CANCER TREATMENT METHODS WITH ANTI-PD-1 ANTIBODIES

专利摘要:
the present invention provides methods of administering certain pd-1 binding agents to cancer patients. also explicitly provided dosage regimens for compositions comprising a pd-1 binding agent
公开号:BR112019014187A2
申请号:R112019014187-1
申请日:2018-01-09
公开日:2020-02-11
发明作者:Jenkins David；Laken Haley；Im Ellie；Diaz Allene；Lu Sharon
申请人:Tesaro, Inc.；
IPC主号:

专利说明:

“METHODS OF TREATING CANCER WITH ANTI-PD1 ANTIBODIES”
CROSS REFERENCE TO RELATED REQUESTS [0001] This application claims the benefit of US Provisional Application No. 62 / 444,336, filed on January 9, 2017, US Provisional Application No. 62 / 477,423, filed on March 27, 2017, Application Provisional US No. 62 / 491,220, filed on April 27, 2017 and Provisional Application No. 62 / 556,386, filed on September 9, 2017, each of which is incorporated by reference in its entirety.
SEQUENCE LISTING [0002] This descriptive report refers to a Sequence Listing provided in electronic format as an ASCII.txt file called “TSR-006 SEQ LIST_ST25” that was generated on January 8, 2018 and is 14,555 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 a recognition that certain dosage regimens for agents that are capable of inhibiting programmed-death anti-protein (PD-1) (e.g., PD-1 binding agents) are useful for treating disorders, such as cancer.
[0005] In the embodiments, a PD-1 inhibitor is a PD-1 binding agent. In one embodiment, a PD-1 binding agent is an antibody, antibody conjugate, or antigen binding fragment thereof. In
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2/169 In some embodiments, a PD-1 binding agent is an antibody agent (i.e., an anti-PD1 antibody agent).
[0006] In the embodiments, a PD-1 binding agent is an anti-PD-1 antibody. In the embodiments, a PD-1 binding agent comprises a heavy chain variable region with 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: 9, 10 or 11. In the embodiments, a PD-1 binding agent comprises a heavy chain variable region with two or three CDR sequences having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity sequence to SEQ ID NOs: 9, 10 or 11.
[0007] In the embodiments, a PD-1 binding agent comprises a light chain variable region with 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: 12, 13 and 14. In the embodiments, a PD-1 binding agent comprises a variable region of light chain with two or three CDR sequences having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of sequence identity to SEQ ID NOs: 12, 13 and 14.
[0008] In the embodiments, a PD-1 binding agent comprises a heavy chain variable region with one or more CDR sequences selected from SEQ ID NOs: 9, 10 and 11 and / or a light chain variable region with a or more CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, a PD-1 binding agent comprises a heavy chain variable region with two or three CDR sequences selected from SEQ ID NOs: 9 10 and 11 and / or light chain variable region with two or more CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, a PD-1 binding agent comprises a heavy chain variable region with three CDRs that have sequences of
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SEQ ID NOs: 9, 10 and 11 and / or a light chain variable region with three CDRs that have sequences of SEQ ID NOs: 12, 13 and 14. In some embodiments, a PD-1 binding agent comprises a region heavy chain variable with three CDRs that have sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region with three CDRs that have sequences of SEQ ID NOs: 12, 13 and 14.
[0009] In some embodiments, a PD-1 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. In some embodiments, a PD-1 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. In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain variable domain comprising a 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: 7.
[0010] In some embodiments, a PD-1 binding agent comprises 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. In some embodiments, a PD-1 binding agent comprises a 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. In some embodiments, a PD-1 binding agent comprises a variable domain of
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4/169 immunoglobulin light chain 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: 8.
[0011] In some embodiments, a PD-1 binding 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.
[0012] In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain 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.
[0013] In some embodiments, the PD-1 binding agent comprises an immunoglobulin light chain 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.
[0014] In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain, whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain, whose amino acid sequence comprises SEQ ID NO: 4 .
[0015] PD-1 binding agents can be any PD-1 binding agent known in the art. In some embodiments, a PD-1 binding agent is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283 , MGA012. , BI-754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN-2034, CS1001, Sym-021 , SHR-1316, PF-06801591,
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LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ-053, CK-301, AK 104, or GLS-010, or any of the PD-1 antibodies disclosed in WO2014 / 179664.
[0016] In some embodiments, a PD-1 binding agent (for example, anti-PD-1 antibody agent) binds to a PD-1 epitope that blocks PD-1 binding to either or more of its putative binders. In some embodiments, a PD-1 binding agent (for example, anti-PD-1 antibody agent) binds to a PD-1 epitope that blocks the binding of PD-1 to two or more of its ligands putative. In some embodiments, a PD-1 binding agent (for example, anti-PD-1 antibody agent) binds to an epitope of a PD-1 protein that blocks the binding of PD-1 to PD-L1 and / or PD-L2. The PD-1 binding agents (e.g., antiPD-1 antibody agents) of the present disclosure can comprise a heavy chain constant region (F _c ) of any suitable class. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) comprises a heavy chain constant region that is based on wild-type IgG1, IgG2 or IgG4 antibodies or variants thereof.
[0017] The present disclosure provides methods of treating a disorder in a subject by administering a therapeutically effective dose of an agent that is capable of inhibiting Programmed Death Protein-1 (PD-1) signaling. In the modalities, a therapeutically effective dose is: about 1, 3 or 10 mg / kg. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 - 2000 mg (for example, 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
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6/169 fixed dose of about 1500 mg; a fixed dose of about 1600 mg; a fixed dose of about 1700 mg; a fixed dose of about 1800 mg; a fixed dose of about 1900 mg; or a fixed dose of about 2000 mg). 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 500 mg. In the embodiments, a therapeutically effective dose is about 800 mg. In the embodiments, a therapeutically effective dose is about 1000 mg. In the embodiments, a PD-1 inhibitor is any PD-1 binding agent described in this document (for example, any anti-PD-1 antibody described in this document).
[0018] The present disclosure provides methods for enhancing T cell activation or T cell effector function in a subject, the method of which comprises administering a therapeutically effective dose of an agent that is capable of inhibiting Programmed Death Protein-1 signaling ( PD-1). In the modalities, a therapeutically effective dose is: about 1, 3 or 10 mg / kg. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 - 2000 mg (for example, 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 fixed dose of about 1500 mg; a fixed dose of about 1600 mg; a fixed dose of about 1700 mg; a fixed dose of about 1800 mg; a fixed dose of about 1900 mg; or a fixed dose of about 2000 mg). In the embodiments, a therapeutically effective dose is about 1 mg / kg. In modalities, a dose
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7/169 therapeutically effective 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 500 mg. In the embodiments, a therapeutically effective dose is about 800 mg. In the embodiments, a therapeutically effective dose is about 1000 mg. In the embodiments, a PD-1 inhibitor is any PD-1 binding agent described in this document (for example, any anti-PD-1 antibody described in this document).
[0019] The present disclosure provides methods to reduce tumors or inhibit tumor cell growth in a subject, the method of which comprises administering a therapeutically effective dose of an agent that is capable of inhibiting Programmed Death Protein-1 (PD-) signaling. 1). In the modalities, a therapeutically effective dose is: about 1, 3 or 10 mg / kg. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 - 2000 mg (for example, 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 fixed dose of about 1500 mg; a fixed dose of about 1600 mg; a fixed dose of about 1700 mg; a fixed dose of about 1800 mg; a fixed dose of about 1900 mg; or a fixed dose of about 2000 mg). 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 500 mg. In the embodiments, a therapeutically effective dose is about 800 mg. In the modalities,
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8/169 a therapeutically effective dose is about 1000 mg. In the embodiments, a PD-1 inhibitor is any PD-1 binding agent described in this document (for example, any anti-PD-1 antibody described in this document).
[0020] The present disclosure provides methods to induce an immune response in a subject, the method of which comprises administering a therapeutically effective dose of an agent capable of inhibiting Programmed Death Protein-1 (PD-1) signaling. In the modalities, a therapeutically effective dose is: about 1, 3 or 10 mg / kg. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 - 2000 mg (for example, 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 fixed dose of about 1500 mg; a fixed dose of about 1600 mg; a fixed dose of about 1700 mg; a fixed dose of about 1800 mg; a fixed dose of about 1900 mg; or a fixed dose of about 2000 mg). 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 500 mg. In the embodiments, a therapeutically effective dose is about 800 mg. In the embodiments, a therapeutically effective dose is about 1000 mg. In the embodiments, a PD-1 inhibitor is any PD-1 binding agent described in this document (for example, any anti-PD-1 antibody described in this document).
[0021] This disclosure provides methods to enhance a
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9/169 immune response or increase the activity of an immune cell in a subject, whose method comprises administering a therapeutically effective dose of an agent capable of inhibiting Programmed Death Protein-1 (PD-1) signaling. In the modalities, an immune response is a humoral or cell-mediated immune response. In the modalities, an immune response is a CD4 or CD8 T cell response. 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. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 - 2000 mg (for example, 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 fixed dose of about 1500 mg; a fixed dose of about 1600 mg; a fixed dose of about 1700 mg; a fixed dose of about 1800 mg; a fixed dose of about 1900 mg; or a fixed dose of about 2000 mg). 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 500 mg. In the embodiments, a therapeutically effective dose is about 800 mg. In the embodiments, a therapeutically effective dose is about 1000 mg. In the embodiments, a PD-1 inhibitor is any PD-1 binding agent described in this document (for example, any antiPD-1 antibody described in this document).
[0022] The present disclosure provides cancer treatment methods that include administering compositions that deliver binding agents
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10/169 to PD-1 in particular. In the embodiments, a PD-1 binding agent is administered in an amount that is about 1, 3 or 10 mg / kg. In the embodiments, a PD-1 binding agent administered in an amount that is about 100 - 2000 mg (e.g., about 100 mg; about 200 mg; about 300 mg; about 400 mg; about 500 mg; about 600 mg; about 700 mg about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg). In the embodiments, a PD-1 binding agent is administered in an amount that is about 1 mg / kg. In the embodiments, a PD-1 binding agent is administered in an amount that is about 3 mg / kg. In the embodiments, a PD-1 binding agent is administered in an amount that is about 10 mg / kg. In the embodiments, a PD-1 binding agent is administered in an amount that is about 500 mg. In the embodiments, a therapeutically effective dose is about 800 mg. In the embodiments, a PD-1 binding agent is administered in an amount that is about 1000 mg. In the embodiments, a PD-1 inhibitor is any PD-1 binding agent described in this document (for example, any anti-PD-1 antibody described in this document).
[0023] The present disclosure provides cancer treatment methods comprising administering to a patient in need of treatment an anti-programmed death protein-1 (PD-1) in a therapeutically effective dose within an administration interval for a period sufficient to achieve a clinical benefit. In the embodiments, an antiPD-1 antibody comprises a heavy chain variable region with three CDR sequences selected from SEQ ID NOs: 9, 10 and 11 and a light chain variable region comprising CDR sequences from SEQ ID NOs: 12, 13 and 14. In the embodiments, an anti-PD-1 antibody comprises a variable domain of
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11/169 immunoglobulin heavy chain, whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7 and / or an immunoglobulin light chain variable domain, whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In the embodiments, an anti-PD-1 antibody comprises an immunoglobulin heavy chain polypeptide, the amino acid sequence of which comprises SEQ ID NO: 3 and / or immunoglobulin light chain polypeptide, the amino acid sequence of which comprises SEQ ID NO: 4. In the modalities, a therapeutically effective dose is: about 1, 3 or 10 mg / kg. In the embodiments, a therapeutically effective dose is a fixed dose of about 100 - 2000 mg (for example, 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 fixed dose of about 1500 mg; a fixed dose of about 1600 mg; a fixed dose of about 1700 mg; a fixed dose of about 1800 mg; a fixed dose of about 1900 mg; or a fixed dose of about 2000 mg). 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 500 mg. In the embodiments, a therapeutically effective dose is about 800 mg. In the embodiments, a therapeutically effective dose is about 1000 mg.
[0024] The present disclosure provides cancer treatment methods comprising administering to a patient in need of treatment an anti-programmed death protein-1 (PD-1) antibody in a therapeutically effective dose in a first administration interval by a
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12/169 first; and administering anti-PD-1 antibody to the patient in a second dose at a second interval for a second period. In the embodiments, an anti-PD-1 antibody comprises a heavy chain variable region with three CDR sequences selected from SEQ ID NOs: 9, 10 and 11 and a light chain variable region comprising CDR sequences from SEQ ID NOs: 12 , 13 and 14. In the embodiments, an anti-PD-1 antibody 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 a variable chain domain light immunoglobulin, whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In the embodiments, an anti-PD-1 antibody comprises an immunoglobulin heavy chain polypeptide, whose amino acid sequence comprises SEQ ID NO: 3 and / or immunoglobulin light chain polypeptide, whose amino acid sequence comprises SEQ ID NO: 4. In the modalities, a dose is about 1.3 or 10 mg / kg. In the embodiments, a dose is a fixed dose of about 100 - 2000 mg (for example, a fixed dose of about 100 mg; a fixed dose of about 200 mg; a fixed dose of about 300 mg; a fixed dose 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; a fixed dose of about 1600 mg; a fixed dose of about 1700 mg; a fixed dose of about 1800 mg; a fixed dose of about 1900 mg; or a fixed dose of about 2000 mg ). In the embodiments, a therapeutically effective dose is about 1 mg / kg. In the modalities, a dose is about 3 mg / kg. In the modalities, a dose is about 10 mg / kg. In the embodiments, a therapeutically effective dose is a fixed dose of about 500 mg. In the embodiments, a therapeutically effective dose is a fixed dose of about 800 mg. In
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13/169 modalities, a therapeutically effective dose is about 1000 mg. In the modalities, the first dose and the second dose are different. In the modalities, the first dose is about 500 mg and the second dose is about 1000 mg. In the modalities, the first interval and the second interval are different. In modalities, the first interval is once every three weeks and the second interval is once every six weeks. In the embodiments, the anti-PD-1 antibody is administered in the first dose of 500 mg once every three weeks during the first period of 2-6 dosing cycles (for example, the first 3, 4 or 5 dosing cycles) and the second 1000 mg dose once every six weeks until therapy is stopped (for example, due to disease progression, an adverse event or as determined by a doctor). In the embodiments, the anti-PD-1 antibody is administered in the first dose of 500 mg once every three weeks during the first three dosing cycles and in the second dose of 1000 mg once every six weeks or more until therapy be discontinued (for example, due to disease progression, an adverse event or as determined by a doctor). In the embodiments, the anti-PD-1 antibody is administered in the first dose of 500 mg once every three weeks during the first four dosing cycles and in the second dose of 1000 mg once every six weeks or more until therapy is discontinued (for example, due to disease progression, an adverse event or as determined by a doctor). In the embodiments, an anti-PD-1 antibody is administered in the first dose of 500 mg once every three weeks during the first five dosing cycles and in the second dose of 1000 mg once every six weeks or more until therapy is interrupted (for example, due to the progression of the disease, an adverse event or as determined by a doctor). In the modalities, the second dose is administered once every six weeks.
[0025] In any of the methods described in this document, a therapeutically effective dose is about 1 mg / kg of a
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PD-1. In any of the methods described in this document, a therapeutically effective dose is about 3 mg / kg of a PD-1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 10 mg / kg of a PD1 binding agent. In the embodiments, a PD-1 binding agent is any anti-PD1 antibody described in this document.
[0026] In any of the methods described in this document, a therapeutically effective dose is about 100 mg of a PD-1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 200 mg of a PD-1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 300 mg of a PD-1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 400 mg of a PD-1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 500 mg of a PD-1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 600 mg of a PD-1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 700 mg of a PD-1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 800 mg of a PD-1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 900 mg of a PD-1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 1000 mg of a PD1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 1100 mg of a PD1 binding agent. In any of the methods described in this document, a dose
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15/169 therapeutically effective is about 1200 mg of a PD1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 1300 mg of a PD1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 1400 mg of a PD1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 1500 mg of a PD1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 1600 mg of a PD1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 1700 mg of a PD1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 1800 mg of a PD1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 1900 mg of a PD1 binding agent. In any of the methods described in this document, a therapeutically effective dose is about 2000 mg of a PD1 binding agent. In the embodiments, a PD-1 binding agent is any anti-PD1 antibody described in this document.
[0027] In the modalities, a PD-1 binding agent 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 PD-1 binding agent is administered at an interval of administration (or treatment cycle) once a week (Q1W). In the embodiments, a PD-1 binding agent is administered at an interval of administration (or treatment cycle) once every 2 weeks (Q2W). In the embodiments, a PD-1 binding agent is administered at an interval of administration (or cycle of
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16/169 treatment) once every three weeks (Q3W). In the embodiments, a PD-1 binding agent is administered at an administration interval (or treatment cycle) once every 4 weeks (Q4W). In the embodiments, a PD-1 binding agent is administered at an interval of administration (or treatment cycle) once every 5 weeks (Q5W). In the embodiments, a PD-1 binding agent is administered at an administration interval (or treatment cycle) once every 6 weeks (Q6W). In the embodiments, a PD-1 binding agent 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 embodiments, a PD-1 binding agent 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 PD-1 binding agent is any anti-PD-1 antibody described in this document.
[0028] In the embodiments, a PD-1 binding agent 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 doctor, including dosage modifications). In the embodiments, a PD-1 binding agent 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 a complete response (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 embodiments, a PD-1 binding agent is administered for a longer period to maintain the clinical benefit. In the modalities, a PD-1 binding agent is
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17/169 any anti-PD-1 antibody described in this document.
[0029] In the embodiments, a PD-1 binding agent is administered periodically to a subject at a dose of about 500 mg or about 1000 mg. In the embodiments, a PD-1 binding agent is administered periodically to a subject at a dose of about 500 mg (for example, once every three weeks (Q3W) and / or for 2, 3, 4, 5, 6 or more cycles). In the embodiments, a PD-1 binding agent is administered periodically to a subject at a dose of about 1000 mg (for example, once every three weeks (Q3W) and / or for 2, 3, 4, 5, 6 or more cycles). In the embodiments, a PD-1 binding agent is administered to a subject at a dose of about 500 mg according to once every three weeks (Q3W) for 3 cycles. In the embodiments, a PD-1 binding agent is administered to a subject at a dose of about 500 mg according to once every three weeks (Q3W) for 4 cycles. In the embodiments, a PD-1 binding agent is administered to a subject at a dose of about 500 mg according to once every three weeks (Q3W) for 5 cycles. In the embodiments, a PD-1 binding agent is administered to a subject at a dose of about 1000 mg according to once every six weeks or more (Q3W). In the embodiments, a PD-1 binding agent is administered to a subject at a dose of about 1000 mg according to once every six weeks (Q3W). In the embodiments, a PD-1 binding agent 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 every 6 weeks or more (for until treatment is discontinued). In the embodiments, a PD-1 binding agent 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 discontinued). In the modalities, a PD-1 binding agent is administered in a first dose of about 500 mg once every 3 weeks for 5
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18/169 cycles, followed by a second dose of about 1000 mg every 6 weeks or more (for example, until treatment is discontinued). In the modalities, a second dose is about 1000 mg once every six weeks (for example, until treatment is discontinued). In the embodiments, a PD-1 binding agent is any anti-PD-1 antibody described in this document.
[0030] In the embodiments, a therapeutic agent has been additionally administered or will be additionally administered to a subject, such that the subject receives a PD-1 binding agent and an additional therapeutic agent (for example, one, two, three, four or more additional therapeutic agents). In the embodiments, a PD-1 binding agent is any anti-PD-1 antibody described in this document.
[0031] In the modalities, an immunological checkpoint inhibitor has been additionally administered or will be additionally administered to a subject, such that the subject receives a PD-1 binding agent and an immunological checkpoint inhibitor. That is, a PD-1 binding agent in combination with at least one immunological checkpoint inhibitor can be administered to a subject. In the embodiments, a PD-1 binding agent is any anti-PD-1 antibody described in this document.
[0032] In the embodiments, 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.
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In the embodiments, a checkpoint inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof.
[0033] In the modalities, an immunological checkpoint inhibitor is an agent that inhibits T cell immunoglobulin and mucin protein 3 (TIM-3), 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).
[0034] In the modalities, an immunological checkpoint inhibitor is a TIM-3 inhibitor. In the embodiments, a TIM-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 binding agent. In the embodiments, a TIM-3 inhibitor is a TIM-3 binding agent (for example, an antibody, antibody conjugate or antigen binding fragment thereof). In the embodiments, a TIM-3 inhibitor is a TIM-3 inhibitor described in WO 2016/161270, which is incorporated herein by reference in its entirety. In the embodiments, a TIM-3 inhibitor is TSR-022. For example, a TIM-3 inhibitor (for example, TSR-022) can be administered at a dose of about 1, 3 or 10 mg / kg (for example, about 1 mg / kg; about 3 mg / kg) kg; or about 10 mg / kg) or a fixed dose between 100 1500 mg (for example, a fixed dose of about 100 mg; a flat dose of about 200 mg; a flat dose of about 300 mg; a flat dose of about 400 mg; fixed dose of about 500 mg, flat dose of about 600 mg, flat dose of about 700 mg, flat dose of about 800 mg, flat dose of about 900 mg, flat dose about 1000 mg flat dose of about 1100 mg flat dose of about 1200 mg (a fixed dose of about 1300 mg, a fixed dose of about 1400 mg, or a flat dose of about 1500 mg).
[0035] In the embodiments, an immunological checkpoint inhibitor is a CTLA-4 inhibitor (for example, an antibody, a conjugate
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20/169 antibody or an antigen-binding fragment thereof). In the 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 the embodiments, a CTLA-4 inhibitor is a small molecule. In the embodiments, a CTLA-4 inhibitor is a CTLA-4 binding agent. In the embodiments, a CTLA-4 inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof. In the embodiments, a CTLA-4 inhibitor is ipilimunab (Yervoy), AGEN1884 or tremelimumab.
[0036] In the 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 the embodiments, a LAG-3 inhibitor is a small molecule. In the embodiments, a LAG-3 inhibitor is a LAG-3 binding agent. In the embodiments, a LAG-3 inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof. In the 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.
[0037] In the modalities, an immunological checkpoint inhibitor is a TIGIT inhibitor (for example, an antibody, an antibody conjugate or an antigen-binding fragment thereof). In the 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 the modalities, a TIGIT inhibitor is a small molecule. In the embodiments, a TIGIT inhibitor is a TIGIT binding agent. In the modalities, a
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21/169 TIGIT inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof. In the embodiments, a TIGIT inhibitor is MTIG7192A, BMS-986207 or OMP-31M32.
[0038] In the modalities, an immunological checkpoint inhibitor is an IDO inhibitor. In the 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 the embodiments, an IDO inhibitor is a small molecule. In the embodiments, an IDO inhibitor is an IDO binding agent. In the embodiments, an IDO inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof.
[0039] In the modalities, an immunological checkpoint inhibitor is a CSF1R inhibitor. In the 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 the embodiments, a CSF1R inhibitor is a small molecule. In the embodiments, a CSF1R inhibitor is a CSF1R binding agent. In the embodiments, a CSF1R inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof.
[0040] In the 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 PD-1 binding agent and a PARP inhibitor.
[0041] In the embodiments, a PARP 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 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,
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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).
[0042] In the modalities, one or more immunological checkpoint inhibitors (for example, a TIM-3 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 PD-1 binding agent, a PARP inhibitor (e.g., niraparib) and one or more immunological checkpoint inhibitors. In the embodiments, a PD-1 binding agent, a PARP inhibitor (e.g., niraparib) and a TIM-3 inhibitor. In the embodiments, a PD-1 binding agent, a PARP inhibitor (e.g., niraparib) and an LAG-3 inhibitor. In the embodiments, a PD-1 binding agent, a PARP inhibitor (e.g., niraparib), a TIM-3 inhibitor and a LAG-3 inhibitor.
[0043] In the embodiments, a therapeutic agent (for example, a PD-1 binding agent, an immunological checkpoint inhibitor, or a PARP inhibitor) described in this document is administered according to the demonstrated dosing regimens to achieve a clinical benefit in some patients (for example, according to a regimen as determined by a doctor, including changes in dosage).
[0044] 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%,
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9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of patients get 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 10% of patients achieve a clinical benefit. In some modalities, at least 10% of patients achieve DS. In some modalities, at least 10% of patients achieve at least one PR. In some modalities, at least 20% of patients achieve a clinical benefit. In some modalities, at least 20% of patients achieve DS.
[0045] 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. 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.
[0046] In the modalities, a patient has a disorder that is a dysfunctional T-cell disorder.
[0047] In the modalities, a patient has a disorder that is cancer.
[0048] In modalities, cancer is associated with a high burden
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24/169 tumor mutation (BMR).
[0049] In the modalities, a cancer is from stable microsatellites (MSS).
[0050] In the modalities, a cancer is characterized by microsatellite instability.
[0051] In modalities, a cancer has a high instability microsatellite instability status (MSI-H).
[0052] In modalities, a cancer has a low instability microsatellite instability status (MSI-L).
[0053] In the modalities, a cancer is associated with high BMR and MSI-H.
[0054] 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.
[0055] In the modalities, a cancer that has a defective DNA incompatibility repair system.
[0056] In the modalities, a cancer has a defect in the DNA incompatibility repair gene.
[0057] In the modalities, a cancer is a hypermutated cancer.
[0058] In modalities, a cancer has homologous recombination repair deficiency / homologous repair deficiency (HRD).
[0059] In the modalities, a cancer comprises a mutation in the delta polymerase (POLD).
[0060] In the modalities, a cancer comprises a mutation in the epsilon polymerase (POLE).
[0061] 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
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25/169 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, squamous cell carcinoma of the cervix, squamous cell carcinoma of the vagina, or squamous cell carcinoma of the vulva.
[0062] 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, 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, cancer salivary gland, 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, non-Hodgkin'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, is characterized by microsatellite instability, is MSI-H, has high BMR, has high BMR and is
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MSS or MSI-L, has a 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 the epsilon polymerase (POLE).
[0063] In 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 [0064] In some modalities, a patient has cancer, such as a head and neck cancer, a lung cancer (for example, a non-small cell lung cancer (NSCLC) ), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, uterine cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma or carcinoma of squamous cells (for example, from the lung; from the anogenital region, including anus, penis, cervix, vagina or vulva; or from the esophagus). In some modalities, a patient has anal cancer, fallopian tube cancer, ovarian cancer or lung cancer. In some
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27/169 modalities, a patient has anal cancer. In some certain modalities, a patient has cancer of the fallopian tubes. In some specific modalities, a patient has ovarian cancer. In some cases, a patient has lung cancer.
[0065] In some modalities, a patient has 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. In some embodiments, microsatellite instability is stable for microsatellite (eg MSS status). In some embodiments, cancer with microsatellite instability is head and neck cancer, lung cancer (eg, non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma , Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, uterine tube cancer, breast cancer, prostate cancer, gland tumor salivary, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma or squamous cell carcinoma (for example, of the lung; of the anogenital region, including anus, penis, cervix, vagina or vulva, or esophagus). In some modalities, a cancer with microsatellite instability is an anal cancer, a fallopian tube cancer, an ovarian cancer or a lung cancer. In some specific modalities, a patient has endometrial cancer with microsatellite instability. In some modalities, a patient has endometrial cancer that is stable to microsatellites (MSS).
[0066] In some modalities, a patient has a cancer characterized by the expression of PD-1 and / or PD-L1. In some modalities,
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28/169 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.
[0067] In the 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).
[0068] 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
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29/169 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).
[0069] 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 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).
[0070] 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).
[0071] 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
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30/169 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). 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).
[0072] 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).
[0073] 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 modalities, a melanoma is a
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31/169 melanoma MSI-H. 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).
[0074] In the modalities, a cancer is the squamous cell carcinoma of the anogenital region (for example, of the anus, penis, cervix, 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”).
[0075] 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
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32/169 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.
[0076] 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 fallopian tube cancer 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.
[0077] 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, a peritoneal cancer
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Primary 33/169 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.
[0078] In the modalities, a cancer is acute lymphoblastic leukemia (ALL). In the modalities, acute lymphoblastic leukemia is advanced acute lymphoblastic leukemia. In the modalities, acute lymphoblastic leukemia is metastatic acute lymphoblastic leukemia. 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).
[0079] 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).
[0080] 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
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34/169 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).
[0081] In the modalities, a cancer is Hodgkin's lymphoma (HL). In modalities, Hodgkin's lymphoma is advanced Hodgkin's lymphoma. In the modalities, Hodgkin's lymphoma is metastatic Hodgkin's lymphoma. In the modalities, Hodgkin's lymphoma is MSI-H's Hodgkin's lymphoma. 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).
[0082] 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).
[0083] 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 modalities, a CNS tumor is a CNS tumor
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MSS. 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).
[0084] 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. 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).
[0085] 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).
[0086] 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, a
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36/169 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).
[0087] 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).
[0088] 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 a deficiency of recombination repair
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37/169 homologous / homologous repair deficiency (HRD). In the modalities, a soft tissue sarcoma is leiomyosarcoma.
[0089] In modalities, one cancer is tumor Wilms. In modalities, tumor in Wilms is one tumor in Wilms advanced. In modalities, tumor in 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 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).
[0090] In the modalities, a subject has previously been treated with one 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 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).
[0091] In the modalities of methods described in this document, a method also comprises the administration of one or more among surgery, a
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38/169 radiotherapy, chemotherapy, immunotherapy, an antiangiogenic agent or an anti-inflammatory. In the embodiments, a method additionally comprises administering chemotherapy.
[0092] In the modalities, a subject is resistant to treatment with an agent that inhibits PD-1.
[0093] In the modalities, a subject is refractory to treatment with an agent that inhibits PD-1.
[0094] In the modalities, a method described in this document sensitizes a subject to treatment with an agent that inhibits PD-1.
[0095] In the modalities, a subject comprises an exhausted immune cell (for example, an exhausted immune cell which is an exhausted T cell).
[0096] 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.
[0097] In the embodiments, a PD-1 binding agent (for example, any anti-PD-1 antibody) is administered intravenously (for example, by intravenous infusion).
[0098] The present disclosure also provides, in some embodiments, methods for treating cancer that comprise administering to a patient in need of treatment an anti-programmed death protein-1 (PD-1) antibody in a therapeutically effective dose at an interval of administration for a period sufficient to achieve the clinical benefit. In the embodiments, the anti-PD-1 antibody comprises a variable heavy chain region comprising CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region comprising CDR sequences of SEQ ID
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NOs: 12, 13 and 14. In the modalities, the heavy chain variable region comprises SEQ ID NO: 1 and the light chain variable domain comprises SEQ ID NO: 2. In the modalities, the heavy chain variable region comprises SEQ ID NO: 7 and the light chain variable region comprises SEQ ID NO: 8. In the embodiments, the heavy chain variable region comprises SEQ ID NO: 3 and the light chain variable region comprises SEQ ID NO: 4.
[0099] The present disclosure provides, in some embodiments, methods for treating cancer in a patient in need of it, the method comprising administering a composition that delivers a PD-1 binding agent according to a regime demonstrated to achieve a rate of response in the relevant patient population, such that no more than 50% to 80% of patients show disease progression after 2, 4, 6, 8, 10, 12, 14, 16, 18 or 20 weeks after initiation of the treatment. In some modalities, no more than 80% of patients show progressive disease after at least 10 weeks after starting treatment.
[00100] In some embodiments, a PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9. 10 and 11 and / or light chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain variable domain, the amino acid sequence of which comprises the 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, a PD-1 binding agent comprises an immunoglobulin heavy chain, whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain, whose amino acid sequence comprises SEQ ID NO: 4.
[00101] The present disclosure provides, in some modalities,
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40/169 methods of treating cancer in a patient in need thereof, the method comprising administering a composition that provides a sufficient PD-1 binding agent to achieve an average PD1 receptor occupancy of at least about 50% to about 90% after 1,2, 3, 4 or 5 days after a single dose of the composition. In some embodiments, administration of a composition that provides a PD-1 binding agent is sufficient to achieve an average PD-1 receptor occupancy of at least 85% after 3 days after a single dose of the composition. In some embodiments, a PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9. 10 and 11 and / or light chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain variable domain, whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7 and an immunoglobulin light chain variable domain, the amino acid sequence of which comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, a PD-1 binding agent comprises a chain immunoglobulin heavy chain, whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain, whose amino acid sequence comprises SEQ ID NO: 4.
[00102] The present disclosure provides, in some embodiments, methods of treating cancer in a patient in need thereof, the method comprising administering a composition that delivers a sufficient PD-1 binding agent to achieve an average stimulation ratio of at least minus 1 in a functional PD-1 receptor occupation assay after 3 days following a single dose of PD-1 binding agent. In some embodiments, a PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9. 10 and 11 and / or light chain variable region with one, two or
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41/169 three CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, a PD-1 binding 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 an immunoglobulin light chain variable domain, the amino acid sequence of which comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, a PD1 binding agent comprises a heavy chain of immunoglobulin, whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain, whose amino acid sequence comprises SEQ ID NO: 4.
[00103] The present disclosure provides, in some embodiments, methods of treating cancer in a patient in need thereof, the method comprising administering a composition that provides a sufficient PD-1 binding agent to achieve an average PD1 receptor occupation at least 75% over a first period of time (e.g., about 15 days to about 60 days, in some embodiments, about 29 days) following a single dose of the PD-1 binding agent. In some embodiments, a PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9. 10 and 11 and / or light chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain variable domain, whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7 and an immunoglobulin light chain variable domain, the amino acid sequence of which comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, a PD1 binding agent comprises a heavy chain of immunoglobulin, whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain, whose amino acid sequence comprises SEQ ID NO: 4.
[00104] The present disclosure provides, in some modalities,
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42/169 methods of treating cancer in a patient in need thereof, the method comprising administering a composition that provides a sufficient PD-1 binding agent to achieve an average stimulation ratio of at least 1 in a receptor receptor assay. PD-1 functional over a first period of time (e.g., about 15 days to about 60 days, in some embodiments, about 29 days) following a single dose of the PD-1 binding agent. In some embodiments, a PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9. 10 and 11 and / or light chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain variable domain, whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7 and an immunoglobulin light chain variable domain, the amino acid sequence of which comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, a PD-1 binding agent comprises a chain immunoglobulin heavy chain, whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain, whose amino acid sequence comprises SEQ ID NO: 4.
[00105] In some embodiments, a patient for treatment with a composition to deliver a PD-1 binding agent has a tumor. In some embodiments, the patient has a solid tumor. In some modalities, the patient has a solid, advanced stage tumor. In some embodiments, a patient has a solid metastatic tumor.
[00106] In some modalities, the patient has head and neck cancer, lung cancer (for example, non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, cancer
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43/169 ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, cancer appendix, a urothelial cell carcinoma or a squamous cell carcinoma.
[00107] In some modalities, the patient has cancer at an advanced stage, including head and neck cancer, lung cancer (for example, non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, uterine cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, cancer of esophagus, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma or squamous cell carcinoma (for example, of the lung; of the anogenital region, including anus, penis, cervix, vagina or vulva; or esophagus). In some certain modalities, a patient has an advanced stage of anal cancer, fallopian tube cancer, ovarian cancer, breast cancer, endometrial cancer or lung cancer. In some modalities, the patient has advanced stage cancer such that advanced stage endometrial cancer, triple negative breast cancer, ovarian cancer, squamous cell carcinoma of the lung or squamous cell carcinoma of the anogenital region (for example, example, squamous cell carcinoma of the anus, penis, cervix, vagina or vulva).
[00108] 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 modalities,
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44/169 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.
[00109] In some modalities, a patient has a cancer with microsatellite instability (for example, MSI-H status). In some embodiments, microsatellite instability is MSI-Low. In some embodiments, microsatellite instability is stable for microsatellite (eg MSS status). In some modalities, the patient has endometrial cancer. In some modalities, a patient has endometrial cancer with microsatellite instability. In some modalities, a patient has advanced stage cancer with microsatellite instability. In some modalities, an advanced stage cancer with microsatellite instability is endometrial cancer, triple negative breast cancer, ovarian cancer, non-small cell lung cancer, squamous cell carcinoma of the lung or carcinoma squamous cells in the anogenital region (for example, squamous cell carcinoma of the anus, penis, cervix, vagina or vulva). In some embodiments, the patient has a solid tumor (for example, a solid advanced stage tumor or a solid metastatic tumor). In some embodiments, the patient has a solid MSI-H tumor.
[00110] 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.
[00111] In some modalities, the patient has not been previously
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[00112] 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 was previously treated with surgery. In some modalities, the patient has previously been treated with chemotherapy (for example, platinum-based chemotherapy). In some of these modalities, the platinum agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin. In some modalities, a patient has cancer that responded to platinum-inducing therapy. In some modalities, cancer is sensitive to platinum at the beginning of treatment. In some modalities, fallopian tube cancer responded to the latest platinum-based chemotherapy regimen before treatment started. In some modalities, the response to the latest platinum-based chemotherapy regimen is a complete response. In some modalities, the response to the most recent platinum-based chemotherapy regimen is a partial response.
[00113] In some embodiments, a composition that delivers a PD-1 binding agent (for example, an anti-PD-1 antibody agent) is administered in an amount that delivers at a dose of 1, 3 or 10 mg / kg of PD-1 binding agent. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 1, 3 or 10 mg / kg 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 delivers a dose of 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 delivers a dose of 1, 3 or 10 mg / kg every four
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46/169 weeks.
[00114] In some embodiments, a composition that provides a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered in an amount that provides a dose (for example, a therapeutically effective dose) within from a range of about 100 mg to about 2,000 mg of PD-1 binding agent. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered at a dose ranging from about 100 mg to about 1,200 mg, as an effective therapeutic dose that is about 100 mg, about 300 mg, about 500 mg, or about 1000 mg. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered at a dose of about 400 mg, about 500 mg, about 800 mg and / or about 1000 mg of PD-1 binding agent. In some embodiments, a dose of a PD-1 binding agent in particular is considered to be a dose of about [an indicated amount] if a relevant biological or pharmacological effect is achieved that is comparable to that obtained with a dose of the indicated amount of a special binding agent reference to PD-1 (for example, a particular anti-PD-1 antibody, such as a particular anti-PD-1 monoclonal antibody or other anti-PD-1 antibody agent, including, for example, an anti-PD-1 antibody exemplified in this document). In some embodiments, such a dose of the PD-1 binding agent in particular can be described as a dose corresponding to the indicated amount of the reference PD-1 binding agent.
[00115] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that includes a plurality of individual doses (for example, as set out above), separated from each other for a period of time. In some embodiments, individual doses can be separated from each other for a period of two weeks, three weeks, four weeks, five weeks,
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47/169 six weeks or more. In the modalities, the anti-PD-1 antibody is administered at 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. In modalities, the administration interval is once every 3 weeks. In the modalities, the administration interval is once every 6 weeks. In the embodiments, the antiPD-1 antibody is administered for a period of at least 2, 4, 6, 8, 10, 12.14, 16.18 or 20 weeks.
[00116] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered in a dose of 100 mg of the PD-1 binding agent. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 100 mg every two weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that delivers a dose of 100 mg 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 delivers a dose of 100 mg every four weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that delivers a dose of about 100 mg every five weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered at a dose of 100 mg every six weeks.
[00117] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered in a dose of 300 mg of the PD-1 binding agent. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 300 mg every two weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD antibody
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1) is administered according to a regimen that delivers a dose of 300 mg 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 delivers a dose of 300 mg every four weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that delivers a dose of about 300 mg every five weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered at a dose of 300 mg every six weeks.
[00118] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered in a 400 mg dose of the PD-1 binding agent. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a 400 mg dose every two weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that delivers a 400 mg dose 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 delivers a dose of 400 mg every four weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that delivers a dose of about 400 mg every five weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered at a dose of 400 mg every six weeks.
[00119] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered in a dose of 500 mg. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 500 mg every two weeks. In some embodiments, a liaison officer
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49/169 to PD-1 (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 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 delivers a dose of 500 mg 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 delivers a dose of about 500 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 delivers a dose of 500 mg every six weeks.
[00120] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered at a dose of 600 mg. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 600 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 delivers a dose of 600 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 delivers a dose of 600 mg 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 delivers a dose of about 600 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 delivers a dose of 600 mg every six weeks.
[00121] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered in a dose of 700 mg. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of
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700 mg 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 delivers a dose of about 700 mg every five weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 700 mg every six weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 700 mg every seven weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 700 mg every eight weeks.
[00122] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered in a dose of 800 mg. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 800 mg 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 delivers a dose of about 800 mg every five weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 800 mg every six weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 800 mg every eight weeks.
[00123] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered in a 900 mg dose. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a 900 mg dose every four weeks. In some modalities, an insurance agent
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51/169 binding to PD-1 (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of about 900 mg every five weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a 900 mg dose every six weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a 900 mg dose every seven weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a 900 mg dose every eight weeks.
[00124] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered at a dose of 1,000 mg. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 1,000 mg 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 delivers a dose of 1,000 mg every five weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 1,000 mg every six weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 1,000 mg every seven weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of 1,000 mg every eight weeks.
[00125] In some particular embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that comprises or consists of at least one cycle of: a single dose (eg example, a single 400 mg dose or a single 500 mg dose)
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52/169 once every two weeks, a single dose once every three weeks, a single dose once every four weeks, a single dose once every five weeks, a single dose every six weeks, etc. In some embodiments, a cycle includes 1,2,3, 4, 5, 6, 7, 8,9, 10 or more single doses. In some embodiments, a regime includes a plurality of cycles. In some embodiments, individual cycles can be separated from one another by a rest period (that is, without dosing).
[00126] 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, 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 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 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 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 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).
[00127] In some modalities, the administration of a dose can
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53/169 be achieved by administering a single unit dose composition (i.e., a single composition comprising and / or administering the relevant dose amount). In some embodiments, administration of a dose can be achieved by administering a plurality of single unit dose compositions. In some embodiments, administration of a dose can be achieved by administering a portion of a single dose composition.
[00128] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that provides a first dose of PD-1 binding agent every three weeks for the first 2-6 dosing cycles (for example, the first 3, 4 or 5 dosing cycles) and then administering a second dose of a PD-1 binding agent once every six weeks until progression of the disease. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a first dose of a PD-1 binding agent once every three weeks for the first 3, 4, or 5 dosing cycles, and then administer a second dose of a PD-1 binding agent once every six weeks or more until the disease progresses. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a first dose of a PD-1 binding agent once every three weeks for the first 3, 4, or 5 dosing cycles, and then administer a second dose of a PD-1 binding agent once every six weeks or more until the disease progresses. In some embodiments, the first and / or second dose of a PD-1 binding agent (for example, an anti-PD-1 antibody) is from about 100 mg to about 2,000 mg. In some embodiments, the first dose and the second dose are the same. In some embodiments, the first dose and the second dose are different.
[00129] In some embodiments, a PD-1 binding agent (for example
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54/169 example, an anti-PD-1 antibody) is administered according to a regimen comprising administering a dose of about 500 mg every 3 weeks for 3, 4 or 5 doses followed by administration of at least one dose of 1,000 mg every six weeks after the third, fourth or fifth 500 mg dose. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen comprising administering a dose of about 500 mg every 3 weeks for 3 doses followed by administration of at least one 1,000 mg dose every six weeks or more after the third 500 mg dose. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen comprising administering a dose of about 500 mg every 3 weeks for 4 consecutive doses. administration of at least a dose of 1,000 mg every six weeks or more after the fourth dose of about 500 mg. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen comprising administering a dose of about 500 mg every 3 weeks for 5 doses followed by administration of at least one 1,000 mg dose every six weeks or more after the fifth 500 mg dose. In some modalities, additional doses of about 1,000 mg are administered every six weeks or more after the first dose of about 1000 mg, until no further clinical benefit is achieved. In some particular embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a dosage regimen that includes 500 mg over 4 Q3W cycles followed by 1000 mg Q6W.
[00130] In some embodiments, the PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen comprising administering a dose of 300 mg every 3 weeks for 3, 4 or 5 doses followed by the administration of at least one dose of 800 mg or 1000 mg every six weeks after the third, fourth or fifth dose of 300 mg.
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In some embodiments, doses of an additional 800 mg or 1000 mg are administered every six weeks after the first dose of 800 mg or 1000 mg until no further clinical benefit is achieved. In some particular embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a dosage regimen that includes 300 mg during Q3W cycles followed by 800 mg or 1000 Q6W mg.
[00131] In some embodiments, the PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen comprising administering a dose of 400 mg every 3 weeks for 3, 4 or doses followed by administration of at least one dose of 800 mg or 1000 mg every six weeks after the third, fourth or fifth dose of 400 mg. In some embodiments, doses of an additional 800 mg or 1000 mg are administered every six weeks after the first dose of 800 mg or 1000 mg until no further clinical benefit is achieved. In some particular embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a dosage regimen that includes 400 mg during Q3W cycles followed by 800 mg or 1000 Q6W mg.
[00132] In some embodiments, the PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen comprising administering a dose of 600 mg every 3 weeks for 3, 4 or doses followed by the administration of at least one dose of 800 mg or 1000 mg every six weeks after the third, fourth or fifth dose of 600 mg. In some embodiments, doses of an additional 800 mg or 1000 mg are administered every six weeks after the first dose of 800 mg or 1000 mg until no further clinical benefit is achieved. In some particular embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a dosage regimen that includes 600 mg over 4 Q3W cycles followed by 800 mg Q6W or 1000 mg.
[00133] In some embodiments, a PD-1 binding agent (for example
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56/169 example, an anti-PD-1 antibody) is administered according to a regimen that is shown to achieve a PD-1 binding agent Cmax in a patient population that is within 10 pg / mL to 500 pg / ml. In some embodiments, the regimen has been shown to achieve an average Cmax of PD-1 binding agent in a patient population that is about 20 pg / mL, about 65 pg / mL or about 200 pg / mL. In some embodiments, the regimen has been shown to achieve an average Cmax of PD-1 binding agent in a patient population that is about 140 pg / mL, about 180 pg / mL, or about 200 pg / mL, about 230 pg / ml, about 290 pg / ml. In the embodiments, administration of the anti-PD-1 antibody results in an average Cmax within 10 pg / mL to 500 pg / mL in the patient (for example, an average Cmax of about 20 pg / mL, about 65 pg / mL) ml or about 200 pg / ml in the patient).
[00134] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that has been shown to achieve an average AUCo-336h of the agent concentration-time curve of binding to PD-1 in a patient population ranging from 2500 h * pg / mL to 50,000 h * pg / mL. In some modalities, the regimen has been shown to achieve an average AUCo-336h of the concentration-time curve of the PD-1 binding agent in a patient population that is about 3400 h * pg / mL, about 11000 h * pg / ml or about 36800h * pg / ml. In the embodiments, administration of the anti-PD-1 antibody results in an average AUC-336h within 2500 h * pg / mL at 50000 h * pg / mL in the patient (for example, an average AUC-336h is approximately 3400 h * pg / mL, approximately 11000 h * pg / mL or approximately 36800 h * pg / mL).
[00135] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that has been shown to achieve a peak serum concentration of a PD-1 binding agent 1 within 0.5-3 hours after administration.
[00136] In some embodiments, a PD-1 binding agent has
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57/169 a terminal half-life of approximately 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 days. In some embodiments, a PD-1 binding agent has a terminal half-life of approximately 12 days.
[00137] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered intravenously. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered by intravenous infusion.
[00138] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is aseptically placed in a clear glass vial. In some embodiments, the glass bottle is capped with a chlorobutyl elastomer stopper laminated with fluoropolymer and sealed with an aluminum cap. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is stored at 2-8 ° C. In some embodiments, a PD-1 binding agent (for example, an antiPD1 antibody) is free of preservatives.
[00139] In some embodiments, the patient is receiving or will receive one or more additional therapies in combination with the PD-1 binding agent. In some modalities, the additional therapy is surgery, radiotherapy, chemotherapy or immunotherapy. In some embodiments, additional therapy includes treatment with a composition that provides a LAG-3 binding agent (for example, any 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) and / or a TIM-3 binding agent (for example, any described in WO 2016/161270). In the embodiments, an anti-TIM-3 therapy (for example, an anti-TIM-3 antibody) can be administered at 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; an
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58/169 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. In some embodiments, additional therapy is a PARP inhibitor. In some embodiments, the PARP inhibitor is niraparib, olaparib, rucaparib, talazoparib and veliparib.
[00140] In some embodiments, the present disclosure provides a method of administering a PD-1 binding agent in combination with niraparib to a patient with a recurrent and / or platinum-sensitive cancer. In some embodiments, a recurrent and / or platinum-sensitive cancer is head and neck cancer, lung cancer (for example, non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer , a melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, uterine tube cancer, breast cancer, prostate cancer, an salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma or squamous cell carcinoma (for example, of the lung; from the region; anogenital, including anus, penis, cervix, vagina or vulva, or esophagus). In some modalities, a recurrent and / or platinum-sensitive cancer is an anal cancer, a cancer of the fallopian tubes, an ovarian cancer or a lung cancer. In some certain modalities, a recurrent and / or platinum-sensitive cancer is endometrial cancer, triple negative breast cancer, squamous cell lung cancer (NSCLC), squamous cell carcinoma of the lung or squamous cell carcinoma of the anogenital region (for example, squamous cell carcinoma of the anus, penis, cervix, vagina
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59/169 or the vulva).
[00141] In some embodiments, niraparib is administered to a patient in a dose of 5 mg to 500 mg. In some embodiments, niraparib is administered according to a regimen comprising a single daily dose of 50 mg to 500 mg of niraparib. In some embodiments, a single daily dose of niraparib ranges from 100 mg to 300 mg. In some embodiments, a single daily dose of niraparib comprises 100 mg, 200 mg or 300 mg. In some modalities, a single daily dose of niraparib is administered orally.
[00142] In some embodiments, the method further comprises a step of reducing the therapeutically effective dose of the anti-PD-1 antibody and / or extending the administration interval after reaching the clinical benefit.
[00143] The present disclosure provides, in some embodiments, methods for treating cancer comprising administering to a patient in need of treatment an anti-programmed death protein-1 (PD-1) antibody in a first dose at a first interval during a period of time; administering anti-PD-1 antibody to the patient in a second dose at a second interval for a second period; wherein the anti-PD1 antibody comprises a heavy chain variable region comprising CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region comprising CDR sequences of SEQ ID NOs: 12, 13 and 14. In some embodiments, the first dose and the second dose are different. In some embodiments, the first dose is about 500 mg and the second dose is about 1000 mg. In the modalities, the first interval and the second interval are different. In modalities, the first interval is once every three weeks and the second interval is once every six weeks. In the embodiments, the anti-PD-1 antibody is administered in the first dose once every three weeks during the first period of 2-6 dosing cycles (for
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60/169 example, the first 3, 4 or 5 dosing cycles) and the second dose once every six weeks until disease progression.
[00144] The present disclosure provides, in some embodiments, compositions comprising a PD-1 binding agent for use in the treatment of cancer in a selected cancer patient population, wherein the composition is administered according to a demonstrated regimen for achieve a clinical benefit. In some embodiments, a PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9.10 and 11 and / or light chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, a PD-1 binding 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 an immunoglobulin light chain variable domain, the amino acid sequence of which comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, a PD-1 binding agent comprises a heavy chain of immunoglobulin, whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain, whose amino acid sequence comprises SEQ ID NO: 4.
[00145] 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 in a patient population achieve a clinical benefit. In some modalities, at least 5% of
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61/169 patients in a patient population reach DS. In some modalities, at least 5% of patients in a patient population achieve at least one PR. In some modalities, at least 5% of patients in a patient population achieve CR. In some modalities, at least 20% of patients in a patient population achieve a clinical benefit. In some modalities, at least 20% of patients in a patient population reach DS.
[00146] 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).
[00147] The present disclosure provides, in some embodiments, compositions comprising a PD-1 binding agent for use in the treatment of cancer in a selected cancer patient population, in which the composition is administered according to a regimen that has demonstrated achieve an average PD-1 receptor occupancy of at least 50% to 85% within 1 to 5 days after administration of a single dose of the PD-1 binding agent. In some embodiments, a PD-1 binding agent comprises a heavy chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 9. 10 and 11 and / or light chain variable region with one, two or three CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain variable domain, whose amino acid sequence comprises SEQ ID NO: 1 or
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SEQ ID NO: 7 and an immunoglobulin light chain variable domain, the amino acid sequence of which comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, a PD-1 binding agent comprises a heavy chain of immunoglobulin, whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain, whose amino acid sequence comprises SEQ ID NO: 4.
[00148] The present disclosure provides, in some embodiments, compositions comprising a PD-1 binding agent for use in the treatment of cancer in a selected cancer patient population, in which the composition is administered according to a regimen that has demonstrated achieve an average PD-1 receptor occupancy of at least 75% over the first period of time (for example, about 15 days to about 60 days; in some embodiments, about 29 days). In some embodiments, a PD-1 binding 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 an immunoglobulin light chain variable domain, whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain, the amino acid sequence of which comprises SEQ ID NO: 3 and a light chain immunoglobulin, whose amino acid sequence comprises SEQ ID NO: 4.
[00149] 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 modalities,
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63/169 patients in the cancer patient population each have cancer, such as head and neck cancer, lung cancer (for example, non-small cell lung cancer (NSCLC)), one kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma or carcinoma of squamous cells (for example, from the lung; from the anogenital region, including anus, penis, cervix, vagina or vulva; or from the esophagus). In some modalities, patients in the cancer patient population have cancer, such as anal cancer, fallopian tube cancer, ovarian cancer or lung cancer. In some modalities, patients in the cancer patient population each have cancer with microsatellite instability (for example, MSIH status). In some embodiments, microsatellite instability is MSI-Low. In some embodiments, microsatellite instability is stable for microsatellite (eg MSS status). In some modalities, patients in the cancer patient population each have endometrial cancer. In some modalities, at least some of the patients in the cancer patient population have an endometrial cancer with microsatellite instability or an endometrial cancer that is microsatellite stable (MSS).
[00150] 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), lymphoma
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64/169 follicular (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.
[00151] 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 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).
[00152] 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.
BRIEF DESCRIPTION OF THE FIGURES [00153] The drawing included in this document, which is composed of the following Figures, is for illustrative purposes only and not for limitation.
[00154] Figure 1 represents a graphical representation of the log-linear mean concentration versus the time profile after a single dose administration of an anti-PD-1 antibody. The dots represent a dose of 1 mg / kg, the squares represent a dose of 3 mg / kg and the triangles represent a dose of 10 mg / kg. The x-axis indicates the time since administration (in hours) and the y-axis indicates the serum concentration of the anti-PD-1 antibody in ng / mL. The error bars represent ± standard deviation.
[00155] Figure 2A-2B represents graphical representations of the average log-linear concentration versus the time profile after a single dose administration of an anti-PD-1 antibody at different dosages. (A) The points
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65/169 represents a dose of 1 mg / kg, squares represent a dose of 3 mg / kg and triangles represent a dose of 10 mg / kg. (B) The dots represent a dose of 500 mg and the squares represent a dose of 1000 mg. The x-axes indicate the time since administration (in hours) and the y-axes indicate the serum concentration of the anti-PD-1 antibody in pg / ml. The error bars represent ± standard deviation.
[00156] Figure 3 represents a graphical representation of the dose and exposure relationship of an exemplary anti-PD-1 antibody. AUCo-336hr (hr * pg / mL) was used as a model for exposure and was observed to increase linearly with the dosage of the anti-PD-1 antibody.
[00157] Figure 4 represents a graphical representation of the relationship between slack and body weight. Body weight was not found to be a significant covariant for the elimination of an anti-PD-1 antibody.
[00158] Figures 5A-5B describe results for receptor occupation tests for doses of 1, 3 and 10 mg / kg. Panel A describes the% occupancy of PD-1 receptors in CD3 + cells. Panel B represents the IL-2 stimulation ratio.
[00159] Figures 6A-6D describe results for receptor occupation assays for 500 mg Q3W and 1000 mg Q6W doses. Panels A and C represent the% of PD-1 receptor occupation in CD3 + cells. Panels B and C represent the IL-2 stimulation ratio.
[00160] Figures 7A-7B represent a summary of treatment responses to an anti-PD-1 antibody. Panel A in Figure 7 depicts a swimmer's stripe and Panel B shows a spider graph of treatment responses to the exemplary PD-1 binding agent.
[00161] Figure 8 represents the percentage of occupation of PD-1 receptors by an anti-PD-1 antibody measured in circulating CD3 ⁺ T cells by flow cytometry before the first and second doses of 500 mg and again at the end of the treatment.
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DETAILED DESCRIPTION OF CERTAIN MODALITIES
Definitions [00162] 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 of the referenced value.
[00163] 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 the modalities, intravenous administration is intravenous infusion. In some particular embodiments, administration can be bronchial (for example, by bronchial instillation), buccal, dermal (which can be or comprise, for example, one or more topical for the dermis, intradermal, interd dermal, transdermal, etc.) , enteric, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (eg, intrahepatic), mucosa, nasal, oral, rectal, subcutaneous,
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67/169 sublingual, topical, tracheal (for example, 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.
[00164] 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.
[00165] For administration by inhalation, the compounds are distributed in the form of an aerosol sprayed from a pressurized container or dispenser that contains a suitable propellant, for example, a gas such as carbon dioxide, or a nebulizer.
[00166] 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
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68/169 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.
[00167] 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.
[00168] Affinity ·. As is 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).
[00169] 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 150 kD tetrametric agents 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 Y-shaped structure. Each heavy chain consists of at least four domains (each about 110
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69/169 amino acids in length) - 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 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 framework regions
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70/169 invariable (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 embodiments, the sequence elements are humanized, primatized, 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,
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71/169 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.].
[00170] Antibodies include antibody fragments. Antibodies also include, but are not limited to, polyclonal monoclonal antibody, chimeric dAb antibody (antibody domain), single chain, Fab expression libraries, Fab F (ab) 2, scFvs and Fab. An antibody can be a complete antibody , or immunoglobulin, or an antibody fragment.
[00171] 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 structural elements of immunoglobulin
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72/169 enough to check specific connection. 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 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 fraction
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73/169 catalytic, etc.] or another pending group [eg 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 antibody agent 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 a reference antibody. In some embodiments, an included CDR is substantially identical to a reference CDR, so it is either identical in sequence or contains between 1-5 amino acid substitutions compared to the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in that it has 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 that at least one amino acid within the included CDR is excluded, added or substituted compared to the reference CDR, but the included CDR has an amino acid sequence which is moreover identical to that of the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in that 1-5 amino acids within the included CDR are excluded, added or substituted compared to the reference CDR, but the included CDR has an amino acid sequence which is otherwise identical to the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in so far as
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74/169 that 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 to that of the reference CDR. In some embodiments, an included CDR is substantially identical to a reference CDR in that 1-5 amino acids within the included CDR are excluded, added or substituted compared to the reference CDR, but the included CDR has an amino acid sequence which 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.
[00172] Connection. It will be understood that the term bond, 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, binding refers to non-covalent interactions of the types that occur between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific. The strength or affinity of immunological binding interactions can be expressed in terms of the dissociation constant (Kd) of the interaction, where a smaller Kd represents greater affinity. The immunological binding properties of the selected polypeptides can be quantified using well-established methods
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75/169 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 ff) can be determined by calculating the concentrations and the effective association and dissociation rates. (See Nature 361: 186-87 (1993)). The K _O ff / K _O n ratio 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).
[00173] 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 binding agent may comprise a generic binding fraction (for example, a biotin / avidin / streptavidin and / or a specific class antibody) and a binding fraction specific (for example, an antibody or aptamers with a particular molecular target) that is linked to the generic link fraction partner. In some embodiments, such an approach may allow the modular assembly of multiple bonding agents by connecting different fractions of
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76/169 specific link with the same partner as the generic link fraction. 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.
[00174] 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 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 (for example, a metastatic solid tumor or an advanced solid tumor). In some modalities, a relevant cancer
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77/169 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.
[00175] Caireador: 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. The prevention of the action of microorganisms can be achieved 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. Absorption
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78/169 prolonged use of injectable compositions may be caused by the inclusion, in the composition, of an agent that delays absorption, for example, aluminum monostearate and gelatin.
[00176] 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 (eg, as part of a single chemical complex or covalent entity) by the same route of administration and / or at the same time.
[00177] Complete Response: In this document, the term complete response or CR is used to refer to the disappearance of all or
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79/169 substantially all target injuries. 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, EA Eisenhauer, et al., “New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.),” Eur. J. of Cancer, 45: 228-247 (2009).
[00178] 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.
[00179] Dosage regimen or regimen: Those skilled in the art will appreciate that the term regimen can be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some modalities, a particular therapeutic agent has a regimen of
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80/169 dosage, 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, a PD-1 binding 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 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).
[00180] Reason for Risk: In this document, a “risk ratio” is the
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81/169 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.
[00181] 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 type can often be considered a homologous substitution.
[00182] 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
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82/169 of length designated in a 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 the PAM120 residue weight table, 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 GCG software using a
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83/169 matrix NWSgapdna.CMP [00183] Kd: 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 the which the antibody or its binding component binds).
[00184] Koft: 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 which the antibody or its binding component binds).
[00185] 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).
[00186] Niraparib As used herein, the term niraparib includes any of the free base compounds ((3S) -3- [4- {7 (aminocarbonyl) -2H-indazol-2-yl} phenyl] piperidine), a salt form, including pharmaceutically acceptable salts, of (3S) -3- [4- {7- (aminocarbonyl) -2H-indazol-2yl} phenyl] piperidine (eg (3S) -3- [4- {7 - (aminocarbonyl tosylate) -2Hindazol-2-yl} phenyl] piperidine), or a solvated or hydrated form thereof (for example, (3S) -3- [4- {7- (aminocarbonyl) -2H monohydrate tosylate) -indazol2-yl} phenyl] piperidine). In some embodiments, such forms can be individually referred to as niraparib free base, niraparib tosylate and niraparib monohydrate tosylate, respectively. Unless otherwise indicated, the term niraparib includes all forms of the compound (3S) -3- [4- {7 (aminocarbonyl) -2H-indazol-2-yl} phenyl] piperidine.
[00187] 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
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84/169 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, 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 the embodiments, the animals are, for example, mammals, such as mice, rats, rabbits, non-human and human primates; insects; worms; etc. In some modalities, 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.
[00188] 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, etal., “New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.),” Eur. J. of Cancer, 45: 228-247 (2009).
[00189] Pharmaceutical composition: In this document, the term pharmaceutical composition refers to a composition in which an active agent
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85/169 (for example, 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, purges (aqueous or non-aqueous solutions or suspensions), tablets, for example, those directed at absorption buccal, sublingual and systemic, bolus, 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, a PD-1 binding agent) is formulated for parenteral administration.
[00190] 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 .
[00191] 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
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86/169 assessed as a period of time in which there is no progression of tumor growth and / or in which 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.
[00192] 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 the 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 not related 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 of
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87/169 according to the GCIG criteria.
[00193] 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, solid tumors may be or comprise adrenal, bile duct, bladder, bone, breast, cervical, colon, endometrial, esophageal, ocular, gallbladder, gastrointestinal tract tumors, kidneys, larynx, liver, lung, nasal cavity, nasopharynx, oral cavity, ovary, penis, pituitary, prostate, retina, salivary gland, skin, small intestine, stomach , testis, thymus, thyroid, uterine, vaginal and / or vulva.
[00194] 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 al., “New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.),” Eur. J. of Cancer, 45: 228-247 (2009).
[00195] 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 a quantity
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88/169 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 therapeutically effective amount can 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.
[00196] 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
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89/169 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 [00197] Methods of treating disorders in a subject (for example, disorders that benefit from the administration of anti-PD-1 therapy) are described in this document. For example, an anti-PD-1 therapy 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 regimen determined by a physician. (for example, anti-PD-1 therapy is administered in dosage quantities and number of treatment cycles determined by a doctor).
[00198] In the modalities, the methods described in this document are useful for treating dysfunctional T cell disorders (eg, cancer). In the embodiments, the methods described in this document are useful for reducing tumors or inhibiting the growth of tumor cells in a subject.
[00199] 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.
[00200] In the modalities, the methods described in this document are useful to induce an immune response in a subject.
[00201] 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.
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90/169 [00202] 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 specific virus (for example, live attenuated vaccines, subunit vaccines, recombinant vector vaccines and small molecule antiviral therapies (for example, viral replication inhibitors and analogs of nucleosides).
[00203] 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).
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91/169 [00204] As discussed in this document, PD-1 is abnormally expressed in a variety of cancers (see, for example, Brown et al, J. Immunol., 170: 1257-1266 (2003); and Flies et al , Yale Journal of Biology and Medicine, 84: 409-421 (2011)), and the expression of PD-L1 in some patients with renal cell carcinoma correlates with tumor aggressiveness. Inventive methods can be used to treat any type of cancer known in the art.
[00205] 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. triple negative breast cancer (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, lymphoma Hodgkin's disease (HL) / primary mediastinal B cell lymphoma, kidney cancer, clear cell kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell carcinoma, mesothelioma, monocytic leukemia , multiple myeloma, myeloma, neuroblastic derived CNS tumor, non-Hodgkin's lymphoma (NHL), non-small cell lung cancer (NSCLC), oral cancer, osteosarcoma, ovarian cancer, ovarian carcinoma, pancreatic cancer, peritoneal cancer, cancer primary peritoneal, prostate cancer, relapsed or refractory classic Hodgkin's lymphoma (cHL), renal cell carcinoma, rectal cancer, salivary gland cancer (eg
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92/169 example, a salivary gland tumor), sarcoma, skin cancer, small cell lung cancer, small intestine cancer, 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, T-cell leukemia, T-cell lymphoma , thymus cancer, thymoma, thyroid cancer, uveal melanoma, urothelial cell carcinoma, uterine cancer, uterine endometrial cancer, uterine sarcoma, vaginal cancer, vulva cancer or Wilms tumor.
[00206] In other modalities, a cancer is a cancer of the head and neck, a lung cancer (for example, a non-small cell lung cancer (NSCLC)), a kidney cancer, a bladder cancer, a melanoma, Merkel cell carcinoma (see, for example, Bhatia et al., Curr. Oncol. Rep., 13 (6): 488-497 (2011), cervical cancer, vaginal cancer, vulva cancer, cancer uterine cancer, endometrial cancer, ovarian cancer, cancer of the fallopian tubes, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma or squamous cell carcinoma (for example, from the lung; from the anogenital region, including anus, penis, cervix, vagina or vulva; or from the esophagus). some modalities, 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, gall bladder cancer, larynx cancer, liver cancer, thyroid cancer, stomach cancer, cancer salivary gland, prostate cancer, pancreatic cancer or Merkel cell carcinoma.
[00207] In some modalities, a patient or patient population has hematological cancer. In some modalities, the patient has
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93/169 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 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 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), hair cell leukemia and multiple myeloma; acute and chronic leukemias such as lymphoblastic, myeloid, lymphocytic and myelocytic leukemias.
[00208] 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.
[00209] 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 squamous cell carcinoma of the head and neck (HNSCC).
[00210] In the modalities, a cancer is the squamous cell carcinoma of the anogenital region (for example, of the anus, penis, cervix, vagina or vulva).
[00211] In the modalities, a cancer is bladder cancer, breast cancer (for example, triple negative breast cancer (TNBC)), fallopian tube cancer, collagiocarcinoma, colon adenocarcinoma, endometrial cancer, esophageal cancer, sarcoma Ewing's disease, gastric cancer, clear cell kidney cancer, lung cancer (e.g., adenocarcinoma or squamous cell lung cancer), mesothelioma, ovarian cancer,
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94/169 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.
[00212] 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, ependomy , acoustic neuroma, oligodendroglioma, meningioma, vestibular schwannoma, adenoma, metastatic brain tumor, meningioma, spinal tumor or medulloblastoma. In the modalities, a cancer is a CNS tumor.
[00213] 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 cancer, non-small cell lung cancer (NSCLC), carcinoma of
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95/169 small cell lung, 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. In some embodiments, the patient has a solid MSI-H tumor.
[00214] 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).
[00215] 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, vulvar 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.
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96/169 [00216] 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).
[00217] 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 abdominal cavity, called the 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
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97/169 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.
[00218] 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 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
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98/169 (<1% cells), negative for progesterone receptor expression (<1% cells) and HER-2 negative.
[00219] In the 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).
[00220] In some modalities, a breast cancer is a 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.
[00221] In some modalities, a patient or a population of patients who must be treated by the methods of the present disclosure have or are susceptible to endometrial cancer (EC). Endometrial carcinoma is the most common cancer of the female genital tract, accounting for 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
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99/169 (less than 10%), clear cells 4%, mucinous 1%, squamous less than 1% and combined about 10%.
[00222] From a 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 edematous papillae 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 .
[00223] Endometrial cancers can also be classified
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100/169 in the picture 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.
[00224] In the modalities, an endometrial cancer is a metastatic endometrial cancer.
[00225] In the modalities, a patient has an MSS endometrial cancer.
[00226] In the modalities, a patient has an MSI-H endometrial cancer.
[00227] 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 lung cancer is a lung cancer with an EGFR mutation (for example, NSCLC with an EGFR mutation).
[00228] 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 cancer
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101/169 high colorectal TMB.
[00229] 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.
[00230] In the modalities, a cancer is an advanced cancer.
[00231] In the modalities, a cancer is a metastatic cancer.
[00232] 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).
[00233] 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 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 mutation in the delta polymerase (POLD) and cancers that comprise a mutation in the epsilon polymerase (POLE).
[00234] In some modalities, a tumor to be treated is characterized by instability for microsatellite. In some modalities,
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102/169 a tumor is characterized by 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).
[00235] The instability for microsatellite arises from a failure to repair errors associated with replication due to a defective DNA incompatibility repair (MMR) 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 high microsatellite
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103/169 instability for microsatellite (for example, MSI-H status). 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 an instability status of stable to microsatellite (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.
[00236] In the modalities, a patient has an MSI-L cancer.
[00237] 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.
[00238] In the modalities, a patient has an MSS cancer. In the modalities, an MSS cancer is an MSS endometrial cancer.
[00239] In the modalities, a cancer is associated with a POLE mutation (DNA polymerase epsilon) (ie, 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 modalities, a mutation of
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POLE 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.
[00240] In the modalities, a cancer is associated with a POLD (DNA polymerase delta) mutation (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.
[00241] In some modalities, a patient has an incompatible repair deficient cancer (MMRd).
[00242] In the modalities, an MMRd cancer is a colorectal cancer.
[00243] Microsatellite instability can arise from a failure 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, the status of MSI-H 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.
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105/169 [00244] In the modalities, a cancer (for example, an MMRd cancer) is characterized by a high mutational tumor burden (that is, 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.
[00245] 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 the modalities, a cancer with elevated TIL is a metastatic cancer (for example, a metastatic breast cancer).
[00246] In modalities, 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.
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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.
[00247] 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.
[00248] 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.
[00249] In some modalities, a subject has previously been treated with one 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 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).
[00250] In the modalities of methods described in this document, a method further comprises the administration of one or more among surgery, a
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107/169 radiotherapy, chemotherapy, immunotherapy, antiangiogenic agent or anti-inflammatory. In the embodiments, a method additionally comprises administering chemotherapy.
[00251] In some modalities, at least some of the patients in the cancer patient population have been previously treated with chemotherapy (for example, platinum-based chemotherapy). For example, a patient who has received two cancer treatment lines can be identified as a 2L cancer patient (for example, a 2L NSCLC patient). 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).
[00252] In the modalities, a subject is resistant to treatment with an agent that inhibits
PD-1.
[00253] In the modalities, a subject is refractory to treatment with an agent that inhibits PD-1.
[00254] In the modalities, a method described in this document sensitizes the subject to treatment with an agent that inhibits PD-1.
[00255] In the modalities, a subject comprises an exhausted immune cell (for example, an exhausted immune cell which is an exhausted T cell).
[00256] In the modalities, the methods described in this document, a
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108/169 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.
[00257] In the embodiments, a PD-1 inhibitor (for example, an anti-PD-1 antibody) is administered intravenously (for example, by intravenous infusion).
Programmed Death 1 (PD-1) [00258] Programmed Death 1 (PD-1) (also known as Programmed Cell Death 1) is a type I transmembrane protein of 268 amino acids originally identified by subtractive hybridization of a T cell line of mice suffering from apoptosis (Ishida et al. Embo J., 11: 3887-95 (1992)). PD-1 is a member of the CD28 / CTLA-4 T cell regulator family and is expressed in activated T cells, B cells and T cells and myeloid lineage (Greenwald et al. Annu. Rev. Immunol.23 '. 515-548 (2005); and Sharpe et al. Nat. Immunol. 8: 239-245 (2007)). PD-1 is an inhibitory member of the CD28 receptor family, which also includes CD28, CTLA-4, ICOS and BTLA. PD-1 is expressed in activated B cells, T cells and myeloid cells (Agata et al., Supra; Okazaki et al. (2002) Curr. Opin. Immunol 14: 391779-82; Bennett et al. (2003) J Immunol 170: 711-8).
[00259] Two ligands have been identified for PD-1, the PD 1 ligand (PD-L1) and the PD 2 ligand (PD-L2), both of which belong to the B7 protein superfamily (Greenwald et al, supra). PD-L1 is expressed in a variety of cell types, including lung, heart, thymus, spleen and kidney cells (see, for example, Freeman et al. J. Exp. Med., 192 (7): 1027-1034 (2000); and Yamazaki et al. J. Immunol.169 (10): 5538-5545 (2002)). PD-L1 expression is up-regulated in macrophages and dendritic cells (DC) in response to treatment with lipopolysaccharides (LPS) and GM-CSF, and in T cells and B cells
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109/169 after signaling via T-cell and B-cell receptors. PD-L1 is also expressed in a variety of murine tumor cell lines (see, for example, Iwai et al, Proc. Nat.l Acad. Sci. USA, 99 (9): 12293-12297 (2002); and Blank et al, Cancer Res., 64 (3): 1140-1145 (2004)). In contrast, PD-L2 exhibits a more restricted expression pattern and is expressed primarily by antigen-presenting cells (eg, dendritic cells and macrophages), and some tumor cell lines (see, for example, Latchman et al. Nat. Immunol .2 (3): 261-238 (2001)). The high expression of PD-L1 in tumors, whether in the tumor cell, stroma or other cells within the tumor microenvironment, correlates with poor clinical prognosis, presumably through the inhibition of effector T cells and positive regulation of regulatory T cells (Treg) in the tumor.
[00260] PD-1 down-regulates T cell activation and this inhibitory function is linked to an immunoreceptor tyrosine-based (ITSM) exchange motif in the cytoplasmic domain (see, for example, Greenwald et al. Supra; and Parry et al. Mol. Cell. Biol.25: 9543-9553 (2005)). PD-1 deficiency can lead to autoimmunity. For example, C57BL / 6 PD-1 knockout mice have been found to develop a lupus-like syndrome (see, for example, Nishimura et al. Mmunityl 1: 141-1151 (1999)). In humans, a single nucleotide polymorphism in the PD-1 gene is associated with a higher incidence of systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis and progression of multiple sclerosis (see, for example, Nielsen et al, Tissue Antigens, 62 ( 6): 492-497 (2003); Bertsias et al., Arthritis Rheum., 60 (1): 207-218 (2009); Ni et al, Hum. Genet., 121 (2): 223-232 (2007 ); Tahoori et al, Clin. Exp. Rheumatol., 29 (5): 763-767 (2011); and Kroner et al, Ann. Neurol., 58 (1): 50-57 (2005)). The abnormal expression of PD-1 has also been implicated in T-cell dysfunctions in various pathologies, such as tumor immune evasion and chronic viral infections (see, for example, Barber et al. Nature, 439: 682-687 (2006); and Sharpe et al, supra).
[00261] Recent studies show that suppression of T cells
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110/169 induced by PD-1 also plays a role in suppressing antitumor immunity. For example, PD-L1 is expressed in a variety of human and mouse tumors, and binding of PD-1 to PD-L1 in tumors results in suppression of T cells and tumor avoidance and immune protection (Dong et al. / Vat. Med8: 793-800 (2002)). Expression of PD-L1 by tumor cells was directly associated with its resistance to lysis by anti-tumor T cells in vitro (Dong et al. Supra ^- , and Blank et al. Cancer Res., 64: 1140-1145 (2004 )). PD-1 knockout mice are resistant to the tumor challenge (Iwai et al. Int. LmmunoT 7: 133-144 (2005)), and PD-1 knockout mice T cells are highly effective in tumor rejection when adoptively transferred for tumor-bearing mice (Blank et al. supra). Blocking PD-1 inhibitory signals using a monoclonal antibody can enhance host antitumor immunity in mice (Iwai et al. Supra ^- , and Hirano et al. Cancer Res., 65: 1089-1096 (2005)), and high levels of PD-L1 expression in tumors are associated with a poor prognosis for many types of human cancer (Hamanishi et al., Proc. Natl. Acad. Sci. USA, 104: 3360-335 (2007), Brown et al , J. Immunol., 170: 1257-1266 (2003); and Flies et al, Yale Journal of Biology and Medicine, 84 (4): 409-421 (2011)).
[00262] In view of the above, strategies to inhibit PD1 activity to treat various types of cancer and for immunopotentiation (for example, to treat infectious diseases) have been developed (see, for example, Ascierto et al. Clin. Cancer. ResVã (5): 1009-1020 (2013)). In this regard, monoclonal antibodies against PD-1 have been developed for the treatment of cancer (see, for example, Weber, Semin. Oncol., 37 (5): 430-4309 (2010); and Tang et al. Current Oncology Reports, 15 (2): 98-104 (2013)). For example, ο nivolumab (also known as BMS-936558) produced complete or partial responses in non-small cell lung cancer, melanoma and renal cell cancer in a Phase I clinical trial (see, for example, Topalian, New England J. Med., 366: 2443-2454 (2012)), and is
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111/169 currently in Phase III clinical trials. MK-3575 is a humanized monoclonal antibody directed against PD-1 that has shown evidence of antitumor activity in Phase I clinical trials (see, for example, Patnaik et al., 2012 American Society of Clinical Oncology (ASCO), Abstract # 2512). In addition, recent evidence suggests that therapies targeting PD-1 may improve immune responses against pathogens, such as HIV (see, for example, Porichis et al., Curr. HIV / AIDS Rep., 9 (1): 81-90 (2012)). Despite these advances, however, the effectiveness of these potential therapies in humans may be limited.
PD-1 Binding Agents [00263] The present disclosure provides cancer treatment methods that 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 (for example, anti-PD-1 antibody agent) binds to an epitope of PD-1 that blocks the binding of PD1 to any one or more of its putative ligands . In some embodiments, a PD-1 binding agent (e.g., anti-PD-1 antibody agent) binds to a PD-1 epitope that blocks the binding of PD-1 to two or more of its putative ligands. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody agent) binds to an epitope of a PD-1 protein that blocks the binding of PD-1 to PD-L1 and / or PD-L2. The PD-1 binding agents (e.g., anti-PD-1 antibody agents) of the present disclosure can comprise a heavy chain constant region (F _c ) of any suitable class. In some embodiments, the PD1 binding agent (for example, anti-PD-1 antibody) comprises a heavy chain constant region that is based on IgG1, IgG2 or IgG4-type antibodies
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112/169 wild or its variants. In some embodiments, a PD-1 binding agent is a monoclonal antibody.
[00264] In the embodiments, a PD-1 binding agent comprises a heavy chain variable region with one or more CDR sequences selected from SEQ ID NOs: 9, 10 and 11 and / or a light chain variable region with a or more CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, a PD-1 binding agent comprises a heavy chain variable region with two or three CDR sequences selected from SEQ ID NOs: 9 10 and 11 and / or light chain variable region with two or more CDR sequences selected from SEQ ID NOs: 12, 13 and 14. In some embodiments, a PD-1 binding agent comprises a heavy chain variable region with three CDRs that have sequences of SEQ ID NOs: 9, 10 and 11 and / or a variable light chain region with three CDRs that have sequences of SEQ ID NOs: 12, 13 and 14.
SEQ ID NO: 9 (HCDR1) - SYDMS
SEQ ID NO: 10 (HCDR2) - TISGGGSYTYYQDSVKG
SEQ ID NO: 11 (HCDR3) - PYYAMDY
SEQ ID NO: 12 (LCDR1) - KASQDVGTAVA
SEQ ID NO: 13 (LCDR2) - WASTLHT
SEQ ID NO: 14 (LCDR3) - QHYSSYPWT [00265] In some embodiments, a PD-1 binding 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
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEW VSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYY AMDYWGQGTTVTVSSA
SEQ ID NO: 7
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EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEW VSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYY AMDYWGQGTTVTV [00266] In some modalities, a domain ID: a variable domain, a link-agent: a chain-to-agent, an agent
SEQ ID NO: 2
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYW ASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTK LEIKR
SEQ ID NO: 8
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYW ASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTK LIDK [00267] In some modalities, a domain-to-domain: a variable-domain, a domain-to-domain, immunoglobulin light chain variable, whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8. In some embodiments, a PD-1 binding agent is or comprises a humanized immunoglobulin G4 monoclonal antibody (mAb) (lgG4). 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
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114/169 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.
[00268] In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain polypeptide, the amino acid sequence of which comprises SEQ ID NO: 3.
SEQ ID NO: 3 - A heavy polypeptide chain of anti-PD-1 antibody (CDR sequences) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTIS GGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDY WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDK RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQE DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKC KVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV MHEALHNHYTQKSLSLSLGK [00269] In some embodiments, a binding agent to PD-1 comprises a polypeptide of immunoglobulin light chain whose amino acid sequence comprises SEQ ID NO: 4.
SEQ ID NO: 4 - An anti-PD-1 antibody light chain polypeptide (CDR sequences) DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTL HTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYQH
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TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [00270] SEK ID NOs: 3 and 4 anti-human e-chain that uses an anti-human . 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, corresponding to residue 224 in SEQ ID NO: 3. Without wishing to be bound by theory, it is predicted that this point mutation serves to stabilize the articulation of the antibody heavy chain.
[00271] The biopharmaceutical and biochemical characterization of this exemplary humanized monoclonal anti-PD-1 antibody is consistent with the expected disulfide binding pattern for an IgG4 molecule. The residues involved in the expected inter and intrachain disulfide bonds are tabulated below (Tables 1 and 2).
Table 1 - Expected residues involved in disulfide bonds of an exemplary anti-PD-1 antibody heavy chain having an amino acid sequence as shown in SEQ ID NO: 3.
ID of cysteine residue after Edelman ^one HC residue of anti-PD-1 mAb (SEQ ID NO: 3 position) 1 22 II 96 III 130 IV 143 V 199 SAW 222 VII 225 VIII 257 IX 317 X 363
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XI 421
Table 2 - Expected residues involved in disulfide bonds of an exemplary anti-PD-1 antibody light chain having an amino acid sequence as set out in SEQ ID No. 4.
ID of cysteine residue after Edelman ^one LC residue of anti-PD-1 mAb (SEQ ID NO: 4 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: 3). Nglycosylation expressed at this site is a mixture of oligosaccharide species typically 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 3).
Table 3 - Glycan analysis of an antiPD-1 antibody binding agent
Species Abundance (% of total oligosaccharides) Description of Glycan G0 <0.1% Complex type oligosaccharidesnon-fucosylated agalactobiantenary G0F 19.5% Complex type oligosaccharidesfucosylated core agalactobiantenary
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Species Abundance (% of total oligosaccharides) Description of Glycan 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, Male5GlcNAc ₂
[00273] 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: 3 and at least one immunoglobulin light chain having an amino acid sequence as shown in SEQ ID NO: 4. 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: 3 Alternatively or additionally, 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: 4. In some embodiments, an antibody agent anti-PD-1 has a canonical antibody format.
[00274] In some embodiments, a PD-1 binding agent is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab or any of the antibodies disclosed in WO2014 / 179664.
[00275] Pembrolizumab is an anti-PD-1 monoclonal antibody (“mAb”) (also known as MK-3475, SCH 9000475, Keytruda). Pembrolizumab is a humanized mAb of the immunoglobulin G4 / kappa isotype.
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118/169 pembrolizumab's mechanism consists of binding the mAb to the PD-1 lymphocyte receptor to block the interaction of PD-1 with the PD-L1 and PDL2 ligands produced by other cells in the body, including tumor cells of certain types of cancer.
[00276] Similar to pembrolizumab, nivolumab (also known as BMS-936558, Opdivo) was approved by the FDA in 2014 to treat melanoma that cannot be surgically removed or that has metastasized after treatment with ipilimumab and a BRAF inhibitor when appropriate.
[00277] In some embodiments, a PD-1 antibody agent is as disclosed in International Patent Application Publication WO2014 / 179664, the entirety of which is incorporated herein.
[00278] In some embodiments, a heavy chain, light chain and / or antibody agent provided 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.
[00279] 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 encompasses 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).
[00280] The term glycoform is used in this document to refer to a specific form of a glycoprotein. That is, when a
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119/169 glycoprotein includes a particular polypeptide that has the potential to be linked to different glycans or sets of glycans, so each different version of the glycoprotein (that is, where the polypeptide is linked to a specific glycan or set of glycans) 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.
[00281] In some embodiments, a PD-1 ligase binding agent with high affinity to PD cynomolgus monkey and human. In some embodiments, the binding of a binding agent to PD-1 can be characterized by surface plasma resonance (SPR). In some embodiments, SPR measurements can demonstrate or confirm the binding of a PD-1 binding agent to a fusion of human and / or monkey cynomolgus PD-1 Fc. In some embodiments, a PD-1 binding agent binds to human and cynomolgus PD-1 with a fast association rate, slow dissociation rate and high affinity (Table 4). For example, with an exemplary PD-1 binding agent, the binding kinetics of PD of the cynomolgus monkey and human was similar, with a difference less than 2 times in Kd values. In addition, the binding of an exemplary PD-1 binding agent to cynomolgus monkey or human PD-1 expressed in CHO-K1 cells was assessed by flow cytometry. This exemplary anti-PD-1 antibody was determined to bind cynomolgus monkey and human cell surface PD-1 with an ECso of 2.0 and 3.4 nM, respectively.
Table4: Binding of a binding agent to PD-1 (comprising SEQ ID NOs: 1 and 2) to PD-1 as determined by Surface Plasma Resonance and bound to CHO cells expressing PD-1
Kinetic Parameters (SPR) CHO cells expressing PD1
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Kinetic Parameters (SPR) CHO cells expressing PD1 Species Kassociado (Ms) Dissociated K (S ^) K _D (nM) ECso (nM) Human PD-1 5.7x10 ⁵ 1.7x10- ⁴ 0.30 2.0 PD-1 Cyno 4.3x10 ⁵ 2.3x10 ⁴ 0.53 3.4
CHO = Chinese hamster ovary; cyno = monkey cynomolgus, EC ₅ q = effective concentration at half the maximum effect; K _assO c = association rate constant; K _D = dissociation constant; K _d issoc = dissociation rate constant; PD-1 = programmed cell death-1; SPR = surface plasma resonance.
[00282] 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 IgG1 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 a lgG4 isotype control.
[00283] 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), demonstrating increased production of interleukin (IL) -2 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 [00284] In some embodiments, a PD-1 binding agent is expressed from a vector comprising one or more acid sequences
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121/169 nucleic. In some embodiments, a PD-1 binding agent comprises an immunoglobulin heavy chain polypeptide that is encoded by a nucleotide sequence comprising SEQ ID NO: 5.
SEQ ID NO: 5GAG GTG CAG CTG TTG GAG TCT GGG GGA GGC TTG GTA CAG OCT GGG GGG TCC CTG AGA CTC TCC TGT GCA GCC TCT GGA TTC ACT TTC AGT AGC TAT GAC ATG TCT TGG GTC CGC CG GG GAG CC TGG GTC TCA ACC ATT AGT GGT GGT GGT AGT TAC ACC TAC TAT CAA GAC AGT GTG AAG GGG CGG TTC ACC ATC TCC AGA GAC AAT TCC AAG AAC ACG CTG TAT CTG CAA ATG AAC AGC CTG AGA GCC GAG GAC TAC ACG GCG TCC CCT TAC TAT GCT ATG GAC TAC TGG GGG CAA GGG ACC ACG GTC ACC GTC TCC TCA GCA TCC ACC AAG GGC CCA TCG GTC TTC CCG CTA GCA CCC TGC TCC AGG AGC ACC TCC GAG AGC ACA GCC GCC CTG GGC TGC GAC TAC TTC CCC GAA CCA GTG ACG GTG TCG TGG AAC TCA GGC GCC CTG ACC AGC GGC GTG CAC ACC TTC CCG GCT GTC CTA CAG TCC TCA GGA CTC TAC TCC CTC AGC AGC GTG GTG ACC GTG CCC TCC AGC AGC TTG GG ACG TAC ACC TGC AAC GTA GAT CAC AAG CCC AGC AAC ACC AAG GTG GAC AAG AGA GTT GAG TCC AAA TAT GGT CCC CCA TGC CCA CCA TGC CCA GCA CCT GAG TTC CTG GGG GGA CCA TCA GTC TTC CTG TTC CCC CCA AAA CCC A CTC ATG ATC TCC CGG ACC CCT GAG GTC ACG TGC GTG GTG GTG GAC GTG AGC CAG GAA GAC CCC GAG GTC CAG TTC AAC TGG TAC GTG GAT GGC GTG GAG GTG CAT AAT GCC AAG ACA AAG CCG CGG GAG GAG CAG TTC AAC AGC ACG TTC GTG GTC AGC GTC CTC ACC GTC CTG CAC CAG GAC TGG CTG AAC GGC AAG GAG TAC AAG TGC AAG GTC TCC AAC AAA GGC CTC CCG TCC TCC ATC GAG AAA ACC ATC TCC AAA GCC AAA GGG CAG CCC CGA GAG CCA CAG GT GAG 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
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ATC GCC GTG GAG TGG GAG AGC AAT GGG CAG CCG GAG AAC AAC TAC AAG ACC ACG CCT CCC GTG CTG GAC TCC GAC GGC TCC TTC TTC CTC TAC AGC AGG CTA ACC GTG GAC AAG AGC AGG TGG CAG GAG GGG AAT GTC TG GTG ATG CAT GAG GCT CTG CAC AAC CAC TAC ACA CAG AAG AGC CTC TCC CTG TCT CTG GGT AAA [00285] In some embodiments, a PD-1 binding agent comprises an immunoglobulin light chain polypeptide that is encoded by a sequence nucleotide comprising SEQ ID NO: 6.
SEQ ID NO: 6GAC 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 GCC TGG TAT CAG CAA AAA CCA GGG AAA GCC CCT A CTG ATC TAT TGG GCA TCC ACC CTG CAC ACT GGG GTC CCA TCA AGG TTC AGC GGC AGT GGA TCT GGG ACA GAA TTC ACT CTC ACA ATC AGC AGC CTG CAG CCT GAA GAT TTT GCA ACT TAT TAC TGT CAG CAT TAT AGG AGC TAT CCG ACG TTT GGC CAG 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 AA CAG TGG AAG GTG GAT AAC GCC CTC CAA TCG GGT AAC TCC CAG GAG AGT GTC ACA GAG CAG GAC AGC AAG GAC AGC ACC TAC AGC CTC AGC AGC ACC CTG ACG CTG AGC AAA GCA GAC TAC GAG AAA CAC AAA GTC TAC GCC TGA ACC CAT CAG GGC CTC AGC TCG CCC GTC ACA AAG AGC TTC AAC AGG GGA GAG TGT [00286] In some embodiments, a PD-1 binding agent is expressed from a vector comprising one or more sequences those of nucleic acid encoding a PD-1 binding immunoglobulin heavy-chain variable domain polypeptide and / or a PD-1 binding immunoglobulin light-chain variable domain polypeptide. In some
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123/169 embodiments, a PD-1 binding agent is expressed from a vector comprising one or more nucleic acid sequences encoding a PD-1 binding immunoglobulin heavy chain polypeptide and / or a polypeptide from PD-1 binding immunoglobulin light chain. The vector can be, for example, a plasmid, episome, cosmid, viral vector (e.g., retroviral or adenoviral) or phage. Vectors and suitable vector preparation methods are well known in the art (see, e.g., Sambrook et al., Cloning Molecular, 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)).
[00287] In some embodiments, the vector (s) for expression of PD-1 binding agents further comprises expression control sequences, such as promoters, enhancers, polyadenylation signals, transcription terminators, internal sites of ribosome entry (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).
[00288] The vector (s) comprising the nucleic acid (s) encoding PD-1 binding agents of the present disclosure can be introduced ( s) in a host cell that is capable of expressing the polypeptides encoded by means of these (s), 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.
[00289] In some embodiments, mammalian cells are used.
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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 No. 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 No. CRL1573) and 3T3 cells (ATCC No. CCL92). Other suitable mammalian cell lines are monkey cell lines COS-1 (ATCC No. CRL1650) and COS-7 (ATCC No. CRL1651), as well as the CV-1 cell line (ATCC No. CCL70).
[00290] 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.
[00291] In some embodiments, the mammalian cell is a human cell. 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.
[00292] In some embodiments, a PD-1 binding agent is formulated as a pharmaceutical composition, containing one or one
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125/169 combination of monoclonal antibodies, or antigen-binding portions thereof, formulated with a pharmaceutically acceptable carrier. An anti-PD-1 antibody agent can be formulated alone or in combination with other drugs (for example, as an adjuvant). For example, a PD-1 binding agent can be administered in combination with other agents for the treatment or prevention of the diseases disclosed in this document (for example, cancer).
[00293] 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 may be useful 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.
[00294] 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 methods
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126/169 of the preparation may include vacuum drying and freeze drying (lyophilization) to produce a powder of the active ingredient plus any additional desired ingredient from a previously filtered sterile solution thereof.
[00295] 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 (for example, a citrate buffer). In some embodiments, the composition comprises a PD-1 binding agent and two or more of the following: citrate, arginine, sodium chloride and polysorbate 80.
[00296] In some embodiments, a therapeutic composition of the present disclosure (for example, a PD-1 binding agent) is aseptically filled into a clear glass bottle. In some embodiments, such a glass bottle is capped with a chlorobutyl elastomer stopper laminated with fluoropolymer and sealed with an aluminum cap.
[00297] In some embodiments, a PD-1 binding agent is stored at 2-8 ° C. In some embodiments, a drug product of the present disclosure is free of preservatives.
General Protocol [00298] As described in this document, the methods provided comprise administering a PD-1 binding agent to a patient, a subject, or a population of subjects, according to a regimen that achieves a clinical benefit.
[00299] The methods provided can provide several benefits (for example, a clinical benefit). In the modalities, a method described in this document achieves a clinical benefit. 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).
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127/169 [00300] In the modalities, a combination therapy achieves a clinical benefit for each therapy administered to a patient. For example, a combination therapy can improve a clinical benefit obtained with a PD-1 inhibitor (for example, any anti-PD-1 antibody described in this document).
[00301] In the modalities, a patient or subject is an animal. In the modalities, a patient or subject is a human.
[00302] In some embodiments, the regimen comprises at least one parenteral dose of a PD-1 binding agent. In some embodiments, the regimen comprises a plurality of parenteral doses.
[00303] In some embodiments, the parenteral dose is an amount of a PD-1 binding agent within the range of about 5 to about 5000 mg (for example, about 5 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, or a range defined by any two of the previous values). In some embodiments, the parenteral dose of a PD-1 binding agent is 500 mg or 1000 mg.
[00304] In some modalities, the dose is in an amount relative to body weight. In some embodiments, the parenteral dose of a PD-1 binding 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 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
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128/169 of 10 mg / kg, about 12 mg / kg, about 15 mg / kg, about 20 mg / kg or a range defined by any of the two above).
[00305] In some embodiments, a composition that delivers a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered to a patient at a dose of about 1, 3 or 10 mg / kg. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that delivers 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) is administered according to a regimen that delivers 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 delivers 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) is administered according to a regimen that delivers a dose of about 1 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 delivers a dose of about 3 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 delivers a dose of about 10 mg / kg every three weeks.
[00306] In some embodiments, a composition that delivers a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered to a patient at a dose of about 400 mg. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of about 400 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 delivers a dose of about 400 mg every three weeks. In some
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129/169 modalities, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that delivers a dose of about 400 mg every four weeks.
[00307] In some embodiments, a composition that delivers a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered to a patient at a dose of about 500 mg. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of about 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 delivers 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 delivers a dose of about 500 mg every four weeks.
[00308] In some embodiments, a composition that delivers a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered to a patient at a dose of about 800 mg. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of about 800 mg 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 delivers a dose of about 800 mg every four weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that delivers a dose of about 800 mg every six weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of about 800 mg every eight weeks.
[00309] In some embodiments, a composition that delivers a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered
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130/169 to a patient at a dose of about 1,000 mg. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of about 1,000 mg 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 delivers a dose of about 1,000 mg every four weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that delivers a dose of about 1,000 mg every five weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of about 1,000 mg every six weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of about 1,000 mg every seven weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that delivers a dose of about 1,000 mg every eight weeks. In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a dose of about 1,000 mg every nine weeks.
[00310] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers 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 delivers a dose of about 1000 mg every six weeks.
[00311] In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that delivers a first dose of PD-1 binding agent during the first few 2-6 dosing cycles (for example, the first 3, 4 or 5 dosing cycles)
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131/169 and then administer a second dose of a PD-1 binding agent in subsequent dosing cycles until therapy is discontinued (for example, due to disease progression or an adverse effect or as directed by a physician). In some embodiments, the duration of the first set of 2-6 dosing cycles (for example, the first 3, 4 or 5 dosing cycles) is different from the duration of the subsequent dosing cycles. In the embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that provides a first dose of PD-1 binding agent once every three weeks for the first few weeks. three dosing cycles, and then provides a second dose of PD-1 binding agent once every six weeks or more during the remaining dosing cycles (for example, a second dose of PD-1 binding agent one every six weeks during the remaining dosing cycles). In the embodiments, a PD-1 binding agent (for example, an antiPD-1 antibody) is administered according to a regimen that provides a first dose of PD-1 binding agent once every three weeks for the first few weeks. four dosing cycles, and then provides a second dose of PD-1 binding agent once every six weeks or more during the remaining dosing cycles (for example, a second dose of PD-1 binding agent one every six weeks during the remaining dosing cycles). In the embodiments, a PD-1 binding agent (for example, an antiPD-1 antibody) is administered according to a regimen that provides a first dose of PD-1 binding agent once every three weeks for the first few weeks. five dosing cycles, and then delivers a second dose of PD-1 binding agent every six weeks or for the remaining dosing cycles (for example, a second dose of PD-1 binding agent once every six weeks during the remaining dosing cycles). In some embodiments, a PD-1 binding agent (for example, an anti-PD1 antibody) is administered according to a regimen that delivers a first dose
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132/169 PD-1 binding agent once every three weeks for the first 2-6 dosing cycles (eg, the first 3, 4 or 5 dosing cycles) and then administering a second dose of a PD-1 binding agent binding to PD-1 once every six weeks or until therapy is discontinued (for example, due to disease progression or an adverse effect, or as directed by a physician). In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that provides a first dose of a PD-1 binding agent every three weeks for the first 3, 4 or 5 dosing cycles (for example, the first 4 dosing cycles) and then administering a second dose of a PD-1 binding agent once every six weeks or more until therapy is discontinued (for example, due to disease progression or an adverse effect, or as directed by a doctor). In the embodiments, the method comprises administering a second dose of PD-1 binding agent once every six weeks until therapy is discontinued.
[00312] In some embodiments, the first and / or second dose of a PD-1 binding agent (for example, an anti-PD-1 antibody) is from about 100 mg to about 2,000 mg (for example, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg ). In some embodiments, the first dose and the second dose are the same. In some embodiments, the first dose and the second dose are different. In the embodiments, the first dose is about 500 mg of a PD-1 binding agent (for example, an anti-PD-1 antibody). In the embodiments, the first dose is about 1000 mg of a PD-1 binding agent (for example, an anti-PD-1 antibody).
[00313] In some embodiments, a PD-1 binding agent (for example,
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133/169 example, a PD-1 binding antibody) 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 a dose of 1,000 mg 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 binding agent (for example, an anti-PD-1 antibody) is administered according to a dosage regimen that includes 500 mg over 4 Q3W cycles followed by 1000 mg Q6W.
[00314] In some embodiments, a PD-1 binding agent (for example, a PD-1 binding antibody) is administered according to a regimen comprising administering a dose of about 400 mg every 3 weeks for four doses, followed by administration of at least one 800 mg dose every six weeks after the fourth 400 mg dose. In some modalities, additional doses of 800 mg are administered every six weeks or more after the first dose of 800 mg, until no further clinical benefit is achieved. In some particular embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a dosage regimen that includes 400 mg over 4 Q3W cycles followed by 800 mg Q6W.
[00315] 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 can be 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.
[00316] The desired dosage can be applied by a single bolus administration of the composition, by multiple bolus administrations
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134/169 of the composition, or by administering continuous infusion of the composition.
[00317] In some embodiments, the PD-1 binding 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.
[00318] In some embodiments, the PD-1 binding agent is administered to a patient or population of subjects who have 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.
[00319] 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 the modalities, a method described in this document sensitizes the subject to treatment with an agent that inhibits PD-1.
[00320] In the embodiments, a PD-1 binding 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 a PD-1 binding agent and one or more additional therapies are administered to a subject in such a way that the subject receives each therapy.
[00321] In the modalities, an additional therapy is surgery. In the modalities, an additional therapy is radiotherapy. In modalities, an additional therapy is chemotherapy. In the modalities, an additional therapy is immunotherapy.
[00322] In some embodiments, a PD-1 binding 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 gene 3 of lymphocyte activation (LAG-3) or mucin domain 3 protein and T cell immunoglobulin (TIM-3)) and / or a
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135/169 chemotherapeutic agent (for example, niraparib). In some embodiments, a PD-1 binding agent is administered before, during or after the administration of an additional therapeutic agent. In some embodiments, a PD-1 binding agent is administered before, during or after administration of a chemotherapeutic agent (for example, niraparib).
[00323] An anti-PD-1 antibody agent can be administered alone or in combination with other drugs (for example, as an adjuvant). For example, the PD-1 binding 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, the PD-1 binding agent can be used in combination with at least one other anticancer agent including, for example, any chemotherapeutic agent known in the art, ionization radiation, small molecule anticancer agents, vaccines against cancer, biological therapies (for example, other monoclonal antibodies, cancer killing viruses, gene therapy and adoptive T cell transfer) and / or surgery.
[00324] The administration of a PD-1 binding agent simultaneously or sequentially with an additional therapeutic agent (for example, a chemotherapeutic agent) is called "combination therapy". In combination therapy, the PD-1 binding 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, 3 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 PD-1 binding agent
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136/169 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 4 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 interval, 11 hours to 12 hours interval, with a maximum interval of 24 hours or with a maximum interval of 48 hours.
PARP inhibitors [00325] In the modalities, an additional therapy is a poly (ADP-ribose) polymerase (PARP) inhibitor.
[00326] In the modalities, a PARP inhibitor inhibits PARP-1 and / or PARP-2. In some embodiments, the agent is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, or a toxin. In the related modalities, the agent is ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib (SHR 3162), IMP 4297, INO1001, JPI 289, JPI 547 , 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. 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.
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137/169 [00327] Niraparib, (3S) -3- [4- {7- (aminocarbonyl) -2H-indazol-2yl} phenyl] piperidine, is a poly (adenosine diphosphate [ADP] ribose) (PARP) 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.
[00328] 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.
[00329] 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:
Θ
[00330] Niraparib is a potent and selective inhibitor of PARP-1 and PARP-2 with an inhibitory concentration at 50% of the control (ICso) = 3.8 and 2.1 nM, respectively, and is at least 100 times selective in other members of the PARP family. Niraparib inhibits PARP activity, stimulated as a result of DNA damage caused by the addition of hydrogen peroxide, in various cell lines with ICso and inhibitory concentration at 90% of the control (IC90) of about 4 and 50 nM, respectively.
[00331] In the modalities, 0 niraparib is administered in a dose
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138/169 equivalent to about 100 mg of niraparib free base (e.g., a pharmaceutically acceptable salt of niraparib, such as niraparib tosylate monohydrate, is administered in a dose equivalent to about 100 mg of niraparib free base). In the 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 the embodiments, niraparib is administered in a dose equivalent to about 300 mg of niraparib free base (for example, a pharmaceutically acceptable salt of niraparib tai as niraparib monohydrate tosylate is administered in a dose equivalent to about 300 mg niraparib free base).
Checkpoint inhibitors [00332] In the modalities, an additional therapy is an immunotherapy. In the 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).
[00333] 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-PD-1 therapy described in this document.
[00334] In the modalities, a checkpoint inhibitor is a small molecule, a nucleic acid, a polypeptide (for example, an antibody), a
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139/169 carbohydrate, a lipid, a metal, a toxin or a binding agent. In the embodiments, a checkpoint inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof.
[00335] In the modalities, an immunological checkpoint inhibitor is an agent that inhibits TIM-3, CTLA-4, LAG-3, TIGIT, IDO or CSF1R.
[00336] In the modalities, an immunological checkpoint inhibitor is a TIM-3 inhibitor. In the embodiments, a TIM-3 inhibitor is a TIM-3 binding agent (for example, an antibody, an antibody conjugate or an antigen binding fragment thereof). In the embodiments, a TIM3 inhibitor is a TIM-3 inhibitor described in WO 2016/161270, which is incorporated herein by reference in its entirety. In the embodiments, a TIM-3 inhibitor is TSR-022. For example, a TIM-3 inhibitor (for example, TSR-022) can be administered at a dose of about 1.3 or 10 mg / kg (for example, about 1 mg / kg; about 3 mg / kg) kg; or about 10 mg / kg) or a fixed dose between 100 - 1500 mg (for example, a fixed dose of about 100 mg; a flat dose of about 200 mg; a flat dose of about 300 mg; a flat dose of about 400 mg, fixed dose of about 500 mg, flat dose of about 600 mg, flat dose of about 700 mg, flat dose of about 800 mg, flat dose of about 900 mg, dose flat dose of about 1000 mg flat dose of about 1100 mg flat dose of about 1200 mg a fixed dose of about 1300 mg, a fixed dose of about 1400 mg, or a flat dose of about 1500 mg).
[00337] In the embodiments, an immunological checkpoint inhibitor is a CTLA-4 inhibitor (for example, an antibody, antibody conjugate or antigen-binding fragment thereof). In the 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 the embodiments, a CTLA-4 inhibitor is a small molecule. In the embodiments, a CTLA-4 inhibitor is a binding agent to
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CTLA-4. In the embodiments, a CTLA-4 inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof. In the embodiments, a CTLA-4 inhibitor is ipilimunab (Yervoy), AGEN1884 or tremelimumab.
[00338] In the embodiments, 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 the embodiments, a LAG-3 inhibitor is a small molecule. In the embodiments, a LAG-3 inhibitor is a LAG-3 binding agent. In the embodiments, a LAG-3 inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof. In the 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.
[00339] In the embodiments, an immunological checkpoint inhibitor is a TIGIT inhibitor (for example, an antibody, an antibody conjugate or an antigen-binding fragment thereof). In the 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 the modalities, a TIGIT inhibitor is a small molecule. In the embodiments, a TIGIT inhibitor is a TIGIT binding agent. In the embodiments, a TIGIT inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof. In the embodiments, a TIGIT inhibitor is MTIG7192A, BMS-986207 or OMP-31M32.
[00340] In the modalities, an immunological checkpoint inhibitor is an IDO inhibitor. In the modalities, an IDO inhibitor is a small molecule,
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141/169 a nucleic acid, a polypeptide (for example, an antibody), a carbohydrate, a lipid, a metal, or a toxin. In the embodiments, an IDO inhibitor is a small molecule. In the embodiments, an IDO inhibitor is an IDO binding agent. In the embodiments, an IDO inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof.
[00341] In the modalities, an immunological checkpoint inhibitor is a CSF1R inhibitor. In the 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 the embodiments, a CSF1R inhibitor is a small molecule. In the embodiments, a CSF1R inhibitor is a CSF1R binding agent. In the embodiments, a CSF1R inhibitor is an antibody, antibody conjugate or antigen-binding fragment thereof.
[00342] In the modalities, a checkpoint inhibitor (for example, a TIM-3 inhibitor such as TSR-022) can be administered at a dose of about 1.3 or 10 mg / kg (for example, about 1 mg / kg; about 3 mg / kg; or about 10 mg / kg) or a fixed dose between 100 - 1500 mg (for example, 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).
[00343] In the embodiments, an anti-PD-1 agent is administered in combination with at least one additional immune checkpoint inhibitor or at least two or at least three additional immune checkpoint inhibitors. In the embodiments, a PARP inhibitor is additionally administered.
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142/169 [00344] In the embodiments, an anti-PD-1 agent is administered in combination with a TIM-3 inhibitor and an LAG-3 inhibitor. In the embodiments, an anti-PD-1 agent is administered in combination with a TIM-3 inhibitor, a LAG-3 inhibitor and a CTLA-4 inhibitor.
[00345] In the embodiments, an anti-PD-1 agent is administered in combination with a LAG-3 inhibitor and a PARP inhibitor (for example, niraparib). In the embodiments, an anti-PD-1 agent is administered in combination with a TIM-3 inhibitor, a LAG-3 inhibitor and a PARP inhibitor (for example, niraparib).
[00346] 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 a PD-1 binding agent. It is also preferable for female patients of childbearing potential and male patients to 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.
Measuring Tumor Response [00347] 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
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143/169 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.
[00348] 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.
[00349] 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 al., “New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.),” Eur. J. of Cancer, 45: 228-247 (2009), which is incorporated by reference in its entirety. In some modalities, the RECIST guidelines can serve as a basis for all protocol guidelines related to the state of the disease. In some modalities, the RECIST guidelines are used to assess the tumor response to treatment and / or the date of disease progression.
[00350] The RECIST guidelines first require estimating the total tumor load at baseline, which is 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 .
[00351] When more than one measurable lesion is present in the
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144/169 beginning, 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 measured at baseline (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).
[00352] 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.
[00353] 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 criterion of a short axis of P15 mm 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 involved in 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 acquisition plane can be axial, sagittal or coronal). The smallest of these measures is the short axis.
[00354] 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.
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145/169 [00355] A sum of diameters (the longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the sum diameters of the baseline. If lymph nodes are to be included in the sum, then, as noted above, only the short axis is added to the sum. The sum 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.
[00356] 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).
[00357] 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 CT or MRI) for non-nodal lesions and greater than or equal to 15 mm for nodal lesions, or at least 20 mm by radiography of chest.
[00358] 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
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4958 and Nishino et al., (2013) Clin. Cancer Res. 19 (14): 3936-43.
[00359] 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 [00360] 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.
[00361] In some modalities, a patient population includes one or more subjects ("a population of subjects") suffering from metastatic disease.
[00362] In some modalities, a patient population includes one or more subjects who are suffering from or are susceptible to cancer. In some embodiments, cancer is head and neck cancer, lung cancer (eg, non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, cell carcinoma Merkel, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, uterine tube cancer, breast cancer, prostate cancer, gland tumor
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147/169 salivary, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma or squamous cell carcinoma (for example, of the lung; from the region; anogenital, including anus, penis, cervix, vagina or vulva, or esophagus). In some modalities, the cancer is endometrial cancer, NSCLC, kidney cancer, melanoma, cervical cancer, squamous cell carcinoma (for example, lung) or 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.
[00363] In some embodiments, pharmacokinetic parameters can be any suitable parameters to describe the present composition. For example, in some embodiments, Cmax 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 Cmax to describe a pharmacokinetic profile of a PD-1 binding agent.
[00364] In some modalities, Tmax 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 Tmax to describe a pharmacokinetic profile of a PD-1 binding agent.
[00365] In general, AUC as described in this document is the measure of
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148/169 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.
[00366] 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, 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, a binding agent to PD-1). In some embodiments, a PD-1 binding agent (for example, an anti-PD-1 antibody) is administered according to a regimen that has been shown to achieve an average AUCo-336h of the concentration-time curve of the binding agent PD-1 in a patient population ranging from 2500 h * pg / mL to 50,000 h * pg / mL. In some modalities, the regimen has been shown to achieve an average AUCo-336h of the concentration-time curve of the PD-1 binding agent in a patient population that is about 3400 h * pg / mL, about 11000 h * pg / ml or about 36800h * pg / ml.
[00367] In some embodiments, the AUC of 0 hours at the end of the dosing period is determined (AUC (o-Tau)). In some modalities, the period of
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149/169 dosage 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 dosage period is 3 weeks. In some embodiments, the dosing period is six weeks.
[00368] In some embodiments, a PD-1 binding agent 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 disease progressive 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.
[00369] In some embodiments, a PD-1 binding agent is administered according to a regimen that is sufficient to achieve an average PD-1 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 provides a PD-1 binding agent is sufficient to achieve an average PD-1 receptor occupancy of at least 85% after 3 days after a single dose of the composition.
[00370] In some embodiments, a PD-1 binding agent is administered according to a regimen sufficient to achieve an average stimulation ratio of at least 1 in a functional PD-1 receptor occupation trial after 3 days after a single dose of PD-1 binding agent.
[00371] In some embodiments, a PD-1 binding agent is administered according to a regimen that is sufficient to achieve an average PD-1 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 PD-1 binding agent. In some embodiments, a PD-1 binding agent is administered according to a regimen sufficient to achieve an average PD-1 receptor occupancy of at least
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150/169 minus 75% over the first period of time (e.g., about 15 days to about 60 days; in some embodiments, about 29 days) after a single dose of the PD-1 binding agent.
[00372] In some embodiments, a PD-1 binding agent is administered according to a regimen that is sufficient to achieve an average stimulus ratio of at least 1 in a functional PD-1 receptor occupancy assay over from a first period of time, for example, about 14 days to about 60 days after a single dose of the PD1 binding agent. In some embodiments, a PD-1 binding agent is administered according to a regimen sufficient to achieve an average stimulus ratio of at least 1 in a functional PD-1 receptor occupation assay over the first period of time ( for example, about 15 days to about 60 days; in some embodiments, about 29 days) after a single dose of the PD-1 binding agent.
EXAMPLES [00373] The following examples are provided to illustrate, but not to limit, the claimed invention.
Example 1. Dosage Regimens for an Exemplary PD-1 Binding Agent [00374] This example describes a Phase 1, multicenter, open-label, first-administration study in humans, evaluating a PD-1 binding agent (an antibody anti-PD-1), in patients with tumors. Specifically, this example describes the dosage effects of treatment with a particular PD-1 binding agent on patients, and in particular patients with advanced solid tumors or solid metastatic tumors. A PD1 binding agent as described in the present study comprises a humanized anti-PD-1 monoclonal antibody. Specifically, a particular PD-1 binding agent comprising a heavy chain variable region comprising CDR sequences of SEQ ID NOs: 9, 10 and 11 and a region
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151/169 light chain variable comprising CDR sequences of SEQ ID NOs: 12, 13 and 14. This exemplary anti-PD-1 antibody uses a human IGHG4 * 01 heavy chain gene and an IGKC kappa light chain gene * 01 human, like 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.
[00375] 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).
[00376] This study comprises 2 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-PD-1 antibody. A 3 + 3 model was used for dose escalation at 1 mg / kg, 3 mg / kg and 10 mg / kg every 2 weeks (Q2W). The dose increase continued until a dose administered to a maximum of 10 mg / kg Q2W and an BAT was not identified. No DLT was observed. Preliminary safety findings indicate that the exemplary PD-1 binding agent is safe and well tolerated.
[00377] Part 2 of the study aims, inter alia, to assess the safety and tolerability profile, PK and PDy of the anti-PD-1 antibody in fixed doses of 400 mg or 500 mg administered every 3 weeks (Q3W) and 800 mg or 1000 mg administered every 6 weeks (Q6W) using a modified 6 + 6 model. Part 2 of this study assesses the effects in patients who have certain types of tumor, such as: endometrial cancer in separate cohorts consisting of MSS and MSI-H tumors, triple negative breast cancer, ovarian cancer, NSCLC and squamous cell carcinoma the anogenital region (for example, squamous cell carcinoma of the anus, penis, cervix, vagina or vulva).
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152/169 [00378] Pharmacokinetic parameters of a PD-1 binding agent in patients who received different doses were determined. As described in this document, at least 18 patients were included in the study, with at least 12 subjects in the dose-limiting toxicity assessment (DLT) cohorts and at least 6 subjects in the PK / PDy cohorts. The clearance of a PD-1 binding agent was determined in patients after a single IV infusion. The administration was made by means of an infusion of 30 minutes. The mean serum log-linear concentrations as a function of time after a single dose of anti-PD-1 antibody at concentrations of 1 mg / kg, 3 mg / kg and 10 mg / kg are shown in Figure 1 and Figure 2, panel THE.
[00379] This treatment with anti-PD-1 antibody exhibited dose-proportional PK in all tested dosing groups, see Table 5. Average cmax was approximately 21, 66 and 224 pg / mL and average AUCo-336h was approximately 3378 , 10999 and 39303 h * pg / mL for dose levels 1, 3 and 10 mg / kg, respectively. The maximum serum concentration time ranged from 0.5-3 hours for all three treatment groups, with a median of 1.5 hours. The average clearances were 0.201, 0.117 and 0.152 mL / h / kg for dose groups of 1, 3 and 10 mg / kg, respectively. The terminal half-life ranged from approximately 201 to 438 hours. In addition, as shown in Figure 3, an exemplary anti-PD-1 antibody exhibited exposure, as assessed by Cmax and AUC, which was linearly proportional to the dose.
Table 5: Average of the Pharmacokinetic Parameters for PD-1 Binding Agent Treatment Groups (with a heavy chain variable region comprising CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region comprising sequences of CDR of SEQ ID NOs: 12, 13 and 14) after intravenous infusion in patients.
Dose Cmax C336h tmax tl / 2 AUCo-336h Vss CL (mg / kg) (pg / mL) (pg / mL) (H) (H) (h x pg / mL) (mL / kg) (mL / h / kg) 1 mg / kg 21.4 ± 4.43 5.99 ± 2.38 1.5 311 ± 149 3378 ± 1141 74.2 ± 23.7 0.201 ± 0.121
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Dose(mg / kg) Cmax(pg / mL) C336h(pg / mL) tmax(H) tl / 2(H) AUCo-336h(h x pg / mL) Vss(mL / kg) CL(mL / h / kg) (n = 6) (0.5-3.0) 3 mg / kg(n = 3) 66.4 ± 6.25 23.4 ± 1.52 1.5(1.5-3.0) 438 ± 114 10,999 ± 841 71.7 ± 11.4 0.117 ± 0.010 10 mg / kg(n = 11) 244 ± 52.7 76.6 ± 25.1 1.5(1.5-3.0) 317 ± 155 39,303 ± 10,301 60.7 ± 16.6 0.152 ± 0.052
Abbreviations: AUCo-336h = area under the concentration curve versus time from 0 to 336 hours; C336h = concentration at 336 hours; CL = clearance; C _m max = maximum concentration; n = number; PD-1 = programmed cell death-1; SD = standard deviation; tv ₂ = half-life; t _max = time to reach the maximum concentration; V _ss = volume of distribution at steady state. Note: The data are presented as the mean ± SD for the values of Cmax, C ₃ 36h, ti / ₂ , AUCo-336h, V _ss and CL and median (range) for the values of t _max .
[00380] After repeated doses of a PD-1 binding agent in two-week cycles (Q2W), the PK profiles of 2 patients in the 1 mg / kg group and 2 patients in the 3 mg / kg group reached the state stationary after 3 doses. The accumulation ratio based on the concentration at the end of the dosing interval (Cmínima) ranged from 1.45 to 2.93.
[00381] For the selection of fixed doses, a two-compartment model was used to describe the observed PK data and predict the appropriate dose and regimen. The effect of body weight on the clearance of a PD-1 binding agent was also explored. Body weight over a range of 45 kg to 146 kg was not seen as a significant covariant for clearance (see Figure 4). Complete receptor occupation was achieved at serum concentrations of anti-PD-1 antibody of 2.43 pg / ml and above. The expected minimum of the model at steady state for the 500 mg Q3W and 1000 mg Q6W were 51.1 and 29.2 pg / mL with a 90% confidence interval of (13.4, 111.1) and (4.1 , 78.5), respectively. The projected average and 90% less bound of Cmínima at 500 mg Q3W and 1000 mg Q6W were around 21.0 and 12.0; 5.5 and 1.7 times higher than the level required for the complete occupation of the receiver
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154/169 of peripheral blood cells. The evaluation of dose data and steady-state regimens are provided in Table 6 below.
Table 6: Pharmacokinetic parameters for different treatment regimens with a PD-1 binding agent (with a heavy chain variable region comprising CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region comprising sequences of CDR of SEQ ID NOs: 12, 13 and 14).
| gj | ÍÍ | giiliBiiiliíug / mLjsis ®Í® · 400 mg Q3W 40.9 (10.7, 88.9) 142.9 35864 500 mg Q3W 51.1 (13.4, 111.1) 181.7 45445 800 mg Q6W 23.4 (3.3, 62.8) 230.8 66469 1000 mgQ6W 29.2 (4.1, 78.5) 291.8 90848
[00382] These data support a fixed dosage, including 400mg, 500mg, 800mg and / or 1000mg.
[00383] Clearance of a PD-1 binding agent after a single dose of 500 mg and 1000 mg is determined. Linear mean serum concentration in log versus time following a single dose of anti-PD-1 antibody at concentrations of 500 mg and 1000 mg are shown in Figure 2, panel B, and single dose pharmacokinetic summaries are provided in Table 7 below . The average maximum concentration was approximately 174 and 322 pg / mL for 500 mg Q3W and 1000 mg Q6W, respectively; the averages of the area under the concentration versus time curve from 0 to 504 hours (AUCo-5O4h) and AUCo-wosh were approximately 36,424 and 91,376 hxpg / mL, respectively. The peak serum concentration time ranged from 0.5 to 3.0 hours for both treatment groups, with the median at 1.0 and 1.5 hours, respectively. Exemplary serum concentrations of the PD-1 binding agent observed 3 weeks after the 500 mg dose
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155/169 were comparable to those seen 6 weeks after the 1000 mg dose.
Table 7: Average of Pharmacokinetic Parameters for PD-1 Binding Agent Fixed Dose Treatment Groups (with a heavy chain variable region comprising CDR sequences of SEQ ID NOs: 9, 10 and 11 and a variable chain region light comprising CDR sequences of SEQ ID NOs: 12, 13 and 14) after intravenous infusion in patients.
Dose(mg / kg) Cmax(pg / mL) Last(pg / mL) tmax(H) AUCo-last(h x pg / mL) 500 mg(n = 6) 174 ± 35.2 40.2 ± 9.31 1.0(0.5-3.0) 36,424 ± 6674 1000 mg(n = 7) 322 ± 101 43.7 ± 18.2 ^a 1.5(0.5-3.0) 91,376 ± 26,808 AUCo-ultima = area under the concentration curve versus time from 0 to 504 hours (500 mg cohort) or with / without 1008 extrapolated hours (1000 mg cohort); Cuitima = last measurable plasma concentration; C _m max = maximum concentration; n = number; Q3W = every 2 weeks; Q6W = every 6 weeks; SD = standard deviation; t _max = time to reach the maximum concentration; the data are presented as the mean ± SD for C _m á _X , Ο _ύΒΜ , AUCo-last, values and median (interval) for t _max values C _m á _X was measured in 504 hours for the 500 mg group Q3W and 1008 hours for the 1000 mg Q6W group. ^a n = 5
Example 2. Target PD-1 Coupling of an Exemplary PD-1 Binding Agent [00384] This example describes the ability of an exemplary PD-1 binding agent, that is, a humanized anti-PD-1 monoclonal antibody , in attaching to its target (for example, the PD-1 receptor). Specifically, an exemplary anti-PD-1 antibody comprising a heavy chain variable region comprising the CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region comprising CDR sequences of SEQ ID NOs: 12 , 13 and 14. The target coupling of an antiPD-1 antibody agent was determined by measuring the PD-1 receptor occupation in the blood
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156/169 peripheral patients after a first dose with an anti-PD-1 antibody agent. Two assays were employed: the first assay, called conventional receptor occupation (cRO), provides a measurement of the direct binding of the anti-PD-1 antibody agent to CD3 + cells, and the second assay, called functional receptor occupation (fRO) , measures the production of IL-2 by T cells stimulated ex vivo after administration of the antiPD-1 antibody agent.
Results of the cRO Assay [00385] To measure direct binding in the cRO assay, PBMCs were isolated from patients at baseline, as well as on Days 3 and 15 after administration of a first dose of the anti-PD-1 antibody agent. In addition, additional samples from certain patients were collected on Days 22 and 29 after the first dose. The occupation of the PD-1 receptor by an anti-PD-1 antibody agent in circulating CD3 + T cells was measured by flow cytometry.
[00386] After a single dose of the anti-PD-1 antibody agent at 1 mg / kg, 3 mg / kg or 10 mg / kg, the average occupancy percentage on Day 3 by all dose levels was about 90%. Consistent with published data for nivolumab (Brahmer et al., 2010), an average occupancy of approximately 80% is maintained for all the first 29 days after a single dose at 1 mg / kg (Table 8; data limit 30 of September 2016)
Table 8: Average Occupancy Rate of PD-1 for Anti-PD-1 antibody agent in CD3 + Cells at Dose Levels 1.3 and 10 mg / kg
Dose Percentage of Occupation of PD-1 Mean ± SD (N) Initial assessment Day 3 Day 15 Day 22 Day 29 1 mg / kg 3.23 ± 3.12(6) 95.6 ± 17.1(6) 84.3 ± 4.27(6) 82.8 ± 3.67(3) 77.8 ±0.514(2)
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Dose Percentage of Occupation of PD-1Mean ± SD (N) Initial assessment Day 3 Day 15 Day 22 Day 29 3 mg / kg 5.75 ± 1.72(3) 88.0 ± 5.42(3) 85.9 ± 2.49(3) ND ND 10 mg / kg 2.42 ±0.898(5) 86.9 ± 4.08(5) 85.8 ± 7.45(3) ND ND Abbreviations: CD = cluster of d iferientation; n = number; N D = no data available;
PD-1 = programmed cell death-1; SD = standard deviation.
[00387] Results for receptor occupation assessed for dosage at the dosage levels of 1.3 and 10 mg / kg of the exemplary PD1 binding agent are also shown in Figure 5, panel A.
[00388] Additionally, PD-1 receptor occupation, as assessed above, was maintained over three and six weeks for fixed dosage levels of 500 mg in Q3W (n = 6) and 1000 mg in Q6W (n = 7 ), respectively. The results for the occupation of the exemplary PD-1 binding agent receptor at the dose levels of 500 mg and 1000 mg are shown in Figure 6, panels A and C, respectively.
Results of the fRO Assay [00389] To obtain a functional reading of receptor occupation in the fRO assay, whole blood was collected at the initial assessment, as well as on Days 3 and 15 after the first dose. Additionally, in certain patients, samples were additionally collected on Days 22 and 29 after the first dose. The occupation of the PD-1 receptor by the anti-PD-1 antibody agent in circulating T cells was measured as a function of IL-2 production after ex vivo stimulation with the staphylococcal enterotoxin B superantigen (SEB) in the presence of saturating concentrations of the anti-PD-1 antibody agent or isotype control (Patnaik et al., 2015). In this assay, an IL-2 ratio of 1 reflects stimulation close to maximum stimulation and is reflective of maximum occupancy
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158/169 of the receiver.
[00390] After a single dose of the anti-PD-1 antibody agent, an average IL-2 stimulation ratio of 1 is achieved on Day 3 for all dose levels. An average IL-2 ratio of approximately 1 is maintained at 29 days after a single dose at 1 mg / kg (Table 9).
Table 9: Average IL-2 Stimulation Ratio in the fRO Assay at Dose Levels of 1.3 and 10 mg / kg of anti-PD-1 Antibody Agent
Dose Percentage of PD-1 Occupancy Average ± SD (n =) Initial assessment Day 3 Day 15 Day 22 Day 29 1 mg / kg 1.69 ±0.241(6) 1.01 ± 0.073(6) 1.00 ± 0.0513(6) 1.32 ±0.276(2) 1.08 ±0.064(2) 3 mg / kg 1.62 ±0.236(3) 0.927 ± 0.0473(3) 0.977 ± 0.0702(3) ND ND 10 mg / kg 1.86 ±0.547(4) 1.05 ± 0.0603(3) 0.860(1) ND ND
[00391] Results for stimulation of IL-2 for dosage at dose levels of 1, 3 and 10 mg / kg of the exemplary PD-1 binding agent are also shown in Figure 5, panel B. Additionally, stimulation of exemplary PD-1 binding agent IL-2 at 500 mg in Q3W (n = 6) and 1000 mg in Q6W (n = 7) are shown in Figure 6, panels B and D, respectively.
[00392] The receptor occupation and IL-2 stimulation experiments demonstrate that the antibody agent against PD-1 binds completely to PD-1 in T cells on the periphery of treated patients at all dose levels tested. The lowest concentration of the anti-PD-1 antibody agent that resulted in complete receptor occupation was calculated to be
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2.43 pg / ml. In addition, the data demonstrate that the anti-PDD-1 antibody agent that binds to PD-1 is maintained for at least 29 days after a single dose at 1 mg / kg. These results demonstrate the effectiveness and stability of a single dose of an anti-PD-1 antibody agent.
[00393] In addition, for the fixed dosing regimens (500 mg Q3W and 1000 Q6W) the average Cmín in which the complete receptor occupation was observed was ~ 2 ug / ml. Taking the receptor occupation studies in view of the pharmacokinetic data, advantageous properties of a dosing schedule for a 500 mg Q3W PD-1 binding agent followed by 1000 mg Q6W are revealed. A benefit of this dosing schedule is that it provides minimum concentrations that are at least 20 times above the lowest concentration at which complete peripheral receptor occupation is achieved (40.2 ug / ml) for 500 mg Q3W and 43.7 pg / mL for 1000 mg Q6W).
[00394] Receptor occupation (RO) for this 500 mg Q3W / 1000 mg Q6W fixed dose regimen of anti-PD-1 antibody has also been studied in patients with MSS endometrial cancer, MSI-H endometrial cancer and NSCLC.
[00395] To measure direct binding in the RO assay, PBMCs were isolated from patients at the initial assessment (Day 1 pre-dose), as well as before the second dose (Day 22 pre-dose) in a 500 mg Q3W scheme . The occupation of the PD-1 receptor by the anti-PD-1 antibody in circulating CD3 ⁺ T cells was measured by flow cytometry using a method similar to that reported for nivolumab (Brahmer, JCO 2010). PBMCs from treated patients were pre-incubated ex vivo with a saturating concentration of unlabeled human IgG4 (isotype control) or with anti-PD-1 antibody. After washing and staining with anti-CD3 and anti-human IgG4, the occupation of PD-1 by the infused anti-PD-1 antibody was estimated as the ratio between CD3 ⁺ cells stained with anti-human IgG4 after ex vivo saturation with antibody of control isotype (indicating in vivo binding) and after saturation of the anti-PD-1 antibody (indicating total available binding sites).
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160/169 [00396] The RO trial data are shown in Figure 8, with ο number of patients indicated in parentheses. In this graph, the line in the center of the box graph indicates the median, with the box extending to indicate the 25th and 75th percentiles. The bars represent the minimum and maximum values and show that the high occupation of the anti-PD-1 antibody is reached.
Example 3. Treatment of patients with an exemplary PD1 binding agent [00397] This example describes the clinical efficacy of an exemplary PD-1 binding agent in cancer patients, for example, patients with advanced solid tumors. It was found that administration of a PD-1 binding agent by a dosage regimen of the present disclosure conferred clinical benefits to patients. An exemplary PD-1 binding agent, as described in the present study, is a humanized monoclonal anti-PD-1 antibody. For example, a specific PD-1 binding agent with a heavy chain variable region comprising CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region comprising CDR sequences of SEQ ID NOs: 12 , 13 and 14 are evaluated. This anti-PD-1 antibody uses a human IGHG4 * 01 heavy chain gene, and a human IGKC * 01 kappa light chain gene, as scaffold structures. 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.
[00398] In addition, administration of a composition comprising the anti-PD-1 antibody after intravenous infusion was found to confer clinical benefits to patients at each of the doses tested. The tumor response in patients who were evaluated as of September 2016 is described in Table 10.
Table 10: Tumor response in a patient administered with different dosage regimens for a PD-1 binding agent.
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Tumor type Cohort Tumor response Addition of intra-patient dose Y / N jiiieiiiiiiiiiiB £: ¾¾¾¾¾¾¾¾ ^^ ovarianιιιιιιβ ggg J Ιβ »Adenocarcinomaovarian 3 mg / kg PR N .... ^ jjS Carcinoma of the French HornFallopian 3 mg / kg SD s// FOgwoy iiii ··ihhhOaOiWhhhh ^ ΛΐοΒΒββΜΐΐΜ ^^ iiiiiiiliÉloAnal cancer 1 mg / kg PK / PDy SD s 11 «^Small cell lung cancer 10 mg / kg PR ÍÍÉÍe®É®lÍíSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSS: bbbíglítóètôOtèbbbí ·: ·: ·: ^ ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: · · · : ·: ·: ·: ·: · Χ ibbbbbbbbbbbbbbbbbBBbbbbbbbbbbbbbbbbbbi iiiiiiiiiiiliiii i®i »IBIBISIBLE bíÍéíiHBÍÍíb ! ΙΙβ ^^ ·: ·: ·: ^ ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: ·: · · · : ·: ·: ·: ·: · Χ Ovarian adenocarcinoma 10 mg / kg PK / Pdy SDCervical cancer 10 mg / kg PK / Pdy ND
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162/169 [00399] "PD" = Progressive Disease; "SD" = Stable disease; "PR" = Partial Response; “ND” = not determined at the time of assessment [00400] A wide variety of tumor types have been tested, thus including tumors of the anus, rectum, parotid gland, ovaries, breast, fallopian tube, endometrium, uterus, appendix, prostate, lung, cervix, esophagus, peritoneum, kidney and colon. As of July 2017, 19 patients had a follow-up screening in part 1, and 2 of the 19 patients were categorized as responsive. Both of these 2 patients reached a PR: one patient with ovarian cancer had a response duration of 26 weeks and ended treatment at week 36 without progression, and one patient with small cell lung cancer, for which treatment was underway. , with duration of response> 31 weeks. Five patients had stable disease, two of whom were under continuous treatment (fallopian tube cancer, n = 1; ovarian cancer, n = 1). Responses to treatment are summarized in Figure 7. Panel A in Figure 7 depicts a swimmer stripe and Panel B shows a spider chart of treatment responses to the exemplary PD-1 binding agent.
[00401] Patients also received 500 mg of anti-PD1 antibody every three weeks (Q3W) for the first four cycles followed by 1000 mg every 6 weeks (Q6W) for all subsequent cycles. The effect of a composition of this anti-PD-1 antibody administered according to this regimen has been studied in patients with MSS endometrial cancer (Table 11). Patients also received 500 mg of anti-PD-1 antibody every three weeks (Q3W) for the first three cycles followed by 1000 mg every 6 weeks (Q6W) for all subsequent cycles, or patients could receive 500 mg of anti-PD-1 antibody every three weeks (Q3W) for the first five cycles followed by 1000 mg every 6 weeks (Q6W) for all subsequent cycles.
Table 11. Tumor Assessments in the MSS A2 Endometrial Cohort
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Best Overall Answer by IrRECIST A2 cohort (N = 25) [n (%)] irCR 0 irPR 6 (24) irSD 7 (28) irPD 11 (44) Not evaluable 0 Not produced 1 (4)
[00402] Twenty-five patients with advanced / recurrent MSS endometrial cancer were treated with anti-PD-1 antibody and had at least one CT scan for tumor evaluation. These patients are patients who progress during or after platinum doublet therapy and patients who have received no more than two lines of anticancer therapy for recurrent or advanced disease. Of the six patients who reached IrPR, an answer was confirmed. Five patients remained on treatment and one patient discontinued treatment due to disease progression. These clinical outcomes with the anti-PD-1 antibody are surprising in contrast to previous results using agents, such as atezolizumab and pembrolizumab.
[00403] The dosage regimen of 500 mg anti-PD-1 antibody every three weeks (Q3W) for the first four cycles followed by 1000 mg every 6 weeks (Q6W) for all subsequent cycles can also be useful for patients with non-small cell lung cancer (NSCLC) and patients with MSI-H cancers (for example, MSI-H endometrial cancer). Other dosing regimens include 500 mg of anti-PD-1 antibody every three weeks (Q3W) for the first three cycles followed by 1000 mg every 6 weeks (Q6W) for all subsequent cycles or 500 mg of antiPD-1 antibody every three weeks (Q3W) for the first five cycles followed by 1000 mg every 6 weeks (Q6W) for all subsequent cycles.
[00404] In this sense, this example demonstrates that the
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164/169 binding to the exemplary PD-1 with a heavy chain variable region comprising the CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region comprising CDR sequences of SEQ ID NOs: 12, 13 and 14 shows encouraging clinical benefits in patients with several types of cancer.
Example 4. Treatment of ovarian cancer with PD-1 binding agent exemplary in combination with niraparib [00405] This example describes a clinical trial of niraparib in combination with an anti-PD-1 antibody in first-line maintenance treatment of patients with advanced ovarian cancer who responded to platinum induction therapy. An exemplary PD-1 binding agent can be a humanized monoclonal anti-PD-1 antibody. For example, a specific PD-1 binding agent with a heavy chain variable region comprising CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region comprising CDR sequences of SEQ ID NOs: 12 , 13 and 14, as described in Example 1, can be evaluated.
[00406] Patients with solid histological or cytologically proven advanced (non-resectable) or metastatic gynecological tumor (eg, ovarian cancer) and who responded to platinum chemotherapy may be included.
[00407] Specifically, this study will evaluate the effectiveness of treating patients with advanced recurrent ovarian cancer with an exemplary PD-1 binding agent in combination with niraparib. The exemplary PD-1 binding agent can comprise a heavy chain variable region with CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region with CDR sequences of SEQ ID NOs: 12, 13 and 14 in combination with niraparib. The combination treatment may include 100300 mg of oral administration of niraparib once daily (for example, one to three capsules of intensity of 100 mg may be taken in
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165/169 administration of each dose). It is anticipated that the PD-1 binding agent can be administered at a dose of 200-1000 mg of an antibody agent against PD-1 (for example, intravenous administration). The exemplary anti-PD-1 antibody can be administered in fixed doses, for example, 400 mg or 500 mg administered every 3 weeks (Q3W), followed by the administered and 800 mg or 1000 mg administered every 6 weeks (Q6W) . In some embodiments, an antibody agent against PD-1 is administered at a dose of 1, 3 and 10 mg / kg. Treatment cycles can be 14-42 days, for example, 21 days, 28 days, etc.
[00408] The criteria for assessing response in tumor assessment of solid tumors (RECIST) using clinically validated imaging methods can be performed at the end of every 1 to 3 cycles until progression.
[00409] Patients continued to receive their assigned treatment until disease progression, unacceptable toxicity, death, withdrawal of consent and / or loss of follow-up.
Example 5. Treatment of lung cancer with niraparib [00410] This example describes a clinical trial of niraparib alone and / or in combination with an exemplary PD-1 antibody agent for the treatment of lung cancer (for example, NSCLC and / or squamous cell carcinoma). An exemplary PD-1 binding agent can be a humanized monoclonal anti-PD-1 antibody. For example, a specific PD-1 binding agent with a heavy chain variable region comprising CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region comprising CDR sequences of SEQ ID NOs: 12 , 13 and 14, as described in Example 1, can be evaluated.
[00411] Patients with solid histological or cytologically proven advanced (non-resectable) or metastatic lung cancer (eg, NSCLS and / or squamous cell carcinoma) may be included. In some modalities, a patient will have had disease progression after
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166/169 treatment with available therapies that are known to confer clinical benefit or that are intolerant to other known treatment (s).
[00412] This study will evaluate the effectiveness of treating patients with advanced lung cancer with niraparib and / or with the exemplary PD-1 binding agent. Patients with advanced lung cancers, for example, squamous cell carcinoma or NSCLC, can be treated with niraparib alone and / or in combination with the exemplary PD-1 binding agent. Treatment with niraparib may include 100-300 mg of oral administration once daily of niraparib (for example, one to three capsules of 100 mg in intensity may be taken with each dose). It is anticipated that the PD-1 binding agent can be administered at a dose of 200-1000 mg of an antibody agent against PD-1 (for example, intravenous administration). The exemplary anti-PD-1 antibody can be administered in fixed doses of 400 mg or 500 mg administered every 3 weeks (Q3W), followed by administration and 800 mg or 1000 mg administered every 6 weeks (Q6W). In some embodiments, an antibody agent against PD-1 is administered at a dose of 1, 3 and 10 mg / kg. Treatment cycles can be 14-42 days, for example, 21 days, 28 days, etc.
[00413] Response evaluation criteria in tumor evaluation of solid tumors (RECIST) using clinically validated imaging methods can be performed at the end of every 1 to 3 cycles until progression.
[00414] Patients continued to receive their assigned treatment until disease progression, unacceptable toxicity, death, withdrawal of consent and / or loss of follow-up.
Example 6. Treatment of lung cancer expressing PD-1 with PD-1 binding agent in combination with niraparib [00415] This example describes a clinical trial of an exemplary PD-1 antibody agent in combination with niraparib for treatment of lung cancer (for example, NSCLS and / or cell carcinoma
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167/169 scaly) that expresses PD-1 and / or PD-L1, including subjects whose levels of PD-1 or PD-L1 are considered high. An exemplary PD-1 binding agent can be a humanized monoclonal anti-PD-1 antibody. For example, a specific PD-1 binding agent with a heavy chain variable region comprising CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region comprising CDR sequences of SEQ ID NOs: 12 , 13 and 14, as described in Example 1, can be evaluated. The effectiveness of the lung cancer combination treatment that expresses PD-1 / PD-L1 with the exemplary PD-1 binding agent in combination with niraparib can be compared with the effectiveness of treatment with the PD-1 binding agent alone.
[00416] Patients with solid histological or cytologically proven advanced (non-resectable) or metastatic lung cancer (eg, NSCLS and / or squamous cell carcinoma) may be included. In some modalities, a patient will have had disease progression after treatment with available therapies that are known to confer clinical benefit or that are intolerant to other known treatment (s). In some modalities, lung cancer is characterized by a high level of expression of PD-1 and / or PD-L1.
[00417] This study will evaluate the effectiveness of treating patients with advanced lung cancer with the exemplary PD-1 binding agent in combination with niraparib compared to treatment with the PD-1 binding agent alone in cancer patients of lung that expresses PD1 / PD-L1. Patients will include those with advanced lung cancers, for example, squamous cell carcinoma or NSCLC. It is anticipated that the PD-1 binding agent can be administered at a dose of 200-1000 mg of an antibody agent against PD-1 (for example, intravenous administration). Treatment with niraparib may include 100-300 mg of oral administration of niraparib once daily (for example, one to three 100 mg capsules of
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168/169 intensity can be taken in the administration of each dose). The exemplary anti-PD-1 antibody can be administered in fixed doses of 400 mg or 500 mg administered every 3 weeks (Q3W), followed by administration and 800 mg or 1000 mg administered every 6 weeks (Q6W). In some embodiments, an antibody agent against PD-1 is administered at a dose of 1, 3 and 10 mg / kg. Treatment cycles can be 14-42 days, for example, 21 days, 28 days, etc.
[00418] Response evaluation criteria in tumor evaluation of solid tumors (RECIST) using clinically validated imaging methods can be performed at the end of every 1 to 3 cycles until progression.
[00419] Patients continued to receive their assigned treatment until disease progression, unacceptable toxicity, death, withdrawal of consent and / or loss of follow-up.
[00420] Having thus described at least several aspects and modalities of this invention, it should be appreciated that various changes, modifications and improvements will be easily evident to those skilled in the art. These changes, modifications and improvements are intended to be part of this disclosure, and are intended to be within the spirit and scope of the invention. Accordingly, the foregoing description and figures are by way of example only and the invention is described in more detail by the following claims.
EQUIVALENTS [00421] Articles one and one, as used in this document in the specification and in the claims, unless otherwise indicated, 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
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169/169 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 is to be understood that the invention 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, where relevant, any other claim), unless otherwise stated 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 (267)
[1]
1. Method of treating a disorder in a subject, characterized by the fact that the method comprises the administration of a therapeutically effective dose of an agent that is capable of inhibiting the signaling of Programmed Death Protein-1 (PD-1), wherein the therapeutically effective dose is: about 1, 3 or 10 mg / kg; a fixed dose between about 100 - 2000 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; a fixed dose of about 1600 mg; a fixed dose of about 1700 mg; a fixed dose of about 1800 mg; a fixed dose of about 1900 mg; a fixed dose of about 2000 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, characterized by the fact that the method comprises the administration of a therapeutically effective dose of an agent that is able to inhibit the signaling of the Protein of Death Programmed-1 (PD-1), where the therapeutically effective dose is: about 1, 3 or 10 mg / kg; a fixed dose between about 100 - 2000 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; a fixed dose of about 1600 mg; a fixed dose of about 1700 mg; a fixed dose of about 1800 mg; a fixed dose of about 1900 mg; a fixed dose of about 2000 mg; about 1 mg / kg; fence
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2/31 of 3 mg / kg; or about 10 mg / kg.
[3]
3. Method of tumor reduction or inhibition of tumor cell growth in a subject, characterized by the fact that the method comprises the administration of a therapeutically effective dose of an agent that is able to inhibit Programmed Death Protein-1 signaling (PD-1), where the therapeutically effective dose is: about 1, 3 or 10 mg / kg; a fixed dose between about 100 - 2000 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; a fixed dose of about 1600 mg; a fixed dose of about 1700 mg; a fixed dose of about 1800 mg; a fixed dose of about 1900 mg; a fixed dose of about 2000 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, characterized by the fact that the method comprises the administration of a therapeutically effective dose of an agent that is capable of inhibiting the signaling of Programmed Death Protein-1 (PD-1) , wherein the therapeutically effective dose is: about 1, 3 or 10 mg / kg; a fixed dose between about 100 - 2000 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; a fixed dose of about 1600 mg; a fixed dose of about 1700 mg; a fixed dose of about 1800 mg; a fixed dose of about 1900 mg; a fixed dose of about
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3/31 of 2000 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 activity of an immune cell in a subject, characterized by the fact that the method comprises the administration of a therapeutically effective dose of an agent that is capable of inhibiting the signaling of the Protein of Death Programmed-1 (PD-1), where the therapeutically effective dose is: about 1, 3 or 10 mg / kg; a fixed dose between about 100 - 2000 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; a fixed dose of about 1600 mg; a fixed dose of about 1700 mg; a fixed dose of about 1800 mg; a fixed dose of about 1900 mg; a fixed dose of about 2000 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
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4/31 mg / kg.
[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 characterized by the fact that the dose of about 1000 mg.
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 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
[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 claims 1-8, characterized in that the therapeutically effective dose is a fixed dose of about 1600 mg.
[28]
28. Method according to any one of claims 1-8, characterized in that the therapeutically effective dose is a fixed dose of about 1700 mg.
[29]
29. Method according to any one of claims 1-8, characterized in that the therapeutically effective dose is a fixed dose of about 1800 mg.
[30]
30. Method according to any one of claims 1-8, characterized in that the therapeutically effective dose is a fixed dose of about 1900 mg.
[31]
31. Method according to any of claims 1-8, characterized in that the therapeutically effective dose is a fixed dose of about 2000 mg.
[32]
32. Method, according to any of the preceding claims,
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6/31 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, once every 6 weeks, or more.
[33]
33. Method according to claim 32, characterized in that the agent is administered in the interval of administration once every 3 weeks or once every 6 weeks.
[34]
34. Method according to any one of the preceding claims, characterized by the fact that the agent is administered for 2, 3, 4, 5, 6 or more cycles.
[35]
35. Method according to claim 34, characterized in that the agent is administered for 3, 4 or 5 cycles.
[36]
36. Method according to claim 34 or 35, characterized in that the agent is administered for 4 cycles.
[37]
37. Method according to any of the preceding claims, characterized by the fact that the agent is administered for a period sufficient to achieve a clinical benefit.
[38]
38. Method, according to claim 37, characterized by the fact that the clinical benefit is stable disease (“SD”), a partial response (“PR”) and / or a complete response (“CR”).
[39]
39. Method, according to claim 38, 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”).
[40]
40. Method according to any of claims 37-39, characterized in that the agent is administered for a longer period of time to maintain the clinical benefit.
[41]
41. 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.
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7/31
[42]
42. Method according to any one of the preceding claims, characterized in that the agent is administered to the subject periodically in a dose of about 500 mg or 1000 mg.
[43]
43. Method according to claim 42, characterized in that the agent is administered to the subject periodically in a dose of about 500 mg.
[44]
44. Method according to claim 42 or 43, characterized in that the agent is administered to the subject once every 3 weeks.
[45]
45. Method according to any one of claims 42-44, characterized in that the agent is administered for 2, 3, 4, 5, 6, or more cycles.
[46]
46. Method according to claim 45, characterized by the fact that the agent is administered for 3, 4 or 5 cycles.
[47]
47. Method according to any of claims 44-46, characterized in that the agent is administered for 4 cycles.
[48]
48. Method according to claim 42, characterized in that the agent is administered to the subject periodically in a dose of about 1000 mg.
[49]
49. Method according to claim 42 or 48, characterized in that the agent is administered to the subject once every 6 weeks or more.
[50]
50. Method according to claim 42, characterized in that the agent 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.
[51]
51. Method according to claim 50, characterized in that the dose of 1000 mg once every 6 weeks or more is continued to maintain the clinical benefit.
[52]
52. Method according to claim 50 or 51, characterized in that the agent is administered in a first dose of about 500 mg once every 3 weeks for 3 cycles, followed by a second dose of
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8/31 about 1000 mg once every 6 weeks or more.
[53]
53. Method according to claim 50 or 51, characterized in that the agent 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.
[54]
54. Method according to claim 50 or 51, characterized in that the agent 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.
[55]
55. Method according to any one of claims 50-54, characterized in that the second dose is about 1000 mg once every 6 weeks.
[56]
56. Method according to any one of the preceding claims, characterized by the fact that the disorder is a dysfunctional T-cell disorder.
[57]
57. Method according to any of the preceding claims, characterized by the fact that the disorder is cancer.
[58]
58. Method according to claim 57, 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 that has a high status of microsatellite instability (MSI-H),
v) a cancer that has a low microsatellite instability status (MSI-L), 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 repair gene
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9/31 DNA incompatibility,
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, chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin's lymphoma, neuroblastoma, a CNS tumor, diffuse intrinsic pontine glioma (DIPG), Ewing's sarcoma, embryonic rhabdomyosarcoma, osteosarcoma, or Wilms' tumor, or xv) a xiv cancer), in which cancer is MSS or MSI-L, is characterized by microsatellite instability, is MSI-H, has high TMB, has high TMB and is MSS or MSI-L, has high TMB and is MSI-H, has a repair system
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10/31 defective DNA mismatch, has a defect in a DNA mismatch 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).
[59]
59. Method according to claim 58, characterized by the fact that cancer is a cancer that has homologous recombination repair deficiency / homologous repair deficiency (“HRD”).
[60]
60. Method according to claim 58, characterized by the fact that the cancer is endometrial cancer, optionally MSI-H or MSS / MSI-L endometrial cancer.
[61]
61. Method according to claim 58, 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.
[62]
62. Method according to claim 58, characterized by the fact that cancer is breast cancer, optionally triple negative breast cancer (TNBC).
[63]
63. Method according to claim 58, characterized by the fact that the cancer is ovarian cancer, optionally epithelial ovarian cancer.
[64]
64. Method according to claim 58, characterized by the fact that the cancer is lung cancer, optionally non-small cell lung cancer.
[65]
65. Method according to claim 58, characterized by the fact that cancer is melanoma.
[66]
66. Method according to claim 58, characterized by the fact that cancer is colorectal cancer.
[67]
67. Method according to claim 58, 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.
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11/31
[68]
68. Method according to claim 58, characterized by the fact that cancer is acute myeloid leukemia.
[69]
69. Method according to claim 58, characterized by the fact that the cancer is acute lymphoblastic leukemia.
[70]
70. Method according to claim 58, characterized by the fact that the cancer is non-Hodgkin's lymphoma.
[71]
71. Method according to claim 58, characterized by the fact that the cancer is Hodgkin's lymphoma.
[72]
72. Method according to claim 58, characterized by the fact that the cancer is neuroblastoma.
[73]
73. Method according to claim 58, characterized by the fact that cancer is a CNS tumor.
[74]
74. Method according to claim 58, characterized by the fact that cancer is diffuse intrinsic pontine glioma (DIPG).
[75]
75. Method according to claim 58, characterized by the fact that the cancer is Ewing's sarcoma.
[76]
76. Method according to claim 58, characterized by the fact that cancer is embryonic rhabdomyosarcoma.
[77]
77. Method according to claim 58, characterized by the fact that the cancer is osteosarcoma.
[78]
78. Method according to claim 58, characterized by the fact that the cancer is Wilms' tumor.
[79]
79. Method according to claim 58, characterized by the fact that cancer is soft tissue sarcoma.
[80]
80. Method, according to claim 79, characterized by the fact that cancer is leiomyosarcoma.
[81]
81. 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.
[82]
82. Method, according to claim 81, characterized by the fact
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12/31 that comprises the administration of one, two or three immunological checkpoint inhibitors.
[83]
83. Method according to claim 81 or 82, characterized in that the immunological checkpoint inhibitor is an agent that inhibits T cell immunoglobulin and mucin protein 3 (TIM-3), 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).
[84]
84. Method according to any of claims 81-83, characterized in that the immunological checkpoint inhibitor is a TIM-3 inhibitor.
[85]
85. Method according to claim 84, characterized in that the TIM-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 PD-1 binding agent.
[86]
86. Method according to claim 85, characterized in that the TIM-3 inhibitor is a TIM-3 binding agent.
[87]
87. Method according to claim 86, characterized in that the TIM-3 binding agent is an antibody, an antibody conjugate, or an antigen binding fragment thereof.
[88]
88. Method according to any of claims 81-83, characterized in that the immunological checkpoint inhibitor is a CTLA-4 inhibitor.
[89]
89. Method according to claim 88, 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 PD-1 binding agent.
[90]
90. Method according to claim 89, characterized in that the CTLA-4 inhibitor is a CTLA-4 binding agent.
[91]
91. Method according to claim 90, characterized in that the CTLA-4 binding agent is an antibody, a conjugate of
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13/31 antibody, or an antigen-binding fragment thereof.
[92]
92. The method of any one of claims 81-83, characterized in that the immunological checkpoint inhibitor is an LAG-3 inhibitor.
[93]
93. Method according to claim 92, characterized in that the LAG-3 inhibitor is a small molecule, a nucleic acid, a polypeptide (eg, an antibody), a carbohydrate, a lipid, a metal, a toxin, or a PD-1 binding agent.
[94]
94. Method according to claim 93, characterized in that the LAG-3 inhibitor is a LAG-3 binding agent.
[95]
95. The method of claim 94, characterized in that the LAG-3 binding agent is an antibody, an antibody conjugate, or an antigen binding fragment thereof.
[96]
96. Method according to any of claims 81-83, characterized in that the immunological checkpoint inhibitor is a TIGIT inhibitor.
[97]
97. Method according to claim 96, 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 PD-1 binding agent.
[98]
98. Method according to claim 97, characterized in that the TIGIT inhibitor is a TIGIT binding agent.
[99]
99. The method of claim 98, characterized in that the TIGIT binding agent is an antibody, antibody conjugate, or antigen binding fragment thereof.
[100]
100. Method according to any of claims 81-83, characterized in that the immunological checkpoint inhibitor is an IDO inhibitor.
[101]
101. Method according to claim 100, 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,
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14/31 a toxin, or a PD-1 binding agent.
[102]
102. Method according to claim 101, characterized by the fact that the IDO inhibitor is a small molecule.
[103]
103. Method according to claim 100, 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 thereof.
[104]
104. Method according to any of claims 81-83, characterized in that the immunological checkpoint inhibitor is a CSF1R inhibitor.
[105]
105. Method according to claim 104, characterized in that the CSF1R 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.
[106]
106. Method according to claim 105, characterized in that the CSF1R inhibitor is a small molecule.
[107]
107. Method according to claim 105, characterized in that the CSF1R inhibitor is a CSF1R binding agent, optionally a CSF1R agent which is an antibody, an antibody conjugate, or an antigen binding fragment of same.
[108]
108. Method according to any one of claims 81-107, characterized in that it comprises the administration of at least two of the immunological checkpoint inhibitors.
[109]
109. Method according to claim 108, characterized by the fact that it further comprises the administration of a third checkpoint inhibitor.
[110]
110. Method according to claim 108 or 109, characterized in that the subject receives treatment with each of the agent, an inhibitor of TIM-3 and an inhibitor of LAG-3, so that the subject receives all the three.
[111]
111. Method according to claim 110, characterized by the
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15/31 fact that the subject still understands to receive treatment with a CTLA-4 inhibitor, so that the subject receives all four.
[112]
112. Method according to any 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).
[113]
113. Method according to claim 112, 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.
[114]
114. Method according to claim 112 or 113, characterized in 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, NU1064, 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 -888), WW 46, 2- (4- (trifluoromethyl) phenyl) -7,8-dihydro-5H-thiopyran [4,3d] pyrimidin-4-ol, and salts or derivatives thereof.
[115]
115. Method according to any of claims 112-114, characterized in that the subject receives treatment with each of the agent, a TIM-3 inhibitor and an agent that inhibits PARP, so that the subject receives all three.
[116]
116. Method according to claim 115, characterized in that it further comprises the subject receiving treatment with a LAG-3 inhibitor, so that the subject receives all four.
[117]
117. Method according to any of claims 112-114, characterized in that the subject receives treatment with each of the agent, an LAG-3 inhibitor and an agent that inhibits PARP, so that the subject receives all three.
[118]
118. Method according to claim 117, characterized by the
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16/31 the fact that the subject still receives treatment with a TIM-3 inhibitor, so that the subject receives all four.
[119]
119. Method according to any of the preceding claims, characterized by the fact that the subject is resistant to treatment with an agent that inhibits PD-1.
[120]
120. Method according to any one of the preceding claims, characterized by the fact that the subject is refractory to treatment with an agent that inhibits PD-1.
[121]
121. Method according to any one of the preceding claims, characterized by the fact that the method sensitizes the subject to treatment with an agent that inhibits PD-1.
[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 of the preceding claims, characterized by the fact that the method further comprises the administration of
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17/31 other therapeutic agent or treatment.
[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 130, characterized in that the method further comprises the administration of chemotherapy.
[132]
132. Method according to any one of the preceding claims, characterized in that the agent is a PD-1 binding agent.
[133]
133. The method of claim 132, characterized in that the PD-1 binding agent is an antibody, an antibody conjugate, or an antigen binding fragment thereof.
[134]
134. Method according to any one of the preceding claims, characterized in that the PD-1 binding agent is an antibody.
[135]
135. Method according to claim 133 or 134, characterized in that the PD-1 binding agent comprises a heavy chain variable region with 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: 9, 10 or 11.
[136]
136. Method according to claim 135, characterized in that the PD-1 binding agent comprises a heavy chain variable region with two or three CDR sequences of SEQ ID NOs: 9, 10 or 11.
[137]
137. Method according to any one of claims 133-136, characterized in that the PD-1 binding agent comprises a light chain variable region with 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: 12.13 and 14.
[138]
138. Method according to any of claims 133-137, characterized in that the PD-1 binding agent comprises a light chain variable region with two or three CDR sequences of SEQ ID
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18/31
NOs: 12, 13 and 14.
[139]
139. Method according to claim 133 or 134, characterized in that the PD-1 binding agent comprises a heavy chain variable region with one or more CDR sequences selected from SEQ ID NOs: 9, 10 and 11 and / or a light chain variable region with one or more CDR sequences selected from SEQ ID NOs: 12,13 and 14.
[140]
140. Method according to claim 139, characterized in that the PD-1 binding agent comprises a heavy chain variable region with three CDRs having sequences of SEQ ID NOs: 9, 10 and 11 and / or a light chain variable region with three CDRs that have sequences of SEQ ID NOs: 12, 13 and 14.
[141]
141. Method according to claim 133 or 134, characterized in that the PD-1 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 SEQIDN07.
[142]
142. Method according to claim 133, 134 or 141, characterized in that the PD-1 binding agent comprises 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.
[143]
143. Method according to claim 133 or 134, characterized in that the PD-1 binding agent comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO : 7 and an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8.
[144]
144. Method according to claim 133 or 134, characterized in that the PD-1 binding agent comprises a heavy chain of
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19/31 immunoglobulin comprising an amino acid sequence having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of sequence identity to SEQ ID NO: 3.
[145]
145. Method according to claim 133, 134 or 144, characterized in that the PD-1 binding agent comprises an immunoglobulin light chain 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.
[146]
146. Method according to claim 133 or 134, characterized in that the PD-1 binding agent comprises an immunoglobulin heavy chain whose amino acid sequence comprises SEQ ID NO: 3 and an immunoglobulin light chain whose amino acid sequence comprises SEQ ID NO: 4.
[147]
147. Method according to any of claims 132-146, characterized in that the PD-1 binding agent is administered in an amount that is about 500 mg and / or about 1000 mg.
[148]
148. Method according to claim 147, characterized in that the PD-1 binding agent 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.
[149]
149. Method according to claim 148, characterized in that the PD-1 binding agent is administered in a first dose of about 500 mg once every 3 weeks for 3 cycles, followed by a second dose about 1000 mg once every 6 weeks or more.
[150]
150. Method according to claim 148, characterized in that the PD-1 binding agent is administered in a first dose of about 500 mg once every 3 weeks for 4 cycles, followed by a second dose about 1000 mg once every 6 weeks or more.
[151]
151. Method according to claim 148, characterized in that the PD-1 binding agent is administered in a first dose of about 500 mg once every 3 weeks for 5 cycles, followed by a
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20/31 second dose of about 1000 mg once every 6 weeks or more.
[152]
152. Method according to any of claims 148-151, characterized in that the second dose is about 1000 mg every 6 weeks.
[153]
153. Method according to any one of the preceding claims, characterized by the fact that the agent is administered intravenously.
[154]
154. Method according to claim 153, characterized in that the agent is administered by intravenous infusion.
[155]
155. 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-programmed death protein-1 antibody (PD-1) in a therapeutically effective dose within an administration interval for a period sufficient to achieve a clinical benefit, in which the antibody anti-PD-1 comprises a heavy chain variable region comprising CDR sequences of SEQ ID NOs: 9, 10 and 11 and a light chain variable region comprising CDR sequences of SEQ ID NOs: 12, 13 and 14.
[156]
156. 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-programmed death protein-1 antibody (PD-1) in a therapeutically effective dose within an administration interval for a period sufficient to achieve a clinical benefit, in which the antibody anti-PD-1 comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7 and / or an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8.
[157]
157. Method for treating cancer, the method being characterized by the fact that it comprises:
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21/31 administration, to a patient in need of treatment, of an anti-programmed death protein-1 (PD-1) antibody in a therapeutically effective dose within an administration interval for a period sufficient to achieve a clinical benefit, in that the anti-PD-1 antibody comprises an immunoglobulin heavy chain polypeptide whose amino acid sequence comprises SEQ ID NO: 3 and / or immunoglobulin light chain polypeptide whose amino acid sequence comprises SEQ ID NO: 4.
[158]
158. Method according to any of claims 155-157, characterized by the fact that the clinical benefit is stable disease (“SD”), a partial response (“PR”) and / or a complete response (“CR” ).
[159]
159. Method according to claim 158, characterized by the fact that the clinical benefit is SD.
[160]
160. Method, according to claim 158, characterized by the fact that the clinical benefit is PR.
[161]
161. Method according to claim 158, characterized by the fact that the clinical benefit is CR.
[162]
162. Method according to claim 160 or 161, characterized by the fact that PR or CR is determined according to the Response Assessment Criteria in Solid Tumors (RECIST).
[163]
163. Method according to claim 155, characterized by the fact that the patient has a cancer associated with a mutation of POLE (DNA polymerase epsilon) or POLD (DNA polymerase delta).
[164]
164. Method according to claim 163, characterized by the fact that the POLE or POLD mutation is in an exonuclease domain.
[165]
165. Method according to claim 163 or 164, characterized by the fact that the POLE or POLD mutation is a germline mutation.
[166]
166. Method according to claim 163 or 164, characterized in that the POLE or POLD mutation is a sporadic mutation.
[167]
167. The method of any one of claims 163-166,
Petition 870190064194, of 07/09/2019, p. 28/408
22/31 characterized by the fact that the method also comprises a step of identifying, first, the cancer patient with the POLE or POLD mutation.
[168]
168. Method according to claim 167, characterized by the fact that the POLE or POLD mutation is identified using sequencing.
[169]
169. Method according to any one of claims 155-168, characterized by the fact that the patient has a cancer with microsatellite instability.
[170]
170. Method according to claim 169, characterized by the fact that the patient has an MSI-H cancer.
[171]
171. Method according to claim 170, 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.
[172]
172. Method according to claim 169, characterized by the fact that the patient has an MSI-L cancer.
[173]
173. Method according to any one of claims 155-168, characterized by the fact that the patient has stable microsatellite cancer (MSS).
[174]
174. Method according to any of claims 155-173, characterized by the fact that the patient has a cancer that has homologous recombination repair deficiency / homologous repair deficiency (“HRD”).
[175]
175. Method according to any of claims 155-174, characterized by the fact that the patient has a solid tumor.
[176]
176. Method according to claim 175, characterized by the fact that the patient has a solid tumor in an advanced stage.
[177]
177. Method according to claim 175, characterized by the fact that the patient has a solid metastatic tumor.
[178]
178. Method according to any one of claims 155-177, characterized by the fact that the patient has head and neck cancer,
Petition 870190064194, of 07/09/2019, p. 29/408
23/31 a lung cancer, a kidney cancer, a bladder cancer, a melanoma, Merkel cell carcinoma, a cervical cancer, a vaginal cancer, a vulva cancer, a uterine cancer, a cancer of endometrial cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, prostate cancer, salivary gland tumor, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma, squamous cell carcinoma, soft tissue cell carcinoma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, lymphoma Hodgkin, neuroblastoma, a CNS tumor, diffuse intrinsic pontine glioma (DIPG), Ewing's sarcoma, embryonic rhabdomyosarcoma (ERS), osteosarcoma, or Wilms' tumor.
[179]
179. Method according to any of claims 155-178, characterized by the fact that the cancer has homologous recombination repair deficiency / homologous repair deficiency (“HRD”).
[180]
180. Method according to claim 178, characterized by the fact that the patient has endometrial cancer.
[181]
181. Method, according to claim 180, characterized by the fact that the patient has endometrial cancer with microsatellite instability.
[182]
182. Method according to claim 180, characterized by the fact that the patient has an MSI-H endometrial cancer.
[183]
183. Method according to claim 80, characterized by the fact that the patient has MSS / MSI-L endometrial cancer.
[184]
184. Method according to claim 178, characterized by the fact that the patient has breast cancer.
[185]
185. Method according to claim 184, characterized by the fact that the patient has triple negative breast cancer (TNBC).
[186]
186. Method according to claim 178, characterized by the fact that the patient has ovarian cancer.
[187]
187. Method according to claim 186, characterized by the
Petition 870190064194, of 07/09/2019, p. 30/408
24/31 fact that ovarian cancer is epithelial ovarian cancer.
[188]
188. Method according to claim 178, characterized by the fact that ovarian cancer is serous ovarian cancer or clear cell ovarian cancer.
[189]
189. Method according to claim 178, characterized by the fact that the patient has lung cancer.
[190]
190. Method according to claim 189, characterized by the fact that lung cancer is a non-small cell lung cancer (NSCLC).
[191]
191. Method according to claim 178, characterized by the fact that the patient has a melanoma.
[192]
192. Method according to claim 178, characterized by the fact that the patient has colorectal cancer.
[193]
193. Method according to claim 178, characterized by the fact that the patient has a squamous cell carcinoma.
[194]
194. Method according to claim 193, 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.
[195]
195. Method, according to claim 178, characterized by the fact that the patient has cancer of the fallopian tubes.
[196]
196. Method according to claim 195, characterized by the fact that the patient has cancer of the serous or clear cell fallopian tubes.
[197]
197. Method according to claim 178, characterized by the fact that the patient has primary peritoneal cancer.
[198]
198. Method according to claim 197, characterized by the fact that the patient has primary serous or clear cell peritoneal cancer.
[199]
199. Method according to claim 178, characterized by the
Petition 870190064194, of 07/09/2019, p. 31/408
25/31 fact that the patient has a soft tissue sarcoma.
[200]
200. Method, according to claim 199, characterized by the fact that the patient has leiomyosarcoma.
[201]
201. Method according to any of claims 155-174, characterized by the fact that the patient has hematological cancer.
[202]
202. Method according to claim 201, characterized by the fact that hematological cancer is DLBCL, HL, NHL, FL, AML, ALL or MM.
[203]
203. Method according to any of claims 155-202, characterized by the fact that the patient has not previously been treated with a cancer treatment modality.
[204]
204. Method according to any of claims 155-202, characterized in that the patient has previously been treated with one or more different treatment modalities for cancer.
[205]
205. Method according to claim 204, characterized by the fact that one or more different treatment modalities for cancer comprise surgery, radiotherapy, chemotherapy or immunotherapy.
[206]
206. Method according to any one of claims 155-205, characterized in that the heavy chain variable region comprises SEQ ID NO: 1 and the light chain variable region comprises SEQ ID NO: 2.
[207]
207. Method according to any of claims 155-205, characterized in that the heavy chain variable region comprises SEQ ID NO: 7 and the light chain variable region comprises SEQ ID NO: 8.
[208]
208. Method according to any one of claims 155-205, characterized in that the heavy chain variable region comprises SEQ ID NO: 3 and the light chain variable region comprises SEQ ID NO: 4.
[209]
209. Method according to any of claims 155-208, characterized in that the therapeutically effective dose is 1, 3 or 10 mg / kg.
[210]
210. Method according to any one of claims 155-208, characterized in that the therapeutically effective dose is a fixed dose ranging from about 100 mg to about 2,000 mg.
Petition 870190064194, of 07/09/2019, p. 32/408
26/31
[211]
211. The method of claim 210, characterized in that the therapeutically effective dose is a fixed dose ranging from about 100 mg to about 1,200 mg.
[212]
212. Method according to claim 210, characterized in that the therapeutically effective dose is about 100 mg.
[213]
213. Method according to claim 210, characterized in that the therapeutically effective dose is about 200 mg.
[214]
214. Method according to claim 210, characterized in that the therapeutically effective dose is about 300 mg.
[215]
215. Method according to claim 210, characterized in that the therapeutically effective dose is about 400 mg.
[216]
216. Method according to claim 210, characterized in that the therapeutically effective dose is about 500 mg.
[217]
217. Method according to claim 210, characterized in that the therapeutically effective dose is about 600 mg.
[218]
218. Method according to claim 210, characterized in that the therapeutically effective dose is about 700 mg.
[219]
219. Method according to claim 210, characterized in that the therapeutically effective dose is about 800 mg.
[220]
220. Method according to claim 210, characterized in that the therapeutically effective dose is about 900 mg.
[221]
221. Method according to claim 210, characterized in that the therapeutically effective dose is about 1000 mg.
[222]
222. Method according to claim 210, characterized in that the therapeutically effective dose is about 1100 mg.
[223]
223. The method of claim 210, characterized in that the therapeutically effective dose is about 1200 mg.
[224]
224. Method according to claim 210, characterized in that the therapeutically effective dose is about 1300 mg.
[225]
225. Method according to claim 210, characterized in that the therapeutically effective dose is about 1400 mg.
Petition 870190064194, of 07/09/2019, p. 33/408
27/31
[226]
226. Method according to claim 210, characterized in that the therapeutically effective dose is about 1500 mg.
[227]
227. Method according to claim 210, characterized in that the therapeutically effective dose is about 1600 mg.
[228]
228. Method according to claim 210, characterized in that the therapeutically effective dose is about 1700 mg.
[229]
229. Method according to claim 210, characterized in that the therapeutically effective dose is about 1800 mg.
[230]
230. Method according to claim 210, characterized in that the therapeutically effective dose is about 1900 mg.
[231]
231. The method of claim 210, characterized in that the therapeutically effective dose is about 2000 mg.
[232]
232. Method according to any of claims 155-231, characterized in that the anti-PD-1 antibody is administered in the 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.
[233]
233. Method according to claim 232, characterized in that it comprises an administration interval which is once every 3 weeks.
[234]
234. Method according to claim 232 or 233, characterized in that it comprises an administration interval that is once every 6 weeks.
[235]
235. Method according to any one of claims 155-234, characterized in that the anti-PD-1 antibody is administered for a period of at least 2, 4, 6, 8, 10, 12, 14, 16, 18 or 20 weeks.
[236]
236. Method according to any one of claims 155-210, 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 a second dose of about 1000 mg once every 6 weeks or more.
Petition 870190064194, of 07/09/2019, p. 34/408
28/31
[237]
237. Method according to claim 236, 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.
[238]
238. Method according to claim 236, 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.
[239]
239. Method according to claim 236, 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.
[240]
240. Method according to any one of claims 236-239, characterized in that the second dose is about 1000 mg once every 6 weeks.
[241]
241. Method according to any of claims 155-240, characterized in that the administration of the anti-PD-1 antibody results in an average Cmax within 10 pg / ml to 500 pg / ml in the patient.
[242]
242. Method according to claim 241, characterized by the fact that the average Cmax is about 20 pg / ml, about 65 pg / ml or about 200 pg / ml in the patient.
[243]
243. Method according to any of claims 155-242, characterized in that the administration of the anti-PD-1 antibody results in an average AUCo-336h within 2500 h * pg / mL at 50000 h * pg / mL in the patient.
[244]
244. Method according to claim 243, characterized in that the average AUCo-336h is about 3400 h * pg / ml, about 11000 h * pg / ml, or about 36800 h * pg / ml.
[245]
245. Method according to any of claims 155-244, characterized in that the anti-PD-1 antibody is administered intravenously.
[246]
246. Method according to claim 245, characterized by the
Petition 870190064194, of 07/09/2019, p. 35/408
29/31 the fact that the anti-PD-1 antibody is administered by intravenous infusion.
[247]
247. Method according to any of claims 155-246, characterized in that the anti-PD-1 antibody is administered in conjunction with an additional therapy.
[248]
248. Method according to claim 247, characterized by the fact that the additional therapy is surgery, radiotherapy, chemotherapy or immunotherapy.
[249]
249. Method according to claim 248, characterized in that the additional therapy comprises treatment with an antiLAG-3 antibody and / or an anti-TIM-3 antibody.
[250]
250. Method according to claim 247, characterized in that the additional therapy comprises treatment with a PARP inhibitor.
[251]
251. The method of claim 250, characterized by the fact that the PARP inhibitor is niraparib, olaparib, rucaparib, talazoparib and / or veliparib.
[252]
252. Method according to claim 251, characterized by the fact that the PARP inhibitor is niraparib.
[253]
253. Method according to any one of claims 155-252, characterized in that the method further comprises a step of adjusting the therapeutically effective dose of the anti-PD-1 antibody and / or the administration interval after achieving the benefit clinical.
[254]
254. Method of treating cancer, the method being characterized by the fact that it comprises administering, to a patient in need of treatment, an anti-programmed death protein-1 (PD-1) antibody in a first dose in a first dose break for a first period;
administration to the patient of the anti-PD-1 antibody in a second dose at a second interval for a second period;
wherein the anti-PD-1 antibody comprises a heavy chain variable region comprising CDR sequences of SEQ ID NOs: 9, 10 and 11 and a
Petition 870190064194, of 07/09/2019, p. 36/408
30/31 light chain variable region comprising CDR sequences of SEQ ID NOs: 12, 13 and 14.
[255]
255. Method according to claim 254, characterized in that the first dose and the second dose are different.
[256]
256. Method according to claim 255, characterized in that the first dose is 500 mg and the second dose is 1000 mg.
[257]
257. Method according to any one of claims 254-256, characterized in that the first gap and the second gap are different.
[258]
258. Method according to claim 257, characterized by the fact that the first interval is once every three weeks and the second interval is once every six weeks or more.
[259]
259. Method according to any one of claims 254-258, characterized in that the anti-PD-1 antibody is administered in the first dose of 500 mg once every three weeks for the first period of 2-6 cycles. dosage, and the second 1000 mg dose once every six weeks until disease progression.
[260]
260. Method of treating ovarian cancer, fallopian cancer or primary peritoneal cancer, the method being characterized by the fact that it comprises:
administration, to a patient in need of treatment, of an anti-programmed death protein-1 (PD-1) antibody, and administration of niraparib.
[261]
261. Method according to claim 260, characterized by the fact that the cancer is ovarian cancer.
[262]
262. Lung cancer treatment method, the method being characterized by the fact that it comprises:
administration, to a patient in need of treatment, of an anti-programmed death protein-1 (PD-1) antibody, and administration of niraparib.
[263]
263. Method according to claim 262, characterized by the
Petition 870190064194, of 07/09/2019, p. 37/408
31/31 fact that lung cancer is NSCLC or squamous cell carcinoma.
[264]
264. Method according to claim 262 or 263, characterized by the fact that lung cancer is characterized by the expression of PD-1 and / or PD-L1.
[265]
265. Method according to any of claims 254-264, characterized by the fact that cancer is an advanced stage cancer.
[266]
266. Method according to any one of claims 254-265, characterized in that the anti-PD-1 antibody comprises an immunoglobulin heavy chain variable domain whose amino acid sequence comprises SEQ ID NO: 1 or SEQ ID NO: 7 and / or an immunoglobulin light chain variable domain whose amino acid sequence comprises SEQ ID NO: 2 or SEQ ID NO: 8.
[267]
267. Method according to any one of claims 254-265, characterized in that the anti-PD-1 antibody comprises a heavy chain variable region comprising SEQ ID NO: 3 and a light chain variable region which comprises SEQ ID NO: 4.

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

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