (for example, of the anus, penis, cervix, vagina or vulva) is MSS. In the modalities, a lung cancer is a cancer mutant for POLE. In the modalities, a squamous cell carcinoma of the anogenital region (for example, of the anus, penis, cervix, vagina or vulva) is associated with homologous recombination repair deficiency / homologous repair deficiency (“HRD”).
[0068] In the modalities, a cancer is an ovarian cancer. In the modalities, an ovarian cancer is an advanced ovarian cancer. In the modalities, an ovarian cancer is a metastatic ovarian cancer. In the modalities, an ovarian cancer is an MSI-H ovarian cancer. In the modalities, an ovarian cancer is an MSS ovarian cancer. In the modalities, an ovarian cancer is a mutant ovarian cancer for POLE. In the modalities, an ovarian cancer is a mutant ovarian cancer for POLD. In the modalities, an ovarian cancer is a high BMR ovarian cancer. In the modalities, an ovarian cancer is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD). In the modalities, an ovarian cancer is an ovarian cancer of serous cells. In the modalities, an ovarian cancer is a clear cell ovarian cancer.
[0069] In the modalities, a cancer is a cancer of the fallopian tube. In the modalities, a fallopian tube cancer is an advanced fallopian tube cancer. In the modalities, a fallopian tube cancer is a metastatic fallopian tube cancer. In the modalities, a cancer of
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28/172 fallopian tube is a fallopian tube cancer MSI-H. In the modalities, a fallopian tube cancer is a fallopian tube cancer MSS. In the modalities, a fallopian tube cancer is a fallopian tube cancer mutated to POLE. In the modalities, a fallopian tube cancer is a fallopian tube cancer mutated for POLD. In the modalities, a fallopian tube cancer is a high BMR fallopian tube cancer. In the modalities, a fallopian tube cancer is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD). In the modalities, a fallopian tube cancer is a fallopian tube cancer of serous cells. In the modalities, a fallopian tube cancer is a clear cell fallopian tube cancer.
[0070] In the modalities, a cancer is a primary peritoneal cancer. In the modalities, a primary peritoneal cancer is an advanced primary peritoneal cancer. In the modalities, a primary peritoneal cancer is a metastatic primary peritoneal cancer. In the modalities, a primary peritoneal cancer is a primary peritoneal cancer MSI-H. In the modalities, a primary peritoneal cancer is a primary peritoneal cancer MSS. In the modalities, a peritoneal cancer is a primary peritoneal cancer mutated to POLE. In the modalities, a primary peritoneal cancer is a primary peritoneal cancer mutated for POLD. In the modalities, a primary peritoneal cancer is a primary peritoneal cancer with high BMR. In the modalities, primary peritoneal cancer is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD). In the modalities, a primary peritoneal cancer is a primary peritoneal cancer of serous cells. In the modalities, a primary peritoneal cancer is a primary peritoneal cancer of clear cells.
[0071] In the modalities, a cancer is acute lymphoblastic leukemia (ALL). In the modalities, acute lymphoblastic leukemia is advanced acute lymphoblastic leukemia. In modalities, acute lymphoblastic leukemia and leukemia
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29/172 acute metastatic lymphoblastic. In the modalities, acute lymphoblastic leukemia is acute lymphoblastic leukemia MSI-H. In the modalities, acute lymphoblastic leukemia is acute lymphoblastic leukemia MSS. In the modalities, acute lymphoblastic leukemia is acute lymphoblastic leukemia mutated for POLE. In the modalities, acute lymphoblastic leukemia is acute lymphoblastic leukemia mutated for POLD. In the modalities, an acute lymphoblastic leukemia is associated with homologous recombination repair deficiency / homologous repair deficiency (HDR).
[0072] In the modalities, a cancer is acute myeloid leukemia (AML). In the modalities, acute myeloid leukemia is advanced acute myeloid leukemia. In the modalities, acute myeloid leukemia is acute metastatic myeloid leukemia. In the modalities, acute myeloid leukemia is acute myeloid leukemia MSI-H. In the modalities, acute myeloid leukemia is acute myeloid leukemia MSS. In the modalities, acute myeloid leukemia is acute myeloid leukemia mutated for POLE. In the modalities, acute myeloid leukemia is acute myeloid leukemia mutated for POLD. In the modalities, an acute myeloid leukemia is associated with homologous recombination repair deficiency / homologous repair deficiency (HDR).
[0073] In the modalities, a cancer is non-Hodgkin's lymphoma (NHL). In the modalities, non-Hodgkin's lymphoma is advanced non-Hodgkin's lymphoma. In the modalities, non-Hodgkin's lymphoma is metastatic non-Hodgkin's lymphoma. In the modalities, non-Hodgkin's lymphoma is MSI-H non-Hodgkin's lymphoma. In the modalities, non-Hodgkin's lymphoma is MSH non-Hodgkin's lymphoma. In the modalities, non-Hodgkin's lymphoma is POLE mutant non-Hodgkin's lymphoma. In the modalities, non-Hodgkin's lymphoma is POLD mutant non-Hodgkin's lymphoma. In the modalities, non-Hodgkin's lymphoma is associated with homologous recombination repair deficiency / homologous repair deficiency (HDR).
[0074] In the modalities, a cancer is Hodgkin's lymphoma (HL). In modalities, Hodgkin's lymphoma is advanced Hodgkin's lymphoma. In
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30/172 modalities, lymphoma
Hodgkin's metastatic Hodgkin's lymphoma.
In the modalities, lymphoma of
Hodgkin's Hodgkin's lymphoma from MSI-H.
In modalities, Hodgkin's lymphoma is MSD's Hodgkin's lymphoma.
In the modalities, Hodgkin's lymphoma is POLE mutant Hodgkin's lymphoma. In the modalities, Hodgkin's lymphoma is POLD mutant Hodgkin's lymphoma. In modalities, Hodgkin's lymphoma is associated with homologous recombination repair deficiency / homologous repair deficiency (HDR).
[0075] In the modalities, a cancer is a neuroblastoma (NB). In the modalities, a neuroblastoma is an advanced neuroblastoma.
In the modalities, a neuroblastoma is a metastatic neuroblastoma.
In the modalities, neuroblastoma is an MSI-H neuroblastoma. In the modalities, a neuroblastoma is an MSS neuroblastoma. In the modalities, a neuroblastoma is a POLE mutant neuroblastoma. In the embodiments, a neuroblastoma is a polob mutant neuroblastoma. In the modalities, a neuroblastoma is a neuroblastoma of high BMR. In the modalities, a neuroblastoma is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD).
[0076] In the modalities, a cancer is a CNS tumor. In the modalities, a CNS tumor is advanced. In the modalities, a CNS tumor is a metastatic CNS tumor. In the embodiments, a CNS tumor is an MSI-H CNS tumor. In the embodiments, a CNS tumor is an MSS CNS tumor. In the embodiments, a CNS tumor is a POLE mutant CNS tumor. In the embodiments, a CNS tumor is a POLD mutant CNS tumor. In the modalities, a CNS tumor is a high BMR CNS tumor.
In the modalities, a CNS tumor is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD).
[0077] In the modalities, a cancer is diffuse intrinsic pontine glioma (DIPG). In modalities, a DIPG is an advanced DIPG. In modalities, a DIPG is a metastatic DIPG. In modalities, DIPG is a DIPG MSI-H.
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In modalities, a DIPG is a DIPG MSS. In the modalities, a DIPG is a DIPG mutant for POLE. In the modalities, a DIPG is a DIPG mutant for POLD. In the modalities, a DIPG is a high TMB DIPG. In modalities, a DIPG is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD).
[0078] In the modalities, a cancer is Ewing's sarcoma. In modalities, Ewing's sarcoma is an advanced Ewing's sarcoma. In modalities, Ewing's sarcoma is a metastatic Ewing's sarcoma. In modalities, Ewing's sarcoma is an Ewing's sarcoma MSI-H. In modalities, Ewing's sarcoma is an Ewing's sarcoma MSS. In modalities, Ewing's sarcoma is a POLE mutant Ewing's sarcoma. In modalities, Ewing's sarcoma is a mutant Ewing's sarcoma for POLD. In modalities, Ewing's sarcoma is a high TMB sarcoma. In modalities, Ewing's sarcoma is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD).
[0079] In the modalities, a cancer is embryonic rhabdomyosarcoma (ERS). In the modalities, an embryonic rhabdomyosarcoma is an advanced embryonic rhabdomyosarcoma. In the modalities, an embryonic rhabdomyosarcoma is a metastatic embryonic rhabdomyosarcoma. In the modalities, an embryonic rhabdomyosarcoma is an MSI-H embryonic rhabdomyosarcoma. In the modalities, an embryonic rhabdomyosarcoma is an MSS embryonic rhabdomyosarcoma. In the modalities, an embryonic rhabdomyosarcoma is a pole mutant embryonic rhabdomyosarcoma. In the modalities, an embryonic rhabdomyosarcoma is a pold mutant embryonic rhabdomyosarcoma. In the modalities, an embryonic rhabdomyosarcoma is an embryonic rhabdomyosarcoma of high BMR. In the modalities, an embryonic rhabdomyosarcoma is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD).
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32/172 [0080] In the modalities, a cancer is an osteosarcoma (OS). In the modalities, an osteosarcoma is an advanced osteosarcoma. In the modalities, an osteosarcoma is a metastatic osteosarcoma. In the modalities, an osteosarcoma is an MSI-H osteosarcoma. In the modalities, an osteosarcoma is an MSS osteosarcoma. In the modalities, an osteosarcoma is a mutant osteosarcoma for POLE. In the modalities, an osteosarcoma is a mutant osteosarcoma for POLD. In modalities, an osteosarcoma is a high BMR osteosarcoma. In modalities, an osteosarcoma is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD).
[0081] In the modalities, a cancer is a soft tissue sarcoma. In the modalities, a soft tissue sarcoma is an advanced soft tissue sarcoma. In the modalities, a soft tissue sarcoma is a metastatic soft tissue sarcoma. In the embodiments, a soft tissue sarcoma is an MSI-H soft tissue sarcoma. In the embodiments, a soft tissue sarcoma is an MSS soft tissue sarcoma. In the embodiments, a soft tissue sarcoma is a POLE mutant soft tissue sarcoma. In the embodiments, a soft tissue sarcoma is a pold mutant soft tissue sarcoma. In the modalities, a soft tissue sarcoma is a high BMR soft tissue sarcoma. In the modalities, a soft tissue sarcoma is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD). In the modalities, a soft tissue sarcoma is leiomyosarcoma.
[0082] In modalities, one cancer is tumor Wilms. In modalities, tumor Wilms is one tumor in Wilms advanced. In modalities, tumor Wilms is one tumor in Wilms metastatic. In
modalities, Wilms tumor is a Wilms MSI-H tumor. In the modalities, Wilms tumor is a Wilms MSS tumor. In the modalities, Wilms 'tumor is a POLE mutant Wilms' tumor. In the modalities, Wilms' tumor is
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33/172 a POLD mutant Wilms tumor. In the modalities, Wilms 'tumor is a high BMR Wilms' tumor. In the modalities, a Wilms tumor is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD).
[0083] In the modalities, a subject was previously treated with one or more different cancer treatment modalities (for example, one or more of surgery, radiotherapy, chemotherapy or immunotherapy).
[0084] In the modalities, a subject has previously been treated with one or more cancer treatment modalities (for example, one or more of surgery, radiotherapy, chemotherapy or immunotherapy). In the modalities, a subject was previously treated with two or more different cancer treatment modalities (for example, one or more of surgery, radiotherapy, chemotherapy or immunotherapy). In the modalities, a subject was previously treated with cytotoxic therapy. In the modalities, a subject was previously treated with chemotherapy. In the modalities, a subject was previously treated with two different cancer treatment modalities (for example, one or more of surgery, radiotherapy, chemotherapy or immunotherapy). In the modalities, a subject was previously treated with three cancer treatment modalities (for example, one or more of surgery, radiotherapy, chemotherapy or immunotherapy).
[0085] In the modalities of methods described in this document, a method further comprises the administration of one or more among surgery, radiation therapy, chemotherapy, immunotherapy, an anti-angiogenic agent or an anti-inflammatory. In the embodiments, a method additionally comprises administering chemotherapy.
[0086] In some modalities, at least some of the patients in the cancer patient population have previously been treated with chemotherapy (for example, platinum-based chemotherapy). For example, a patient who has received two cancer treatment lines may be
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34/172 identified as a 2L cancer patient (for example, a patient with 2L NSCLC). In the modalities, a patient received two or more cancer treatment lines (for example, a patient with 2L + cancer, such as a patient with 2L + endometrial cancer). In the modalities, a patient has not been previously treated with anti-PD-1 therapy. In the modalities, a patient previously received at least one cancer treatment line (for example, a patient previously received at least one cancer line or at least two cancer treatment lines). In the modalities, a patient previously received at least one treatment line for metastatic cancer (for example, a patient previously received one or two treatment lines for metastatic cancer).
[0087] In the modalities, a subject is resistant to treatment with an agent that inhibits PD-1.
[0088] In the modalities, a subject is refractory to treatment with an agent that inhibits PD-1.
[0089] In the modalities, a method described in this document sensitizes a subject to treatment with an agent that inhibits PD-1.
[0090] In the modalities, a subject comprises an exhausted immune cell (for example, an exhausted immune cell which is an exhausted T cell).
[0091] In the modalities, the methods described in this document, a subject is an animal (for example, a mammal). In modalities, a subject is a human. In modalities, a subject is a non-human mammal (for example, mice, rats, rabbits or non-human primates). Accordingly, the methods described in this document can be useful in both the treatment of humans and veterinary medicine.
[0092] In the modalities, a TIM-3 inhibitor is administered intravenously (for example, by intravenous infusion).
[0093] The present disclosure provides, in some modalities,
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35/172 methods for treating cancer in a patient in need thereof, the method comprising administering a composition that delivers an anti-TIM-3 antibody agent.
[0094] In some modalities, the patient has not been previously treated with a cancer treatment modality.
[0095] In some modalities, the patient has previously been treated with one or more different cancer treatment modalities. In the modalities, the patient was previously treated with one or more of radiotherapy, chemotherapy or immunotherapy. In some modalities, the patient has previously been treated with chemotherapy (for example, platinum-based chemotherapy).
[0096] In some embodiments, a composition that delivers a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is administered at a dose of 1, 3 or 10 mg / kg. In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of 1, 3 or 10 mg / kg every two weeks. In some embodiments, the composition that delivers an anti-TIM-3 antibody is administered according to a regimen that includes a dose of 1, 3 or 10 mg / kg every three weeks. In some embodiments, the composition that delivers an anti-TIM-3 antibody is administered according to a regimen that includes a dose of 1, 3 or 10 mg / kg every four weeks.
[0097] In some embodiments, a composition that provides an anti-TIM-3 antibody agent in a fixed dose within a range of about 100 mg to about 1500 mg (for example, about 100 mg to 1500 mg). In some embodiments, a composition that delivers a TIM-3 anti-antibody agent in a fixed dose in a range of about 100 mg to about 300 mg, about 300 mg to about 1,000 mg, or about 1000 mg to about 1200 mg. In modalities, the fixed dose is about 100 mg. In
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36/172 modalities, the fixed dose is about 300 mg. In modalities, the fixed dose is about 500 mg. In modalities, the fixed dose is about 900 mg. In the modalities, the fixed dose is about 1200 mg. In some embodiments, the composition that delivers an anti-TIM-3 antibody is administered according to a regimen that includes a fixed dose every two weeks (Q2W). In some embodiments, the composition that delivers an anti-TIM-3 antibody is administered according to a regimen that includes a fixed dose every three weeks (Q3W). In some embodiments, the composition that delivers an anti-TIM-3 antibody is administered according to a regimen that includes a fixed dose every four weeks (Q4W). In the modalities, the anti-TIM-3 antibody is administered at the interval of administration once a week (Q1W), once every 2 weeks (Q2W), once every 3 weeks (S3W), once every 4 weeks (Q4W), once every 5 weeks (Q5W) or once every 6 weeks (Q6W). In the embodiments, the anti-TIM-3 antibody is administered for a period of at least 2, 4, 6, 8, 10, 12, 14, 16, 18 or 20 weeks. In the embodiments, a dose is administered as a monotherapy (for example, a therapeutically effective amount of 1200 mg of an anti-TIM-3 antibody administered Q2W or Q3W) or a dose is administered in combination with one or more other therapies. For example, 100 mg, 300 mg, 500 mg or 900 mg (for example, 100 mg or 300 mg) of an anti-TIM-3 antibody can be administered in combination with an anti-PD-1 antibody according to the regulations described in this document (for example, 500 mg of an anti-PD-1 antibody administered Q3W during four treatment cycles followed by administration of 1000 mg of the anti-PD-1 antibody Q6W until treatment is discontinued (for example, due to progression disease)).
[0098] In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered by intravenous infusion.
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37/172 [0099] In some modalities, a clinical benefit is a complete response (CR), a partial response (PR) or a stable disease (DS). In some modalities, a clinical benefit corresponds to at least SD. In some modalities, a clinical benefit corresponds to at least one PR. In some modalities, a clinical benefit corresponds to at least one CR. In some modalities, 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 obtain a clinical benefit. In some modalities, at least 5% of patients achieve a clinical benefit. In some modalities, at least 5% of patients reach DS. In some modalities, at least 5% of patients achieve at least one PR. In some modalities, at least 5% of patients achieve CR. In some modalities, at least 20% of patients achieve a clinical benefit. In some modalities, at least 20% of patients achieve DS.
[00100] In some modalities, the clinical benefit (for example, SD, PR and / or CR) is determined according to the Response Assessment Criteria in Solid Tumors (RECIST). In some modalities, the clinical benefit (for example, SD, PR and / or CR) is determined according to the RECIST guidelines. In some modalities, the clinical benefit (for example, SD, PR and / or CR) is determined according to the RECIST guidelines (version 1.1). In some modalities, the clinical benefit (for example, SD, PR and / or CR) is determined according to the immunorrelated RECIST guidelines (irRECIST). In some modalities, the tumor response can be assessed either by irRECIST or RECIST version 1.1. In some modalities, the tumor response can be assessed by both irRECIST and RECIST, version 1.1. When used in this document, the term RECIST guidelines can refer to RECIST 1.0, RECIST 1.1 or irRECIST interchangeably.
[00101] In some modalities, the patient is receiving or will receive one or more additional therapies in combination with an
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38/172 anti-TIM-3 antibody. In some modalities, the additional therapy is radiotherapy, chemotherapy or immunotherapy. In some embodiments, additional therapy includes treatment with a composition that delivers a PD-1 inhibitor (e.g., a PD-1 binding agent) and / or a LAG-3 binding agent. In some embodiments, the additional PD-1 inhibitor is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, 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, AK104, GLS-010, PD-1VR or PD-1FL, or any antibodies PD-1 disclosed in WO2014 / 179664. In some embodiments, additional therapy is a PARP inhibitor. In some embodiments, the PARP inhibitor is niraparib, olaparib, rucaparib, talazoparib and veliparib. In some embodiments, the PARP inhibitor is niraparib.
[00102] The present disclosure provides, in some embodiments, methods for treating cancer in a patient in need thereof, the method comprising administering one or more compositions that deliver an anti-TIM-3 antibody agent in combination with a binding agent to PD1. In some embodiments, a patient or a population of patients is receiving combination therapy that comprises administration of an anti-TIM-3 antibody agent and a PD-1 binding agent (for example, an anti-PD-1 antibody ).
[00103] In some embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain, the amino acid sequence of which comprises SEQ ID NO: 1 or SEQ ID NO: 7 and a light chain variable domain of immunoglobulin whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, an anti-TIM-3 antibody agent comprises two chains
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39/172 heavy immunoglobulin, each having an amino acid sequence as set out in SEQ ID NO: 3 and an immunoglobulin light chain whose amino acid sequence comprises SEQ ID NO: 4.
[00104] In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 11 or SEQ ID NO: 17 and an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 12 or SEQ ID NO: 18 ("PD-1VR"). In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain, whose amino acid sequence comprises SEQ ID NO: 13 and an immunoglobulin light chain whose amino acid sequence comprises SEQ ID NO: 14 (“PD1- FL ”).
[00105] In some embodiments, an anti-TIM-3 antibody agent (for example, an anti-TIM-3 antibody) is administered at a dose of about 1, 3 or 10 mg / kg. In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of 1, 3 or 10 mg / kg every two weeks. In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of about 1.3 or 10 mg / kg every three weeks. In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of 1, 3 or 10 mg / kg every four weeks. In some embodiments, an anti-TIM-3 antibody agent is administered at a fixed dose within the range of about 100 mg to 1500 mg. In some embodiments, an anti-TIM-3 antibody agent is administered at a fixed dose within a range of about 300 mg to 1,000 mg, about 100 mg to about 500 mg, about 100 mg to about 1200 mg or about 1000 mg to about 1500 mg. In some embodiments, an anti-TIM-3 antibody agent is administered at a fixed dose of about 100, 200 mg, 300 mg, 400 mg, 500
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40/172 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100. mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg. In some embodiments, an anti-TIM-3 antibody agent is administered at a fixed dose of about 100 mg. In some embodiments, an anti-TIM-3 antibody agent is administered at a fixed dose of about 300 mg. In some embodiments, an anti-TIM-3 antibody agent is administered at a fixed dose of about 500 mg. In some embodiments, an anti-TIM-3 antibody agent is administered at a fixed dose of about 900 mg. In some embodiments, an anti-TIM-3 antibody agent is administered at a fixed dose of about 1200 mg. In some embodiments, an anti-TIM-3 antibody agent is administered according to a regimen that includes a fixed dose every two weeks (Q2W). In some embodiments, an anti-TIM-3 antibody agent is administered according to a regimen that includes a fixed dose every three weeks (Q3W). In some embodiments, an anti-TIM-3 antibody agent is administered according to a regimen that includes a fixed dose every four weeks (Q4W).
[00106] In some embodiments, a therapeutically effective dose is a dose of an anti-TIM-3 antibody from about 100 mg to about 1500 mg, such as a dose that is about 100, 200, 300, 400, 500 , 600, 700, 800., 900, 1000, 1100, 1200 mg, 1300 mg, 1400 mg or 1500 mg. In the embodiments, a therapeutically effective dose is about 100 mg (for example, administered in Q2W and Q3W). In the embodiments, a therapeutically effective dose is about 300 mg (for example, administered in Q2W and Q3W). In the embodiments, a therapeutically effective dose is about 500 mg (for example, administered in Q2W and Q3W). In the embodiments, a therapeutically effective dose is about 900 mg (for example, administered in Q2W and Q3W). In the embodiments, a therapeutically effective dose is about 1200 mg (for example, administered in Q2W and Q3W). In the modalities, the anti-TIM-3 antibody is administered at the interval of administration once a week (Q1W), once every 2 weeks (Q2W), once every 3
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41/172 weeks (S3W), once every 4 weeks (Q4W), once every 5 weeks (Q5W) or once every 6 weeks (Q6W). In the embodiments, the anti-TIM-3 antibody is administered for a period of at least 2, 4, 6, 8, 10, 12, 14, 16, 18 or 20 weeks.
[00107] In the modalities, a therapeutically effective dose is about 100 mg and the agent is administered at an interval of administration once every 2 weeks. In the embodiments, a therapeutically effective dose is about 100 mg and the agent is administered at an interval of administration once every 3 weeks.
[00108] In the modalities, a therapeutically effective dose is about 300 mg and the agent is administered at an interval of administration once every 2 weeks. In the embodiments, a therapeutically effective dose is about 300 mg and the agent is administered at an interval of administration once every 3 weeks.
[00109] In the modalities, a therapeutically effective dose is about 500 mg and the agent is administered at an interval of administration once every 2 weeks. In the embodiments, a therapeutically effective dose is about 500 mg and the agent is administered at an interval of administration once every 3 weeks.
[00110] In the modalities, a therapeutically effective dose is about 900 mg and the agent is administered at an interval of administration once every 2 weeks. In the embodiments, a therapeutically effective dose is about 900 mg and the agent is administered at an interval of administration once every 3 weeks.
[00111] In the modalities, a therapeutically effective dose is about 1200 mg and the agent is administered at an interval of administration once every 2 weeks. In the embodiments, a therapeutically effective dose is about 1200 mg and the agent is administered at an interval of administration once every 3 weeks.
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42/172 [00112] In the embodiments, a dose is administered as a monotherapy (for example, a therapeutically effective amount of 1200 mg of an anti-TIM-3 antibody administered Q2W or Q3W) or a dose is administered in combination with one or more plus other therapies. For example, 100 mg or 300 mg of an anti-TIM-3 antibody can be administered in combination with an anti-PD-1 antibody according to the regulations described in this document (for example, 500 mg of an anti-PD-1 antibody) 1 administered Q3W for four treatment cycles followed by administration of 1000 mg of anti-PD-1 antibody Q6W until treatment was discontinued (for example, due to disease progression)).
[00113] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered in a dose of 0.1, 1, 3 10 or 20 mg / kg. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that includes a dose of 1, 3 or 10 mg / kg every two weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that includes a dose of about 1, 3 or 10 mg / kg every three weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that includes a dose of 1, 3 or 10 mg / kg every four weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) at a dose of 500 mg. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that includes a dose of 500 mg every two weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that includes a dose of about 500 mg every three weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that includes a dose of 500 mg at
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43/172 every four weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that includes a dose of 500 mg every three weeks for at least one treatment cycle ( for one, two, three or four treatment cycles), followed by administration. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that includes a dose of about 1000 mg every three weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that includes a 1000 mg dose every four weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that includes a dose of about 1000 mg every five weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that includes a 1000 mg dose every six weeks. In the embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that includes a dose of 500 mg every three weeks for four treatment cycles, followed by administration a dose of 1000 mg every six weeks until treatment is discontinued (for example, due to disease progression). In the embodiments, an anti-TIM-3 antibody agent is administered Q2W or Q3W in a dose of about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100 or 1200 mg or in a dose that is about 1-10 mg / kg (for example, a dose that is about 1, about 3, or about 10 mg / kg). In the embodiments, an anti-TIM-3 antibody agent is administered either Q2W or Q3W at a dose that is about 100 mg. In the embodiments, an anti-TIM-3 antibody agent is administered Q2W or Q3W in a dose that is about 300 mg.
[00114] In the embodiments, a PD-1 inhibitor (for example, any anti-PD-1 antibody described in this document) is administered in a first
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44/172 dose of about 500 mg once every 3 weeks for 3, 4 or 5 cycles followed by a second dose of about 1000 mg once every 6 weeks or more (for example, a second dose of about 1000 mg every 6 weeks). In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 100 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 300 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 500 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 900 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is administered once every three weeks.
[00115] In the embodiments, a PD-1 inhibitor (for example, any anti-PD-1 antibody described in this document) is administered in a first dose of about 500 mg once every 3 weeks for 3 cycles followed by a second dose of about 1000 mg once every 6 weeks or more (for example, a second dose of about 1000 mg every 6 weeks). In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 100 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 300 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 500 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 900 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is administered once every three weeks.
[00116] In the modalities, a PD-1 inhibitor (for example, any
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45/172 anti-PD-1 antibody described in this document) is administered in a first dose of about 500 mg once every 3 weeks for 4 cycles followed by a second dose of about 1000 mg once every 6 weeks or more (for example, a second dose of about 1000 mg every 6 weeks). In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 100 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 300 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 500 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 900 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is administered once every three weeks.
[00117] In the embodiments, a PD-1 inhibitor (for example, any anti-PD-1 antibody described in this document) is administered in a first dose of about 500 mg once every 3 weeks for 5 cycles followed by a second dose of about 1000 mg once every 6 weeks or more (for example, a second dose of about 1000 mg every 6 weeks). In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 100 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 300 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 500 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is a fixed dose of about 900 mg. In the embodiments, a therapeutically effective dose of the agent (for example, an anti-TIM-3 antibody) is administered once every three weeks.
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46/172 [00118] The present disclosure provides, in some embodiments, compositions comprising an anti-TIM-3 antibody agent for use in the treatment of cancer in a selected cancer patient population. In some embodiments, an anti-TIM-3 antibody agent comprises a heavy chain comprising three CDRs that have sequences of SEQ ID NOs: 21, 22 or 23. In some embodiments, an anti-TIM3 antibody agent comprises a light chain comprising three CDRs that have sequences of SEQ ID NOs: 24, 25 or 26. In some embodiments, an anti-TIM-3 antibody agent comprises a heavy chain comprising three CDRs that have sequences of SEQ ID NOs: 21, 22 or 23; and a light chain comprising three CDRs that have SED ID NOs sequences: 24, 25 or 26. In some embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain, the amino acid sequence of which comprises SEQ ID NO: 1 or SEQ ID NO: 7. In some embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin light chain variable domain, whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, an anti-TIM-3 antibody agent TIM-3 comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7 and an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, an anti-TIM-3 antibody agent comprises two immunoglobulin heavy chains, each having an amino acid sequence as set out in SEQ ID NO: 3. In some embodiments, an antibody agent anti-TIM-3 comprises an immunoglobulin light chain, whose amino acid sequence comprises SEQ ID NO: 4. In some embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain, whose sequence amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain whose sequence of
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47/172 amino acids comprises SEQ ID NO: 4.
[00119] In some modalities, patients in the cancer patient population each have a tumor. In some modalities, patients in the cancer patient population each have a solid tumor. In some modalities, at least some of the patients in the cancer patient population have an advanced solid stage tumor. In some modalities, at least some of the patients in the cancer patient population have a solid metastatic tumor. In some embodiments, the patient has a solid MSI-H tumor. In some embodiments, patients in the cancer patient population have cancer such as non-small cell lung cancer (NSCLC), hepatocellular cancer, kidney cancer, melanoma, cervical cancer, colorectal cancer, carcinoma squamous cell cancer of the anogenital region (for example, squamous cell carcinoma of the anus, penis, cervix, vagina or vulva), head and neck cancer, triple-negative breast cancer, ovarian cancer or cancer endometrial.
[00120] In the modalities, the patient has lung cancer (for example, non-small cell lung cancer (NSCLC)). In the modalities, the patient has a melanoma.
[00121] In some modalities, the patient has a cancer associated with a mutation of POLE (DNA polymerase epsilon) or POLD (DNA polymerase delta). In some embodiments, the POLE or POLD mutation is in an exonuclease domain. In some modalities, the POLE or POLD mutation is a germline mutation. In some embodiments, the POLE or POLD mutation is a sporadic mutation. In some embodiments, a method described in this document comprises a step of first identifying the patient who has the cancer with the POLE or POLD mutation. In some embodiments, a POLE or POLD mutation is identified using sequencing.
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48/172 [00122] In some modalities, patients in the cancer patient population each have a cancer with microsatellite instability. In some modalities, microsatellite instability is considered high, where instability is significantly higher than that observed in a control cell (for example, MSI-H status). In some embodiments, microsatellite instability is MSI-Low (MSI-L). In some embodiments, microsatellite instability is stable microsatellite (eg, MSS status). In some modalities, a patient has an advanced solid stage tumor with microsatellite instability.
[00123] In some modalities, patients in the cancer patient population each have hematological cancer. In some modalities, patients in the cancer patient population each have hematological 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 some modalities, patients in the cancer patient population each have hematological cancer with microsatellite instability.
[00124] In some modalities, at least some of the patients in the cancer patient population have previously been treated with one or more different cancer treatment modalities. In the modalities, at least some of the patients in the cancer patient population have previously been treated with one or more of radiotherapy, chemotherapy or immunotherapy. In some modalities, at least some of the patients in the cancer patient population have previously been treated with chemotherapy (for example, platinum-based chemotherapy).
[00125] In some modalities, at least some of the patients in the cancer patient population have not previously been treated with one or more different cancer treatment modalities.
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49/172 [00126] The present disclosure provides, in some embodiments, a combination therapy for use in the treatment of cancer in a selected cancer patient population, wherein the combination therapy comprises administering an anti-TIM- 3 and a PD-1 binding agent.
BRIEF DESCRIPTION OF THE FIGURES [00127] Figure 1 depicts a schematic illustration, not to scale, of the increased activation of immune cells by anti-TIM-3 and anti-PD1.
[00128] Figures 2A-2B describe results from an exemplary T cell depletion model. (A) Target expression of PD-1 and TIM-3 in sensitive (pre-stimulated) and depleted (post-stimulated cells) cells. (B) Quantification of IFNy production in depleted (post-stimulated) cells treated with a combination of an anti-PD1 antibody agent and an anti-TIM-3 antibody agent, an anti-PD-1 antibody agent, an anti-TIM-3 antibody and isotype control.
[00129] Figure 3 describes the results of an in vivo efficacy study of a combination of an exemplary anti-PD-1 antibody (TSR-042) and an exemplary anti-TIM-3 antibody (TSR-022). In the study, huNOG-EXL mice transplanted neonatal with CD34 + hematopoietic stem cells were implanted with A549 NSCLC cells and treated with unique agents and combinations of anti-PD-1 and anti-TIM-3 antibodies.
[00130] Figure 4A refers to a dose escalation study for an exemplary anti-TIM-3 antibody (TSR-022) as monotherapy or in combination with an anti-PD-1 antibody.
[00131] Figure 4B refers to an expansion cohort to assess the antitumor activity of an exemplary anti-TIM-3 antibody (TSR-022) as a monotherapy and in combination with an anti-PD-1 antibody in patients with specific tumor types.
[00132] Figure 5 describes the demographic characteristics of
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50/172 patients and the reference characteristics of the participants in the dose escalation study.
[00133] Figure 6A represents the average PK profiles of an exemplary anti-TIM-3 antibody (TSR-022) after the first dose.
[00134] Figure 6B describes the occupancy of TIM-3 in circulating monocytes, as measured by flow cytometry from whole blood samples collected from patients treated with an exemplary anti-TIM-3 antibody (TSR-022).
[00135] Figures 7A-7C describe the occupancy of the TIM-3 receptor for an exemplary anti-TIM-3 antibody (TSR-022) at doses of 1 mg / kg (FIG. 7A), 3 mg / kg (FIG .7B) and 10 mg / kg (FIG. 7C) administered once every two weeks (Q2W).
[00136] Figure 8 describes the effects of treatment with an exemplary anti-TIM-3 antibody (TSR-022). The duration of treatment associated with specific dosages is shown, and a partial response is indicated by black squares and stable disease is indicated by black triangles.
[00137] Figure 9 describes the brain tomography of a patient with leiomyosarcoma, metastatic to the lung and kidney, and who received three doses of an exemplary anti-TIM-3 antibody (TSR-022) at 10 mg / kg before re - image generation stage.
[00138] Figure 10 describes a study of receptor occupancy of a fixed dose of 100 mg of an exemplary anti-TIM-3 antibody (TSR-022) administered once every three weeks (Q3W).
[00139] Figure 11 describes an occupancy study of a fixed dose of 300 mg of an exemplary anti-TIM-3 antibody (TSR-022) administered in combination with a fixed dose of 500 mg of an anti-PD-1 antibody example (TSR-042). A second dose of TSR-022 was administered on day 22, with the RO sample collected before the second dose.
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51/172 [00140] Figure 12 is a composite of average receptor occupancy data for doses of an exemplary anti-TIM-3 antibody (TSR-022) of 1 mg / kg, 3 mg / kg, 10 mg / kg and single doses of 100 mg, 300 mg and 1200 mg. The figure shows the occupancy rate (free TIM-3: total TIM-3) measured over a range of days.
DETAILED DESCRIPTION OF CERTAIN MODALITIES
Definitions [00141] About: The term about, when used in this document in reference to a value, refers to a value that is similar, in context, to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variation encompassed by about that context. For example, in some modalities, the term about may encompass a range of values that are within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12% , 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in any direction of the referenced value.
[00142] Administration: As used in this document, the term administration normally refers to the administration of a composition to a subject or system to achieve the distribution of an agent that is, or is included in, the composition. Those of ordinary skill in the art will be aware of a variety of routes that can, in appropriate circumstances, be used for administration to a subject, for example, a human. Examples of routes of administration include parenteral administration, for example, intravenous, intradermal, subcutaneous, oral (e.g., by inhalation), transdermal (i.e., topical), transmucosal and rectal. For example, in some modalities, administration can be ocular, oral, parenteral, topical, etc. In the modalities, the administration is parenteral (for example, intravenous administration). In modalities, intravenous administration is intravenous infusion. In some particular modalities, administration can be bronchial (for example, by bronchial instillation), buccal, dermal (which
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52/172 can be or comprise, for example, one or more topical for the dermis, intradermal, interddermal, transdermal, etc.), enteric, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous , intraventricular, within a specific organ (e.g., intrahepatic), mucous, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreous, etc. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve the application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated over time) and / or periodic dosing (e.g., individual doses separated by a common period of time). In some embodiments, administration may involve continuous dosing (e.g., infusion) for at least a selected period of time.
[00143] Solutions or suspensions used for parenteral, intradermal or subcutaneous application 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 methyl parabens; antioxidants, such as ascorbic acid or sodium bisulfide; chelating agents, such as ethylenediamine tetraacetic acid (EDTA); buffers, such as acetates, phosphate citrates and agents for adjusting tonicity, such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be filled in ampoules, disposable syringes or multi-dose bottles made of glass or plastic.
[00144] For administration by inhalation, the compounds are delivered in the form of an aerosol sprayed from a pressurized container or dispenser containing a suitable propellant, for example, a
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53/172 gas such as carbon dioxide, or a nebulizer.
[00145] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art and include, for example, transmucosal administration, detergents, bile salts and fusidic acid derivatives. Transmucosal administration can be performed through the use of nasal spray or suppositories. For transdermal administration, the active compounds are formulated in ointments, ointments, gels or creams, as is known in the art in general.
[00146] The compounds can also be prepared in the form of suppositories (for example, with conventional suppository bases, such as cocoa butter and other glycerides) or retention enemas for rectal administration.
[00147] Affinity: As known in the art, affinity is a measure of tension with a particular ligand that binds to its partner. Affinities can be measured in different ways. In some embodiments, affinity is measured by a quantitative assay. In some of these embodiments, the concentration of the binding partner can be set to be in excess of the concentration of the ligand in order to mimic physiological conditions. Alternatively or additionally, in some embodiments, the concentration of the binding partner and / or the concentration of ligands can be varied. In some of these modalities, affinity can be compared to a reference under comparable conditions (for example, concentrations).
[00148] Antibody: As used herein, the term antibody refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen. As is known in the art, intact antibodies as produced in nature are approximately
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54/172 tetrametric 150 kD composed of two identical heavy chain polypeptides (about 50 kD each) and two identical light chain polypeptides (about 25 kD each) that associate with each other in what is commonly referred to as a structure Y-shaped. Each heavy chain consists of at least four domains (each about 110 amino acids long) - an amino-terminal variable domain (VH) (located at the ends of the Y structure), followed by three constant domains : CH1, CH2 and the carboxy-terminal CH3 (located at the base of the Y rod). A short region, known as a switch, connects the heavy chain variable and the constant regions. The hinge connects the CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy chain polypeptides to each other in an intact antibody. Each light chain is composed of two domains: an amino-terminal variable domain (VL), followed by a carboxy-terminal constant domain (CL), separated from each other by another switch. Those skilled in the art are well familiar with the antibody structure and sequence elements, recognize variable and constant regions in the sequences provided and understand that there may be some flexibility in defining a boundary between such domains, so that different presentations of the same sequence of antibody strands may, for example, indicate such a boundary at a location that one or a few residues are displaced in relation to a different presentation of the same antibody chain sequence. The intact antibody tetramers are made up of two heavy chain-light chain dimers, in which the heavy and light chains are linked to each other by a single disulfide bond; two other disulfide bonds connect the heavy chain hinge regions to one another, so that the dimers are connected to each other and the tetramer is formed. Naturally produced antibodies are also glycosylated, typically in the CH2 domain. Each domain in a natural antibody has a structure
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55/172 characterized by an "immunoglobulin fold" formed from two beta sheets (for example, sheets of 3, 4 or 5 strips) packaged against each other in a compressed anti-parallel beta drum. Each variable domain contains three hypervariable loops known as “complementarity determining regions” (CDR1, CDR2 and CDR3) and four somewhat invariant “structural” regions (FR1, FR2, FR3 and FR4). When the natural antibodies fold, the FR regions form the beta leaves that provide the structural structure for the domains, and the CDR loop regions of the heavy and light chains are brought together in three-dimensional space to create a single hypervariable antigen binding site. located at the tip of the Y-structure. The Fc region of naturally occurring antibodies binds to elements of the complement system and also to receptors on effector cells, including, for example, effector cells that mediate cytotoxicity. As is known in the art, affinity and / or other attributes of binding of Fc regions to Fc receptors can be modulated through glycosylation or other modification. In some embodiments, antibodies produced and / or used in accordance with the present invention include glycosylated Fc domains, including Fc domains with such modified or engineered glycosylation. For the purposes of the present invention, in certain embodiments, any polypeptide or polypeptide complex that includes sufficient immunoglobulin domain sequences as found in natural antibodies can be referred to and / or used as an "antibody", this polypeptide being naturally produced (for example , generated by an organism that reacts to an antigen), or produced by recombinant manipulation, chemical synthesis or other artificial system or methodology. In some embodiments, an antibody is polyclonal; in some embodiments, an antibody is monoclonal. In some embodiments, an antibody has constant region sequences that are characteristic of mouse, rabbit, primate or human antibodies. In some modalities, the sequence elements are humanized, primatized,
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56/172 chimeric, etc., as is known in the art. In addition, the term antibody, as used in this document, may refer, in the appropriate modalities (unless otherwise indicated or clearly from the context) to any constructs known in the art or developed or formats to use the structure of the antibody and functional characteristics in the alternative presentation. For example, in some embodiments an antibody used in accordance with the present invention is in a format selected from, but not limited to, intact IgA, IgG, IgE or IgM antibodies; bi or multispecific antibodies (for example, Zybodies®, etc.); antibody fragments such as Fab fragments, Fab 'fragments, F (ab') 2 fragments, Fd 'fragments, isolated Fd fragments and CDRs or their assemblies; Single chain Fvs; Fc polypeptide fusions; single domain antibodies (for example, shark single domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; masked antibodies (for example, Probodies®); Small Modular Immunopharmaceuticals (“SMIPs ™); single chain or tandem diabodies (TandAb®); VHHs; Anticalins®; Nanobodies® minibodies; BiTE®s; ankyrin repeat proteins or DARPINs®; Avimers®; DARTs; TCR type antibodies; Adnectins®; Affilins®; Trans-bodies®; Affibodies®; TrimerX®; MicroProteins; Fynomers®; Centyrins®; and KALBITOR®s. In some embodiments, an antibody may not have a covalent modification (for example, a glycan bond) that it would have if it were produced naturally. In some embodiments, an antibody may contain a covalent modification (for example, a glycan bond, a payload [for example, a detectable fraction, a therapeutic fraction, a catalytic fraction, etc.] or another pending group [for example, polyethylene glycol, etc.].
[00149] Antibodies include antibody fragments. Antibodies also include, but are not limited to, polyclonal monoclonal antibody, chimeric dAb antibody (antibody domain), single chain, Fab, Fab, F expression libraries (abj 2, scFvs and F _a b. An antibody can be a antibody
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57/172 complete, or immunoglobulin, or an antibody fragment.
[00150] Antibody agent: As used herein, the term antibody agent refers to an agent that specifically binds to a particular antigen. In some embodiments, the term encompasses any polypeptide or polypeptide complex that includes sufficient immunoglobulin structural elements to confer specific binding. Exemplary antibody agents include, but are not limited to, monoclonal antibodies or polyclonal antibodies. In some embodiments, an antibody agent can include one or more constant region sequences that are characteristic of mouse, rabbit, primate or human antibodies. In some embodiments, an antibody agent can include one or more sequence elements that are humanized, primatized, chimeric, etc., as is known in the art. In many embodiments, the term antibody agent is used to refer to one or more of the constructs or formats known or developed in the art to use structural and functional characteristics of antibody in alternative presentation. For example, in some embodiments an antibody agent used in accordance with the present invention is in a format selected from, but not limited to, intact IgA, IgG, IgE or IgM antibodies; bi or multispecific antibodies (for example, Zybodies®, etc.); antibody fragments such as Fab fragments, Fab 'fragments, F (ab') 2 fragments, Fd 'fragments, isolated Fd fragments and CDRs or their assemblies; Single chain Fvs; Fc polypeptide fusions; single domain antibodies (for example, shark single domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; masked antibodies (for example, Probodies®); Small Modular Immunopharmaceuticals (“SMIPs ™); single chain or tandem diabodies (TandAb®); VHHs; Anticalins®; Nanobodies® minibodies; BiTE®s; ankyrin repeat proteins or DARPINs®; Avimers®; DARTs; TCR-type antibodies;, Adnectins®; Affilins®; Transbodies®; Affibodies®; TrimerX®; MicroProteins; Fynomers®; Centyrins®; and
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58/172
KALBITOR®s. In some embodiments, an antibody may not have a covalent modification (for example, a glycan bond) that it would have if it were produced naturally. In some embodiments, an antibody may contain a covalent modification (for example, a glycan bond, a payload [for example, a detectable fraction, a therapeutic fraction, a catalytic fraction, etc.] or another pending group [for example, polyethylene glycol, etc.]. In many embodiments, an antibody agent is or comprises a polypeptide whose amino acid sequence includes one or more structural elements recognized by those skilled in the art as a complementarity determining region (CDR); In some embodiments, an agent antibody is or comprises a polypeptide whose amino acid sequence includes at least one CDR (for example, at least one heavy chain CDR and / or at least one light chain CDR) that is substantially identical to that found in an antibody reference. In some embodiments, an included CDR is substantially identical to a reference CDR insofar as it is identical in sequence or cont m between 1-5 amino acid substitutions compared to the reference CDRs. In some embodiments, an included CDR is substantially identical to a reference CDR in that it shows at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94 %, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in that it has at least 96%, 96%, 97%, 98%, 99% or 100% sequence identity with the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in which at least one amino acid within the included CDR is excluded, added or substituted in comparison to the reference CDR, but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments, an included CDR is substantially
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59/172 identical to a reference CDR where 1-5 amino acids within the included CDR are deleted, added or substituted compared to the reference CDR, but the included CDR has an amino acid sequence that is otherwise identical to the CDR of reference. In some embodiments, an included CDR is substantially identical to a reference CDR in which at least one amino acid within the included CDR is substituted in comparison to the reference CDR, but the included CDR has an amino acid sequence that is otherwise identical that of the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in which 1-5 amino acids within the included CDR are deleted, added or substituted in comparison to the reference CDR, but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments, an antibody agent is or comprises a polypeptide whose amino acid sequence includes structural elements recognized by those skilled in the art as an immunoglobulin variable domain. In some embodiments, an antibody agent is a polypeptide protein having a binding domain that is homologous or largely homologous to an immunoglobulin binding domain.
[00151] Link: It will be understood that the term link, used in this document, usually refers to a non-covalent association between two or more entities. Direct connection involves physical contact between entities or fractions; Indirect bonding involves physical interaction through physical contact with one or more intermediate entities. The link between two or more entities can normally be assessed in a variety of contexts including whether the entities or fractions of interaction are studied in isolation or in the context of more complex systems (for example, while covalently associated or otherwise with a carrier entity and / or a biological system or cell). In some embodiments, bonding refers to non-covalent interactions of the types that occur between a molecule of
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60/172 immunoglobulin and an antigen for which 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 smaller Kd represents greater affinity. The immunological binding properties of the selected polypeptides can be quantified using methods well known in the art. Such a method implies the measurement of the formation and dissociation rates of the complex antigen / antigen binding site, in which these rates depend on the concentrations of the complex partners, the affinity of the interaction and the geometric parameters that equally influence the rate in both directions. . Thus, the constant of the association rate (K _on ) and the constant of the dissociation rate (K _O ft) can be determined by calculating the concentrations and the effective association and dissociation rates. (See Nature 361: 186-87 (1993)). The ratio K _O ft / K _on allows the cancellation of all parameters not related to affinity and is equal to the dissociation constant Kd. (See, generally, Davies et al. (1990) Annual Rev Biochem 59: 439-473).
[00152] Liaison officer. In general, the term binding agent is used in this document to refer to any entity that binds to a target of interest described in this document. In many embodiments, a liaison officer of interest is one who specifically binds to his target, since he discriminates his target from other potential liaison partners in a context of particular interaction. In general, the linker can be or comprise an entity of any chemical class (e.g., polymer, non-polymer, small molecule, polypeptide, carbohydrate, lipid, nucleic acid, etc.). In some embodiments, a binding agent is a unique chemical entity. In some embodiments, a binding agent is a complex of two or more discrete chemical entities associated with the other under relevant conditions by non-covalent interactions. For example, those skilled in the art will realize that, in some embodiments, a linker may comprise a generic linkage fraction (for example, one of
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61/172 biotin / avidin / streptavidin and / or an antibody of specific class) and a specific binding fraction (e.g., an antibody or aptamers with a particular molecular target) that binds to the partner of the generic binding fraction. In some embodiments, such an approach may allow the modular assembly of multiple binding agents by linking different specific binding moieties with the same partner as the generic binding moiety. In some embodiments, the agents are or comprise polypeptides (including, for example, antibodies or antibody fragments). In some embodiments, the binding agents are or comprise small molecules. In some embodiments, the binding agents are or comprise nucleic acids. In some embodiments, the linkers are aptamers. In some embodiments, the binding agents are polymers; in some embodiments, the binding agents are not polymers. In some embodiments, the binding agents are non-polymeric since they lack polymeric fractions. In some embodiments, the binding agents are or comprise carbohydrates. In some embodiments, the binding agents are or comprise lectins. In some embodiments, the binding agents are or comprise peptidomimetics. In some embodiments, the binding agents are or comprise scaffold structure proteins. In some embodiments, the binding agents are or comprise mimeotopes. In some embodiments, the binding agents are or comprise nucleic acids, such as DNA or RNA.
[00153] Cancer. The terms cancer, malignancy, neoplasm, tumor and carcinoma are used in this document to refer to cells that show relatively abnormal, uncontrolled and / or autonomous growth, so that they present an anomalous growth phenotype characterized by a significant loss of control of cell proliferation. In some embodiments, a tumor may be or comprise cells that are pre-cancerous (eg, benign), malignant, pre-metastatic, metastatic
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62/172 and / or non-metastatic. This disclosure specifically identifies certain cancers for which its teachings may be particularly relevant. In some embodiments, a relevant cancer can be characterized by a solid tumor. In some modalities, a relevant cancer can be characterized by a hematological tumor. In general, examples of different types of cancers known in the art include, for example, hematopoietic cancers that include leukemias, lymphomas (of Hodgkin and non-Hodgkin), myelomas and myeloproliferative disorders; sarcomas, melanomas, adenomas, solid tissue carcinomas, squamous cell carcinomas of the mouth, throat, larynx and lung, liver cancer, genitourinary cancers such as prostate, cervical, bladder, uterine and endometrial cancers and renal cell carcinomas, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, head and neck cancers, breast cancer, gastrointestinal cancers and cancers of the nervous system, benign lesions such as papillomas and the like.
[00154] Carrier: in this document, it refers to a diluent, adjuvant, excipient or vehicle with which a composition is administered. In some exemplary embodiments, carriers include sterile liquids, for example, water and oils, including petroleum oils, of animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components. In some embodiments, the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol and the like) and their suitable mixtures. Proper fluidity can be maintained, for example, by using a coating, such as lecithin, by maintaining the required particle size in the case of dispersion, and by using surfactants. Preventing the action of microorganisms
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63/172 can be obtained by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be caused by the inclusion, in the composition, of an agent that delays absorption, for example, aluminum monostearate and gelatin.
[00155] Combination therapy: In this document, the term combination therapy refers to a clinical intervention in which a subject is simultaneously exposed to two or more therapeutic regimes (for example, two or more therapeutic agents). In some embodiments, two or more therapeutic regimens can be administered simultaneously. In some embodiments, two or more therapeutic regimens can be administered sequentially (for example, a first regimen administered prior to administration of any doses of a second regimen). In some embodiments, two or more therapeutic regimens are administered in overlapping dosing regimens. In some embodiments, the administration of combination therapy may involve administration of one or more therapeutic agents or modalities to a subject receiving another agent (s) or modality. In some embodiments, combination therapy does not necessarily require individual agents to be administered together with a single composition (or even necessarily at the same time). In some embodiments, two or more therapeutic agents or combination therapy modalities are administered to a subject separately, for example, in separate compositions, by means of separate administration routes (for example, one agent by mouth and another agent by intravenously) and / or at different points in time. In some embodiments, two or more therapeutic agents can be administered together in a combination composition or even in a combination compound (for example, as
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64/172 part of a single chemical complex or covalent entity) by the same route of administration and / or at the same time.
[00156] Complete Response: In this document, the term complete response or CR is used to refer to the disappearance of all or substantially all of the target lesions. In some modalities, CR refers to a decrease of about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the sum of the diameters of the target lesions (ie loss of lesions), taking as a reference the diameters of the sum of the baseline. In some modalities, 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 the treatment. Exemplary methods for assessing the complete response are identified by the RECIST guidelines. See, for example, E.A. Eisenhauer, et a!., “New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.),” Eur. J. of Cancer, 45: 228-247 (2009).
[00157] 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 (for example, a therapeutic or diagnostic agent) for administration to a subject. Typically, each unit contains a predetermined amount of active agent. In some embodiments, that amount is a unit dosage amount (or an entire fraction thereof) suitable for administration under a dosage regimen that has been found to correlate with a desired or beneficial result when administered to a relevant population (ie , with a therapeutic dosage regimen). Those of ordinary skill in the art appreciate that the total amount of a composition or therapeutic agent administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.
[00158] Regimen or dosage regimen: Those skilled in the art
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65/172 will appreciate that the term regimen can be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by time periods. In some embodiments, a particular therapeutic agent has a dosage regimen, which may involve one or more doses. In some embodiments, a dosage regimen comprises a plurality of doses, each of which is separated in time from other doses. In some embodiments, individual doses are separated from each other for a period of the same duration; in some embodiments, a regimen comprises a plurality of doses, with at least two different time periods separating individual doses. In some embodiments, all doses within the dosage regimen are the same unit dose amount. In some embodiments, different doses within a dosage regimen are of different amounts. In some embodiments, a dosage regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount other than the first dose amount. In some embodiments, a dosage regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount equal to the first dose amount. In some modalities, a dosage regimen is correlated with the desired or beneficial outcome when administered to the entire relevant population (ie, it is a therapeutic dosage regimen). In some embodiments, a regimen comprises at least one dose, wherein the dose comprises a unit dose of a therapeutic agent (for example, an anti-TIM-3 antibody agent). In some embodiments, a regimen comprises at least one dose, wherein the dose comprises two or more unit doses of a therapeutic agent. For example, a 500 mg dose can be administered as a single 500 mg unit dose or as two 250 mg unit doses. In some
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66/172 modalities, a regimen is correlated with or results in a desired or beneficial outcome when administered through a relevant population (ie, it is a therapeutic regimen).
[00159] Reason for Risk: In this document, a “risk ratio” is the expression of the risk or chance of events occurring in the treatment arm as a reason for the events occurring in the control arm. The risk ratios can be determined by the Cox model, a regression method for survival data, which provides an estimate of the risk ratio and its confidence interval. The risk ratio is an estimate of the ratio between the risk rate in the treated group versus the control group. The risk rate is the probability that, if the event in question has not yet occurred, it will occur in the next interval of time, divided by the duration of that interval. An assumption of proportional risk regression is that the risk ratio is constant over time.
[00160] Homology: In this document, the term homology refers to a general similarity between polymeric molecules, for example, between nucleic acid molecules (for example, DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, polymeric molecules are considered homologous to another 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, polymeric molecules are considered homologous to another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% , 80%, 85%, 90%, 95% or 99% similar (for example, containing residues with related chemical properties in corresponding positions). For example, as is well known to those skilled in the art, certain amino acids are usually classified as similar to other hydrophobic or hydrophilic amino acids and / or having polar or non-polar side chains. The substitution of one amino acid for another of the same
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67/172 type can often be considered a homologous substitution.
[00161] As will be understood by those skilled in the art, a variety of algorithms are available that allow comparison of the sequences to determine their degree of homology, including allowing gaps of designated length in one sequence in relation to the other when considering which residues correspond to each other in different sequences. The calculation of the percentage of homology between two nucleic acid sequences, for example, can be performed by aligning two sequences for an ideal comparison (for example, gaps can be introduced in one or both first and second nucleic acid sequences for optimal alignment and unmatched strings can be disregarded for comparison). In certain embodiments, the length of an aligned sequence for comparison 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 that of the corresponding position in the second sequence, then the molecules are identical in that position; when a position in the first sequence is occupied by a nucleotide similar to the corresponding position in the second sequence, then the molecules are similar in that position. The percentage of homology between the 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, which needs to be introduced for optimal alignment of the two sequences. Representative algorithms and computer programs useful in determining the percentage of homology between two nucleotide sequences include, for example, the Meyers and Miller algorithm (CABIOS, 1989, 4: 11-17), which was incorporated into the ALIGN program (version 2.0 ) using
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68/172 residue weight table PAM120, a gap length penalty of 12 and a gap penalty of 4. The percentage of homology between two nucleotide sequences can alternatively be determined, for example, using the GAP program in the package of GCG software using an NWSgapdna.CMP [00162] Kd matrix: in this document, it refers to the dissociation constant of a binding agent (for example an antibody or its binding component) from a complex with its partner (for example, the epitope to which the antibody or its binding component binds).
[00163] K _{The end} : in this document, it refers to the dissociation rate constant for dissociation of a binding agent (for example, an antibody or its binding component) from a complex with its partner (for example, the epitope to the which the antibody or its binding component binds).
[00164] Kon: in this document, it refers to the association rate constant for the association of a binding agent (for example, an antibody or its binding component) with its partner (for example, the epitope to which the antibody or its connecting component connects).
[00165] Patient or subject: In this document, the term patient or subject refers to any organism to which the compound or compounds described in this document are administered in accordance with the present invention, for example, for experimental, diagnostic, prophylactic and / or therapeutic. Typical subjects include animals. The term animal refers to any member of the animal kingdom. In some modalities, animal refers to humans, at any stage of development. In some embodiments, animal refers to non-human animals at any stage of development. In certain embodiments, the non-human animal is a mammal (for example, a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate and / or a pig) . In some embodiments, animals include, without limitation, mammals, birds, reptiles,
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69/172 amphibians, fish, insects and / or worms. In some embodiments, an animal may be a transgenic animal, a genetically manipulated animal and / or a clone. In some embodiments, animals are mammals, such as mice, rats, rabbits, non-human and human primates; insects; worms; etc. In a preferred embodiment, a subject is a human. In some modalities, a subject may be suffering from or be susceptible to a disease, disorder and / or condition (for example, cancer). In this document, a patient population or subject population refers to patients or subjects.
[00166] Partial Response: In this document, the term "partial response" ("PR") refers to a decrease in tumor progression in a subject as indicated by a decrease in the sum of the diameters of the target lesions, taking as a reference the diameters of the target lesion. sum of the baseline. In some modalities, PR refers to a decrease of at least 30% in the sum of diameters or target lesions, taking as a reference the diameters of the sum of the baseline. Exemplary methods for assessing the partial response are identified by 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).
[00167] Pharmaceutical composition: In this document, the term pharmaceutical composition refers to a composition in which an active agent (for example, an anti-TIM-3 antibody agent and / or 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 of unit dose suitable for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, a pharmaceutical composition can be specially formulated for administration in solid or liquid form, including those adapted for oral administration, for example,
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70/172 purges (aqueous or non-aqueous solutions or suspensions), tablets, for example, those intended for oral, sublingual and systemic absorption, boluses, powders, granules, pastes for application on the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection such as, for example, a sterile solution or suspension or prolonged release formulation; topical application, for example, as a cream, ointment or controlled-release patch or spray applied to the skin, lungs or oral cavity; intravaginal or intrarectal route, for example, as a pessary, cream or foam; sublingual route; ocular route; transdermal route; or nasal, pulmonary and other mucosal surfaces. In some preferred embodiments, an active agent (for example, an anti-TIM-3 antibody agent and / or a PD-1 binding agent) is formulated for parenteral administration.
[00168] Pharmaceutically acceptable: In this document, the term pharmaceutically acceptable applied to the carrier, diluent or excipient used to formulate a composition disclosed in this document means that the carrier, diluent or excipient must be compatible with other ingredients of the composition and not harmful to its container .
[00169] Progression-Free Survival: In this document, the term "progression-free survival" refers to the period of time during which a subject with a disease (for example, cancer) survives, without a significant worsening of the disease state. Progression-free survival can be assessed as a period of time when there is no progression of tumor growth and / or when a patient's disease status is not determined to be a progressive disease. In some modalities, the progression-free survival of a subject with cancer is assessed by assessing the size of the tumor (lesion), number of the tumor (lesion) and / or metastasis.
[00170] Progression or Progressive Disease: The term progression of tumor growth or progressive disease (PD) used in this document in reference to the status of cancer, indicates an increase in the sum of
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71/172 diameters of the target lesions (tumors). In some modalities, the progression of tumor growth refers to an increase of at least 20% in the sum of the diameters of the target lesions, taking as reference the smallest sum in the study (this includes the sum of the baseline if this is the in the study). In some modalities, in addition to a relative increase of 20%, the sum of the diameters of the target lesions must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions can also be considered in determining the progression of tumor growth. The progression to determine progression-free survival can also be determined if at least one of the following criteria is met: 1) CT / MRI tumor evaluation unequivocally shows progressive disease according to the RECIST 1.1 or irRECIST criteria; or 2) additional diagnostic tests (for example, histology / cytology, ultrasound techniques, endoscopy, positron emission tomography) to identify new lesions or to determine existing lesions qualified for unambiguous progressive disease AND CA-125- progression according to the criteria the Gynecologic Cancer Intergroup (GCIG) (see Rustin et al., Int J Gynecol Cancer 2011; 21: 419-423 which is incorporated in this document in its entirety); 3) definitive clinical signs and symptoms of PD unrelated to non-malignant or iatrogenic causes ([i] intractable cancer-related pain; [ii] intestinal dysfunction / malignant worsening; or [iii] unmistakable symptomatic worsening of ascites or pleural effusion) E CA-125-progression according to the GCIG criteria.
[00171] Solid Tumor: In this document, the term solid tumor refers to an abnormal mass of tissue that normally does not contain cysts or areas with fluid. In some embodiments, a solid tumor can be benign; in some embodiments, a solid tumor can be malignant. Those skilled in the art will appreciate that different types of solid tumors are usually named for the type of cells that form them. Examples of solid tumors are carcinomas, lymphomas and sarcomas. In some modalities, tumors
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72/172 solids can be or comprise adrenal, bile duct, bladder, bone, breast, cervical, colon, endometrial, esophageal, ocular, gallbladder, gastrointestinal tract, kidney tumors, larynx, liver, lung, nasal cavity, nasopharynx, oral cavity, ovary, penis, pituitary, prostate, retina, salivary gland, skin, small intestine, stomach, testis , of the thymus, thyroid, uterine, vaginal and / or vulva.
[00172] Stabilization or Stable Disease: In this document, "stabilization" of tumor growth or "stable disease" (SD) does not refer to sufficient shrinkage to qualify for RP or a sufficient increase to qualify for RP. In some modalities, stabilization refers to a change of less than 30%, 25%, 20%, 15%, 10% or 5% (increase or decrease) in the sum of the diameters of the target lesions, taking the diameters as a reference the sum of the baseline. Exemplary methods for assessing tumor growth stabilization or a stable disease are identified by the RECIST guidelines. See, for example, E.A. Eisenhauer, et a!., “New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.),” Eur. J. of Cancer, 45: 228-247 (2009).
[00173] Therapeutically Effective Quantity: In this document, it refers to a quantity that produces 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 that suffers or is susceptible to a disease, disorder and / or condition according to a therapeutic dosage regimen, to treat the disease, disorder and / or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence and / or severity of, and / or delays in initiating, one or more symptoms of the disease, disorder and / or condition. Those skilled in the art will appreciate that the term therapeutically effective amount does not require successful treatment to be achieved in a specific individual. On the contrary, a
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73/172 therapeutically effective amount may be the amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. In some embodiments, the reference to a therapeutically effective amount may be a reference to an amount measured in one or more specific tissues (for example, a tissue affected by the disease, disorder or condition) or fluids (for example, 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 can be formulated and / or administered in a single dose. In some embodiments, a therapeutically effective agent can be formulated and / or administered in a plurality of doses, for example, as part of a dosage regimen.
[00174] Treatment: In this document, the term treatment (also treating or treating) refers to any administration of a therapy that relieves, improves, revives, inhibits, delays, reduces the severity of, and / or reduces the incidence of a or more symptoms, characteristics and / or causes of a particular disease, disorder and / or condition. In some modalities, this treatment may be of a subject who does not show signs of the relevant disease, disorder and / or condition and / or of a subject who displays only early signs of the disease, disorder and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some modalities, treatment may be for a subject who has been diagnosed as suffering from the relevant disease, disorder and / or condition. In some modalities, the treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the disease, disorder and / or relevant condition.
Treatment Methods, Including Cancer Treatment Methods
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74/172 [00175] Methods of treating disorders in a subject (for example, disorders that benefit from the administration of anti-TIM-3 therapy) are described in this document. For example, a therapy with ati-TIM-3 described in this document the agent can be administered, for example, as a monotherapy or in combination therapy, for a period sufficient to achieve clinical benefit or according to a regime determined by a doctor (for example, an anti-TIM-3 therapy is administered in dosage amounts and number of treatment cycles determined by a doctor).
[00176] In the modalities, the methods described in this document are useful to increase the activation of the T cell or the effector function of the T cell in a subject.
[00177] In the modalities, the methods described in this document are useful to induce an immune response in a subject.
[00178] In the modalities, the methods described in this document are useful to enhance an immune response or increase the activity of an immune cell in a subject.
[00179] Inventive methods can be used to treat any type of infectious disease (ie, a disease or disorder caused by a bacterium, a virus, a fungus or a parasite). Examples of infectious diseases that can be treated by the inventive method include, but are not limited to, diseases caused by a human immunodeficiency virus (HIV), a respiratory syncytial virus (RSV), an influenza virus, a dengue virus, a hepatitis B virus (HBV or a hepatitis C virus (HCV)). When the inventive method treats an infectious disease, an anti-TIM-3 antibody agent can be administered in combination with at least one antibacterial agent or at least one antiviral agent. In this regard, the antibacterial agent can be any suitable antibiotic known in the art. The antiviral agent can be any vaccine of any suitable type that specifically targets a virus
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75/172 specific (for example, live attenuated vaccines, subunit vaccines, recombinant vector vaccines and small molecule antiviral therapies (for example, viral replication inhibitors and nucleoside analogs).
[00180] Inventive methods can be used to treat any type of autoimmune disease (that is, as a disease or disorder caused by the activity of the immune system in which the body attacks and damages its own tissues), such as those described, for example, MacKay IR and Rosa N.R., eds., The Auto Diseases, Fifth Edition, Academic Press, Waltham, MA (2014). Examples of autoimmune diseases that can be treated by the inventive method 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 inventive method treats an autoimmune disease, an 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) ) (for example, aspirin, ibuprofen and naproxen).
[00181] In the modalities, the methods described in this document are useful for treating dysfunctional T cell disorders (eg, cancer).
[00182] In the embodiments, the methods described in this document are useful for reducing tumors or inhibiting the growth of tumor cells in a subject.
[00183] Inventive methods can be used to treat any type of cancer known in the art.
[00184] In the modalities, a cancer is adenocarcinoma, lung adenocarcinoma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), adrenocortical carcinoma, anal cancer, appendix cancer, B cell derived leukemia, B cell derived lymphoma , bladder cancer, brain cancer, breast cancer (e.g. breast cancer
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76/172 triple negative (TNBC), fallopian tube cancer, testicular cancer, brain cancer, cervical cancer, choriocarcinoma, chronic myeloid leukemia, CNS tumor, colon adenocarcinoma, colon cancer, colorectal cancer, diffuse intrinsic pontine glioma (DIPG), diffuse large B cell lymphoma (DLBCL), embryonic rhabdomyosarcoma (ERMS), endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, follicular lymphoma (FL), gallbladder cancer, gastric cancer, gastrointestinal cancer , glioma, head and neck cancer, hematological cancer, hepatocellular cancer, Hodgkin's lymphoma (HL) / primary mediastinal B cell lymphoma, kidney cancer, clear cell kidney cancer, laryngeal cancer, leukemia, liver cancer, cancer lung, lymphoma, melanoma, Merkel cell carcinoma, mesothelioma, monocytic leukemia, multiple myeloma, myeloma, neuroblastic-derived CNS tumor (for example, neuroblasts takes (NB)), 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 classic Hodgkin's lymphoma, renal cell carcinoma, rectal cancer, salivary gland cancer (eg, salivary gland tumor), sarcoma, skin cancer, small cell lung cancer, cancer of the small intestine, squamous cell carcinoma of the anogenital region (for example, 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, leukemia derived from T cells, lymphoma derived from T cells, thyroid cancer, thymoma, thyroid cancer, uveal melanoma, carcinoma of urothelial cells, uterine cancer, uterine endometrial cancer, uterine sarcoma, vaginal cancer, vulvar cancer or Wilms' tumor.
[00185] In other modalities, a cancer is a cancer of the head and
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77/172 neck, lung cancer (for example, 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, vulva cancer, uterine cancer, endometrial cancer, ovarian cancer, urn cancer of the fallopian tubes, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, carcinoma of urothelial cells or a squamous cell carcinoma (for example, of the lung; of the anogenital region, including anus, penis, cervix, vagina or vulva; or of the esophagus). In some embodiments, a cancer for treatment in the context of this disclosure is a melanoma, renal cell carcinoma, lung cancer , bladder cancer, breast cancer, cervical cancer, colon cancer, gallbladder cancer, larynx cancer, liver cancer, thyroid cancer, stomach cancer, salivary gland cancer, prostate cancer, pancreatic cancer or carcinoma of Merkel cells.
[00186] In the modalities, a cancer is a lymphoma such as Hodgkin's disease, Non-Hodgkin's lymphoma, Multiple myeloma, Waldenstrom's macroglobulinemia, Heavy chain disease and Polycythemia vera.
[00187] In the modalities, a cancer is a squamous cell carcinoma. In the modalities, a cancer is squamous cell carcinoma of the lung. In the modalities, a cancer is squamous cell carcinoma of the esophagus. In the modalities, a cancer is the squamous cell carcinoma of the anogenital region (for example, the anus, penis, cervix, vagina or vulva). In the modalities, a cancer is squamous cell carcinoma of the head and neck (HNSCC).
[00188] In the modalities, a cancer is bladder cancer, breast cancer (eg triple negative breast cancer (TNBC)), cancer of the fallopian tubes, collagiocarcinoma, colon adenocarcinoma, cancer
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78/172 endometrial, esophageal cancer, Ewing's sarcoma, gastric cancer, clear cell kidney cancer, lung cancer (eg, adenocarcinoma or squamous cell lung cancer), mesothelioma, ovarian cancer, pancreatic cancer, peritoneal cancer , prostate cancer, uterine endometrial cancer or uveal melanoma. In the modalities, a cancer is ovarian cancer, cancer of the fallopian tubes or peritoneal cancer. In certain modalities, cancer is breast cancer (for example, TNBC). In the modalities, a cancer is a lung cancer (for example, non-small cell lung cancer). In the modalities, a cancer is prostate cancer.
[00189] In the modalities, a cancer is cancer of the CNS or brain such as neuroblastoma (NB), glioma, diffuse intrinsic pontine glioma (DIPG), polyocytic astrocytoma, astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, medulloblastoma, craniopharyngoma, pineal, ependymoma, pineal gland , acoustic neuroma, oligodendroglioma, meningioma, vestibular schwannoma, adenoma, metastatic brain tumor, meningioma, spinal tumor or medulloblastoma. In the modalities, a cancer is a CNS tumor.
[00190] In other modalities, a cancer is melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gallbladder cancer, larynx cancer, liver cancer, cancer thyroid cancer, stomach cancer, salivary gland cancer, prostate cancer, pancreatic cancer, adenocarcinoma (eg, lung adenocarcinoma) or Merkel cell carcinoma (see, for example, Bhatia et al., Curr. Oncol. Rep. ., 13 (6): 488-497 (2011)).
[00191] In some modalities, a patient or patient population has hematological cancer. In some modalities, the patient has hematological 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
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79/172 multiple myeloma (“MM”). In the modalities, a cancer is a blood cancer such as acute lymphoblastic leukemia (ALL), acute B-cell lymphoblastic leukemia, acute T-cell lymphoblastic leukemia, myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL ), acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakarioblastic leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), myeloma and leukemia; acute and chronic leukemias such as lymphoblastic, myeloid, lymphocytic and myelocytic leukemias.
[00192] In some embodiments, a patient or patient population has a solid tumor. In the modalities, a cancer is a solid tumor such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliossarcoma, synovioma, mesothelioma, cancer of tumors, Ewing's tumor, tumors colorectal, 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, cell carcinoma basal, adenocarcinoma, carcinoma of the sweat gland, carcinoma of the sebaceous gland, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, carcinoma of the bile duct, chorionic carcinoma, chorionic carcinoma, chorionic carcinoma , cervical cancer, uterine cancer, testicular cancer lo, non-small cell lung cancer (NSCLC), small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, skin cancer, melanoma, neutroblastoma (NB) or retinoblastoma. In some embodiments, the tumor is a solid tumor in an advanced stage. In some embodiments, the tumor is a solid metastatic tumor.
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In some embodiments, the patient has a solid MSI-H tumor.
[00193] In some embodiments, a patient or patient population that is to be treated by the methods of the present invention has or is susceptible to cancer, such as head and neck cancer, lung cancer (e.g., lung cancer non-small cell (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer , uterine tube cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, carcinoma of urothelial cells or a squamous cell carcinoma (for example, of the lung; of the anogenital region, including anus, penis, cervix, vagina or vulva; or of the esophagus). In some embodiments, a patient or patient population that is to be treated by the methods of the present invention has or is susceptible to lung cancer (eg, NSCLC), kidney cancer, melanoma, cervical cancer, colorectal cancer or endometrial cancer (eg , MSS endometrial cancer or MSI-H endometrial cancer).
[00194] In some embodiments, a patient or patient population that should be treated by the methods of the present invention has or is susceptible to non-small cell lung cancer (NSCLC), hepatocellular cancer, kidney cancer, melanoma, a cervical cancer, a colorectal cancer, a squamous cell carcinoma of the anogenital region (for example, squamous cell carcinoma of the anus, penis, cervix, vagina or vulva), a head and neck cancer, a triple breast cancer -negative, ovarian cancer or endometrial cancer. In some modalities, a patient has a solid tumor in an advanced stage such as non-small cell lung cancer (NSCLC), hepatocellular cancer, kidney cancer, melanoma, cervical cancer, colorectal cancer, cell carcinoma
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81/172 squamous anogenital region (eg squamous cell carcinoma of the anus, penis, cervix, vagina or vulva), head and neck cancer, triple-negative breast cancer, ovarian cancer or a endometrial cancer. In some modalities, a patient has an advanced solid stage tumor with microsatellite instability.
[00195] In some modalities, a cancer is a gynecological cancer (that is, a cancer of the female reproductive system such as ovarian cancer, cancer of the fallopian tubes, cervical cancer, vaginal cancer, vulva cancer, uterine cancer, peritoneal cancer or breast cancer). In some modalities, cancers of the female reproductive system include, without limitation, ovarian cancer, fallopian tube cancer, peritoneal cancer and breast cancer.
[00196] In the modalities, a cancer is ovarian cancer (for example, serous or clear cell ovarian cancer). In the modalities, a cancer is cancer of the fallopian tubes (for example, cancer of the serous or clear cell fallopian tubes). In the modalities, a primary peritoneal cancer (for example, serous or clear cell primary peritoneal cancer).
[00197] In the modalities, an ovarian cancer is an epithelial carcinoma. Epithelial carcinomas constitute 85% to 90% of ovarian cancers. Although historically it has been thought to begin on the surface of the ovary, new evidence suggests that at least some cases of ovarian cancer begin in special cells in one part of the fallopian tube. Fallopian tubes are small channels that connect a woman's ovaries to her uterus that are part of a woman's reproductive system. In a normal female reproductive system, there are two fallopian tubes, one located on each side of the uterus. Cancer cells that start in the fallopian tube can go to the surface of the ovary from the beginning. The term ovarian cancer is often used to describe epithelial cancers that start in the ovary, fallopian tubes and from the lining of the
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82/172 abdominal cavity, called peritoneum. In some embodiments, the cancer is or comprises 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, a cancer is or comprises a stromal tumor. Stromal tumors develop in the connective tissue cells that hold the ovaries together, which is sometimes the tissue that produces the female hormones called estrogen. In some embodiments, the cancer is or comprises a granular cell tumor. Granulosa cell tumors can secrete estrogen, resulting in unusual vaginal bleeding at the time of diagnosis. In some modalities, gynecological cancer is associated with homologous recombination repair deficiency / homologous repair deficiency (HRD) and / or BRCA1 / 2 mutation (s). In some modalities, gynecological cancer is sensitive to platinum. In some modalities, gynecological cancer responded to platinum-based therapy. In some modalities, gynecological cancer has developed resistance to platinum-based therapy. In some modalities, a gynecological cancer at one point demonstrated a partial or complete response to platinum-based therapy (for example, a partial or complete response to the last platinum-based therapy or the penultimate platinum-based therapy) . In some modalities, gynecological cancer is now resistant to platinum-based therapy.
[00198] In certain modalities, cancer is breast cancer. Normally, breast cancer begins in the cells of the milk-producing glands known as lobules or in the ducts. Less common breast cancer can start in the stromal tissues. They include adipose and fibrous connective tissues of the breast. Over time, breast cancer cells invade neighboring tissues such as axillary lymph nodes or the lungs in a process known as metastasis. The stage of a breast cancer, the size of the tumor and its speed of growth are all factors that
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83/172 determine the type of treatment that is offered. Treatment options include surgery to remove the tumor, drug treatment that includes chemotherapy and hormone therapy, radiation therapy and immunotherapy. The prognosis and survival rate vary widely; relative five-year 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 in 2012 and the fifth most common cause of death from cancer, with approximately 521,000 deaths. Of these cases, approximately 15% are triple-negative, which do not express the estrogen receptor, progesterone receptor (PR) or HER2. In some modalities, triple-negative breast cancer (TNBC) is characterized as breast cancer cells negative for estrogen receptor expression (<1% cells), negative for progesterone receptor expression (<1% cells ) and negative HER-2.
[00199] In modalities, a 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 breast cancer, BRCA1 / 2 negative cancer or triple negative breast cancer (TNBC). In the modalities, a cancer is triple-negative breast cancer (TNBC). In some modalities, breast cancer is metastatic breast cancer. In some modalities, breast cancer is advanced breast cancer. In some modalities, a cancer is a stage II, stage III or stage IV breast cancer. In some modalities, breast cancer is stage IV breast cancer. In some modalities, breast cancer is triple-negative breast cancer.
[00200] In some modalities, a patient or a population of patients who must be treated by the methods of this disclosure have or are susceptible to endometrial cancer (EC). Endometrial carcinoma is ο
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84/172 most common cancer of the female genital tract representing 10-20 per 100,000 person-years. The annual number of new cases of endometrial cancer (EC) is estimated at around 325,000 worldwide. In addition, EC is the most common cancer in postmenopausal women. About 53% of cases of endometrial cancer occur in developed countries. In 2015, approximately 55,000 cases of EC were diagnosed in the USA and no targeted therapy has currently been approved for use in EC. There is a need for agents and regimens that improve survival for advanced and recurrent EC in situations 1L and 2L. It was estimated that approximately 10,170 people died of EC in the USA in 2016. The most common histological form is endometrioid adenocarcinoma, representing about 75-80% of diagnosed cases. Other histological forms include serous papillary uterus (less than 10%), clear cells 4%, mucinous 1%, squamous less than 1% and combined about 10%.
[00201] From the pathogenetic point of view, EC has two different types, the so-called types I and II. Type I tumors are low-grade, estrogen-related (EEC) endometrioid carcinomas 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) represent the vast majority of cases. EECs are estrogen-related carcinomas that occur in perimenopause patients and are preceded by precursor lesions (endometrial hyperplasia / endometrioid intraepithelial neoplasia). Microscopically, low-grade EEC (EEC 1-2) contains tubular glands, which are very similar to the proliferative endometrium, with architectural complexity with gland fusion and cribriform pattern. High-grade EEC shows solid growth pattern. In contrast, SC occurs in postmenopausal patients in the absence of hyperestrogenism. In the microscopic view, SC shows thick, fibrotic or
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85/172 edematous with prominent stratification of tumor cells, cell sprouting and anaplastic cells with large eosinophilic cytoplasms. The vast majority of EEC are low grade tumors (grades 1 and 2) and are associated with a good prognosis when they are restricted to the uterus. Grade 3 EEC (EEC3) is an aggressive tumor with an increased frequency of lymph node metastasis. Very aggressive SCs, unrelated to the estrogen stimulus, occurring mainly in older women. EEC 3 and SC are considered high-grade tumors. SC and EEC3 were compared using data from the surveillance, epidemiology and Final Results (SEER) program from 1988 to 2001. They represented 10% and 15% of EC, respectively, but reflected 39% and 27% of cancer deaths, respectively . Endometrial cancers can also be classified into four molecular subgroups: (1) POLE mutant / ultra-mutated; (2) hypermutated MSI + (for example, MSI-H or MSI-L); (3) low number of copies / stable for microsatellite (MSS); and (4) high number of copies / serous type. Approximately 28% of cases are MSI-high. (Murali, Lancet Oncol. (2014). In some modalities, a patient has a deficient subset of 2L endometrial cancer incompatibility repair. In modalities, an endometrial cancer is metastatic endometrial cancer. In modalities, a patient has endometrial cancer In the modalities, a patient has MSI-H endometrial cancer.
[00202] In the modalities, a cancer is a lung cancer. In the modalities, a lung cancer is a squamous cell carcinoma of the lung. In the modalities, a lung cancer is small cell lung cancer (SCLC). In the modalities, a lung cancer is a non-small cell lung cancer (NSCLC), such as scaly NSCLC. In the modalities, a lung cancer is an ALK translocated lung cancer (for example, ALK translocated NSCLC). In the modalities, a cancer is NSCLC with an ALK translocation. In the modalities, a lung cancer is a lung cancer with an EGFR mutation (for example, NSCLC with
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86/172 EGFR mutation). In the modalities, a cancer is NSCLC with an EGFR mutation.
[00203] In the modalities, a cancer is a colorectal cancer (CRC) (for example, a solid tumor). In the modalities, a colorectal cancer is an advanced colorectal cancer. In the modalities, a colorectal cancer is a metastatic colorectal cancer. In the modalities, a colorectal cancer is an MSI-H colorectal cancer. In the modalities, a colorectal cancer is an MSS colorectal cancer. In the modalities, a colorectal cancer is a POLE mutant colorectal cancer. In the modalities, a colorectal cancer is a colorectal cancer mutated to POLD. In the modalities, a colorectal cancer is a colorectal cancer of high BMR.
[00204] In the modalities, a cancer is a melanoma. In modalities, a melanoma is an advanced melanoma. In modalities, a melanoma is a metastatic melanoma. In the modalities, a melanoma is an MSI-H melanoma. In the modalities, a melanoma is an MSS melanoma. In the modalities, a melanoma is a mutant melanoma for POLE. In the modalities, a melanoma is a mutant melanoma for POLD. In modalities, a melanoma is a high BMR melanoma.
[00205] In the modalities, a cancer is an advanced cancer.
[00206] In the modalities, a cancer is a metastatic cancer.
[00207] In the modalities, a cancer is a recurrent cancer (for example, a recurrent gynecological cancer such as recurrent ovarian cancer, recurrent fallopian tube cancer, recurrent primary peritoneal cancer or recurrent endometrial cancer).
[00208] cancers that can be treated with methods described in this document include cancers associated with a high mutational tumor burden (BMR), cancers that are stable for microsatellite (MSS) cancers that are characterized by instability for microsatellite, cancers that have a high instability status for microsatellite (MSI-H), cancers that have low
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87/172 instability status for microsatellite (MSI-L), cancers associated with a high BMR and MSI-H (for example, cancers associated with high BMR and MSI-L or MSS) cancers with defective DNA incompatibility repair system , cancers with a defect in the DNA incompatibility repair gene, hypermutated cancers, cancers with homologous recombination repair / homologous repair deficiency (HRD) cancers, cancers that comprise a delta polymerase (POLD) mutation, and cancers that comprise a mutation in epsilon polymerase (POLE).
[00209] In some modalities, a tumor to be treated is characterized by instability for microsatellite. In some modalities, a tumor is characterized by a high status of microsatellite instability (MSI-H). Microsatellite instability (“MSI”) is or comprises a change in the DNA of certain cells (such as tumor cells) in which the number of microsatellite repetitions (short, repeated DNA sequences) is different from the number of repetitions contained in the DNA from which it was inherited. About 15% of sporadic colorectal cancers (CRC) harbor widespread changes in the length of microsatellite (MS) sequences, known as microsatellite instability (MSI) (Boland and Goel, 2010). Sporadic MSI CRC tumors have unique clinicopathological characteristics including karyotype close to the diploid, greater frequency 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 to screen for an inherited genetic disorder (Lynch syndrome) (Umar et al., 2004) is currently applied to the MSI test for CRCs and ECs. However, genes often directed by MSI in CRC genomes rarely harbor DNA slippage events in EC genomes (Gurin et al., 1999).
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88/172 [00210] The microsatellite instability arises from a failure to repair errors associated with replication due to a defective DNA incompatibility (MMR) repair system. This failure allows the persistence of incompatible mutations throughout the genome, but especially in regions of repetitive DNA known as microsatellites, leading to increased mutational load. At least some tumors characterized by MSI-H have been shown to have improved responses to certain anti-PD-1 agents (Le et al., (2015) Λ /. Engl. J. Med. 372 (26): 2509-2520 ; Westdorp et al., (2016) Cancer Immunol. Immunother. 65 (10): 1249-1259). In some modalities, a cancer has an instability for microsatellite of high instability for microsatellite (for example, status MSI-H). In some modalities, a cancer has a status of instability for microsatellite of low instability for microsatellite (for example, status MSI-Baixa). In some modalities, a cancer has a stable microsatellite instability status (for example, MSS status). In some embodiments, microsatellite instability status is assessed by a next generation sequencing-based assay (NGS), an immunohistochemistry-based assay (IHC) and / or a PCR-based assay. In some modalities, microsatellite instability is detected by NGS. In some modalities, microsatellite instability is detected by IHC. In some modalities, microsatellite instability is detected by PCR.
[00211] In the modalities, a patient has an MSI-L cancer.
[00212] In the modalities, a patient has an MSI-H cancer. In some embodiments, a patient has a solid MSI-H tumor. In the modalities, an MSI-H cancer is an MSI-H endometrial cancer. In the modalities, an MSI-H cancer is a solid tumor. In the modalities, an MSI-H cancer is a metastatic tumor. In the modalities, an MSI-H cancer is an endometrial cancer. In the modalities, an MSI-H cancer is a non-endometrial cancer. In the modalities, an MSI-H cancer is a colorectal cancer.
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89/172 [00213] In modalities, a patient has an MSS cancer. In the modalities, an MSS cancer is an MSS endometrial cancer.
[00214] In the modalities, a cancer is associated with a POLE mutation (DNA polymerase epsilon) (that is, a cancer is a cancer with a POLE mutation). In the embodiments, a POLE mutation is a mutation in the exonuclease domain. In the modalities, the POLE mutation is a germline mutation. In the modalities, a POLE mutation is a sporadic mutation. In the modalities, an MSI cancer is also associated with a POLE mutation. In the modalities, an MSS cancer is also associated with a POLE mutation. In the modalities, a POLE mutation is identified using sequencing. In the modalities, a cancer with a POLE mutation is an endometrial cancer. In the modalities, a cancer with a POLE mutation is a colon cancer. In the modalities, a cancer with a POLE mutation is pancreatic cancer, ovarian cancer or cancer of the small intestine.
[00215] In the modalities, a cancer is associated with a POLD mutation (DNA polymerase delta) (ie, a cancer is a cancer with a POLD mutation). In the embodiments, a POLD mutation is a mutation in the exonuclease domain. In the modalities, a POLD mutation is a somatic mutation. In the modalities, a POLD mutation is a germline mutation. In the modalities, a cancer with a POLE mutation is identified using sequencing. In the modalities, a cancer with a POLD mutation is an endometrial cancer. In the modalities, a cancer with a POLD mutation is a colorectal cancer. In the modalities, a cancer with a POLD mutation is a brain cancer.
[00216] In some modalities, a patient has an incompatible repair deficient cancer.
[00217] In the modalities, an MMRd cancer is a colorectal cancer.
[00218] Instability for microsatellite may arise from a failure
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90/172 to repair errors associated with replication due to a defective DNA incompatibility (MMR) repair system. This failure allows incompatible mutations to persist throughout the genome, but especially in regions of repetitive DNA known as microsatellites, leading to an increased mutational load that can improve responses to certain anti-PD-1 agents. Id. In some embodiments, MSI-H status is assessed by an NGS-based assay and / or a PCR-based MSI assay. In some modalities, microsatellite instability is detected by sequencing the next generation. In some embodiments, microsatellite instability is detected using immunohistochemistry (IHC) testing.
[00219] In the modalities, a cancer (for example, an MMRd cancer) is characterized by a high mutational tumor burden (ie, a cancer is a cancer with a high BMR). In some modalities, cancer is associated with elevated BMR and MSI-H. In some modalities, cancer is associated with elevated BMR and MSI-L or MSS. In some modalities, cancer is endometrial cancer associated with elevated BMR. In some related modalities, endometrial cancer is associated with high BMR and MSI-H. In some related modalities, endometrial cancer is associated with high BMR and MSI-L or MSS. In the modalities, a cancer with high BMR is a colorectal cancer. In the modalities, a cancer with a high BMR is lung cancer (for example, small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) such as scaly NSCLC or non-scaly NSCLC). In the modalities, a cancer with high BMR is a melanoma. In the modalities, a cancer with high BMR is an urothelial cancer.
[00220] In the modalities, a patient has a cancer with high expression of tumor infiltrating lymphocytes (TILs), that is, a patient has a cancer with high TIL. In the modalities, a cancer with high TIL is breast cancer (for example, triple-negative breast cancer (TNBC) or HER2 positive breast cancer). In modalities, a cancer with TIL
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91/172 elevated is metastatic cancer (for example, metastatic breast cancer).
[00221] In the modalities, the immunorelated gene expression signatures can be predictive of a response to an anti-PD-1 therapy for cancer, as described in this document. For example, a gene panel that includes genes associated with IFN-γ signaling may be useful in identifying cancer patients who would benefit from antiPD-1 therapy. Exemplary gene panels are described in Ayers et al. J. Clin. Invest., 127 (8): 2930-2940, 2017. In the modalities, a cancer patient has a cancer that is a breast cancer (for example, TNBC) or ovarian cancer. In the modalities, a cancer patient has a cancer that is bladder cancer, gastric cancer, biliary cancer, esophageal cancer or squamous cell carcinoma of the head and neck (HNSCC). In the modalities, a cancer patient has a cancer that is either anal cancer or colorectal cancer.
[00222] In some modalities, a patient has a tumor that expresses PD-L1. In some embodiments, the status of PD-L1 is assessed in a patient or patient population. In some embodiments, a mutational load and baseline gene expression profiles in file or pretreatment biopsies are assessed before, during and / or after treatment with an anti-PD-1 antibody agent. In some modalities, the status and / or expression of TIM-3 and / or LAG-3 are assessed in patients.
[00223] In some modalities, a patient has previously been treated with one or more of the different cancer treatment modalities. In some modalities, at least some of the patients in the cancer patient population have previously been treated with one or more of surgery, radiotherapy, chemotherapy or immunotherapy. In some modalities, at least some of the patients in the cancer patient population have previously been treated with chemotherapy (for example, platinum-based chemotherapy). For example, a patient who received two lines of treatment
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92/172 against cancer can be identified as a patient with 2L cancer (for example, a patient with 2L NSCLC). In the modalities, a patient received two or more cancer treatment lines (for example, a patient with 2L + cancer, such as a patient with 2L + endometrial cancer). In the modalities, a patient has not been previously treated with anti-PD-1 therapy. In the modalities, a patient previously received at least one cancer treatment line (for example, a patient previously received at least one cancer line or at least two cancer treatment lines). In the modalities, a patient previously received at least one treatment line for metastatic cancer (for example, a patient previously received one or two treatment lines for metastatic cancer). In the modalities, a subject is resistant to treatment with an agent that inhibits PD-1. In the modalities, a subject is refractory to treatment with an agent that inhibits PD-1. In modalities, a method described in this document sensitizes the subject to treatment with an agent that inhibits PD-1.
T-Cell Immunoglobulin and Mucine Domain 3 (TIM-3) [00224] Protein T-Cell Immunoglobulin and Mucine-3 Domain (TIM-3), also known as Hepatitis A 2 Cell Receptor (HAVCR2 ), is a specific Th1 cell surface protein that regulates macrophage activation and increases the severity of experimental autoimmune encephalomyelitis in mice. TIM-3 is highly expressed on the surface of multiple types of immune cells, including, for example, Th1 IFN-Y + cells, Th17 cells, natural killer cells (NK), monocytes and tumor-associated dendritic cells (DCs) (see, for example, example, Clayton et al., J. Imunol., 192 (2) ·. 782-791 (2014); Jones et al., J. Exp. Méd .., 205: 2763-2779 (2008); Monney et al ., Nature, 415: 536-541 (2002); Hastings et al., Eur. J. Immunol., 39: 2492-2501 (2009); Seki et al., Clin. Immunol., 127: 78-88 ( 2008); Ju et al., BJ Hepatol., 52: 322-329 (2010); Anderson et al., Science, 318: 11411143 (2007); Baitsch et al., PLoS ONE, 7: e30852 (2012); Ndhlovu et al., Biood,
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119: 3734-3743 (2012). TIM-3 is also highly expressed in depleted or impaired CD8 + T cells in a variety of chronic viral infections (eg, HIV, HCV and HBV) and in certain types of cancer (see, for example, McMahan et al., J. Clin. Invest .., / 20 (12): 4546-4557 (2010); Jin et al., Proc Natl Acad Sei USA, / 07 (33): 14733-14738 (2010); Golden-Mason et al., J. Virol., 83 (18): 9122-9130 (2009); Jones et al., Supra; Fourcade et al., J. Exp. Méd .., 207 (10): 2175-2186 (2010); Sakuishi et al., J. Exp. Méd .., 207 (10): 2187-2194 (2010); Zhou et al., Sangue, 117 (17): 4501-4510 (2011); Ngiow et al., Cancer Res ., 7 / (10): 3540-3551 (2011)).
[00225] Putative ligands for TIM-3 include phosphatidylserine (Nakayama et al., Blood, 113: 3821-3830 (2009)), galectin-9 (Zhu et al., Nat. ImmunoL, 6: 1245-1252 (2005) ), protein 1 of the high mobility group (HMGB1) (Chiba et al., Nature Immunology, 13: 832-842 (2012)) and the carcinoembryonic cell adhesion molecule 1 (CEACAM1) (Huang et al., Nature, 517 (7534): 386-90 (2015)).
[00226] TIM-3 works to regulate several aspects of the immune response. The interaction of TIM-3 and galectin-9 (Gal-9) induces cell death and the in vivo blockade of this interaction exacerbates autoimmunity and nullifies tolerance in experimental models, strongly suggesting that TIM-3 is a negative regulatory molecule. In contrast to its effect on T cells, the interaction of TIM-3-Gal-9 exhibits antimicrobial effects by promoting macrophage clearance of intracellular pathogens (see, for example, Sakuishi et al., Trains in Immunology, 32 (8): 345-349 (2011)). In vivo, suppression of TIM-3 has been shown to increase the pathological severity of experimental autoimmune encephalomyelitis (Monney et al., Supra; and Anderson, AC and Anderson, DE, Curr. Opin. Immunol., 18: 665-669 (2006) ). Studies also suggest that dysregulation of the TIM-3-galectin-9 pathway could play a role in chronic autoimmune diseases, such as multiple sclerosis (Anderson and Anderson, supra). TIM-3 promotes the clearance of apoptotic cells by
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94/172 phosphatidylserine binding through its single binding slit (see, for example, DeKruyff et al., J. Imunol., / 84 (4): 1918-1930 (2010)).
[00227] Inhibition of TIM-3 activity, such as through the use of monoclonal antibodies, is currently under research as an immunotherapy for tumors based on preclinical studies (see, for example, Ngiow et al., Cancer Res. ., 7 / (21): 1-5 (2011); Guo et al., Journal of Tradational Medicine, 1 /: 215 (2013); and Ngiow et al., Cancer Res., 7 / (21): 6567 -6571 (2011)).
[00228] The present disclosure provides antibody agents and particular methods related to it for the treatment of cancer.
Anti-TIM-3 antibody agents [00229] The present disclosure provides methods of treating cancer that include the administration of compositions that deliver anti-TIM-3 antibody agents according to regimens that can obtain clinical benefits. The present disclosure describes, at least in part, anti-TIM-3 antibody agents and various compositions and methods related to them.
[00230] In some embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain, the amino acid sequence of which comprises SEQ ID NO: 1 or SEQ ID NO: 7.
SEQ ID NO: 1
EVQLLESGGGLVQPGGSLRLSCAAASGFTFSSYDMSWVRQAPGKGLD WVSTISGGGTYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASM DYWGQGTTVTVSSA
SEQ ID NO: 7
EVQLLESGGGLVQPGGSLRLSCAAASGFTFSSYDMSWVRQAPGKGLD WVSTISGGGTYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASM DYWGQGTTVTVSS [00231] In some modalities, an immunoglobulin-antigen: a variable-domain, an antigen-agent-timoglobin
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SEQ ID NO: 2
DIQMTQSPSSLSASVGDRVTITCRASQSIRRYLNWYHQKPGKAPKLLIYG ASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTK VEIKR
SEQ ID NO: 8
DIQMTQSPSSLSASVGDRVTITCRASQSIRRYLNWYHQKPGKAPKLLIYG ASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTK VEIK [00232] In some modalities, an immunoglobulin: immunoglobulin light chain variable whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8.
[00233] In some embodiments, an anti-TIM-3 antibody agent comprises a variable heavy chain complementarity determining region 1, 2 and / or 3 (VH-CDR) comprising the amino acid sequences GFTFSSYDMS (SEQ ID NO: 21 ), TISGGGTYTYYQDSVK (SEQ ID NO: 22) and / or MDY (SEQID NO: 23), respectively. In some embodiments, an anti-TIM-3 antibody agent comprises a variable light chain complementarity determining region 1, 2 and / or 3 (VL-CDR) comprising the amino acid sequences RASQSIRRYLN (SEQ ID NO: 24), GASTLQS (SEQ ID NO: 25) and / or QQSHSAPLT (SEQ ID NO: 26), respectively. In some embodiments, an anti-TIM-3 antibody comprises VH-CDR sequences of SEQ ID NOs: 21, 22 and 23 and VL-CDR sequences of SEQ ID NOs: 24, 25 and 26. See Table 1.
Table 1. Amino Acid Sequences of the Light and Heavy Chain Complementarity Determining Regions (CDRs)
Antibody Variable region CDR1 CDR2 CDR3
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Anti-TIM-3 VH GFTFSSYDMS (SEQ ID NO: 21) TISGGGTYTYYQDSVK (SEQ ID NO: 22) MDY(SEQ ID NO: 23) Anti-TIM-3 VL RASQSIRRYLN (SEQ ID NO: 24) GASTLQS(SEQ ID NO: 25) QQSHSAPLT(SEQ ID NO: 26) [00234] In some modalities es, an anti-TIM-3 antibody agent
it is a monoclonal antibody. The specific antibodies of the present invention bind to TIM-3 with high affinity and effectively neutralize TIM-3 activity. The antibody heavy chain polypeptide (SEQ ID NO: 3) and light chain polypeptide (SEQ ID NO: 4) sequences are provided explicitly.
Anti-TIM-3 antibody heavy chain polypeptide (SEQ ID NO: 3)
EVQLLESGGGLVQPGGSLRLSCAAASGFTFSSYDMSWVRQAPGKGLD WVSTISGGGTYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASM DYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTK VDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSC SVMHEALHNHYTQKSLSLSLGK
Anti-TIM-3 antibody light chain polypeptide (SEQ ID NO: 4)
DIQMTQSPSSLSASVGDRVTITCRASQSIRRYLNWYHQKPGKAPKLLIYG ASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTK VEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC [00235] The present disclosure provides immunoglobulin heavy chain isolated polypeptide having an amino acid sequence as shown in SEQ ID NO: 3. The present disclosure further provides an isolated immunoglobulin heavy chain polypeptide or polypeptide
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97/172 with an amino acid sequence that shares at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of general identity with that referred to in SEQ ID NO: 3. In some embodiments, the sequence differences from the sequence shown in SEQ ID NO: 3 are not within the CDRs. In some embodiments, an isolated immunoglobulin heavy chain polypeptide includes all three CDRs of SEQ ID NO: 3. In some embodiments, an immunoglobulin heavy chain polypeptide includes a signal peptide. In some embodiments, an immunoglobulin heavy chain polypeptide that includes a signal peptide has an amino acid sequence as shown in SEQ ID NO: 5.
Anti-TIM-3 antibody heavy chain polypeptide with a signal sequence (SEQ ID NO: 5)
MEFGLSWLFLVAILKGVQCEVQLLESGGGLVQPGGSLRLSCAAASGFTF SSYDMSWVRQAPGKGLDWVSTISGGGTYTYYQDSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCASMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSES TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [00236] In some embodiments, a heavy chain immunoglobulin polypeptide is provided comprising an IgG4 or polypeptide. In some embodiments, an immunoglobulin heavy chain polypeptide provided comprises a human IGHG4 * 01 polypeptide. In some embodiments, an immunoglobulin heavy chain polypeptide provided comprises one or more mutations within the IgG heavy chain region. In some embodiments, an immunoglobulin heavy chain polypeptide provided comprises a heavy chain constant region of IgG4 with
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98/172 one or more mutations in the heavy chain constant region. In some embodiments, an immunoglobulin heavy chain polypeptide provided comprises a heavy chain constant region of IgG4 with one or more mutations in the hinge region. It is anticipated that, in some embodiments, a mutation in the hGG4 hinge region may prevent the exchange of half a molecule with other lgG4 molecules. In some embodiments, one or more mutations in the hgG4 hinge region may include a serine to proline stabilizing mutation that prevents the exchange of half of the molecule with other lgG4 molecules. In some embodiments, one or more mutations in the lgG4 hinge region can include an S228P mutation. See, for example, J. Biol. Chem. 2015; 290 (9): 5462-5469.
[00237] The present disclosure provides an isolated immunoglobulin light chain polypeptide having an amino acid sequence as shown in SEQ ID NO: 4. The present disclosure further provides an isolated immunoglobulin light chain polypeptide having an amino acid sequence that shares at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96% , 97%, 98% or 99% global identity with that shown in SEQ ID NO: 4. In some embodiments, the sequence differences from the sequence shown in SEQ ID NO: 4 are not within the CDRs. In some embodiments, an isolated immunoglobulin light chain polypeptide includes all three CDRs of SEQ ID NO: 4. In some embodiments, an immunoglobulin light chain polypeptide provided is a kappa light chain. In some embodiments, an immunoglobulin light chain polypeptide provided comprises a human IGKC * 01 polypeptide. In some embodiments, the immunoglobulin light chain polypeptide includes a signal peptide. In some embodiments, the immunoglobulin light chain polypeptide that includes a signal peptide has an amino acid sequence as shown in SEQ ID NO: 6.
Anti-TIM-3 antibody light chain polypeptide with a sequence
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99/172 signal (SEQ ID NO: 6)
MDMRVPAQLLGLLLLWLRGARCDIQMTQSPSSLSASVGDRVTITCRASQ SIRRYLNWYHQKPGKAPKLLIYGASTLQSGVPSRFSGSGSGTDFTLTISSLQPE DFAVYYCQQSHSAPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCL LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC [00238] In some embodiments, the present disclosure provides an antibody agent anti-TIM-3 comprising at least one immunoglobulin heavy chain with an amino acid sequence as set forth in SEQ ID NO: 3 and at least an immunoglobulin light chain with an amino acid sequence as set out in SEQ ID NO: 4. In some embodiments, an anti-TIM-3 antibody agent comprises two immunoglobulin heavy chains, each having an amino acid sequence as set out in SEQ ID NO: 3. Alternatively or in addition, in some embodiments an anti-TIM-3 antibody agent comprises two immunoglobulin light chains, each having an amino acid sequence as set out in SEQ ID NO: 4. In some embodiments, an anti-TIM-3 antibody agent has a canonical antibody format.
[00239] In some embodiments, a heavy chain, light chain and / or antibody agent provided are glycosylated and one or more sites. In some embodiments, a glycan is N-linked to an Fc region. In some embodiments, an antibody agent is glycosylated in Asn297 (Kabat numbering). In some embodiments, the present disclosure provides a composition that comprises one or more glycoforms of a heavy chain, light chain and / or antibody agent, as described herein. In some embodiments, a composition provided comprises a plurality of such glycoforms, present in specified absolute and / or relative amounts. In some embodiments, the present disclosure provides compositions that may be substantially free of one or more
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100/172 particular glycoforms of a heavy chain, light chain and / or antibody agent as described herein.
[00240] In the embodiments, a TIM-3 binding agent is an anti-TIM-3 antibody which is TSR-022, which comprises a humanized monoclonal anti-TIM-3 antibody comprising a heavy chain whose amino acid sequence comprises SEQ ID NO: 3 and a light chain whose amino acid sequence comprises SEQ ID NO: 4. This anti-TIM-3 antibody uses a human IGHG4 * 01 heavy chain gene and a human IGKC * 01 kappa light chain gene as scaffolding. In addition, there is a single Ser a Pro point mutation in the hinge region of the lgG4 heavy chain at the canonical position S228, corresponding to residue 240 in SEQ ID NO: 5, which includes the signal sequence. Without wishing to be limited by theory, it is predicted that this point mutation serves to stabilize the articulation of the antibody heavy chain.
[00241] The additional biophysical and biochemical characterization of this exemplary humanized monoclonal anti-TIM-3 antibody is also provided in relation to the observed disulfide bonds and glycosylation. Digested peptides from Lys-C and trypsin were well separated and detected by in-line LC-MS analysis. The disulfide bond bonds were confirmed by comparing total ion chromatograms in the non-reduced (NR) condition with the reduced condition. Disulfide bonds are consistent with the expected disulfide bond pattern for an Igg4 molecule. The residues involved in the expected inter and intra-chain disulfide bonds are tabulated below (Tables 2, 3 and 4).
Table 2 - Expected residues involved in disulfide bonds of an exemplary anti-TIM-3 antibody heavy chain with an amino acid sequence as set out in SEQ ID NO: 1.
Cysteine residue ID HC residue of anti-TIM-3 mAb (position in SEQ ID NO: 1) 1 22
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Cysteine residue ID HC residue of anti-TIM-3 mAb (position in SEQ ID NO: 1) II 96 III 127 IV 140 V 196 SAW 219 VII 222 VIII 254 IX 314 X 360 XI 418
Table 3 - Expected Residues Involved in Disulfide Bonds from an Exemplary Anti-TIM-3 Antibody Agent Light Chain Having an Amino Acid Sequence As Shown in SEQ ID NO: 2.
Cysteine residue ID LC residue of anti-TIM-3 mAb (SEQ ID NO: 2 position) I 23 II 88 III 134 IV 194 V 214
Table 4. Exemplary disulfide binding assignments for an anti-TIM-3 antibody
N ^and disulfide bond Disulfide-containing peptides SiteHC connection (position onSEQ ID NO: 1) LC connection site(position inSEQ ID NO: 2) DS1 VTITCR = FSGSGSGTDFTLTISSLQPEDF AVYYCQQSHSAPLTFGGGTK2388 DS2 SGTASVVCLLNNFYPR = VYACEVTHQGLSSP VTK134194 DS3 SFNRGEC = GPSVFPLAPCSRGEC = GPSVFPLAPCSR 127 214 DS4 LSCAAASGFTFSSFSSSWVR = AEDTA VYYCASMDYWGQGTTVTVSSASTK 2297DS5 STSESTAALGCLVK = TYTCNVDHK STSESTAALGCLVK = TYTCNVDHKPSNTK 140196
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N ^and disulfide bond Disulfide-containing peptides SiteHC connection (position onSEQ ID NO: 1) LC connection site(position inSEQ ID NO: 2) DS6 PPCPPCPPCPAPEFLGGPSVFLFPPK = YGPP CPPCPAPEFLGGPSVFLFPPKPPCPPCPPCPAPEFLGGPSVFLFPPK = YGPPCPPCPAPEFLGGPSVFLFPPKPK 219222DS7 TPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAK = CK 254314DS8 NQVSLTCLVK = WQEGNVFSCSVMHEALHNHYTQK 360418
LC: light chain; HC: heavy chain [00242] This exemplary anti-TIM-3 antibody exhibits an occupied N-glycosylation site on the asparagine residue 290 in the CH2 domain of each heavy chain in the mature protein sequence (SEQ ID NO: 1). The glycosylation expressed on this site is a mixture of oligosaccharide species normally seen in IgGs expressed in mammalian cell culture, for example, shown below is the relative abundance of glycan species from a preparation of this exemplary anti-TIM-3 antibody grown in Chinese Hamster Ovary (CHO) cells (Table 5).
Table 5 - Glycan Analysis of an AntiTIM-3 Antibody Binding Agent
Species Abundance (% of total oligosaccharides) Description of Glycan G0F 20.1% Oligosaccharide nucleus of the type fucosylated agalactobenary complex G1F 41.9% Oligosaccharide of the fucosylated monogalactosylated biantennary complex type G2F 29.0% Oligosaccharide of the type fucosylated galactosylated biantenary complex G2FS1 3.2% Oligosaccharide of the type fucosylated galactosylated biantenary complex of monosialylated nucleus G2FS2 1.2% Oligosaccharide of the type fucosylated galactosylated biatenary complex of disialylated nucleus M5 0.4% Oligosaccharide Oligomanosidic N-linked, Male ₅ GlcNAc2
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PD-1 Binding Agents [00243] The present disclosure provides cancer treatment methods that further include the administration of compositions that deliver programmed cell death protein-1 binding agents (PD-1) according to regimens that can obtain clinical benefit (s). The present disclosure describes, at least in part, PD-1 binding agents (e.g., anti-PD-1 antibody agents) and various compositions and methods related thereto. In some embodiments, a PD-1 binding agent is a monoclonal antibody.
[00244] In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 11 or SEQ ID NO: 17.
SEQ ID NO: 11
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEW VSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYY AM DYWGQGTTVTVSSA
SEQ ID NO: 17
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEW VSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYY AM DYWGQGTTVTVSS [00245] In some modalities, an ID domain: a variable-domain: an agent
SEQ ID NO: 12
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYW ASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTK LEIKR
SEQ ID NO: 18
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYW
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ASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTK LEIK [00246] In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 11 or SEQ ID NO: 17 and SEQ ID NO: 17 immunoglobulin light chain whose amino acid sequence comprises SEQ ID NO: 12 or SEQ ID NO: 18. In some embodiments, a PD-1 binding agent is or comprises a humanized immunoglobulin G4 (lgG4) monoclonal antibody (mAb) . In some embodiments, a PD-1 binding agent comprises a human IGHG4 * 01 polypeptide. In some embodiments, a PD-1 binding agent comprises one or more mutations within the IgG heavy chain region. In some embodiments, a PD-1 binding agent comprises a heavy chain constant region of IgG4 having one or more mutations in the heavy chain constant region. In some embodiments, a PD-1 binding agent comprises a heavy chain constant region of IgG4 having one or more mutations in the hinge region. It is anticipated that, in some embodiments, a mutation in the hGG4 hinge region may prevent the exchange of half a molecule with other lgG4 molecules. In some embodiments, one or more mutations in the hgG4 hinge region may include a serine to proline stabilizing mutation that prevents the exchange of half of the molecule with other lgG4 molecules. In some embodiments, one or more mutations in the lgG4 hinge region can include an S228P mutation. See, for example, J. Biol. Chem. 2015; 290 (9): 5462-5469.
[00247] In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain polypeptide whose amino acid sequence comprises SEQ ID NO: 13.
SEQ ID NO: 13 - An anti-PD-1 heavy chain polypeptide (CDR sequences)
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EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEW VSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYY AMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSN TKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSVMHEALHNHYTQKSLSLSLGK [00248] In some embodiments, a binding agent PD-1 comprises a light chain immunoglobulin polypeptide whose amino acid sequence comprises SEQ ID NO: 14.
SEQ ID NO: 14 - An anti-PD-1 antibody light chain polypeptide (CDR sequences)
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYW ASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTK LEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC [00249] The present disclosure provides a polypeptide isolated immunoglobulin heavy chain having an amino acid sequence as shown in SEQ ID NO: 13. The present disclosure further provides an isolated immunoglobulin heavy chain polypeptide having an amino acid sequence that shares at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% global identity with that shown in SEQ ID NO: 13. In some embodiments, the sequence differences from the sequence shown in SEQ ID NO: 13 are not within the CDRs. In some embodiments, an isolated immunoglobulin heavy chain polypeptide includes all three CDRs of SEQ ID NO: 13. In some modalities,
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106/172 an immunoglobulin heavy chain polypeptide includes a signal peptide. In some embodiments, an immunoglobulin heavy chain polypeptide that includes a signal peptide has an amino acid sequence as shown in SEQ ID NO: 15.
An anti-PD-1 antibody heavy chain polypeptide with a signal sequence (SEQ ID NO: 15)
MEFGLSWLFLVAILKGVQCEVQLLESGGGLVQPGGSLRLSCAASGFTFS SYDMSWVRQAPGKGLEWVSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQ MNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRST SESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [00250] The present disclosure provides a polypeptide isolated immunoglobulin light chain having an amino acid sequence as shown in SEQ ID NO: 14. The present disclosure further provides an isolated immunoglobulin light chain polypeptide having an amino acid sequence that shares at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% global identity with that shown in SEQ ID NO: 14. In some embodiments, the sequence differences from the sequence shown in SEQ ID NO: 14 are not within the CDRs. In some embodiments, an isolated immunoglobulin light chain polypeptide includes all three CDRs of SEQ ID NO: 14. In some embodiments, an immunoglobulin light chain polypeptide provided is a kappa light chain. In some embodiments, an immunoglobulin light chain polypeptide provided comprises a human IGKC * 01 polypeptide. In some embodiments, the immunoglobulin light chain polypeptide includes a
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107/172 signal peptide. In some embodiments, the immunoglobulin light chain polypeptide that includes a signal peptide has an amino acid sequence as shown in SEQ ID NO: 16.
An anti-PD-1 antibody light chain polypeptide with a signal sequence (SEQ ID NO: 16)
MDMRVPAQLLGLLLLWLPGARCDIQLTQSPSFLSAYVGDRVTITCKASQD VGTAVAWYQQKPGKAPKLLIYWASTLHTGVPSRFSGSGSGTEFTLTISSLQPED FATYYCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC [00251] SEQ ID NOs: 13:14 describe an anti-PD-1 exemplary humanized monoclonal antibody (TSR-042) using a heavy chain gene IGHG4 human * 01 and a light chain gene kappa IGKC * 01 human, as scaffold structures. There is a single point mutation from Ser to Pro in the hinge region of the Igg4 heavy chain. This mutation is in the canonical S228 position. Without wishing to be limited by theory, it is predicted that this point mutation serves to stabilize the articulation of the antibody heavy chain.
[00252] This document provides additional biophysical and biochemical characterization of this exemplary humanized monoclonal anti-PD-1 antibody, which is consistent with the expected disulfide binding pattern for an IgG4 molecule. The residues involved in the expected inter and intrachain disulfide bonds are listed in the tables below (Tables 6 and 7).
Table 6 - Expected Residues Involved in Disulfide Bonds of an Exemplary Anti-PD-1 Antibody Antibody Heavy Chain Having an Amino Acid Sequence As Shown in SEQ ID NO: 13.
ID of cysteine residue after Edelman ^one HC residue of anti-PD-1 mAb (position in SEQ ID NO: 13) 1 22 II 96
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ID of cysteine residue after Edelman ^one HC residue of anti-PD-1 mAb (position in SEQ ID NO: 13) III 130 IV 143 V 199 SAW 222 VII 225 VIII 257 IX 317 X 363 XI 421
Table 7 - Expected Residues Involved in Disulfide Bonds from an Exemplary Anti-PD-1 Antibody Agent Light Chain Having an Amino Acid Sequence As Shown in SEQ ID NO: 14.
ID of cysteine residue after Edelman ^one LC residue of anti-PD-1 mAb (SEQ ID NO: 14 position) I 23 II 88 III 134 IV 194 V 214
This exemplary anti-PD-1 antibody has an occupied glycosylation site on the asparagine residue 293 in the CH2 domain of each heavy chain in the mature protein sequence (SEQ ID NO: 13). The glycosylation expressed at this site is a mixture of oligosaccharide species normally seen in IgGs expressed in mammalian cell culture, for example, shown below is the relative abundance of glycan species from a preparation of this exemplary anti-PD-1 antibody grown in Chinese Hamster Ovary (CHO) cells (Table 8).
Table 8 - Glycan Analysis of an AntiPD-1 Antibody Binding Agent
Species Abundance (% of total oligosaccharides) Description of Glycan G0 <0.1% Non-fucosylated agalactobenary complex type oligosaccharide
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Species Abundance (% of total oligosaccharides) Description of Glycan G0F 19.5% Fucosylated core agalactobenzenary complex type oligosaccharide G1 0.1% Non-fucosylated monogalactosylated biantenary complex type oligosaccharide G1F 45.6% Oligosaccharide of the fucosylated monogalactosylated biantennary complex type G2F 27.4% Oligosaccharide type fucosylated galactosylated biantenary complex M5 0.5% Oligomanoside N-glycan, Male ₅ GlcNAc2
[00254] In some embodiments, the present disclosure provides an anti-PD-1 antibody agent that comprises at least one immunoglobulin heavy chain having an amino acid sequence as shown in SEQ ID NO: 13 and at least one immunoglobulin light chain having an amino acid sequence as shown in SEQ ID NO: 14. In some embodiments, an anti-PD-1 antibody agent comprises two immunoglobulin heavy chains each having an amino acid sequence as shown in SEQ ID NO: 13 Alternatively or in addition, in some embodiments, an anti-PD-1 antibody agent comprises two immunoglobulin light chains each having an amino acid sequence as shown in SEQ ID NO: 14. In some embodiments, an antibody agent anti-PD-1 has a canonical antibody format.
[00255] In some embodiments, a supplied 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 are or include a disulfide bond in the position expected for an IgG4 immunoglobulin.
[00256] In some embodiments, a PD-1 binding agent is glycosylated and one or more sites. As used here, "glycan" is a sugar polymer component (half) of a glycoprotein. The term glycan
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110/172 covers free glycans, including glycans that have been cleaved or otherwise released from a glycoprotein. In some embodiments, the present disclosure provides a composition that comprises one or more glycoforms of a heavy chain, light chain and / or antibody agent, as described herein. In some embodiments, a glycan is N-linked to an Fc region. In some embodiments, a PD-1 binding agent is glycosylated in Asn297 (Kabat numbering).
[00257] The term glycoform is used in this document to refer to a specific form of a glycoprotein. That is, when a glycoprotein includes a particular polypeptide that has the potential to be linked to different glycans or sets of glycans, then each different version of the glycoprotein (that is, where the polypeptide is linked to a specific glycan or set of glycans) it is referred to as glycoform. In some embodiments, a composition is provided that comprises a plurality of glycoforms of one or more among a heavy chain, light chain and / or antibody agent, as described herein.
[00258] In some embodiments, the antagonistic activity of a PD-1 binding agent in blocking the interaction of PD-1 / PD-L1 or PD-L2 can be confirmed or determined using an assay based on flow cytometry measuring the binding of labeled PD-L1 and PD-L2 expressed as mouse IgG 1 Fc fusion proteins (PD-L1 mFc or PD-L2 mFc) in PD-1 expressing cells. In some embodiments, a PD-1 binding agent can efficiently block the binding of PD-1 / PD-L1 and PD-1 / PD-L2 compared to an IgG4 isotype control.
[00259] In some embodiments, a PD-1 binding agent can efficiently neutralize PD-1 activity (for example, it can inhibit PD-1 binding to PD-L1 and PD-L2). In some embodiments, the functional antagonistic activity of a PD-1 binding agent can be confirmed or determined in a mixed lymphocytic reaction (MLR), showing greater
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111/172 interleukin (IL) -2 production by adding a PD1 binding agent. In some embodiments, an MLR assay can be performed using primary human CD4 + T cells as responders and dendritic cells as stimulators.
Expression and Formulation [00260] In some embodiments, an anti-TIM-3 antibody agent and / or a PD-1 binding agent are expressed from a vector comprising one or more nucleic acid sequences.
[00261] In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain polypeptide which is encoded by a nucleotide sequence comprising SEQ ID NO: 9.
Nucleotide sequence encoding the anti-TIM-3 antibody heavy chain polypeptide (SEQ ID NO: 9)
GAG GTG CAG CTG TTG GAG TCT GGG GGA GGC TTG GTA CAG CCT GGG GGG TCC CTG AGA CTC TCC TGT GCA GCA GCC TCT GGA TTC ACT TTC AGT AGC TAT GAC ATG TCT TGG GTC CGC CAG GCT CCA GGG TAG GTC GGG ACC ATT AGT GGT GGT GGT ACT TAC ACC TAG 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 TGG 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 A GAG TAC TAC TAC ACG GTG TCG TGG AAC TCA GGC GCC CTG ACC AGC GGC GTG CAC ACC TTC CCG GCT GTC CTA CAG TCC TCA GGA CTC TAC TCC CTC AGC AGC GTG GTG ACC GTG CCC TCC AGC AGC TTG GGC ACG AAG ACC TAC ACC TGC A GAC 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
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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 TAG GTG GAT GGC GTG GAG GTG CAT AAT GCC A GAG A 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 TG AAA GCC AAA 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 AAG A 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 A CTG ACC CAG A TCT CTG GGT AAA [00262] In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin light chain polypeptide that is encoded by a nucleotide sequence that with meets SEQ ID NO: 10.
Nucleotide sequence encoding the anti-TIM-3 antibody light chain polypeptide (SEQ ID NO: 10)
GAC ATC CAG ATG ACC CAG TCT CCA TCC TCC CTG TCT GCA TCT GTA GGA GAC AGA GTC ACC ATC ACT TGC CGG GCA AGT CAG AGC ATT AGG AGG TAT TTA AAT TGG TAT CAC CAG AAA CCA GGG AAA GCC CCT AAG CTC CTG ATG GCA TCC ACC TTG CAA AGT GGG GTC CCA TCA AGG TTC AGT GGT AGT GGA TCT GGG ACA GAT TTC ACT CTC ACC ATC AGC AGT CTG CAA CCT GAA GAT TTT GCA GTG TAT TAC TGT CAA CAG AGT CAC AGT GCC CCC CTC ACT TGA GGG ACC AAG GTG GAG ATC AAA CGA ACT GTG GCT GCA CCA TCT GTC TTC ATC TTC CCG CCA TCT GAT GAG CAA TTG AAA TCT GGA ACT GCC TCT GTT GTG TGC CTG CTG AAT AAC TTC TAT CCC AGA GAG GCC AAA GTA CAG TGG A
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GTG GAT AAC GCC CTC CAA TCG GGT AAC TCC CAG GAG AGT GTC ACA GAG CAG GAC AGC AAG GAC AGC ACC TAG AGC CTC AGC AGC ACC CTG ACG CTG AGC AAA GCA GAC TAG GAG AAA CAC AAA GTC TAC GCC TGC GAA GTC TGC GAA GTC GGC CTC AGC TCG CCC GTC ACA AAG AGC TTC AAC AGG GGA GAG TGT [00263] In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain polypeptide that is encoded by a nucleotide sequence comprising SEQ ID NO: 19.
SEQ ID NO: 19 - Nucleotide sequence encoding a PD-1 binding agent immunoglobulin heavy chain polypeptide
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 A ATT AGT GGT GGT GGT AGT TAC ACC TAG 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 CC T G TAT GCT ATG GAC TAG 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 GGC TGC GAC TAC GAA CCA GTG ACG GTG TCG TGG AAC TCA GGC GCC CTG ACC AGC GGC GTG CAC ACC TTC CCG GCT GTC CTA CAG TCC TCA GGA CTC TAC TCC CTC AGC AGC GTG GTG ACC GTG CCC TCC AGC AGC TTG GGC ACG AG ACC TAC 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 ATGCGG ACC CCT GAG GTC ACG TGC GTG GTG GTG GAC GTG AGC CAG GAA GAC CCC GAG GTC CAG TTC AAC TGG TAG GTG GAT GGC GTG GAG GTG CAT AAT
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GCC AAG ACA AAG COG OGG GAG GAG GAG TTC AAC AGO ACG TAG CGT GTG GTC AGO GTC CTO ACC GTC CTG CAC CAG GAC TGG CTG AAC GGC AAG GAG TAG AAG TGC AAG GTC TCC AAC AAA GGC CTC CCC TCA ATC GTA TCC AAA GCC AAA GGG CAG CCC CGA GAG CCA CAG GTG TAG ACC CTG CCC CCA TCC CAG GAG GAG ATG ACC AAG AAC CAG GTC AGC CTG ACC TGC CTG GTC AAA GGC TTC TAG CCC AGC GAC ATC GCC GTG GAG GG AGG CCG GAG AAC AAC TAG AAG ACC ACG CCT CCC GTG CTG GAC TCC GAC GGC TCC TTC TTC CTC TAG 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 CAG A TAC ACA CAG AAG AGC CTC TCC CTG TCT CTG GGT AAA [00264] In some embodiments, a PD-1 binding agent comprises an immunoglobulin light chain polypeptide that is encoded by a nucleotide sequence comprising SEQ ID NO: 20.
SEQ ID NO: 20 - Nucleotide sequence encoding an immunoglobulin light chain polypeptide from a PD-1 binding agent
GAC ATC CAG TTG ACC CAG TCT CCA TCC TTC CTG TCT GCA TAT GTA GGA GAC AGA GTC ACC ATC ACT TGC AAG GCC AGT CAG GAT GTG GGT ACT GCT GTA TGCC TAT CAG CAA AAA CCA GGG AAA GCC CCT AAG CTC CTG ATC TAT TG 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 TAG TGT CAG CAT TAT AGC AGC TAT CCG TGC ACG TTT GG GGG ACC AAG CTG GAG ATC AAA CGG ACT GTG GCT GCA CCA TCT GTC TTC ATC TTC CCG CCA TCT GAT GAG CAA TTG AAA TCT GGA ACT GCC TCT GTT GTG TGC CTG CTG AAT AAC TTC TAT CCC AGA GAG GCC AAA GTA CAG TGG A 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
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GAA GTC ACC CAT CAG GGC CTC AGC TCG CCC GTC ACA AAG AGC TTC AAC AGG GGA GAG TGT [00265] In some embodiments, an anti-TIM-3 antibody agent and / or a PD-1 binding agent are expressed at from a vector comprising one or more nucleic acid sequences encoding an immunoglobulin heavy chain variable domain polypeptide and / or an immunoglobulin light chain variable domain polypeptide. In some embodiments, an anti-TIM-3 antibody agent and / or a PD-1 binding agent are expressed from a vector comprising one or more nucleic acid sequences encoding an immunoglobulin heavy chain polypeptide and / or an immunoglobulin light chain polypeptide. The vector can be, for example, a plasmid, episome, cosmid, viral vector (e.g., retroviral or adenoviral) or phage. Suitable vectors and vector preparation methods 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, NY (2001), and Ausubel et al, Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, NY (1994)).
[00266] In some embodiments, the vector (s) for expression of an anti-TIM-3 antibody agent and / or a PD-1 binding agent further comprises expression control sequences, such as promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), and the like, which provide expression of the coding sequence in a host cell. Exemplary expression control sequences are known in the art and described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology, Vol. 185, Academic Press, San Diego, Calif. (nineteen ninety).
[00267] The vector (s) comprising the nucleic acid (s) encoding an anti-TIM-3 antibody agent and / or a binding agent
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PD-1 of the present disclosure can be introduced into a host cell that is capable of expressing the encoded polypeptides by means of them, including any prokaryotic or eukaryotic cell. Some preferred qualities of host cells include easy and safe growth, a reasonably rapid growth rate, having well-characterized expression systems and / or ease of transformation or transfection efficiency.
[00268] In some embodiments, mammalian cells are used. Several suitable mammalian host cells are known in the art and many are available from the American Type Culture Collection (ATCC, Manassas, VA). Examples of suitable mammalian cells include, but are not limited to, Chinese hamster ovary (CHO) cells (ATCC n ^Q CCL61), CHO DHFR cells (Urlaub et al., Proc. Natl. Acad. Sci. USA, 97 : 4216-4220 (1980)), human embryonic kidney (HEK) 293 or 293T cells (ATCC n ^Q CRL1573) and 3T3 cells (ATCC n ^Q CCL92). Other suitable mammalian cell lines are the monkey cell lines COS-1 (ATCC No. CRL1650) and COS-7 (ATCC n ^Q CRL1651), as well as the CV-1 cell line (ATCC n ^Q CCL70).
[00269] Other exemplary mammalian host cells include primate cell lines and rodent cell lines, including transformed cell lines. Normal diploid cells, cell strains derived from in vitro culture of primary tissue, as well as primary explants, are also suitable. Other suitable mammalian cell lines include, but are not limited to, mouse neuroblastoma N2A cells, HeLa, mouse L-929 cells and hamster cell lines BHK or HaK, all available from ATCC. Methods for selecting suitable mammalian host cells and methods for cell transformation, culture, amplification, screening and purification are known in the art.
[00270] In some embodiments, the mammalian cell is a cell
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117/172 human. For example, the mammalian cell can be a cell line derived from human lymphoid or lymphoid, such as a cell line of pre-B lymphocyte origin. Examples of human lymphoid cell lines include, without limitation, RAMOS cells (CRL-1596), Daudi (CCL-213), EB-3 (CCL-85), DT40 (CRL-2111), 18-81 (Jack et al, Proc. Natl. Acad. Sci. USA, 85: 1581-1585 (1988)), Raji (CCL-86), and their derivatives.
[00271] In some embodiments, an anti-TIM-3 antibody agent is formulated as a pharmaceutical composition, containing one or a combination of monoclonal antibodies, or antigen-binding portions thereof, formulated with a pharmaceutically acceptable carrier. An anti-TIM-3 antibody agent can be formulated alone or in combination with other drugs (for example, as an adjuvant). For example, an anti-TIM-3 antibody agent can be administered in combination with other agents for the treatment or prevention of the diseases disclosed in this document (for example, cancer).
[00272] Therapeutic compositions should normally be sterile and stable under conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other specific structure suitable for increasing the concentration of the drug. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like) and their suitable mixtures. Proper fluidity can be maintained, for example, by using a coating, such as lecithin, by maintaining the required particle size in the case of dispersion, and by using surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be caused by the inclusion, in the composition, of an agent that delays absorption, for example, monostearate salts and gelatin.
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118/172 [00273] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in a suitable solvent with one or a combination of ingredients listed above, as needed, followed by microfiltration sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the other necessary ingredients from those listed above. The facility of sterile powders is the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying (lyophilization) which produce an active ingredient powder plus any additional desired ingredient from a previously filtered sterile solution of the same.
[00274] In some embodiments, a therapeutic composition is formulated as a sterile liquid. In some embodiments, the composition is free of visible particles. In some embodiments, the composition is formulated in a buffer. In some embodiments, an anti-TIM-3 antibody agent ^Q is stored at 2-8 C. In some embodiments, a drug product of the present disclosure is free of preservatives.
General Protocol [00275] As described in this document, the methods provided comprise administering an anti-TIM-3 antibody agent to a patient, a subject, or a population of subjects (for example, according to a regimen that achieves a clinical benefit).
[00276] The methods provided can provide several benefits (for example, a clinical benefit). In modalities, a method described in this document achieves a clinical benefit. In modalities, a clinical benefit is a stable disease (DS). In modalities, a clinical benefit is a partial response (PR). In modalities, a clinical benefit is a complete response (CR).
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119/172 [00277] In modalities, a combination therapy achieves a clinical benefit for each therapy administered to a patient. For example, a subject may be resistant to treatment with an agent that inhibits PD-1 or a subject may be refractory to treatment with an agent that inhibits PD-1. In modalities, a method described in this document sensitizes the subject to treatment with an agent that inhibits PD-1. Therefore, in embodiments, a benefit of a combination therapy comprising the administration of a TIM-3 inhibitor (for example, any anti-TIM-3 antibody described in this document) and a PD-1 inhibitor (for example, any antibody anti-PD-1 described in this document) is the achievement of a clinical benefit with a PD-1 inhibitor (for example, any anti-PD-1 antibody described in this document) or the improvement of a clinical benefit.
[00278] In modalities, a patient or subject is an animal. In modalities, a patient or subject is a human.
[00279] In embodiments, administration of an anti-TIM-3 antibody agent is parenteral administration. In modalities, parenteral administration is intravenous administration. In modalities, intravenous administration is intravenous infusion.
[00280] In some embodiments, the regimen comprises at least one parenteral dose of an anti-TIM-3 antibody agent. In some embodiments, the regimen comprises a plurality of parenteral doses.
[00281] In some embodiments, the parenteral dose is an amount of a TIM-3 antibody agent within the range of about 5 to about 5000 mg (e.g., about 5 mg, about 10 mg, about 50 mg, about 100 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1200 mg mg, about 1400 mg, about 1500 mg, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, or a range defined by any of the two above). In some modalities, the
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120/172 parenteral dose of an anti-TIM-3 antibody agent is 500 mg or 1000 mg. In some embodiments, the parenteral dose of an anti-TIM-3 antibody agent is about 100 mg, about 300 mg, or about 1200 mg.
[00282] In some modalities, the dose is in an amount relative to body weight. In some embodiments, the parenteral dose of a TIM-3 antibody agent is within a range of about 0.01 mg / kg to 100 mg / kg of animal or human body weight; however, doses below or above this exemplary range are within the scope of the invention. The dose (for example, a daily parenteral dose) can be from about 0.01 mg / kg to about 50 mg / kg of total body weight (for example, about 0.1 mg / kg, about 0, 5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg kg, about 12 mg / kg, about 15 mg / kg, about 20 mg / kg or a defined range any two of the previous values).
[00283] In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered to a patient at a dose of 0.1, 1, 3 or 10 mg / kg. In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of 0.1, 1, 3 or 10 mg / kg every two weeks. In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of 0.1, 1, 3 or 10 mg / kg every three weeks. In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of 0.1, 1.3 or 10 mg / kg every four weeks.
[00284] In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered to a patient at a dose of about 100 to about 500 mg (for example, 200 to 500 mg). In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is
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121/172 administered according to a regimen that includes a dose of about 100 to about 500 mg (for example, 200 mg, 300 mg, 400 mg, 500 mg) every two weeks. In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of about 100 to about 500 mg (for example, 200 mg, 300 mg, 400 mg, 500 mg) every three weeks. In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of about 100 to about 500 mg (for example, 200 mg, 300 mg, 400 mg, 500 mg) every four weeks.
[00285] In some embodiments, a composition that delivers an anti-TIM-3 antibody agent is administered to a patient at a dose of about 800 to about 1500 mg (e.g., 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg). In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of about 800 to about 1500 mg (for example, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg) every four weeks. In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of about 800 to about 1500 mg (for example, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg) every six weeks. In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of about 800 to about 1500 mg (for example, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg) every eight weeks.
[00286] In embodiments, a dose (for example, a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 1 mg / kg of an inhibitor TIM-3 (for example, an anti-antibody agent
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TIM-3). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR042). In embodiments, a TIM-3 inhibitor is an anti-TIM3 antibody agent. In embodiments, an anti-TIM-3 antibody agent is TSR-022. An anti-TIM-3 antibody comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% , 98% or 99% total identity with SEQ ID NO: 4.
[00287] In modalities, one dose (for example, one dose
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123/172 therapeutically effective, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 3 mg / kg of a TIM-3 inhibitor (for example, a anti-TIM-3 antibody). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR042). In embodiments, a TIM-3 inhibitor is an anti-TIM3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. -TIM-3 comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% full identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about
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90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of total identity with SEQ ID NO: 4.
[00288] In embodiments, a dose (for example, a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 10 mg / kg of an inhibitor TIM-3 (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR042). In embodiments, a TIM-3 inhibitor is an anti-TIM3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. -TIM-3 comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least
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125/172 minus about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00289] In embodiments, a dose (for example, a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 100 - 1500 mg / kg of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once a week (Q1W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an inhibitor of TIM-3).
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126/172 immunological checkpoint (for example, an anti-PD-1 antibody, such as TSR042). In embodiments, a TIM-3 inhibitor is an anti-TIM3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. In embodiments, an anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98% or 99% total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of total identity with SEQ ID NO: 4.
[00290] In embodiments, a dose (e.g., a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 100 mg of a TIM inhibitor -3 (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, administration of a TIM-3 inhibitor (for example, an agent
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127/172 of anti-TIM-3 antibody) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR042). In embodiments, a TIM-3 inhibitor is an anti-TIM3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. -TIM-3 comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00291] In any of the methods described in this document, a dose (e.g., a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 200 mg of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In modalities, the administration of a TIM-3 inhibitor (for example,
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128/172 example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR-042). In embodiments, a TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99 % total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00292] In any of the methods described in this document, a dose (for example, a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 300 mg of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks
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129/172 (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR-042). In embodiments, a TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99 % total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00293] In any of the methods described in this document, a dose (e.g., a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 400 mg of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, administration of a dose (for example, intravenous administration, such as
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130/172 intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR-042). In embodiments, a TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99 % total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00294] In any of the methods described in this document, a dose (e.g., a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 500 mg of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of
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131/172 a dose (eg, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR-042). In embodiments, a TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99 % total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00295] In any of the methods described in this document, a dose (e.g., a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 600 mg of a TIM-3 inhibitor (for example,
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132/172 an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR-042). In embodiments, a TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99 % total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00296] In any of the methods described in this document, a
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133/172 dose (for example, a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 700 mg of a TIM-3 inhibitor (eg example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR-042). In embodiments, a TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99 % total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising a sequence of
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134/172 amino acids having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of total identity with SEQ ID NO: 4.
[00297] In any of the methods described in this document, a dose (e.g., a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 800 mg of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR-042). In embodiments, a TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising a
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135/172 amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00298] In any of the methods described in this document, a dose (for example, a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 900 mg of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR-042).
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136/172 TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. In embodiments, an anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96% , 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00299] In any of the methods described in this document, a dose (for example, a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 1000 mg of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In modalities, the administration of a TIM-3 inhibitor (for example,
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137/172 example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-PD-1 antibody, such as TSR-042) In embodiments, a TIM-3 inhibitor is an anti-TIM-3 antibody agent In embodiments, a TIM-3 inhibitor is TSR-022. In embodiments, an anti-TIM3 antibody agent comprises a heavy chain of immunoglobulin comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00300] In any of the methods described in this document, a dose (for example, a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 1100 mg of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an antibody agent
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138/172 anti-TIM-3) is an intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR-042). In embodiments, a TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99 % total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00301] In any of the methods described in this document, a dose (e.g., a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 1200 mg of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six
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139/172 weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR-042). In embodiments, a TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99 % total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00302] In any of the methods described in this document, a dose (for example, a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 1300 mg of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, administration of a dose (for example, administration of
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140/172 intravenous, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR-042). In embodiments, a TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99 % total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00303] In any of the methods described in this document, a dose (e.g., a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 1400 mg of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the
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141/172 administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR-042). In embodiments, a TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99 % total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00304] In any of the methods described in this document, a dose (for example, a therapeutically effective dose, a dose administered by a composition that delivers an anti-TIM-3 antibody agent or a parenteral dose) is about 1500 mg of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent). In embodiments, administration of a dose (for example, intravenous administration, such as intravenous infusion) is
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142/172 once every two weeks (Q2W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every three weeks (Q3W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every four weeks (Q4W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every five weeks (Q5W). In modalities, the administration of a dose (for example, intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is intravenous infusion. In embodiments, the administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for monotherapy. In embodiments, administration of a TIM-3 inhibitor (for example, an anti-TIM-3 antibody agent) is for combination therapy (for example, in combination with an immunological checkpoint inhibitor (for example, an anti-TIM antibody) -PD-1, such as TSR-042). In embodiments, a TIM-3 inhibitor is an anti-TIM-3 antibody agent. In embodiments, a TIM-3 inhibitor is TSR-022. anti-TIM3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99 % total identity with SEQ ID NO: 3 and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% total identity with SEQ ID NO: 4.
[00305] Therapeutic or prophylactic efficacy can be monitored by periodic evaluation of treated patients. For repeated administrations over several days or more, depending on the condition, treatment may be
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143/172 repeated until a desired suppression of the symptoms of the disease occurs. However, other dosage regimens may be useful and are within the scope of the invention. The desired dosage can be applied by a single bolus administration of the composition, by multiple bolus administrations of the composition, or by the administration of continuous infusion of the composition.
[00306] In some embodiments, the anti-TIM-3 antibody agent is administered to a patient or population of subjects who have responded to previous therapy. In some modalities, the patient or the population of subjects showed a response to previous cancer therapy.
[00307] In some embodiments, the anti-TIM-3 antibody agent is administered to a patient or population of subjects that has not responded to previous therapy. In some modalities, the patient or the population of subjects did not receive or did not respond to previous cancer therapy.
[00308] In the modalities, a subject is resistant to treatment with an agent that inhibits PD-1. In the modalities, a subject is refractory to treatment with an agent that inhibits PD-1. In modalities, a method described in this document sensitizes the subject to treatment with an agent that inhibits PD-1.
[00309] In embodiments, an anti-TIM-3 antibody agent, as described in this document, is administered in combination with one or more additional therapies (for example, therapies as described in this document). That is, a subject is treated with an anti-TIM-3 antibody agent and one or more additional therapies are administered to a subject in such a way that the subject receives each therapy.
[00310] In modalities, an additional therapy is surgery. In modalities, an additional therapy is radiotherapy. In modalities, an additional therapy is chemotherapy. In modalities, an additional therapy is immunotherapy.
[00311] In some embodiments, an anti-TIM-3 antibody agent
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144/172 is administered as a monotherapy.
[00312] In some embodiments, an anti-TIM-3 antibody agent is administered in combination therapy. In embodiments, an anti-TIM-3 antibody agent is administered in combination with another treatment modality (for example, with one or more of surgery, radiotherapy, chemotherapy or immunotherapy). In embodiments, an anti-TIM-3 antibody agent is administered in combination with surgery. In embodiments, an anti-TIM-3 antibody agent is administered in combination with radiation therapy. In embodiments, an anti-TIM-3 antibody agent is administered in combination with chemotherapy. In embodiments, an anti-TIM-3 antibody agent is administered in combination with immunotherapy.
[00313] In some embodiments, an anti-TIM-3 antibody agent is administered simultaneously or sequentially with an additional therapeutic agent, such as, for example, another antibody agent (for example, an antibody agent that binds to PD- 1) and / or chemotherapeutic agent (for example, niraparib). In some embodiments, an anti-TIM-3 antibody agent is administered before, during or after the administration of an additional therapeutic agent. In some embodiments, an anti-TIM-3 antibody agent is administered before, during or after the administration of a chemotherapeutic agent (for example, niraparib).
[00314] An anti-TIM-3 antibody agent can be administered alone or in combination with other drugs (for example, as an adjuvant). For example, the anti-TIM-3 antibody agent can be administered in combination with other agents for the treatment or prevention of the diseases disclosed in this document (for example, cancer). In this regard, for example, an anti-TIM-3 antibody agent can be used in combination with at least one other anticancer agent including, for example, any chemotherapeutic agent known in the art, ionization radiation, small molecule anticancer agents, vaccines against cancer,
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145/172 biological therapies (eg, other monoclonal antibodies, cancer killing viruses, gene therapy and adoptive T cell transfer) and / or surgery.
[00315] The administration of an anti-TIM-3 antibody simultaneously or sequentially with an additional therapeutic agent (for example, a chemotherapeutic agent) is called "combination therapy". In combination therapy, the anti-TIM-3 antibody agent can be administered before (for example, 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 before), concomitantly with, or subsequently (for example, 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, weeks, 4 weeks, 5 weeks, 6 weeks , 8 weeks or 12 weeks after) administration of the additional therapeutic agent to a subject in need thereof. In some embodiments, the anti-TIM-3 antibody agent and an additional therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to hours apart, 4 hours to 5 hours apart, 5 to 6 hours apart, 6 to 7 hours apart, 7 to 8 hours apart, 8 to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, with a maximum interval of 24 hours or with a maximum interval of 48 hours.
PARP inhibitors [00316] In modalities, an additional therapy is a poly (ADP-ribose) polymerase inhibitor (PARP).
[00317] In modalities, a PARP inhibitor inhibits PARP-1 and / or PARP-2. In some embodiments, the agent is a small molecule, a
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146/172 nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, or a toxin. In related modalities, the agent is ABT767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib (SHR 3162), IMP 4297, INO1001, JPI 289, JPI 547, conjugated monoclonal antibody B3-LysPE40, MP 124, niraparib (ZEJULA) (MK-4827), NU 1025, NU 1064, NU 1076, NU1085, olaparib (AZD2281), ONO2231, PD 128763, R 503, R554, rucaparib (RUBRACA) (AG-014699, PF-01367338), SBP 101, SC 101914, simmiparib, talazoparib (BMN-673), veliparib (ABT-888), WW 46, 2- (4- (trifluoromethyl) phenyl) -7,8- dihydro-5H-thiopyran [4,3-d] pyrimidin-4-ol, and salts or derivatives thereof. In some related embodiments, an agent is niraparib, olaparib, rucaparib, talazoparib, veliparib, or salts or derivatives thereof. In certain embodiments, an agent is niraparib or a salt or derivative thereof. In certain embodiments, an agent is olaparib or a salt or derivative thereof. In certain embodiments, an agent is rucaparib or a salt or derivative thereof. In certain embodiments, an agent is talazoparib or a salt or derivative thereof. In certain embodiments, an agent is veliparib or a salt or derivative thereof.
[00318] Niraparib, (3S) -3- [4- {7- (aminocarbonyl) -2H-indazol-2yl} phenyl] piperidine, is a poly (adenosine diphosphate [ADP] ribose) (PARP) -1 polymerase inhibitor (PARP) -1 and -2 powerful and orally available. See WO 2008/084261 (published 17 July 2008), WO 2009/087381 (published 16 July 2009) and PCT / US17 / 40039 (deposited 29 June 2017), all of which is incorporated into this document by reference. Niraparib can be prepared according to Scheme 1 of WO 2008/084261.
[00319] In some embodiments, niraparib can be prepared as a pharmaceutically acceptable salt. One skilled in the art will appreciate that such salt forms can exist as solvated or hydrated polymorphic forms. In some embodiments, niriparib can be prepared in the form of a hydrate.
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147/172 [00320] In certain embodiments, niriparib is prepared in the form of a tosylate salt. In some embodiments, niriparib is prepared as a tosylate monohydrate. The molecular structure of the niraparib tosylate monohydrate salt is shown below:
^CH 3 (1).
[00321] Niraparib is a potent and selective inhibitor of PARP-1 and PARP-2 with an inhibitory concentration at 50% of the control (IC50) = 3.8 and 2.1 nM, respectively, and is at least 100 times selective in other members of the PARP family. Nirabibib inhibits PARP activity, stimulated as a result of DNA damage caused by the addition of hydrogen peroxide, in various cell lines with IC50 and inhibitory concentration at 90% of the control (IC90) of about 4 and 50 nM, respectively.
[00322] In embodiments, niraparib is administered in a dose equivalent to about 100 mg of niraparib-free base (for example, a pharmaceutically acceptable salt of niraparib, such as niraparib monohydrate tosylate, is administered in a dose equivalent to about 100 mg of niraparib free base). In embodiments, niraparib is administered in a dose equivalent to about 200 mg of niraparib free base (for example, a pharmaceutically acceptable salt of niraparib, such as niraparib monohydrate tosylate, is administered in a dose equivalent to about 200 mg of base niraparib free In embodiments, niraparib is administered in a dose equivalent to about 300 mg of niraparib free base (for example, a pharmaceutically acceptable salt of niraparib such as niraparib monohydrate tosylate is administered in a dose equivalent to about 300 mg niraparib free base).
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Checkpoint inhibitors [00323] In modalities, an additional therapy is an immunotherapy. In modalities, an immunotherapy comprises the administration of one or more immunological checkpoint inhibitors (for example, administration of one, two, three, four or more immunological checkpoint inhibitors).
[00324] Exemplary immunological checkpoint targets for inhibition include: PD-1 (eg, inhibition via anti-PD-1, anti-PD-L1 or antiPD-L2 therapies), CTLA-4, TIM-3, TIGIT, LAGs (e.g. LAG-3), CEACAM (e.g. CEACAM-1, -3 and / or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7- H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (e.g. beta TGFR), B7-H1, B7-H4 (VTCN1), OX-40, CD137, CD40, IDO and CSF-1R. Thus, agents that inhibit any of these molecules can be used in combination with an anti-TIM-3 therapy described in this document.
[00325] In modalities, an immunological checkpoint inhibitor is an agent that inhibits PD-1, CTLA-4, LAG-3, TIGIT, IDO or CSF1R.
[00326] In the modalities, an immune checkpoint inhibitor is a PD-1 inhibitor. In the embodiments, a PD-1 inhibitor is a PD-1 binding agent (for example, an antibody, antibody conjugate or antigen binding fragment thereof). In the embodiments, a PD1 inhibitor is a PD-L1 or PD-L2 binding agent (for example, an antibody, antibody conjugate or antigen binding fragment thereof). In embodiments, a PD-1 inhibitor is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MG. , 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, PF06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ-053, CK
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149/172
301, AK 104, or GLS-010, or any of the PD-1 antibodies disclosed in WO2014 / 179664. In embodiments, a PD-1 inhibitor is TSR-042. In some embodiments, a PD-1 inhibitor (for example, TSR-042) is administered according to a regimen comprising administering a dose of about 500 mg every 3 weeks for four doses, followed by administration of at least one 1,000 mg dose every six weeks after the fourth dose of about 500 mg. In some modalities, additional doses of about 1,000 mg are administered every six weeks after the first dose of about 1000 mg, until no further clinical benefit is achieved. In some particular embodiments, a PD-1 inhibitor (for example, TSR-042) is administered according to a dosage regimen that includes 500 mg over 4 Q3W cycles followed by 1000 mg Q6W.
[00327] In embodiments, an immunological checkpoint inhibitor is a CTLA-4 inhibitor (for example, an antibody, antibody conjugate or antigen-binding fragment thereof). In embodiments, a CTLA-4 inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, a CTLA-4 inhibitor is a small molecule. In embodiments, a CTLA-4 inhibitor is a CTLA-4 binding agent. In embodiments, a CTLA-4 inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof. In embodiments, a CTLA-4 inhibitor is ipilimunab (Yervoy), AGEN1884 or tremelimumab.
[00328] In embodiments, an immunological checkpoint inhibitor is an LAG-3 inhibitor (for example, an antibody, antibody conjugate or antigen-binding fragment thereof). In some embodiments, a LAG-3 inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, a LAG-3 inhibitor is a small molecule. In embodiments, a LAG-3 inhibitor is a LAG-3 binding agent. In
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150/172 embodiments, a LAG-3 inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof. In embodiments, a LAG-3 inhibitor is an IMP321, BMS-986016, GSK2831781, Novartis LAG525 or an LAG-3 inhibitor described in WO 2016/126858, WO 2017/019894 or WO 2015/138920, each of which is incorporated in this document by reference in its entirety.
[00329] In modalities, an immunological checkpoint inhibitor is a TIGIT inhibitor (for example, an antibody, an antibody conjugate or an antigen-binding fragment thereof). In embodiments, a TIGIT inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, or a toxin. In modalities, a TIGIT inhibitor is a small molecule. In embodiments, a TIGIT inhibitor is a TIGIT binding agent. In embodiments, a TIGIT inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof. In embodiments, a TIGIT inhibitor is MTIG7192A, BMS-986207 or OMP-31M32.
[00330] In modalities, an immunological checkpoint inhibitor is an IDO inhibitor. In embodiments, an IDO inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, an IDO inhibitor is a small molecule. In embodiments, an IDO inhibitor is an IDO binding agent. In embodiments, an IDO inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof.
[00331] In modalities, an immunological checkpoint inhibitor is a CSF1R inhibitor. In embodiments, a CSF1R inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal or a toxin. In embodiments, a CSF1R inhibitor is a small molecule. In embodiments, a CSF1R inhibitor is a CSF1R binding agent. In embodiments, a CSF1R inhibitor is a
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151/172 antibody, an antibody conjugate or antigen-binding fragment thereof.
[00332] In modalities, one method comprises administering a TIM-3 inhibitor with at least two of the immunological checkpoint inhibitors. In modalities, one method comprises administering a third checkpoint inhibitor. In embodiments, one method comprises administering a TIM-3 inhibitor with a PD-1 inhibitor and a LAG-3 inhibitor, so that the subject receives all three. In embodiments, one method comprises administering a TIM-3 inhibitor with a PD-1 inhibitor, a LAG-3 inhibitor and a CTLA-4 inhibitor, so that the subject receives all four.
[00333] In embodiments, an agent that inhibits poly polymerase (ADPribose) (PARP) has been additionally administered or will be administered to a subject, so that the subject receives treatment with a TIM-3 inhibitor and a PARP inhibitor.
[00334] In embodiments, one or more immunological checkpoint inhibitors (for example, a PD-1 inhibitor and / or an LAG-3 inhibitor) are additionally administered or will be administered to a subject, so that the subject receives treatment with a TIM-3 inhibitor, a PARP inhibitor (eg, niraparib) and one or more immunological checkpoint inhibitors. In embodiments, a TIM-3 inhibitor, a PD-1 inhibitor (for example, TSR-042) and a PARP inhibitor (for example, niraparib) are administered to a subject. In embodiments, a TIM-3 inhibitor, a PD-1 inhibitor (for example, TSR042), a LAG-3 inhibitor and a PARP inhibitor (for example, niraparib) are administered to a subject.
[00335] For female patients with the potential to become pregnant, it is preferable that the patient obtain a negative serum pregnancy test within 72 hours before the date of administration of the first dose of an anti-TIM-3 antibody agent. It is also preferable for female patients of childbearing potential and male patients
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152/172 agree to use 2 suitable methods of contraception with the partner. In some modalities, a patient agrees to use 2 contraceptive methods, from the screening visit up to 150 days after the last dose of study therapy.
[00336] The present disclosure provides, in some embodiments, methods for treating cancer in a patient in need thereof, the method comprising administering one or more compositions that deliver an anti-TIM-3 antibody agent in combination with a PD- inhibitor. 1 (for example, a PD-1 binding agent, such as an anti-PD-1 antibody). Figure 1 provides an exemplary scheme of combining anti-TIM-3 and anti-PD-1 antibodies in order to increase anti-tumor efficiency. In some embodiments, a patient or a population of patients receives combination therapy that comprises administration of an anti-TIM-3 antibody agent and a PD-1 binding agent. In some embodiments, the PD-1 binding agent is nivolumab or pembrolizumab. In the embodiments, a PD-1 inhibitor is a PD-1 binding agent (for example, an antibody, antibody conjugate or antigen binding fragment thereof). In embodiments, a PD-1 binding agent is nivolumab, pembrolizumab, TSR042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI- 308, camrelizumab (HR-301210), BCD100, JS-001, CX-072, AMP-514 / MEDI-0680, AGEN-2034, CS1001, TSR-042, Sym-021, PF-06801591, LZM009, KN-035 , AB122, genolimzumab (CBT-501), AK 104, or GLS-010, or derivatives thereof. In the embodiments, a PD1 inhibitor is a PD-L1 or PD-L2 binding agent (for example, an antibody, antibody conjugate or antigen binding fragment thereof). In embodiments, a PD-1 inhibitor is a PD-L1 or PD-L2 binding agent that is durvalumab, atezolizumab, avelumab, BGB-A333, SHR-1316, FAZ-053, CK-301, or PD millamolecule -L1, or derivatives thereof.
[00337] In some modalities, a population of patients or
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153/172 patient receives a combination therapy comprising administration of an anti-TIM-3 antibody agent comprising an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7 and a immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, an anti-TIM-3 antibody agent comprises two immunoglobulin heavy chains, each having a sequence of amino acids as set out in SEQ ID NO: 3 and an immunoglobulin light chain whose amino acid sequence comprises SEQ ID NO: 4.
[00338] In some embodiments, a patient population or patient receives combination therapy that comprises administration of a PD-1 binding agent comprising an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 11 or SEQ ID NO: 17 and an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 12 or SEQ ID NO: 18. In some embodiments comprising combinations, the PD-1 binding agent comprises a chain immunoglobulin heavy chain, whose amino acid sequence comprises SEQ ID NO: 13 and an immunoglobulin light chain whose amino acid sequence comprises SEQ ID NO: 14.
[00339] In some embodiments, an anti-TIM-3 antibody agent (for example, an anti-TIM-3 antibody) is administered at a dose of 0.1, 1.3 or 10 mg / kg. In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of 0.11, 3 or 10 mg / kg every two weeks. In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of 1.3 or 10 mg / kg every three weeks.
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154/172 [00340] In some embodiments, the composition that delivers an anti-TIM-3 antibody agent is administered according to a regimen that includes a dose of 1, 3 or 10 mg / kg every four weeks. In some embodiments, an anti-TIM-3 antibody agent at a fixed dose within the range of 200 mg to 1500 mg. In some embodiments, an anti-TIM-3 antibody agent at a fixed dose within a range of 300 mg to 1,000 mg. In some embodiments, an anti-TIM-3 antibody agent is administered according to a regimen that includes a fixed dose every two weeks. In some embodiments, an anti-TIM-3 antibody agent is administered according to a regimen that includes a fixed dose every three weeks. In some embodiments, an anti-TIM-3 antibody agent is administered according to a regimen that includes a fixed dose every four weeks.
[00341] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody such as TSR-042) is administered at a dose of about 1.3 or 10 mg / kg. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody such as TSR-042) is administered according to a regimen that includes a dose of about 1, 3 or 10 mg / kg every two weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody such as TSR-042) is administered according to a regimen that includes a dose of about 1.3 or 10 mg / kg every three weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that includes a dose of about 1, 3 or 10 mg / kg every four weeks. . In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody such as TSR-042) at a dose of about 500 mg. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody such as TSR-042) is administered according to a regimen that includes a dose of about 500 mg every two weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody such as TSR
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042) is administered according to a regimen that includes a dose of approximately 500 mg every three weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody such as TSR-042) is administered according to a regimen that includes a dose of about 500 mg every four weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody such as TSR-042) is administered according to a regimen that includes a dose of about 1000 mg every six weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody, such as TSR-042) is administered according to a regimen that includes a first dose of about 500 mg every three weeks (Q3W) for the first 2-6 (for example, the first 2, 3, 4, 5 or 6) dosing cycles, and a second dose of about 1000 mg every six weeks (Q6W) until treatment is discontinued (for example, due to disease progression, adverse effects or as determined by a doctor). In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody, such as TSR-042) is administered according to a regimen that includes a first dose of about 500 mg every three weeks (Q3W) for the first four dosing cycles and a second dose of about 1000 mg every six weeks (Q6W) until treatment is discontinued (for example, due to disease progression, adverse effects or as determined by a doctor) . In embodiments, a PD-1 binding agent is an antiPD-1 antibody. In embodiments, a PD-1 binding agent is TSR-042.
[00342] In certain methods, the anti-TIM-3 antibody agent can be administered before (for example, 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 before), concomitantly with, or subsequently (for example, 5 minutes , 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72
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156/172 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks after) administration of the PD-1 binding agent to a subject in need thereof .
Measuring Tumor Response [00343] In some modalities, a clinical benefit is a complete response (CR), a partial response (PR) or a stable disease (DS). In some modalities, a clinical benefit corresponds to at least SD. In some modalities, a clinical benefit corresponds to at least one PR. In some modalities, a clinical benefit corresponds to at least one CR. In some modalities, 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 obtain a clinical benefit. In some modalities, at least 5% of patients achieve a clinical benefit. In some modalities, at least 5% of patients reach DS. In some modalities, at least 5% of patients achieve at least one PR. In some modalities, at least 5% of patients achieve CR. In some modalities, at least 20% of patients achieve a clinical benefit. In some modalities, at least 20% of patients achieve DS.
[00344] In some modalities, the clinical benefit (for example, SD, PR and / or CR) is determined according to Response Assessment Criteria in Solid Tumors (RECIST). In some modalities, the clinical benefit (for example, SD, PR and / or CR) is determined according to the RECIST guidelines.
[00345] In some modalities, the tumor response can be measured, for example, by the RECIST v 1.1 guidelines. The guidelines are provided by EA Eisenhauer, et a!., “New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.),” Eur. J. of Cancer, 45: 228-247 (2009), which is incorporated by reference in its entirety. The guidelines require, first, an estimate of the total tumor load at baseline, which is
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157/172 used as a comparator for subsequent measurements. Tumors can be measured using any imaging system known in the art, for example, by CT scan, or X-ray. Measurable disease is defined by the presence of at least one measurable lesion. In studies in which the primary endpoint is tumor progression (time to progression or proportion progressing on a fixed date), the protocol must specify whether entry is restricted to those with measurable disease or whether patients with non-measurable disease are also eligible .
[00346] When more than one measurable injury is present at the start, all injuries up to a maximum of five total injuries (and a maximum of two injuries per organ) representative of all organs involved must be identified as target injuries and will be recorded and baseline measurements (this means that in cases where patients have only one or two organs involved, a maximum of two and four lesions, respectively, will be recorded).
[00347] The target lesions must be selected based on their size (lesions with a larger diameter), be representative of all the organs involved, but they must be those that can undergo repeated reproducible measurements.
[00348] Lymph nodes deserve special mention, since they are normal anatomical structures that can be visible by imaging exams, even if they are not involved by the tumor. Pathological lymph nodes that are defined as measurable and can be identified as target lesions must meet the criteria of a short axis of P15mm by CT scan. Only the short axis of these nodules will contribute to the sum of the baseline. The short axis of the nodule is the diameter normally used by radiologists to judge whether a nodule is surrounded by a solid tumor. The nodal size is usually reported as two dimensions in the plane in which the image is obtained (for CT scan this is almost always the axial plane; for MRI, the
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158/172 acquisition plan can be axial, sagittal or coronal). The smallest of these measures is the short axis.
[00349] For example, an abdominal nodule that is reported to be 20mm 30mm has a short axis of 20mm and qualifies as a measurable and malignant nodule. In this example, 20 mm must be recorded as the nodule measurement. All other pathological nodules (those with a short axis P10mm but <15 mm) should be considered non-target lesions. Nodules that have a short axis <10mm are considered non-pathological and should not be registered or monitored.
[00350] A sum of the diameters (the longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then, as noted above, only the short axis is added to the sum. The sum diameters of the baseline will be used as a reference to further characterize any objective regression of the tumor in the measurable dimension of the disease.
[00351] All other lesions (or disease sites), including pathological lymph nodes, must be identified as non-target lesions and must also be recorded at the baseline. Measurements are not necessary and these lesions must be monitored as 'present', 'absent' or, in rare cases, 'unequivocal progression'. In addition, it is possible to register multiple non-target lesions involving the same organ as a single item on the case record form (for example, multiple enlarged pelvic lymph nodes or multiple liver metastases).
[00352] In some modalities, the tumor response can be measured, for example, by the RECIST (irRECIST) guidelines for the immune system, which include the Response Criteria (irRC) for the immune system. In irRC, measurable lesions are measured that have at least one dimension with a minimum size of 10 mm (in the largest diameter by
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CT or MRI) for non-nodal lesions and greater than or equal to 15 mm for nodal lesions, or at least 20 mm by chest radiography.
[00353] In some modalities, the Response Criteria Relating to the Immune System include CR (complete disappearance of all lesions (measurable or not, and absence of new lesions)); PR (tumor load decreased by 50% or more compared to the baseline); SD (does not meet the criteria for CR or PR in the absence of PD); or PD (an increase in tumor burden of 25% or more compared to nadir). The 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.
[00354] In some modalities, the tumor response can be assessed either by irRECIST or RECIST version 1.1. In some modalities, the tumor response can be assessed by both irRECIST and RECIST, version 1.1.
Pharmacokinetics [00355] Pharmacokinetic data can be obtained by methods known in the art. Due to the inherent variation in pharmacokinetic and pharmacodynamic parameters of drug metabolism in human subjects, components of the appropriate pharmacokinetic and pharmacodynamic profile that describe a particular composition may vary. Typically, pharmacokinetic and pharmacodynamic profiles are based on determining the average parameters of a group of subjects. The subject group includes any reasonable number of suitable subjects to determine a representative average, for example, 5 subjects, 10 subjects, 16 subjects, 20 subjects, 25 subjects, 30 subjects, 35 subjects, or more. The average is determined by calculating the average of all measurements of the subject for each parameter measured.
[00356] In some modalities, a patient population includes one or more subjects ("a population of subjects") suffering from a disease
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160/172 metastatic.
[00357] In some modalities, a patient population includes one or more subjects who are suffering from or are susceptible to cancer. In some such modalities, the cancer is non-small cell lung cancer (NSCLC), hepatocellular cancer, kidney cancer, melanoma, cervical cancer, colorectal cancer, squamous cell carcinoma of the anogenital region (for example, squamous cell carcinoma of the anus, penis, cervix, vagina or vulva), head and neck cancer, triple-negative breast cancer, ovarian cancer or endometrial cancer. In embodiments, a cancer is a solid tumor (for example, an advanced solid tumor, a metastatic solid tumor, a solid MSS tumor, a solid MSI-H tumor, or a solid POLE mutant tumor). In modalities, a cancer is a melanoma (for example, an advanced melanoma, a metastatic melanoma, an MSS melanoma, an MSI-H melanoma or a POLE mutant melanoma). In embodiments, a cancer is a lung cancer such as NSCLC (e.g., advanced NSCLC, metastatic NSCLC, NSCLC MSI-H, NSCLC MSS, POLE mutant NSCLC, EGFR mutant NSCLC or ALK translocated NSCLC). In modalities, a cancer is colorectal cancer (for example, advanced colorectal cancer, metastatic colorectal cancer, MSS colorectal cancer, MSI-H colorectal cancer or POLE mutant colorectal cancer). In some embodiments, a patient population includes one or more subjects (for example, comprises or consists of subjects) suffering from cancer. For example, in some modalities, a population of cancer patients may have previously been treated with previous therapy, for example, radiation and / or chemotherapy.
[00358] In some embodiments, pharmacokinetic parameters can be any suitable parameters to describe the present composition.
[00359] In some embodiments, pharmacokinetic parameters
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161/172 can be any parameters suitable to describe the present composition. For example, in some embodiments, the C _max is about 1 pg / ml; about 5 pg / ml, about 10 pg / ml, about 15 pg / ml, about 20 pg / ml, about 25 pg / ml, about 30 pg / ml, about 35 pg / ml, about about 40 pg / ml, about 45 pg / ml, about 50 pg / ml, about 55 pg / ml, about 60 pg / ml, about 65 pg / ml, about 70 pg / ml, about 75 pg / ml, about 80 pg / ml, about 85 pg / ml, about 90 pg / ml, about 95 pg / ml, about 100 pg / ml, about 150 pg / ml, about 200 pg / ml , about 250 pg / ml, about 300 pg / ml, or any other appropriate C _max to describe a pharmacokinetic profile of an anti-TIM-3 antibody.
[00360] In some modalities, the T _max is, for example, not more than about 0.5 hours, not more than about 1.0 hours, not more than about 1.5 hours, not more than about 2.0 hours, not more than about 2.5 hours or not more than about 3.0 hours, or any other suitable T _max to describe a pharmacokinetic profile of an anti-TIM-3 antibody.
[00361] In general, AUC as described in this document is the measurement of the area under the curve that corresponds to the concentration of an analyte over a selected period of time after administration of a dose of a therapeutic agent. In some embodiments, this time period begins with dose administration (ie, 0 hours after dose administration) and extends for about 2, about 6, about 12, about 36, about 48, about 48 72, about 168, about 336, about 514, about 682, or more hours after dose administration. In some embodiments, the AUC is reached from 0 to 336 hours after the administration of a dose described in this document.
[00362] The AUC (o -336h) can be, for example, about 500 pg * hr / mL, about 1000 pg * hr / mL, about 1500 pg * hr / mL, about 2000 pg * hr / mL, about 2500 pg * hr / mL, about 3000 pg * hr / mL, about 3500 pg * hr / mL, about 4000 pg * hr / mL, about 4500 pg * hr / mL, about 5000 pg * hr / mL, about 7500 pg * hr / mL, about 10,000 pg * hr / mL, about 15,000 pg * hr / mL,
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162/172 about 20,000 pg * hr / mL, about 25,000 pg * hr / mL, about 30,000 pg * hr / mL, about 35,000 pg * hr / mL, about 40,000 pg * hr / mL, about 45,000 pg * hr / mL, about 50,000 pg * hr / mL, about 65,000 pg * hr / mL, about 75,000 pg * hr / mL, about 90,000 pg * hr / mL, or any other AUC (o- 336h) appropriate to describe a pharmacokinetic profile of a therapeutic agent (for example, an anti-TIM-3 antibody). In some embodiments, an anti-TIM-3 antibody is administered according to a regimen that has been shown to achieve an average AUCo-336h of the anti-TIM-3 antibody concentration curve in a patient population that is 2500 h * pg / ml_ at 50000 h * pg / ml_.
[00363] In some embodiments, the AUC of 0 hours at the end of the dosing period is determined (AUC (o-Tau)). In some embodiments, the dosing period is one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks or ten weeks. In some embodiments, the dosing period is 2 weeks. In some embodiments, the dosage period is 3 weeks.
[00364] In some embodiments, an anti-TIM-3 antibody is administered according to a regimen that has been shown to achieve a response rate in the relevant patient population such that no more than 50% to 80% of patients have progressive disease after 2, 4, 6 8, 10, 12, 14, 16, 18 or 20 weeks after starting treatment. In some modalities, no more than 80% of patients show progressive disease after at least 10 weeks after starting treatment.
[00365] In some embodiments, an anti-TIM-3 antibody is administered according to a regimen that is sufficient to achieve an average TIM-3 receptor occupancy of at least 50% to 90% after 1,2, 3, 4 or 5 days after a single dose of the composition. In some embodiments, administration of a composition that delivers an anti-TIM-3 antibody is sufficient to achieve an average TIM-3 receptor occupancy of at least 50%, at least 55%, at least 60%, at least 65% at least 70%,
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163/172 at least 75%, at least 80%, at least 85%, or at least 90% after 3 days after a single dose of the composition.
[00366] In some embodiments, an anti-TIM-3 antibody is administered according to a regimen sufficient to achieve an average stimulation ratio of at least 1 in a functional TIM-3 receptor occupation trial after 3 days after a single dose of the TIM-3 binding agent.
[00367] In some embodiments, an anti-TIM-3 antibody is administered according to a regimen that is sufficient to achieve an average TIM-3 receptor occupancy of at least 75% over a first period of time, for example , about 14 days to about 60 days after a single dose of the anti-TIM-3 antibody. In some embodiments, an anti-TIM-3 antibody is administered according to a regimen sufficient to achieve an average TIM-3 receptor occupancy of at least 75% over the first period of time (for example, about 15 days at about 60 days; in some embodiments, about 29 days) after a single dose of the anti-TIM-3 antibody.
[00368] In some embodiments, an anti-TIM-3 antibody is administered according to a regimen that is sufficient to achieve an average stimulation ratio of at least 1 in a TIM-3 receptor functional occupation assay over a first period of time, for example, about 14 days to about 60 days after a single dose of the anti-TIM-3 antibody. In some embodiments, an anti-TIM-3 antibody is administered according to a regimen sufficient to achieve an average stimulation ratio of at least 1 in a TIM-3 receptor functional occupation assay over the first period of time (eg example, about 15 days to about 60 days; in some embodiments, about 29 days) after a single dose of the anti-TIM-3 antibody.
EXAMPLES [00369] The following examples are provided to illustrate, but not
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164/172 to limit the claimed invention.
Example 1. Combinatory Blocking of TIM-3 and PD-1 in Mouse Model Systems [00370] The effect of inhibition of TIM-3 and PD-1 in a mouse T-cell exhaustion assay was studied (Burkhart et al Int Immunol 1999; 11: 1625-1634). In this system, in vitro stimulation of transgenic mouse T cells receiving CD4 + T cells with a super-agonist altered peptide ligand leads to an exhausted phenotype, characterized by increased expression of PD-1 and TIM-3 (Figure 2A). As shown in Figure 2B, the combination of anti-PD-1 and anti-TIM-3 antibodies was more effective than any of the isolated agents in increasing IFNy production in this system.
Example 2. In vivo efficacy study of the combination of TSR-042 and TSR-022 [00371] In addition to evaluating the combinatorial effect of targeting PD-1 and TIM-3 in vitro, the combination was tested in an animal model of cancer lung. A humanized mouse tumor model, consisting of human A549 lung cancer cells (5x10 ⁶ cells per mouse) implanted in huNOG-EXL mice, was used. CD34 + hematopoietic stem cells derived from neonates were grafted into the mouse, and the animals were treated with blocking monoclonal antibodies directed at PD-1 (TSR-042) and TIM-3 (TSR-022). Here, we show that the combination of anti-PD-1 and anti-TIM-3 has a beneficial anti-tumor effect when compared to any of the isolated agents (Figure 3).
Example 3. Exemplary Dosing Regimes for an TIM-3 Binding Agent [00372] This example describes a Phase 1, multicenter, open-label, first administration study in humans, evaluating a binding agent
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165/172 to TIM-3 (an anti-TIM-3 antibody), in patients with tumors. Specifically, the dosing effects in patients with advanced solid tumors treated with a particular TIM-3 binding agent. A TIM-3 binding agent (TSR-022) as described in the present study comprises a humanized anti-TIM-3 antibody comprising a heavy chain whose amino acid sequence comprises SEQ ID NO: 3 and a light chain whose amino acid sequence comprises SEQ ID NO: 4 were evaluated. This anti-TIM-3 antibody uses a human IGHG4 * 01 heavy chain gene and a human IGKC * 01 kappa light chain gene as scaffolding. In addition, there is a single point mutation of Ser a Pro in the hinge region of the heavy chain of lgG4 at the canonical position S228.
[00373] Patients with solid tumors histologically or cytologically proven to be advanced (unresectable) or metastatic and who suffered disease progression after treatment with available therapies known to confer clinical benefit, or who are intolerant to other treatment (s) were included known (s).
[00374] The study comprises several parts: dose escalation and cohort expansion. Part 1a of the study (dose escalation) is intended, inter alia, to assess the safety profile, PK and PDy, tolerability and anticancer effect of the anti-TIM-3 antibody. A modified 3 + 3 model was used for dose escalation at 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 1.0 mg / kg, 3 mg / kg and 10 mg / kg and additionally elevated every 2 weeks (Q2W) with the dose of TIM-3 antibody not exceeding 20 mg / kg. Dose escalation continued to 1.0 mg / kg Q2W and an BAT has not yet been identified. Part 1a may also comprise testing a “single” dose, or a specific fixed number of milligrams of antibody (as opposed to weight-based dosing, mg / kg). Simple doses can range from 200 mg to 1500 mg of anti-TIM-3 antibody. Part 1b of the study (combination with PD1 dose escalation cohorts) is intended, inter alia, to assess the safety profile, PK and PDy, tolerability and
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166/172 anti-cancer effect of the anti-TIM-3 antibody in combination with an antiPD-1 antibody, in which the anti-TIM-3 antibody is administered as a dose escalation. The dosage will comprise anti-TIM-3 at 1.0 mg / kg, 3 mg / kg and 10 mg / kg or more every 2 weeks (Q2W) or every 3 weeks (Q3W) with the dose of anti-TIMT-3 exceeding the BAT defined in part 1a of the study, each in combination with an anti-PD-1 (examples of anti-PD-1 antibodies are a humanized anti-PD-1 monoclonal antibody comprising a heavy chain whose amino acid sequence comprises SEQ ID NO: 13, and a light chain whose amino acid sequence comprises SEQ ID NO: 14, nivolumab or pembrolizumab). The anti-PD-1 antibody can be dosed with an approved dose and programmed for a marketed agent and based on weight at a dose of 3 or 10 mg / kg Q2W or Q3W, or in a fixed dose of 500 mg of antibody Q2W or Q3W using a modified 3 + 3 model.
[00375] Primary objectives include determining the safety and tolerability of TSR-022 by Common Terminology Criteria for Adverse Events (CTCAE v4) and determining the recommended phase 2 dose (RP2D), and scheduling for monotherapy and combination with a antiPD-1 antibody. Secondary objectives include: pharmacokinetics (PK), overall response rate, duration of response, disease control rate, progression-free survival, overall survival and immunogenicity. Exploratory objectives include pharmacodynamics.
[00376] Figure 4A shows the doses used in the Part 1a dose escalation study for TSR-022 monotherapy. In the dose escalation study, 38 patients with advanced cancer were enrolled until October 27. Doses of 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg and 10 mg / kg were administered to patients.
[00377] Adult patients with advanced or metastatic solid tumors who had disease progression or treatment in tolerance after treatment with available therapies and organ functioning
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167/172 adequate and ECOG [Eastern Cooperative Oncology Group] performance status were addressed. Previous treatment with immunological checkpoint inhibitors was allowed. A summary of patient demographics is shown in Figure 5 for the 38 enrolled patients. In the Part 1a study, there were 21 male patients and 17 female patients. The mean age was 60.1 years (SD = 13.5), with a median of 61.0 years (min = 25; max = 85). The average number of previous treatment lines was 3.2 (SD = 2.3), with a median of 2.0 (min = 1; max = 10). 10 patients had an ECOG performance status of 0, and 28 had an ECOG performance status of 1. Tumor sites included colon, skin, ovary, breast, brain, head and neck, testicles, pleura, lung, rectum, thyroid , liver or esophagus.
[00378] After patients received the first dose of TSR-022 at various levels (0.03-10 mg / kg), the concentration of TSR-022 in serum was monitored for two weeks and pharmacokinetic behaviors (PK) were characterized . Figure 6A shows the serum concentration versus time profiles for all treatment groups in Part 1. TSR-022 demonstrated linear PK behavior for the studied doses of 0.03-10 mg / kg.
[00379] Figure 6B shows the occupation of TIM-3 in circulating monocytes, measured by flow cytometry from whole blood samples collected from patients treated with anti-TIM-3. Receptor occupation in peripheral monocytes correlated with exposure to TSR-022.
[00380] The occupation of the TIM-3 (RO) receptor by TSR-022 in circulating CD14 ⁺ monocytes was measured by flow cytometry. Briefly, whole blood samples from patients treated with TSR-022 were stained with anti-CD14, a non-competitive anti-TIM-3 antibody (indicating total TIM-3) and a competing anti-TIM-3 antibody (indicating TIM-3 free or not connected). TIM-3 occupation by infused TSR-022 was estimated as the ratio of free TIM-3 in CD14 + cells to total TIM-3 in CD14 + cells. A decrease
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168/172 in the ratio indicates an increase in the TIM-3 receptor linked to TSR-022. To measure the binding in the RO assay, whole blood was collected from patients at baseline (Day 1 pre-dose), 48 hours after the first dose (Day 3) and before the second dose (Day 15 pre-dose) for the Q2W schedule. Additional samples were collected on Day 22 and Day 29 after the first dose for a subset of patients who did not receive the second dose. Samples for measuring occupancy in the Q3W schedule were collected as follows: Day 1 pre-dose, Day 5, Day 15 and Day 22. Samples from healthy donors saturated with TSR-022 ex vivo (sat), as well as controls without detection antibodies (Bkgd) were included as controls.
[00381] Figures 7A-7C, respectively, show studies of occupation of the anti-TIM-3 antibody receptor (TSR-022) administered in doses of 1 mg / kg (Fig. 7A), 3 mg / kg (Fig. 7B) and 10 mg / kg (Fig. 7C) every two weeks (Q2W). All samples were pre-dose, with occupancy measured after a single dose on day 1. The occupancy ratio (free TIM-3: total TIM-3) is determined at various times (for example, points in time may include the day 1, day 3, day 15, day 22 and day 29). Receptor occupancy is maximal on day 3 through TSR-022 doses. At 3 mg / kg, the maximum occupancy is maintained until the 29th, and comparable results are obtained for the 10 mg / kg dose across the days with the available data.
[00382] Figure 8 provides a summary of dosages administered to patients (0.03-10 mg / kg) and the duration of treatment during the Part 1 a studies.
[00383] The best response observed was also evaluated in patients evaluable for efficacy (for example, patients who received at least two doses and had at least one evaluation after initiation or discontinued treatment due to clinical progression before the initial evaluation of the tumor) . Stable disease (5/25 patients) and partial response (1/25 patients with 10 mg / kg) were found to be the best response in
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169/172 patients with rectal, thyroid, neuroendocrine, head and neck cancer, or with soft tissue sarcoma.
[00384] Figure 9 describes the brain exams of the patient with partial response at the level of 10 pg / mg. The 42-year-old patient has leiomyosarcoma that is metastatic to the lung and kidney (leiomyosarcoma confirmed by renal biopsy: PTEN splice site, MYC amplification, ATRX mutation, CD36 mutation, RB loss, p53 loss; low mutation load). The patient received 3 doses of TSR-022 at 10mg / kg before re-examining. In addition, the patient received gemcitabine and docetaxel for 5 months with demonstrated progression before entering the study. Depending on the confirmatory test, there appears to be a tumor reduction of 32% at a dose of 10 mg / kg, and treatment is ongoing.
[00385] From the studies, monotherapy with TSR-022 has been shown to be well tolerated at various dose levels.
[00386] Part 2 of the study is intended, inter alia, to assess the safety and tolerability profile, PK and PDy and the anticancer effect of (i) anti-TIM-3 antibody in fixed doses Q2W or Q3W or (ii) antibody anti-TIM-3 in fixed doses Q2W or Q3W in combination with anti-PD-1 antibodies in weight-based or single doses, as indicated above. An anti-PD-1 antibody can be administered according to a 500 mg regimen every three weeks (Q3W) for the initial treatment cycles (for example, 500 mg administered Q3W for four treatment cycles) followed by administration of 1000 mg every six weeks (Q6W) until treatment is discontinued (for example, due to disease progression).
[00387] Single doses of about 100 mg to 1500 mg of the anti-TIM-3 antibody can be administered as monotherapy or in combination therapy. For example, a dose of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg of anti-TIM-3 antibody can be administered
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170/172
Q1W, Q2W, Q3W, Q4W, Q5W or Q6W as monotherapy or in combination with an anti-PD-1 antibody administered at 500 mg Q3W over four treatment cycles, and then at 1000 mg Q6W until treatment is discontinued (for example, due to disease progression). In embodiments, a dose of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg of anti-TIM-3 antibody can be administered Q2W or Q3W as monotherapy or in combination with an anti-PD-1 antibody which is administered at 500 mg Q3W over four treatment cycles and at 1000 mg Q6W until treatment is discontinued (for example, due to disease progression). A dose of 100 mg, 200 mg, 300 mg, 500 mg, 800 mg, 1000 mg or 1200 mg of antiTIM-3 antibody can be administered as monotherapy once a week (Q1W), once every two weeks (Q2W) , once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W) or once every three weeks (Q6W). A dose of 100 mg, 200 mg, 300 mg, 500 mg, 800 mg, 1000 mg or 1200 mg of anti-TIM-3 antibody can be administered as monotherapy once every two weeks (Q2W) or once every three weeks (Q3W).
[00388] Receptor occupation studies were performed based on a simple 100 mg dose of anti-TIM-3 antibody administered once every three weeks (Q3W). All samples were pre-dose, with occupancy measured after a single dose on day 1. As shown in Figure 10, target coverage at the periphery is achieved at 100 mg over the duration of the dosing interval. In addition, the occupancy of the 100 mg Q3W receptor is comparable to 3 mg / kg Q2W (Figure 7B).
[00389] Receptor occupation studies after administration of a single 300 mg dose of an exemplary anti-TIM-3 antibody (TSR-022) administered in combination with a fixed dose of 500 mg of an anti-PD-1 antibody model (TSR-042) were also conducted in accordance with the
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171/172 methods described in this document, and data are shown in Figure 11. A second dose of TSR-022 was administered on day 22, with the RO sample collected before the second dose. Using a simple 300 mg dose of TSR-022, high RO can be maintained for the measured period of time.
[00390] Figure 12 is a composite of average receptor occupancy data for doses of an exemplary anti-TIM-3 antibody (TSR-022) of 1 mg / kg, 3 mg / kg, 10 mg / kg and single doses 100 mg, 300 mg and 1200 mg. The figure shows that high occupancy rates (free TIM-3: total TIM-3) can be achieved using various doses of TSR-022 as measured over a period of days.
[00391] These monotherapy or combination regimens will be tested on specific types of tumors, which may include melanoma treated with antiPD1 / L1, NSCLC treated with anti-PD1 / L1, colorectal cancer, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma and / or breast cancer. Figure 4B provides an overview of the Part 2 expansion cohort study.
EQUIVALENTS [00392] Articles one and one, as used in this document in the specification and in the claims, unless otherwise stated, should be understood as including plural referents. Claims or descriptions that include or between one or more members of a group are considered to be satisfied if one, or more than one, or all members of the group are present, employed, or otherwise relevant to a particular product or process, unless otherwise indicated or otherwise evidenced by the context. The invention includes modalities in which exactly one member of the group is present, employed, or otherwise relevant to a particular product or process. The invention also includes modalities in which more than one, or members of the entire group are present, employed, or otherwise relevant to a particular product or process. In addition, it should be understood that the invention
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172/172 covers all variations, combinations and exchanges in which one or more limitations, elements, clauses, descriptive terms, etc., of one or more of the listed claims are introduced in another claim dependent on the claim of the same basis (or, when relevant, any other claim), unless otherwise indicated or unless it is evident to those skilled in the art that a contradiction or inconsistency would arise. When elements are presented as lists (for example, in a Markush group or in a similar format), it should be understood that each subgroup of elements will also be disclosed, and any (any) element (s) can be removed of the group. It should be understood that, in general, when the invention, or aspects of the invention, is / are referred to as comprising elements, specific features, etc., certain embodiments of the invention or aspects of the invention will consist, or will essentially consist of, those elements, characteristics, etc. For the sake of simplicity, these modalities have not been specified in each case established so extensively in this document. It should also be understood that any modality or aspect of the invention can be explicitly excluded from the claims, regardless of whether the specific exclusion is reported in the specification. The publications, websites and other reference materials referred to in this document to describe the fundamentals of the invention and to provide additional details in relation to its practice are incorporated herein by reference.

权利要求:
Claims (246)
[1]
1. Method of treating a disorder in a subject that is responsive to the inhibition of T-Cell Immunoglobulin and Protein Mucine 3 (TIM3), characterized by the fact that the method comprises the administration of a therapeutically effective dose of an agent that is capable to inhibit TIM-3 signaling, where the therapeutically effective dose is: about 1.3 or 10 mg / kg; a fixed dose between about 100 - 1500 mg; a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; a fixed dose of about 1500 mg; about 1 mg / kg; about 3 mg / kg; or about 10 mg / kg.
[2]
2. Method of increasing T cell activation or T cell effector function in a subject that is responsive to inhibition of T Cell Immunoglobulin and Protein Mucine 3 (TIM-3), characterized by the fact that the method comprises administration a therapeutically effective dose of an agent that is capable of inhibiting TIM-3 signaling, wherein the therapeutically effective dose is: about 1.3 or 10 mg / kg; a fixed dose between about 100 - 1500 mg; a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; a fixed dose of about 1500 mg; about 1 mg / kg; about 3 mg / kg; or about 10 mg / kg.
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2/31
[3]
3. Method of tumor reduction or inhibition of tumor cell growth in a subject that is responsive to the inhibition of T-Cell Immunoglobulin and Protein Mucine 3 (TIM-3), characterized by the fact that the method comprises the administration of a dose therapeutically effective agent that is capable of inhibiting TIM-3 signaling, wherein the therapeutically effective dose is: about 1.3 or 10 mg / kg; a fixed dose between about 100 - 1500 mg; a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; a fixed dose of about 1500 mg; about 1 mg / kg; about 3 mg / kg; or about 10 mg / kg.
[4]
4. Method of inducing an immune response in a subject that is responsive to the inhibition of T-Cell Immunoglobulin and Protein Mucine 3 (TIM3), characterized by the fact that the method comprises the administration of a therapeutically effective dose of an agent that is capable of inhibiting TIM-3 signaling, where the therapeutically effective dose is: about 1.3 or 10 mg / kg; a fixed dose between about 100 - 1500 mg; a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; a fixed dose of about 1500 mg; about 1 mg / kg; about 3 mg / kg; or about 10 mg / kg.
[5]
5. Method of enhancing an immune response or increasing the
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3/31 activity of an immune cell in a subject that is responsive to the inhibition of T Cell Immunoglobulin and Protein Mucine 3 (TIM-3), characterized by the fact that the method comprises the administration of a therapeutically effective dose of an agent that is able to inhibit TIM-3 signaling, where the therapeutically effective dose is: about 1, 3 or 10 mg / kg; a fixed dose between about 100 - 1500 mg; a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; a fixed dose of about 1500 mg; about 1 mg / kg; about 3 mg / kg; or about 10 mg / kg.
[6]
6. Method according to claim 5, characterized by the fact that the immune response is a humoral or cell-mediated immune response.
[7]
7. Method according to claim 6, characterized by the fact that the immune response is a CD4 or CD8 T cell response.
[8]
8. Method according to claim 6, characterized by the fact that the immune response is a B cell response.
[9]
Method according to any one of claims 1-8, characterized in that the therapeutically effective dose is about 1 mg / kg.
[10]
Method according to any one of claims 1-8, characterized in that the therapeutically effective dose is about 3 mg / kg.
[11]
11. Method according to any one of claims 1-8, characterized in that the therapeutically effective dose is about 10 mg / kg.
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[12]
12. Method, according to characterized by the fact that the dose of about 100 mg.
[13]
13. Method, according to characterized by the fact that the dose of about 200 mg.
[14]
14. Method, according to characterized by the fact that the dose of about 300 mg.
[15]
15. Method, according to characterized by the fact that the dose of about 400 mg.
[16]
16. Method, according to characterized by the fact that the dose of about 500 mg.
[17]
17. Method, according to characterized by the fact that the dose of about 600 mg.
[18]
18. Method, according to characterized by the fact that the dose of about 700 mg.
[19]
19. Method, according to characterized by the fact that the dose of about 800 mg.
[20]
20. Method, according to characterized by the fact that the dose of about 900 mg.
[21]
21. Method, according to the fact that the dose any one of claims 1-8, therapeutically effective is a fixed dose any one of claims 1-8, therapeutically effective is a fixed dose any one of claims 1-8, therapeutically effective is a fixed dose any of claims 1-8, therapeutically effective is a fixed dose any of claims 1-8, therapeutically effective is a fixed dose any of claims 1-8, therapeutically effective is a fixed dose any of claims 1-8, therapeutically effective is a fixed dose any of claims 1-8, therapeutically effective is a fixed dose any of claims 1-8, therapeutically effective is a fixed dose any of claims 1-8, therapeutically effective is a fixed dose
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5/31 of about 1000 mg.
[22]
22. Method according to any one of claims 1-8, characterized in that the therapeutically effective dose is a fixed dose of about 1100 mg.
[23]
23. Method according to any one of claims 1-8, characterized in that the therapeutically effective dose is a fixed dose of about 1200 mg.
[24]
24. Method according to any one of claims 1-8, characterized in that the therapeutically effective dose is a fixed dose of about 1300 mg.
[25]
25. Method according to any one of claims 1-8, characterized in that the therapeutically effective dose is a fixed dose of about 1400 mg.
[26]
26. Method according to any one of claims 1-8, characterized in that the therapeutically effective dose is a fixed dose of about 1500 mg.
[27]
27. Method according to any one of the preceding claims, characterized by the fact that the agent is administered in the interval of administration once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks.
[28]
28. Method according to claim 27, characterized by the fact that the agent is administered in the interval of administration once every 3 weeks.
[29]
29. Method according to claim 28, characterized in that the therapeutically effective dose is a fixed dose of about 100 mg, 300 mg, 500 mg or 900 mg.
[30]
30. Method according to any of the preceding claims, characterized by the fact that the agent is administered for a period
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6/31 enough to achieve a clinical benefit.
[31]
31. Method, according to claim 30, characterized by the fact that the clinical benefit is stable disease (DS), a partial response (PR) and / or a complete response (CR).
[32]
32. Method, according to claim 31, characterized by the fact that the PR or CR is determined according to the Response Evaluation Criteria in Solid Tumors (RECIST - Response Evaluation Criteria in Solid Tumors).
[33]
33. Method according to any of claims 30-32, characterized in that the agent is administered for a longer period of time to maintain the clinical benefit.
[34]
34. Method according to any one of the preceding claims, characterized by the fact that the agent is administered for a period of at least 2, 3, 4, 5, 6,7,8,9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, 20 weeks, or more.
[35]
35. Method according to any one of the preceding claims, characterized by the fact that the disorder is a dysfunctional T-cell disorder.
[36]
36. Method, according to any of the preceding claims, characterized by the fact that the disorder is cancer.
[37]
37. Method according to claim 36, characterized by the fact that cancer is:
i) a cancer associated with a high tumor mutation load (BMR);
ii) a cancer that is stable to microsatellites (MSS), iii) a cancer that is characterized by instability of microsatellites,
iv) a cancer what has a high status in instability in microsatellites (MSI-H), v) cancer what has a bass status in instability in microsatellites (MSI-L),
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7/31 vi) a cancer associated with high BMR and MSI-H, vii) a cancer associated with high BMR and MSI-L or MSS, viii) a cancer that has a defect in the DNA incompatibility repair system, ix) a cancer that has a defect in a DNA incompatibility repair gene,
x) a hypermutated cancer, xi) a cancer that comprises a mutation in the delta polymerase (POLD), xii) a cancer that comprises a mutation in the epsilon polymerase (POLE), xiii) a cancer that has homologous recombination repair deficiency / deficiency homologous repair (HRD);
xiv) adenocarcinoma, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, testicular cancer, primary peritoneal cancer, colon cancer, colorectal cancer, stomach cancer, small intestine cancer, cell carcinoma squamous anus, squamous cell carcinoma of the penis, squamous cell carcinoma of the cervix, squamous cell carcinoma of the vagina, squamous cell carcinoma of the vulva, soft tissue sarcoma, 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, larynx cancer, salivary gland cancer, cancer esophageal cancer, head and neck cancer, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer , mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, hematological cancer, multiple myeloma, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma / primary mediastinal B cell lymphoma, leukemia
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8/31 chronic myeloid, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, neuroblastoma, CNS tumor, diffuse intrinsic pontine glioma (DIPG), Ewing's sarcoma, embryonic rhabdomyosarcoma, osteosarcoma, or Wilms tumor, or xi tumor, ) a cancer of xiv), in which the cancer is MSS or MSI-L, is characterized by microsatellite instability, is MSI-H, has high BMR, has high BMR and is MSS or MSI-L, has high BMR and is MSI-H, has a defective DNA incompatibility repair system, has a defect in a DNA incompatibility repair gene, is a hypermutated cancer, is a cancer with HRD, comprises a mutation in the delta polymerase (POLD), or comprises a mutation in epsilon polymerase (POLE).
[38]
38. Method according to claim 36, characterized by the fact that cancer is a cancer that has homologous recombination repair deficiency / homologous repair deficiency (HRD).
[39]
39. Method, according to claim 35, characterized by the fact that the cancer is endometrial cancer, optionally MSI-H or MSS / MSI-L endometrial cancer.
[40]
40. Method according to claim 35, characterized in that the cancer is an MSI-H cancer comprising a mutation in POLE or POLD, optionally a non-endometrial cancer MSI-H comprising a mutation in POLE or POLD.
[41]
41. Method according to claim 35, characterized by the fact that the cancer is breast cancer, optionally triple negative breast cancer (TNBC).
[42]
42. Method according to claim 35, characterized by the fact that the cancer is ovarian cancer, optionally epithelial ovarian cancer.
[43]
43. Method according to claim 35, characterized by the fact that the cancer is lung cancer, optionally non-small cell lung cancer.
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[44]
44. Method, according to claim 35, characterized by the fact that cancer is melanoma.
[45]
45. Method, according to claim 35, characterized by the fact that cancer is colorectal cancer.
[46]
46. Method according to claim 35, characterized by the fact that 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.
[47]
47. Method, according to claim 35, characterized by the fact that cancer is acute myeloid leukemia.
[48]
48. Method according to claim 35, characterized by the fact that cancer is acute lymphoblastic leukemia.
[49]
49. Method according to claim 35, characterized by the fact that the cancer is non-Hodgkin's lymphoma.
[50]
50. Method according to claim 35, characterized by the fact that the cancer is Hodgkin's lymphoma.
[51]
51. Method according to claim 35, characterized by the fact that the cancer is neuroblastoma.
[52]
52. Method according to claim 35, characterized by the fact that cancer is a CNS tumor.
[53]
53. Method according to claim 35, characterized by the fact that cancer is diffuse intrinsic pontine glioma (DIPG).
[54]
54. Method according to claim 35, characterized by the fact that the cancer is Ewing's sarcoma.
[55]
55. Method according to claim 35, characterized by the fact that cancer is embryonic rhabdomyosarcoma.
[56]
56. Method according to claim 35, characterized by the fact that the cancer is osteosarcoma.
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[57]
57. Method according to claim 35, characterized by the fact that the cancer is Wilms' tumor.
[58]
58. Method according to claim 35, characterized by the fact that cancer is soft tissue sarcoma.
[59]
59. Method according to claim 48, characterized by the fact that cancer is leiomyosarcoma.
[60]
60. Method, according to any one of the preceding claims, characterized by the fact that the subject has been administered or will be administered still with an immunological checkpoint inhibitor, so that the mammal receives the agent and the immunological checkpoint inhibitor.
[61]
61. Method according to claim 60, characterized by the fact that it comprises the administration of one, two or three immunological checkpoint inhibitors.
[62]
62. Method according to claim 60 or 61, characterized by the fact that the immunological checkpoint inhibitor is an agent that inhibits signaling of programmed death protein-1 (PD-1), protein 4 associated with cytotoxic T lymphocytes (CTLA-4), lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin and ITIM domain (TIGIT), indoleamine 2,3-dioxigenase (IDO), or colony stimulating factor 1 receptor (CSF1R).
[63]
63. The method of claim 62, characterized by the fact that the immunological checkpoint inhibitor is a PD-1 inhibitor.
[64]
64. Method according to claim 63, characterized in that the PD-1 inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, a toxin, or a PD-1 binding agent.
[65]
65. The method of claim 63 or 64, characterized in that the PD-1 inhibitor is a PD-1 binding agent.
[66]
66. Method according to claim 65, characterized by the fact that the PD-1 binding agent is an antibody, an antibody conjugate,
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11/31 or an antigen-binding fragment thereof.
[67]
67. Method according to claim 66, characterized by the fact that the PD-1 inhibitor is nivolumab, pembrolizumab, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283 , MGA012, BI-754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, AMP-514 / MEDI-0680, AGEN-2034, CS1001, TSR-042, Sym- 021, PF06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), AK 104, or GLS-010, or derivatives thereof.
[68]
68. The method of claim 63 or 64, characterized in that the PD-1 inhibitor is a PD-L1 / L2 binding agent.
[69]
69. Method according to claim 68, characterized in that the PD-L1 / L2 binding agent is an antibody, antibody conjugate, or antigen binding fragment thereof.
[70]
70. Method according to claim 69, characterized in that the PD-L1 / L2 binding agent is durvalumab, atezolizumab, avelumab, BGB-A333, SHR-1316, FAZ-053, CK-301, or millamolecule of PD-L1, or derivatives thereof.
[71]
71. Method according to any one of claims 63-65, characterized in that the PD-1 binding agent is an antiPD-1 antibody comprising a heavy chain comprising SEQ ID NO: 13 and a light chain comprising SEQ ID NO: 14.
[72]
72. Method according to any one of claims 63-71, characterized in that the PD-1 inhibitor is administered to the subject periodically in a dose of about 500 mg or 1000 mg.
[73]
73. The method of claim 72, characterized in that the PD-1 inhibitor is administered to the subject periodically in a dose of about 500 mg.
[74]
74. Method according to claim 72 or 73, characterized in that the PD-1 inhibitor is administered to the subject once every 3
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12/31 weeks.
[75]
75. Method according to any one of claims 71-74, characterized in that the PD-1 inhibitor is administered for 2, 3, 4, 5, 6, or more cycles.
[76]
76. Method according to claim 75, characterized in that the PD-1 inhibitor is administered for 3, 4, or 5 cycles.
[77]
77. Method according to claim 72, characterized in that the PD-1 inhibitor is administered to the subject periodically in a dose of about 1000 mg.
[78]
78. Method according to claim 72 or 77, characterized in that the PD-1 inhibitor is administered to the subject once every 6 weeks or more.
[79]
79. Method according to claim 78, characterized in that the PD-1 inhibitor is administered to the subject once every six weeks.
[80]
80. Method according to claim 78, characterized in that the PD-1 inhibitor is administered in a first dose of about 500 mg once every 3 weeks for 3, 4 or 5 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more.
[81]
81. Method according to claim 80, characterized in that the PD-1 inhibitor is administered in a first dose of about 500 mg once every 3 weeks for 3, 4 or 5 cycles, followed by a second dose of about 1000 mg once every 6 weeks.
[82]
82. Method according to claim 80, characterized in that the PD-1 inhibitor is administered in a first dose of about 500 mg once every 3 weeks for 3 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more.
[83]
83. Method according to claim 80, characterized in that the PD-1 inhibitor is administered in a first dose of about 500
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13/31 mg once every 3 weeks for 4 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more.
[84]
84. Method according to claim 80, characterized in that the PD-1 inhibitor is administered in a first dose of about 500 mg once every 3 weeks for 5 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more.
[85]
85. Method according to any of claims 82-74, characterized in that the second dose of 1000 mg is administered once every 6 weeks.
[86]
86. Method according to claim 60 or 61, characterized in that the immunological checkpoint inhibitor is a CTLA-4 inhibitor.
[87]
87. Method according to claim 86, characterized in that the CTLA-4 inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, a toxin, or a CTLA-4 binding agent.
[88]
88. Method according to claim 87, characterized in that the CTLA-4 inhibitor is a CTLA-4 binding agent.
[89]
89. The method of claim 88, characterized in that the CTLA-4 binding agent is an antibody, an antibody conjugate, or an antigen binding fragment thereof.
[90]
90. Method according to claim 60 or 61, characterized in that the immunological checkpoint inhibitor is an LAG-3 inhibitor.
[91]
91. Method according to claim 90, characterized in that the LAG-3 inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, a toxin, or a LAG-3 binding agent.
[92]
92. The method of claim 91, characterized in that the LAG-3 inhibitor is a LAG-3 binding agent.
[93]
93. Method, according to claim 92, characterized by the fact
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14/31 that the LAG-3 binding agent is an antibody, antibody conjugate, or antigen binding fragment thereof.
[94]
94. Method according to claim 60 or 61, characterized in that the immunological checkpoint inhibitor is a TIGIT inhibitor.
[95]
95. Method according to claim 94, characterized in that the TIGIT inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, a toxin , or a TIGIT binding agent.
[96]
96. Method according to claim 95, characterized in that the TIGIT inhibitor is a TIGIT binding agent.
[97]
97. The method of claim 96, characterized by the fact that the TIGIT binding agent is an antibody, an antibody conjugate, or an antigen binding fragment thereof.
[98]
98. Method according to claim 60 or 61, characterized in that the immunological checkpoint inhibitor is an IDO inhibitor.
[99]
99. Method according to claim 98, characterized in that the IDO inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, a toxin , or an IDO binding agent.
[100]
100. Method according to claim 99, characterized in that the IDO inhibitor is a small molecule.
[101]
101. Method according to claim 99, characterized in that the IDO inhibitor is an IDO binding agent, optionally an IDO binding agent which is an antibody, an antibody conjugate, or a binding fragment the antigen of it.
[102]
102. Method according to claim 60 or 61, characterized in that the immunological checkpoint inhibitor is a CSF1R inhibitor.
[103]
103. Method according to claim 102, characterized by the fact that the CSF1R inhibitor is a small molecule, a nucleic acid,
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15/31 a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, a toxin, or an IDO binding agent.
[104]
104. Method according to claim 103, characterized in that the CSF1R inhibitor is a small molecule.
[105]
105. Method according to claim 103, characterized in that the CSF1R inhibitor is a CSF1R binding agent, optionally a CSF1R binding agent which is an antibody, an antibody conjugate, or a binding fragment the antigen of it.
[106]
106. Method according to any one of claims 60-105, characterized in that it comprises the administration of at least two of the immunological checkpoint inhibitors.
[107]
107. Method according to claim 106, characterized by the fact that it further comprises the administration of a third checkpoint inhibitor.
[108]
108. Method according to claim 106 or 107, characterized in that the subject receives treatment with each of the agent, a PD-1 inhibitor and a LAG-3 inhibitor, so that the subject receives all the three.
[109]
109. Method according to claim 108, characterized in that it further comprises the subject receiving treatment with a CTLA-4 inhibitor, so that the subject receives all four.
[110]
110. Method according to any one of the preceding claims, characterized by the fact that the subject has been administered or will be administered further with an agent that inhibits poly (ADP-ribose) polymerase (PARP).
[111]
111. Method according to claim 110, characterized in that the agent that inhibits PARP is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, or a toxin.
[112]
112. Method according to claim 110 or 111, characterized
Petition 870190064097, of 07/09/2019, p. 20/195
16/31 by the fact that the agent that inhibits PARP is selected from the group consisting of: ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib (SHR 3162 ), IMP 4297, INO1001, JPI 289, JPI 547, monoclonal antibody conjugate B3-LysPE40, MP 124, niraparib (ZEJULA) (MK-4827), NU 1025, NU 1064, NU 1076, NU1085, olaparib (AZD2281), ONO2231, PD 128763, R 503, R554, rucaparib (RUBRACA) (AG-014699, PF01367338), SBP 101, SC 101914, simmiparib, talazoparib (BMN-673), veliparib (ABT-888), WW 46, 2- ( 4- (trifluoromethyl) phenyl) -7,8-dihydro-5H-thiopyran [4,3d] pyrimidin-4-ol, and salts or derivatives thereof.
[113]
113. Method according to any of claims 110-112, characterized in that the subject receives treatment with each of the agent, a PD-1 inhibitor and an agent that inhibits PARP, so that the subject receives all three.
[114]
114. Method according to claim 113, characterized in that it further comprises the subject receiving treatment with a LAG-3 inhibitor, so that the mammal receives all four.
[115]
115. Method according to any one of claims 60-114, characterized in that the therapeutically effective dose of the agent is a fixed dose of about 100 mg.
[116]
116. Method according to any one of claims 60-114, characterized in that the therapeutically effective dose of the agent is a fixed dose of about 300 mg.
[117]
117. Method according to any one of claims 60-114, characterized in that the therapeutically effective dose of the agent is a fixed dose of about 500 mg.
[118]
118. Method according to any one of claims 60-114, characterized in that the therapeutically effective dose of the agent is a fixed dose of about 900 mg.
[119]
119. Method according to any of the preceding claims,
Petition 870190064097, of 07/09/2019, p. 21/195
17/31 characterized by the fact that the subject is resistant to treatment with a PD-1 inhibitor.
[120]
120. Method according to any one of the preceding claims, characterized by the fact that the subject is refractory to treatment with a PD-1 inhibitor.
[121]
121. Method according to any one of the preceding claims, characterized in that the method sensitizes the subject to treatment with a PD-1 inhibitor.
[122]
122. Method according to any one of the preceding claims, characterized by the fact that the subject comprises an exhausted immune cell.
[123]
123. The method of claim 122, characterized in that the depleted immune cell is an exhausted T cell.
[124]
124. Method, according to any of the preceding claims, characterized by the fact that the subject is human.
[125]
125. Method according to any of the preceding claims, characterized by the fact that the subject has previously been treated with one or more different treatment modalities for cancer.
[126]
126. Method according to claim 125, characterized by the fact that the subject was previously treated with one or more of surgery, radiotherapy, chemotherapy or immunotherapy.
[127]
127. Method according to claim 125 or 126, characterized in that the subject has previously been treated with cytotoxic therapy.
[128]
128. Method according to any of claims 125-127, characterized in that the subject has previously been treated with chemotherapy.
[129]
129. Method according to any one of the preceding claims, characterized in that the method further comprises the administration of another therapeutic agent or treatment.
Petition 870190064097, of 07/09/2019, p. 22/195
18/31
[130]
130. Method according to claim 129, characterized by the fact that the method further comprises the administration of one or more among surgery, radiation therapy, chemotherapy, immunotherapy, an anti-angiogenic agent or an anti-inflammatory.
[131]
131. Method according to claim 129, characterized in that the method further comprises the administration of chemotherapy.
[132]
132. Method according to any one of the preceding claims, characterized by the fact that the agent is a TIM-3 binding agent.
[133]
133. The method of claim 132, characterized in that the TIM-3 binding agent is an antibody, an antibody conjugate, or an antigen binding fragment thereof.
[134]
134. Method according to claim 133, characterized in that the TIM-3 binding agent is an antibody.
[135]
135. Method according to any of claims 132-134, characterized in that the TIM-3 binding agent comprises a heavy chain comprising one or more CDR sequences having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NOs: 21.22 or 23.
[136]
136. Method according to claim 135, characterized in that the TIM-3 binding agent comprises a heavy chain comprising two or three CDRs that have sequences of SEQ ID NOs: 21, 22 or 23.
[137]
137. Method according to any one of claims 132-136, characterized in that the TIM-3 binding agent comprises a light chain comprising one or more CDR sequences having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NOs: 24, 25 or 26.
[138]
138. Method according to claim 137, characterized in that the TIM-3 binding agent comprises a light chain
Petition 870190064097, of 07/09/2019, p. 23/195
19/31 comprising two or three CDRs that have sequences of SEQ ID NOs: 24, 25 or 26.
[139]
139. Method according to any of claims 132-134, characterized in that the TIM-3 binding agent comprises a heavy chain comprising one or more CDR sequences selected from SEQ ID NOs: 21, 22 or 23 ; and / or a light chain variable region with one or more CDR sequences selected from SEQ ID NOs: 24, 25 or 26.
[140]
140. Method according to claim 139, characterized in that the TIM-3 binding agent comprises a heavy chain comprising three CDRs having sequences of SEQ ID NOs: 21, 22 or 23; and / or a light chain comprising three CDRs that have SED ID NOs sequences: 24, 25 or 26.
[141]
141. Method according to any of claims 132-134, characterized in that the TIM-3 binding agent comprises an immunoglobulin heavy chain variable domain comprising an amino acid sequence having 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; and / or an immunoglobulin light chain variable domain comprising an amino acid sequence having 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.
[142]
142. Method according to claim 141, characterized in that the TIM-3 binding agent comprises an immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 7 ; and an immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 8.
[143]
143. Method according to any of claims 132-134,
Petition 870190064097, of 07/09/2019, p. 24/195
20/31 characterized by the fact that the TIM-3 binding agent comprises an immunoglobulin heavy chain polypeptide comprising an amino acid sequence having at least about 80%, 85%, 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 3.
[144]
144. Method according to any one of claims 132-134 and 143, characterized in that the TIM-3 binding agent comprises an immunoglobulin light chain polypeptide comprising an amino acid sequence having at least about 80% , 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4.
[145]
145. The method of any one of claims 132-134, characterized in that the TIM-3 binding agent comprises a heavy chain polypeptide comprising SEQ ID NO: 3 and a light chain polypeptide comprising SEQ ID NO: 4.
[146]
146. Method according to any one of claims 132-145, characterized in that the TIM-3 binding agent is administered in an amount that is about 1 mg / kg, 3 mg / kg, or 10 mg / kg; or in an amount that is about a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; or a fixed dose of about 1500 mg.
[147]
147. Method according to claim 146, characterized in that the TIM-3 binding agent is administered in an amount that is a fixed dose of about 100 mg; a fixed dose of about 200 mg; an
Petition 870190064097, of 07/09/2019, p. 25/195
21/31 fixed dose of about 300 mg, a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; or a fixed dose of about 900 mg.
[148]
148. Method according to claim 146, characterized by the fact that the TIM-3 binding agent is administered once every two weeks, once every three weeks, or once every four weeks.
[149]
149. Method according to any one of claims 132-148, characterized in that the TIM-3 binding agent is administered once every three weeks.
[150]
150. Method according to any one of the preceding claims, characterized by the fact that the agent is administered intravenously.
[151]
151. Method according to claim 150, characterized in that the agent is administered by intravenous infusion.
[152]
152. Method for treating cancer, the method being characterized by the fact that it comprises:
administration, to a patient in need of treatment, of an anti-T cell immunoglobulin antibody and Mucin-3 Domain (TIM-3) in a therapeutically effective dose over an administration interval for a period sufficient to achieve a clinical benefit, wherein the antibody comprises a heavy chain comprising three CDRs that have sequences of SEQ ID NOs: 21, 22 or 23; and / or a light chain comprising three CDRs that have SED ID NOs sequences: 24, 25 or 26.
[153]
153. Method for treating cancer, the method being characterized by the fact that it comprises:
administration, to a patient in need of treatment, of an anti-T cell immunoglobulin antibody and Mucin-3 Domain (TIM-3) in a therapeutically effective dose over an administration interval for a period sufficient to achieve a clinical benefit,
Petition 870190064097, of 07/09/2019, p. 26/195
22/31 wherein the anti-TIM-3 antibody comprises an immunoglobulin heavy chain variable domain comprising SEQ ID NO: 1 or SEQ ID NO: 7 and an immunoglobulin light chain variable domain comprising SEQ ID NO: 2 or SEQ ID NO: 8.
[154]
154. Method for treating cancer, the method being characterized by the fact that it comprises:
administration, to a patient in need of treatment, of an anti-T cell immunoglobulin antibody and Mucin-3 Domain (TIM-3) in a therapeutically effective dose over an administration interval for a period sufficient to achieve a clinical benefit, wherein the anti-TIM-3 antibody comprises a heavy chain polypeptide comprising SEQ ID NO: 3 and a light chain polypeptide comprising SEQ ID NO: 4.
[155]
155. Method according to any of claims 152-154, characterized by the fact that the clinical benefit is stable disease (“SD”), a partial response (“PR”) and / or a complete response (“CR” ).
[156]
156. Method according to any one of claims 152-155, characterized by the fact that the PR or CR is determined according to the Response Assessment Criteria in Solid Tumors (RECIST).
[157]
157. Method according to any one of claims 152-157, characterized in that the patient has a cancer associated with a mutation of POLE (DNA polymerase epsilon) or POLD (DNA polymerase delta).
[158]
158. Method according to claim 157, characterized by the fact that the POLE or POLD mutation is in an exonuclease domain.
[159]
159. Method according to claim 157 or 158, characterized in that the POLE or POLD mutation is a germline mutation.
[160]
160. Method according to claim 157 or 159, characterized in that the POLE or POLD mutation is a sporadic mutation.
Petition 870190064097, of 07/09/2019, p. 27/195
23/31
[161]
161. Method according to any one of claims 157-160, characterized in that the method further comprises a step of identifying, first, the cancer patient with the POLE or POLD mutation.
[162]
162. Method according to claim 161, characterized by the fact that the POLE or POLD mutation is identified using sequencing.
[163]
163. Method according to any of claims 152-162, characterized by the fact that the patient has a cancer with microsatellite instability.
[164]
164. Method according to claim 163, characterized by the fact that the patient has an MSI-H cancer.
[165]
165. Method according to claim 164, characterized in that the cancer is an MSI-H cancer comprising a mutation in POLE or POLD, optionally a non-endometrial cancer MSI-H comprising a mutation in POLE or POLD.
[166]
166. Method according to claim 164, characterized by the fact that the patient has an MSI-L cancer.
[167]
167. Method according to any of claims 152-162, characterized by the fact that the patient has stable microsatellite cancer (MSS).
[168]
168. Method according to any of claims 152-167, characterized by the fact that the patient has a solid tumor.
[169]
169. Method according to claim 168, characterized by the fact that the patient has a solid tumor in an advanced stage.
[170]
170. Method according to claim 168, characterized by the fact that the patient has a solid metastatic tumor.
[171]
171. Method according to any one of claims 152-170, characterized by the fact that the patient has a cancer selected from:
Petition 870190064097, of 07/09/2019, p. 28/195
Head and neck 24/31, lung cancer, kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulva cancer, cancer of the uterus, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, a colorectal cancer, an appendix cancer, a urothelial cell carcinoma, a squamous cell carcinoma, a soft tissue sarcoma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, Hodgkin's lymphoma, neuroblastoma, a CNS tumor, diffuse intrinsic pontine glioma (DIPG), Ewing's sarcoma, embryonic rhabdomyosarcoma (ERS), osteosarcoma, or Wilms' tumor.
[172]
172. Method according to any of claims 152-171, characterized in that the cancer has homologous recombination repair deficiency / homologous repair deficiency (HRD).
[173]
173. Method according to claim 171, characterized by the fact that the patient has endometrial cancer.
[174]
174. Method according to claim 173, characterized by the fact that the patient has endometrial cancer with microsatellite instability.
[175]
175. Method according to claim 173, characterized by the fact that the patient has an MSI-H endometrial cancer.
[176]
176. Method according to claim 173, characterized by the fact that the patient has MSS / MSI-L endometrial cancer.
[177]
177. Method according to claim 171, characterized by the fact that the patient has breast cancer.
[178]
178. Method according to claim 177, characterized by the fact that the patient has triple negative breast cancer (TNBC).
[179]
179. Method according to claim 171, characterized by the
Petition 870190064097, of 07/09/2019, p. 29/195
25/31 fact that the patient has ovarian cancer.
[180]
180. Method according to claim 179, characterized by the fact that ovarian cancer is epithelial ovarian cancer.
[181]
181. Method according to claim 171, characterized by the fact that the patient has lung cancer.
[182]
182. Method according to claim 181, characterized by the fact that lung cancer is a non-small cell lung cancer (NSCLC).
[183]
183. Method according to claim 171, characterized by the fact that the patient has a melanoma.
[184]
184. Method according to claim 171, characterized by the fact that the patient has colorectal cancer.
[185]
185. Method according to claim 171, characterized by the fact that the patient has a squamous cell carcinoma.
[186]
186. Method according to claim 185, characterized by the fact that squamous cell carcinoma is squamous cell carcinoma of the anus, squamous cell carcinoma of the penis, squamous cell carcinoma of the cervix, squamous cell carcinoma of the cervix vagina, or squamous cell carcinoma of the vulva.
[187]
187. Method according to claim 171, characterized by the fact that the patient has a soft tissue sarcoma.
[188]
188. Method, according to claim 187, characterized by the fact that the patient has leiomyosarcoma.
[189]
189. Method according to any of claims 152-167, characterized by the fact that the patient has hematological cancer.
[190]
190. Method according to claim 189, characterized by the fact that hematological cancer is DLBCL, HL, NHL, FL, AML, ALL or MM.
[191]
191. Method according to any of claims 152-190, characterized by the fact that the patient has not previously been treated with
Petition 870190064097, of 07/09/2019, p. 30/195
26/31 a cancer treatment modality.
[192]
192. Method according to any of claims 152-190, characterized in that the patient has previously been treated with one or more different treatment modalities for cancer.
[193]
193. Method according to claim 192, characterized by the fact that one or more different treatment modalities for cancer comprise surgery, radiotherapy, chemotherapy or immunotherapy.
[194]
194. Method according to any of claims 152-193, characterized in that the therapeutically effective dose is about 1, 3 or 10 mg / kg.
[195]
195. Method according to any of claims 152-193, characterized in that the therapeutically effective dose is a fixed dose between about 100 - 1500 mg.
[196]
196. The method of claim 195, characterized in that the therapeutically effective dose is a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose of about 400 mg; a fixed dose of about 500 mg; a fixed dose of about 600 mg; a fixed dose of about 700 mg; a fixed dose of about 800 mg; a fixed dose of about 900 mg; a fixed dose of about 1000 mg; a fixed dose of about 1100 mg; a fixed dose of about 1200 mg; a fixed dose of about 1300 mg; a fixed dose of about 1400 mg; or a fixed dose of about 1500 mg.
[197]
197. Method according to claim 195, characterized in that the therapeutically effective dose is a fixed dose between about 100 500 mg.
[198]
198. Method according to claim 195, characterized in that the therapeutically effective dose is a fixed dose between about 1000 - 1500 mg.
[199]
199. Method according to claim 195, characterized by the
Petition 870190064097, of 07/09/2019, p. 31/195
27/31 the fact that the therapeutically effective dose is a fixed dose of about 100 mg.
[200]
200. Method according to claim 195, characterized in that the therapeutically effective dose is a fixed dose of about 200 mg.
[201]
201. Method according to claim 195, characterized in that the therapeutically effective dose is a fixed dose of about 300 mg.
[202]
202. Method according to claim 195, characterized in that the therapeutically effective dose is a fixed dose of about 500 mg.
[203]
203. Method according to claim 195, characterized in that the therapeutically effective dose is a fixed dose of about 900 mg.
[204]
204. Method according to claim 195, characterized in that the therapeutically effective dose is a fixed dose of about 1000 mg.
[205]
205. Method according to claim 195, characterized in that the therapeutically effective dose is a fixed dose of about 1100 mg.
[206]
206. Method according to claim 195, characterized in that the therapeutically effective dose is a fixed dose of about 1200 mg.
[207]
207. Method according to claim 195, characterized in that the therapeutically effective dose is a fixed dose of about 1300 mg.
[208]
208. Method according to claim 195, characterized in that the therapeutically effective dose is a fixed dose of about 1400 mg.
[209]
209. Method according to claim 195, characterized in that the therapeutically effective dose is a fixed dose of about 1500 mg.
[210]
210. Method according to any of claims 152-209, characterized in that the anti-TIM-3 antibody is administered in the
Petition 870190064097, of 07/09/2019, p. 32/195
28/31 administration interval once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks.
[211]
211. Method according to claim 210, characterized by the fact that the anti-TIM-3 antibody is administered within the administration interval once every 2 weeks.
[212]
212. Method according to claim 210, characterized by the fact that the anti-TIM-3 antibody is administered within the administration interval once every 3 weeks.
[213]
213. Method according to claim 212, characterized in that about 100 mg of the anti-TIM-3 antibody is administered.
[214]
214. Method according to claim 212, characterized in that about 300 mg of anti-TIM-3 antibody is administered.
[215]
215. Method according to claim 212, characterized in that about 500 mg of the anti-TIM-3 antibody is administered.
[216]
216. Method according to claim 212, characterized in that about 900 mg of anti-TIM-3 antibody is administered.
[217]
217. Method according to any one of claims 152-216, characterized in that the anti-TIM-3 antibody is administered for a period of at least 2, 4, 6, 8, 10, 12, 14, 16, 18 or 20 weeks.
[218]
218. Method according to any of claims 152-217, characterized in that the anti-TIM-3 antibody is administered intravenously.
[219]
219. Method according to claim 218, characterized in that the anti-TIM-3 antibody is administered by intravenous infusion.
[220]
220. Method according to any one of claims 152-219, characterized in that the anti-TIM-3 antibody is administered in conjunction with an additional therapy.
[221]
221. Method according to claim 220, characterized by the
Petition 870190064097, of 07/09/2019, p. 33/195
29/31 the fact that the additional therapy is surgery, radiotherapy, chemotherapy or immunotherapy.
[222]
222. Method according to claim 220, characterized in that the additional therapy is treatment with a PARP inhibitor.
[223]
223. Method according to claim 222, characterized in that the PARP inhibitor is niraparib, olaparib, rucaparib, talazoparib or veliparib.
[224]
224. Method according to claim 220, characterized in that the additional therapy comprises treatment with an antiPD-1 antibody.
[225]
225. Method according to claim 224, characterized in that the anti-PD-1 antibody is or comprises TSR-042, nivolumab, pembrolizumab, PD-1VR or PD-1FL.
[226]
226. Method according to claim 224 or 225, characterized in that the anti-PD-1 antibody is or comprises TSR-042.
[227]
227. Method according to any of claims 224-226, characterized in that the anti-PD-1 antibody comprises a heavy chain comprising SEQ ID NO: 13 and a light chain comprising SEQ ID NO: 14 .
[228]
228. Method according to any of claims 224-227, characterized in that the anti-PD-1 antibody is administered to the patient periodically at a dose between about 100-1000 mg.
[229]
229. Method according to claim 228, characterized in that the anti-PD-1 antibody is administered to the patient periodically in a dose of about 500 mg.
[230]
230. Method according to claim 229, characterized in that the anti-PD-1 antibody is administered to the patient once every 3 weeks.
[231]
231. The method of claim 229 or 230, characterized
Petition 870190064097, of 07/09/2019, p. 34/195
30/31 by the fact that the anti-PD-1 antibody is administered for 2-6 cycles.
[232]
232. Method according to claim 231, characterized in that the anti-PD-1 antibody is administered for 3 cycles.
[233]
233. Method according to claim 231, characterized in that the anti-PD-1 antibody is administered for 4 cycles.
[234]
234. Method according to claim 231, characterized in that the anti-PD-1 antibody is administered for 5 cycles.
[235]
235. Method according to claim 228, characterized in that the anti-PD-1 antibody is administered to the patient periodically in a dose of about 1000 mg.
[236]
236. Method according to claim 235, characterized in that the anti-PD-1 antibody is administered to the patient once every 6 weeks or more.
[237]
237. Method according to claim 228, characterized in that the anti-PD-1 antibody is administered in a first dose of about 500 mg once every 3 weeks for 3, 4, or 5 cycles, followed by for a second dose of about 1000 mg once every 6 weeks or more.
[238]
238. Method according to claim 237, characterized in that the anti-PD-1 antibody is administered in a first dose of about 500 mg once every 3 weeks for 3 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more.
[239]
239. Method according to claim 237, characterized in that the anti-PD-1 antibody is administered in a first dose of about 500 mg once every 3 weeks for 4 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more.
[240]
240. Method according to claim 237, characterized in that the anti-PD-1 antibody is administered in a first dose of about 500 mg once every 3 weeks for 5 cycles, followed by a second dose of about 1000 mg once every 6 weeks or more.
Petition 870190064097, of 07/09/2019, p. 35/195
31/31
[241]
241. Method according to any one of claims 237-240, characterized in that the second 1000 mg dose is administered once every 6 weeks.
[242]
242. Method according to any one of claims 237-241, characterized in that the therapeutically effective dose of the anti-TIM-3 antibody is a fixed dose of about 100 mg.
[243]
243. Method according to any one of claims 237-241, characterized in that the therapeutically effective dose of the anti-TIM-3 antibody is a fixed dose of about 300 mg.
[244]
244. Method according to any one of claims 237-241, characterized in that the therapeutically effective dose of the anti-TIM-3 antibody is a fixed dose of about 500 mg.
[245]
245. Method according to any one of claims 237-241, characterized in that the therapeutically effective dose of the anti-TIM-3 antibody is a fixed dose of about 900 mg.
[246]
246. Method according to any of claims 242-245, characterized in that the anti-TIM-3 antibody is administered once every three weeks.

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法律状态:
2021-10-13| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201762444354P| true| 2017-01-09|2017-01-09|

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US62/444,354|2017-01-09|

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US201762582272P| true| 2017-11-06|2017-11-06|

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US62/582,272|2017-11-06|

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PCT/US2018/013021|WO2018129553A1|2017-01-09|2018-01-09|Methods of treating cancer with anti-tim-3 antibodies|

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