Combination Therapy for Colorectal Cancer

Abstract

The present invention provides a method of treating colorectal cancer with a combination of an anti-LAG-3 antibody and an anti-PD-1 or anti-PD-LI antibody. In some embodiments, the combination includes 480 mg of each antibody, such as 480 mg of an anti-LAG-3 antibody (e.g., relatolimab) and 480 mg of an anti-PD-1 antibody (e.g., nivolumab). In some embodiments, the colorectal cancer is unresectable, advanced or metastatic, including, for example, microsatellite stable or microsatellite unstable high colorectal cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This PCT application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 314,137, filed February 25, 2022, which is incorporated by reference in its entirety herein.

[0002] Reference to Electronically Submitted Sequence Listing The contents of the electronically submitted Sequence Listing (Name: 3338_293PC01_SeqListing_ST26; Size: 101,963 bytes; and Creation Date: February 7, 2023) submitted with this application are hereby incorporated by reference in their entirety.

[0003] The present disclosure provides a method of treating a human subject suffering from colorectal cancer (CRC), the method comprising an anti-lymphocyte-activation gene 3 (LAG-3) antibody and an anti-programmed death 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) antibody. [Background technology]

[0004] Globally, CRC is the second most common form of cancer in women and the third most common form of cancer in men annually. The disease occurs primarily in developed regions, with the highest incidence in Australia / New Zealand and Western Europe, and to a lesser extent in Africa and South and Central Asia. There are approximately 880,800 deaths from CRC annually, which represents approximately 9% of all cancer deaths, making CRC the second most common cause of cancer death. At the time of initial diagnosis, approximately 25% of patients present with metastatic disease, and almost 50% of patients will go on to develop metastases, contributing to the high mortality reported in CRC patients. Summary of the Invention [Problem to be solved by the invention]

[0005] There is a need for improved methods of treating human subjects with CRC. [Means for solving the problem]

[0006] The present disclosure relates to a method of treating a human subject suffering from colorectal cancer (CRC), comprising administering to the subject (a) about 480 mg of an anti-LAG-3 antibody, and (b) about 480 mg of an anti-PD-1 or anti-PD-L1 antibody.

[0007] In some aspects, the anti-LAG-3 antibody is a full-length antibody. In some aspects, the anti-LAG-3 antibody is a monoclonal, human, humanized, chimeric or multispecific antibody. In some aspects, the multispecific antibody is a dual affinity retargeting antibody (DART), DVD-Ig or bispecific antibody.

[0008] In some aspects, the anti-LAG-3 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.

[0009] In some embodiments, the anti-LAG-3 antibody is selected from the group consisting of BMS-986016 (leratolimab), IMP731 (H5L7BW), MK4280 (28G-10, favezelimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, yelamirimab), aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P 13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501 or an antigen-binding portion thereof.

[0010] In some aspects, the anti-LAG-3 antibody comprises the CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:3, and the CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:4.

[0011] In some aspects, the anti-LAG-3 antibody comprises (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:5; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:6; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:7; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:8; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:9; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:10.

[0012] In some aspects, the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 3 and 4, respectively.

[0013] In some aspects, the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 1 and 2, respectively.

[0014] In some aspects, the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs:21 and 2, respectively.

[0015] In some embodiments, the anti-PD-1 antibody is a full-length antibody.

[0016] In some aspects, the anti-PD-1 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. In some aspects, the multispecific antibody is a DART, DVD-Ig, or a bispecific antibody.

[0017] In some aspects, the anti-PD-1 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0018] In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, cemiplimab, JS001, PF-06801591, BGB-A317, BI 754091, INCSHR1210, GLS-010, AM-001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, SSI-361, or comprises an antigen-binding portion thereof.

[0019] In some aspects, the anti-PD-1 antibody comprises the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:13, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:14.

[0020] In some aspects, the anti-PD-1 antibody comprises (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 15; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 16; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 17; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 18; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 19; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 20.

[0021] In some aspects, the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively.

[0022] In some aspects, the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the sequences as set forth in SEQ ID NOs:11 and 12, respectively.

[0023] In some aspects, the anti-PD-L1 antibody is a full-length antibody.

[0024] In some aspects, the anti-PD-L1 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody, hi some aspects, the multispecific antibody is a DART, DVD-Ig, or a bispecific antibody.

[0025] In some aspects, the anti-PD-L1 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0026] In some aspects, the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301, or comprises an antigen-binding portion thereof.

[0027] In some aspects, the anti-LAG-3 antibody is formulated for intravenous administration and / or the anti-PD-1 antibody or anti-PD-L1 antibody is formulated for intravenous administration.

[0028] In some aspects, the anti-LAG-3 antibody and / or anti-PD-1 antibody or anti-PD-L1 antibody is administered about once every week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, about once every 10 weeks, about once every 11 weeks, or about once every 12 weeks.

[0029] In some aspects, the anti-PD-1 antibody or the anti-PD-L1 antibody is administered prior to the anti-LAG-3 antibody.

[0030] In some aspects, the anti-LAG-3 antibody is administered prior to the anti-PD-1 antibody or the anti-PD-L1 antibody.

[0031] In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody or anti-PD-L1 antibody are administered simultaneously.

[0032] In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody or anti-PD-L1 antibody are formulated separately.

[0033] In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody or anti-PD-L1 antibody are formulated together.

[0034] The present disclosure relates to a method of treating a human subject suffering from colorectal cancer (CRC), comprising administering to the subject (a) about 480 mg of an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 3, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 4, and (b) about 480 mg of an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 13, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 14.

[0035] In some aspects, the anti-LAG-3 antibody is a full-length antibody. In some aspects, the anti-LAG-3 antibody is a monoclonal, human, humanized, chimeric or multispecific antibody. In some aspects, the multispecific antibody is a dual affinity retargeting antibody (DART), DVD-Ig or bispecific antibody.

[0036] In some aspects, the anti-LAG-3 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.

[0037] In some aspects, the anti-LAG-3 antibody is BMS-986016 (relatolimab) or comprises an antigen-binding portion thereof.

[0038] In some aspects, the anti-LAG-3 antibody comprises (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:5; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:6; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:7; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:8; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:9; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:10.

[0039] In some aspects, the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 3 and 4, respectively.

[0040] In some aspects, the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 1 and 2, respectively.

[0041] In some aspects, the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs:21 and 2, respectively.

[0042] In some embodiments, the anti-PD-1 antibody is a full-length antibody.

[0043] In some aspects, the anti-PD-1 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. In some aspects, the multispecific antibody is a DART, DVD-Ig, or a bispecific antibody.

[0044] In some aspects, the anti-PD-1 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0045] In some aspects, the anti-PD-1 antibody is nivolumab or comprises an antigen-binding portion thereof.

[0046] In some aspects, the anti-PD-1 antibody comprises (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 15; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 16; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 17; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 18; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 19; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 20.

[0047] In some aspects, the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively.

[0048] In some aspects, the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the sequences as set forth in SEQ ID NOs:11 and 12, respectively.

[0049] In some aspects, the anti-LAG-3 antibody and / or the anti-PD-1 antibody are formulated for intravenous administration.

[0050] In some aspects, the anti-LAG-3 antibody and / or anti-PD-1 antibody is administered about once every week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, about once every 10 weeks, about once every 11 weeks, or about once every 12 weeks.

[0051] In some embodiments, the anti-PD-1 antibody is administered prior to the anti-LAG-3 antibody.

[0052] In some embodiments, the anti-LAG-3 antibody is administered prior to the anti-PD-1 antibody.

[0053] In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody or antibodies are administered simultaneously.

[0054] In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody or anti-PD-L1 antibody are formulated separately.

[0055] In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody or anti-PD-L1 antibody are formulated together.

[0056] In some aspects, the method is a first line therapy.

[0057] In some aspects, the method is a second line therapy.

[0058] In some aspects, the method is a third line therapy.

[0059] In some embodiments, the subject has progressed on or is intolerant to prior therapy, hi some embodiments, prior therapy includes fluoropyrimidines, oxaliplatin, irinotecan, anti-vascular endothelial growth factor (VEGF) therapy, anti-epidermal growth factor receptor (EGFR) therapy for CRC containing a Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, regorafenib, TAS-102, or any combination thereof.

[0060] In some aspects, the subject has not received prior systemic therapy for advanced and / or metastatic CRC.

[0061] In some aspects, the subject has no prior immuno-oncology therapy, the subject has no prior immuno-oncology therapy for CRC, or the CRC has no prior immuno-oncology therapy.

[0062] In some embodiments, the CRC comprises adenocarcinoma histology.

[0063] In some aspects, the CRC is unresectable, advanced and / or metastatic.

[0064] In some aspects, the CRC is microsatellite stable (MSS) CRC.

[0065] In some aspects, MSS CRC comprises high T cell activation and LAG-3 upregulation.

[0066] In some embodiments, the CRC is microsatellite instability high (MSI-H) CRC.

[0067] In some embodiments, the CRC comprises a KRAS mutation.

[0068] In some embodiments, the CRC comprises a wild-type KRAS.

[0069] In some aspects, one or more immune cells in a tumor tissue from a subject express LAG-3. In some aspects, at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the immune cells express LAG-3. In some aspects, at least about 1% of the immune cells express LAG-3. In some aspects, the immune cells are tumor infiltrating lymphocytes. In some aspects, the tumor infiltrating lymphocytes are CD8 + It is a cell.

[0070] In some embodiments, at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of nucleated cells in tumor tissue from a subject express LAG-3. In some embodiments, at least about 1% of nucleated cells express LAG-3.

[0071] In some aspects, one or more cells in a tumor tissue from a subject express PD-L1. In some aspects, the tumor tissue comprises a PD-L1 Tumor Proportion Score (TPS) and / or Combined Positive Score (CPS) of at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the tumor cells, where TPS is the percentage of tumor cells in the tumor tissue that express PD-L1, and CPS is the number of tumor and immune cells in the tumor tissue that express PD-L1 as a percentage of the total number of viable tumor cells. In some aspects, the tumor tissue comprises at least about 1% PD-L1 TPS and / or CPS.

[0072] In some aspects, at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of nucleated cells in a tumor tissue from a subject express PD-L1. In some aspects, at least about 1% of nucleated cells express PD-L1.

[0073] In some aspects, the CRC is colon cancer.

[0074] In some aspects, the CRC is rectal cancer.

[0075] In some aspects, any of the above methods further comprise administering to the subject an additional therapeutic agent. In some aspects, the additional therapeutic agent comprises an anti-cancer agent. In some aspects, the anti-cancer agent comprises a tyrosine kinase inhibitor, a checkpoint inhibitor, a checkpoint stimulator, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topoisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof. In some aspects, the checkpoint inhibitors are selected from the group consisting of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, T-cell immunoglobulin and ITIM domain (TIGIT) inhibitors, T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B- and T-cell lymphocyte attenuator (BTLA) inhibitors, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitors, killer cell immunoglobulin-like receptor (KIR) inhibitors, adenosine A2a receptor (A2aR) inhibitors, transforming The checkpoint inhibitors include transforming growth factor beta (TGF-β) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, CD47 inhibitors, CD48 inhibitors, CD73 inhibitors, CD113 inhibitors, sialic acid-binding immunoglobulin-like lectin 7 (SIGLEC-7) inhibitors, SIGLEC-9 inhibitors, SIGLEC-15 inhibitors, glucocorticoid-inducible TNFR-related protein (GITR) inhibitors, galectin-1 inhibitors, galectin-9 inhibitors, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) inhibitors, G protein-coupled receptor 56 (GPR56) inhibitors, glycoprotein A repeat dominant (GARP) inhibitors, 2B4 inhibitors, programmed death 1 homolog (PD1H) inhibitors, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitors, or any combination thereof. In some aspects, the checkpoint inhibitor comprises a CTLA-4 inhibitor. In some embodiments, the CTLA-4 inhibitor is an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is a full-length antibody.In some aspects, the anti-CTLA-4 antibody is a monoclonal, human, humanized, chimeric or multispecific antibody. In some aspects, the multispecific antibody is a DART, DVD-Ig or bispecific antibody. In some aspects, the anti-CTLA-4 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment or a single chain binding polypeptide. In some aspects, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, MK-1308, AGEN-1884 or comprises an antigen-binding portion thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0076] The present disclosure provides a method of treating a human subject suffering from colorectal cancer (CRC), comprising administering to the subject an anti-LAG-3 antibody and an anti-PD-1 or anti-PD-L1 antibody. Some embodiments of the present disclosure relate to a method of treating a human subject suffering from CRC, the method being a first, second or third line therapy, and / or the subject has progressed on or is intolerant to a previous therapy. Some embodiments of the present disclosure relate to a method of treating a human subject suffering from unresectable, advanced and / or metastatic CRC. Some embodiments of the present disclosure relate to a method of treating a human subject suffering from microsatellite stable CRC. Some embodiments of the present disclosure relate to a method of treating a human subject suffering from microsatellite instability high CRC. Some embodiments of the present disclosure relate to a method of treating a human subject suffering from CRC, comprising administering to the subject an additional therapeutic agent (e.g., an anti-cancer agent).

[0077] I. Terminology In order that this disclosure may be more readily understood, certain terms are first defined. As used herein, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout this application.

[0078] It should be noted that the term "a" or "an" entity refers to one or more of that entity. For example, a "nucleotide sequence" is understood to refer to one or more nucleotide sequences. Thus, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

[0079] The term "and / or" as used herein should be interpreted as a specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" when used herein in phrases such as "A and / or B" is intended to include "A and B", "A or B", "A" (single) and "B" (single). Similarly, when used in phrases such as "A, B and / or C", the term "and / or" is intended to encompass each of the following aspects: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (single); B (single); and C (single).

[0080] Whenever an embodiment is described herein with the term "comprising," it is understood that otherwise similar embodiments described with the terms "consisting of" and / or "consisting essentially of" are also provided.

[0081] The terms "about" or "consisting essentially of" refer to a value or composition that is within an acceptable range of error for a particular value or composition as determined by one of ordinary skill in the art, and such error will depend, in part, on how the value or composition is measured or determined, i.e., on the limitations of the measurement system. For example, "about" or "consisting essentially of" can mean within one standard deviation or within more than one standard deviation, as is customary in the art. Alternatively, "about" or "consisting essentially of" can mean within a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%). Additionally, particularly with respect to biological systems or processes, these terms can mean up to an order of magnitude or up to 5 times a value. When a specific value or composition is provided in the present application and claims, unless otherwise specified, the meaning of "about" or "consisting essentially of" should be assumed to be within an acceptable range of error for that particular value or composition.

[0082] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include, unless otherwise indicated, any integer value within the stated range and fractions thereof, where appropriate (such as tenths and hundredths of an integer).

[0083] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 5th ed., 2013, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, 2006, Oxford University Press provide those of ordinary skill in the art with a general dictionary of many of the terms used in this disclosure.

[0084] Units, prefixes and symbols are written in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.

[0085] The headings provided herein are not limitations of the various aspects of the disclosure which can be had by reference to the specification as a whole, and therefore the terms defined immediately below are more fully defined by reference to the specification as a whole.

[0086] "Antagonist" is intended to include, without limitation, any molecule that has the ability to block, reduce or otherwise limit the interaction or activity of a target molecule (e.g., LAG-3). In some aspects, antagonists are antibodies. In other aspects, antagonists include small molecules. The terms "antagonist" and "inhibitor" are used interchangeably herein.

[0087] "Antibody" (Ab) is intended to include, without limitation, a glycoprotein immunoglobulin that specifically binds to an antigen and comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each H chain contains a heavy chain variable region (herein referred to as V H ) and a heavy chain constant region (abbreviated as C HThe heavy chain constant region comprises three constant domains, C H1 , C H2 and C H3 Each light chain comprises a light chain variable region (referred to herein as V L ) and a light chain constant region (abbreviated as C L The light chain constant region comprises one constant domain, C L Includes: V H and V L The regions can be further divided into regions of hypervariability called complementarity determining regions (CDRs) interspersed with regions of greater conservedness called framework regions (FRs). H and V L contains three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of the antibody may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The heavy chain may or may not have a C-terminal lysine. Unless otherwise specified herein, amino acids in the variable regions are numbered using the Kabat numbering system and amino acids in the constant regions are numbered using the EU system.

[0088] Immunoglobulins may be derived from any of the commonly known isotypes, including, but not limited to, IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those skilled in the art, including, but not limited to, human IgG1, IgG2, IgG3, and IgG4. "Isotype" refers to the antibody class or subclass (e.g., IgM or IgG1) that is encoded by the heavy chain constant region genes. By way of example, the term "antibody" includes both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human or non-human antibodies; fully synthetic antibodies; single-chain antibodies; monospecific antibodies; bispecific antibodies; and multispecific antibodies. Non-human antibodies can be humanized by recombinant methods to reduce their immunogenicity in humans. Unless expressly specified and unless the context dictates otherwise, the term "antibody" also includes antigen-binding fragments or portions of any of the aforementioned immunoglobulins, including monovalent and bivalent fragments or portions that retain the ability to specifically bind to the antigen to which the whole immunoglobulin binds. Examples of "antigen-binding portions" or "antigen-binding fragments" include: (1) Fab fragments (fragments from papain cleavage) or V L , V H , L C and C H1 (2) a similar monovalent fragment comprising an F(ab')2 fragment (a fragment from pepsin cleavage) or two Fab fragments linked by a disulfide bridge at the hinge region; (3) an Fd fragment consisting of the VH and CH1 domains; (4) a single-arm V L and V H (5) Fv fragment consisting of V domains; H (6) single-domain antibody (dAb) fragments, which consist of two V domains (Ward et al., (1989) Nature 341:544-46); (7) two V fragments linked by a hinge H (6) bi-single domain antibodies (dual affinity retargeting antibodies (DART)); or (7) dual variable domain immunoglobulins. In addition, the two domains of the Fv fragment, V L and V Hare encoded by separate genes, but they can be joined together by synthetic linkers using recombinant methods to form the V L and V H This allows them to be produced as a single protein chain in which the domains pair to form monovalent molecules (known as single-chain Fvs (scFvs); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).

[0089] An "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds to LAG-3 is substantially free of antibodies that do not specifically bind to LAG-3). However, an isolated antibody that specifically binds to an antigen may have cross-reactivity with other antigens (e.g., an antibody that specifically binds to LAG-3 that has cross-reactivity with LAG-3 molecules from different species). Moreover, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0090] The term "monoclonal antibody" ("mAb") refers to antibody molecules of single molecular composition, i.e., a non-naturally occurring preparation of antibody molecules essentially identical in their primary sequence and which display a single binding specificity and affinity for a particular epitope. A mAb is an example of an isolated antibody. mAbs can be produced by hybridoma, recombinant, transgenic, or other techniques known to those of skill in the art.

[0091] A "human" antibody (HuMAb) refers to an antibody having a variable region in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region is also derived from a human germline immunoglobulin sequence. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced in vitro by random or site-specific mutagenesis or introduced in vivo by somatic mutation). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The terms "human" antibody and "fully human" antibody are used synonymously.

[0092] "Humanized antibody" refers to an antibody in which some, most or all of the amino acids outside the CDR domains of a non-human antibody are replaced with the corresponding amino acids from a human immunoglobulin. In one embodiment of a humanized form of an antibody, some, most or all of the amino acids outside the CDR domains are replaced with amino acids from a human immunoglobulin, while some, most or all of the amino acids within one or more CDR regions remain unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abolish the ability of the antibody to bind to a particular antigen. A "humanized" antibody retains the same antigen specificity as the original antibody.

[0093] "Chimeric antibody" refers to an antibody in which the variable region is derived from one species and the constant region is derived from another species, such as an antibody in which the variable region is derived from a murine antibody and the constant region is derived from a human antibody.

[0094] An "anti-antigen" antibody refers to an antibody that specifically binds to an antigen. For example, an anti-LAG-3 antibody specifically binds to LAG-3.

[0095] "LAG-3" refers to lymphocyte activation gene 3. The term "LAG-3" includes variants, isoforms, homologs, orthologs, and paralogs. For example, an antibody specific for human LAG-3 protein may in certain cases cross-react with LAG-3 protein from species other than human. In other embodiments, an antibody specific for human LAG-3 protein may be completely specific for human LAG-3 protein and exhibit no species or other types of cross-reactivity, or may cross-react with LAG-3 from certain other species but not with any other species (e.g., cross-react with monkey LAG-3 but not with mouse LAG-3). The term "human LAG-3" refers to human sequence LAG-3, such as the complete amino acid sequence of human LAG-3 having GenBank Accession No. NP_002277. The term "mouse LAG-3" refers to the mouse sequence LAG-3, such as the complete amino acid sequence of mouse LAG-3 having GenBank Accession No. NP_032505. LAG-3 is also known in the art, for example, as CD223. A human LAG-3 sequence can differ from human LAG-3 having GenBank Accession No. NP_002277, for example, by having conserved mutations or mutations in non-conserved regions, and the LAG-3 has substantially the same biological function as human LAG-3 having GenBank Accession No. NP_002277. For example, the biological function of human LAG-3 is that it has an epitope in the extracellular domain of LAG-3 to which an antibody of the present disclosure specifically binds, or the biological function of human LAG-3 is that it binds to an MHC class II molecule.

[0096] A particular human LAG-3 sequence generally has an amino acid sequence that is at least about 90% identical to the human LAG-3 of GenBank Accession No. NP_002277 and contains amino acid residues that identify the amino acid sequence as human when compared to the LAG-3 amino acid sequence of other species (e.g., mouse). In particular cases, the human LAG-3 may have an amino acid sequence that is at least about 95% identical to the LAG-3 of GenBank Accession No. NP_002277, or even at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the LAG-3 of GenBank Accession No. NP_002277. In particular embodiments, the human LAG-3 sequence will show no more than 10 amino acid differences from the LAG-3 of GenBank Accession No. NP_002277. In particular embodiments, the human LAG-3 may show no more than 5 amino acid differences, or even no more than 4, 3, 2, or 1 amino acid differences from the LAG-3 of GenBank Accession No. NP_002277.

[0097] "Programmed Death 1 (PD-1)" refers to an immunosuppressive receptor belonging to the CD28 family. PD-1 is expressed primarily on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. The term "PD-1" as used herein includes human PD-1 (hPD-1), variants, isoforms and species homologs of hPD-1, and analogs that share at least one epitope in common with hPD-1. The complete hPD-1 sequence can be found at GenBank Accession No. U64863. "PD-1" and "PD-1 receptor" are used interchangeably herein.

[0098] "Cytotoxic T-lymphocyte antigen 4 (CTLA-4)" refers to an immunosuppressive receptor belonging to the CD28 family. CTLA-4 is expressed in vivo only on T cells and binds two ligands, CD80 and CD86 (also called B7-1 and B7-2, respectively). The term "CTLA-4" as used herein includes human CTLA-4 (hCTLA-4), variants, isoforms and species homologs of hCTLA-4, and analogs that share at least one epitope in common with hCTLA-4. The complete hCTLA-4 sequence can be found at GenBank Accession No. AAB59385.

[0099] "Programmed death-ligand 1 (PD-L1)" is one of two cell surface glycoprotein ligands for PD-1 (the other is PD-L2) that downregulates T cell activation and cytokine secretion upon binding to PD-1. The term "PD-L1" as used herein includes human PD-L1 (hPD-L1), variants, isoforms and species homologs of hPD-L1, and analogs that share at least one epitope in common with hPD-L1. The complete hPD-L1 sequence can be found at GenBank Accession No. Q9NZQ7.

[0100] "Programmed Death-Ligand 2 (PD-L2)" as used herein includes human PD-L2 (hPD-L2), variants, isoforms and species homologues of hPD-L2, and analogues that share at least one epitope in common with hPD-L2. The complete hPD-L2 sequence can be found at GenBank Accession No. Q9BQ51.

[0101] A "patient," as used herein, includes any patient afflicted with CRC (e.g., metastatic CRC). The terms "subject" and "patient" are used interchangeably herein.

[0102] "Administering" refers to the physical introduction of a therapeutic agent (e.g., a composition or formulation comprising a therapeutic agent) into a subject using any of a variety of methods and delivery systems known to those of skill in the art. Exemplary routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion. The phrase "parenteral administration" as used herein means a mode of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. In some embodiments, the formulation is administered by a non-parenteral route, in some embodiments orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, such as intranasal, vaginal, rectal, sublingual or topical. Administration can be, for example, once, multiple times, and / or over one or more successive periods of time.

[0103] As used herein, "Eastern Cooperative Oncology Group Performance Status (ECOG PS)" is a numbering scale used to define the patient population under study in a clinical trial in a way that is uniform and reproducible among the physicians who enroll the patients. ECOG PS utilizes standardized criteria to measure how much the disease affects the patient's ability to perform daily activities. Exemplary definitions of ECOG PS include "0" for patients who are fully active and can do everything they were able to do before the onset of the disease without any limitations; "1" for patients who are limited in physically strenuous activities but can walk and perform light or sedentary tasks; "2" for patients who are ambulatory and can take care of themselves completely and are able to get up and move around more than 50% of the day but cannot perform any occupational activities; "3" for patients who can only take care of themselves to a limited extent and spend more than 50% of the day in bed or chair; and "4" for patients who are completely immobile, cannot take care of themselves at all, and spend all of the day in bed or chair.

[0104] "Treatment" or "therapy" of a subject refers to any type of intervention or process performed on a subject or administration of an active agent to a subject with the goal of reversing, alleviating, ameliorating, inhibiting, or slowing the progression, onset, severity, or recurrence of a symptom, complication, or condition, or biochemical indicators associated with a disease. Response Evaluation Criteria in Solid Tumors (RECIST) is a measure of treatment effectiveness and is an established set of rules that define when a tumor responds, stabilizes, or progresses during treatment. RECIST v1.1 is the current guideline for solid tumor measurement and definition to objectively determine changes in tumor size used in adult and pediatric cancer clinical trials.

[0105] As used herein, "effective treatment" refers to a treatment that results in a beneficial effect, e.g., an improvement in at least one symptom of a disease or disorder. A beneficial effect can take the form of an improvement compared to a baseline, i.e., an improvement compared to a measurement or observation made before the initiation of therapy according to the method. A beneficial effect can also take the form of a prevention, slowing, deceleration, or stabilization of the adverse progression of solid tumor markers. Effective treatment can refer to a reduction in at least one symptom of a solid tumor. Such effective treatment can, for example, reduce a patient's pain, reduce the size and / or number of lesions, reduce or prevent tumor metastasis, and / or slow tumor growth.

[0106] The term "effective amount" refers to an amount of an agent that provides a desired biological, therapeutic and / or prophylactic result. Such a result may be reduction, amelioration, alleviation, mitigation, delay and / or relief of one or more of the signs, symptoms or causes of a disease, or any other desired change to a biological system. In the context of solid tumors, an effective amount includes an amount sufficient to cause tumor shrinkage and / or a decrease in the rate of tumor growth (such as tumor growth inhibition) or other slowing of undesirable cell proliferation. In some aspects, an effective amount is an amount sufficient to prevent or delay tumor recurrence. An effective amount can be administered in one or more administrations. An effective amount of a drug or composition is capable of (i) reducing the number of cancer cells; (ii) reducing tumor size; (iii) inhibiting, retarding, slowing to some extent, or halting cancer cell invasion into peripheral organs; (iv) inhibiting (i.e., slowing to some extent, or halting tumor metastasis; (v) inhibiting tumor growth; (vi) preventing or delaying the onset and / or recurrence of tumors; and / or (vii) alleviating to some extent one or more symptoms associated with cancer. In one example, an "effective amount" is an amount of anti-LAG-3 antibody alone, or an amount of anti-LAG-3 antibody in combination with an additional therapeutic agent (e.g., an anti-PD-1 antibody), that has been clinically found to affect a significant reduction in cancer or a slowing of cancer progression, such as advanced solid tumors.

[0107] As used herein, the terms "fixed dose," "constant dose," and "constant fixed dose" are used interchangeably and refer to a dose administered to a patient without consideration of the patient's weight or body surface area (BSA). Thus, a fixed or constant dose is not provided as a mg / kg dose, but rather as an absolute amount of drug (e.g., an amount in μg or mg).

[0108] Use of the term "fixed dose combination" in reference to compositions of the invention means that two or more different inhibitors as described herein (e.g., an anti-LAG-3 antibody and an anti-PD-1 antibody) in a single composition are present in the composition in a specific (fixed) ratio relative to each other. In some aspects, the fixed dose is based on the weight (e.g., mg) of the inhibitor. In certain aspects, the fixed dose is based on the concentration (e.g., mg / ml) of the inhibitor. In some embodiments, the ratio is at least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, About 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1 mg of the first inhibitor to mg of the second inhibitor. For example, a 1:1 ratio of the first inhibitor and the second inhibitor can mean that a vial can contain about 480 mg of the first inhibitor and 480 mg of the second inhibitor.

[0109] The term "body weight dose" as referred to herein means that the dose administered to a patient is calculated based on the patient's body weight.

[0110] "Dosing interval," as used herein, refers to the amount of time that elapses between administration of multiple doses of the formulations disclosed herein to a subject. Dosing intervals may thus be indicated as ranges.

[0111] The term "dose frequency" as used herein refers to the frequency with which a dose of a formulation disclosed herein is administered within a given time period. Dose frequency can be indicated as the number of doses per given time period, such as, for example, once a week or once every two weeks.

[0112] The terms "about once a week," "about once every week," "about once every 2 weeks," or any other similar dosing interval term, as used herein, refer to approximate numbers, and "about once a week" or "about once every week" may include every 7 days ± 2 days, i.e., every 5 to 9 days. A "weekly" dose administration frequency may thus be every 5, 6, 7, 8, or 9 days. "About once every 3 weeks" may include every 21 days ± 3 days, i.e., every 25 to 31 days. Similar approximations apply to, for example, about once every 2 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, about once every 10 weeks, about once every 11 weeks, and about once every 12 weeks. In some embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose can be administered on any day in week 1, followed by the next dose on any day in week 6 or week 12, respectively. In other embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose is administered on a particular day in week 1 (e.g., Monday), followed by the next dose on the same day in week 6 or week 12 (i.e., Monday), respectively.

[0113] An "adverse event" (AE), as used herein, is any unfavourable, generally unintended or undesirable sign (including abnormal clinical laboratory findings), symptom or disease associated with the use of a medical treatment. For example, an adverse event may be associated with activation of the immune system or an increase in immune system cells (e.g., T cells) in response to the treatment. A medical treatment may be accompanied by one or more associated AEs, each of which may present with the same or different levels of severity.

[0114] The term "tumor," as used herein, refers to any mass of tissue resulting from excessive cell growth or proliferation, either benign (non-cancerous) or malignant (cancerous), including pre-cancerous lesions.

[0115] The term "biological sample" as used herein refers to biological material isolated from a subject. Biological samples can include any biological material suitable for analysis, for example, by sequencing the nucleic acid of a tumor (or circulating tumor cells) and identifying genomic alterations in the sequenced nucleic acid. Biological samples can be any suitable biological tissue or body fluid, such as, for example, tumor tissue, blood, plasma, and serum. Biological samples can be test tissue samples (e.g., tissue samples that contain tumor cells and tumor-infiltrating inflammatory cells). In one aspect, the sample is a tumor tissue biopsy, such as formalin-fixed paraffin-embedded (FFPE) tumor tissue or fresh frozen tumor tissue. In another aspect, the biological sample is a liquid biopsy, which in some embodiments includes one or more of blood, serum, plasma, circulating tumor cells, exoRNA, ctDNA, and cfDNA.

[0116] By way of example, an "anti-cancer agent" promotes cancer regression in a subject. In a preferred embodiment, a therapeutically effective amount of the agent promotes cancer regression to the point where the cancer disappears. "Promoting cancer regression" means that administration of an effective amount of an anti-cancer agent, alone or in combination with another agent, results in a reduction in tumor growth or size, tumor necrosis, a decrease in the severity of at least one disease symptom, an increase in the frequency and duration of disease-free periods, or prevention of disability or incapacity due to disease exposure. In addition, the terms "effective" and "effectiveness" in relation to treatment include both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of an agent to promote cancer regression in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (adverse effects) at the cell, organ and / or organism level caused by administration of the agent.

[0117] As an example for the treatment of tumors, a therapeutically effective amount of an anti-cancer agent can inhibit cell growth or tumor growth by at least about 20%, at least about 40%, at least about 60%, or at least about 80% compared to untreated subjects. In other aspects of the present disclosure, tumor regression can be observed and continue to regress for a period of at least about 20 days, more preferably at least about 40 days or at least about 60 days. Notwithstanding these measures of therapeutic efficacy, evaluation of immunotherapeutic agents must also take into account immune-related response patterns.

[0118] As used herein, "immuno-oncology" therapy or "IO" or "IO" therapy refers to a therapy that involves using the immune response to target and treat a tumor in a subject. Thus, as used herein, IO therapy is a type of anti-cancer therapy. In some aspects, IO therapy includes administering to the subject an antibody. In some aspects, IO therapy includes administering to the subject an immune cell, such as a T cell, such as a modified T cell, such as a T cell modified to express a chimeric antigen receptor or a specific T cell receptor. In some aspects, IO therapy includes administering to the subject a therapeutic vaccine. In some aspects, IO therapy includes administering to the subject a cytokine or chemokine. In some aspects, IO therapy includes administering to the subject an interleukin. In some aspects, IO therapy includes administering to the subject an interferon. In some aspects, IO therapy includes administering to the subject a colony stimulating factor.

[0119] "Immune response" refers to the actions of cells of the immune system (e.g., T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells, and neutrophils) and soluble macromolecules (including antibodies, cytokines, and complement) produced by any of these cells or the liver, resulting in the selective targeting, binding to, damaging, destroying, and / or elimination from the vertebrate body of invading pathogens, pathogen-infected cells or tissues, cancerous or other abnormal cells, or, in the case of autoimmunity or pathological inflammation, normal human cells or tissues.

[0120] "Tumor-infiltrating inflammatory cells" or "tumor-associated inflammatory cells" are any type of cell that is typically involved in an inflammatory response in a subject and that infiltrates tumor tissue. Such cells include tumor-infiltrating lymphocytes (TILs), macrophages, monocytes, eosinophils, histiocytes, and dendritic cells.

[0121] The terms "LAG-3 positive" or "positive LAG-3 expression" with respect to LAG-3 expression refer to tumor tissue (e.g., a test tissue sample) that is scored as expressing LAG-3 based on the proportion (i.e., percentage) of immune cells (e.g., tumor infiltrating lymphocytes such as CD8+ T cells) that express LAG-3 (e.g., expression of 1% or more) or based on the proportion (i.e., percentage) of nucleated cells that express LAG-3 (i.e., immune cells that express LAG-3 as a percentage of total nucleated cells, e.g., expression of 1% or more).

[0122] "LAG-3 negative" or "negative for LAG-3 expression" refers to a tumor tissue (e.g., a tissue sample tested) that does not score as expressing LAG-3 (e.g., less than 1% LAG-3 expression).

[0123] The terms "PD-L1 positive" or "positive PD-L1 expression", with reference to cell surface PD-L1 expression, refer to tumor tissue (e.g., a test tissue sample) that achieves a score as expressing PD-L1 based on the Tumor Proportion Score (TPS), which is the proportion (i.e., percentage) of tumor cells that express PD-L1 (e.g., expression ≥ 1%), or based on the Combined Positive Score (CPS), which is the number of tumor and immune cells (e.g., tumor cells, lymphocytes, and macrophages) that express PD-L1 in the tumor tissue as a percentage of the total number of viable tumor cells (i.e., the number of tumor and immune cells that express PD-L1 divided by the total number of viable tumor cells multiplied by 100 (i.e., e.g., expression ≥ 1%), or based on the proportion (i.e., percentage) of nucleated cells that express PD-L1 (i.e., tumor cells expressing PD-L1 as a percentage of total nucleated cells, e.g., expression ≥ 1%).

[0124] The terms "PD-L1 negative" or "PD-L1 expression negative" refer to a tumor tissue (e.g., a test tissue sample) that does not score as expressing PD-L1 (e.g., less than 1% expression).

[0125] Various aspects of the invention are described in further detail in the following subsections.

[0126] II. Methods of the Disclosure Provided herein is a method of treating a human subject suffering from colorectal cancer (CRC), comprising administering to the subject an anti-LAG-3 antibody and an anti-PD-1 or anti-PD-L1 antibody.

[0127] In some aspects, the CRC is colon cancer, rectal cancer, or a combination thereof.

[0128] There are five stages of colon cancer: stage 0 (intraepithelial carcinoma), stage I, stage II, stage III, and stage IV. Standard care treatments for colon cancer include: 1) surgery, including local resection, removal of the colon with anastomosis, or removal of the colon with colostomy; 2) radiofrequency ablation; 3) cryosurgery; 4) chemotherapy; 5) radiation therapy; and 6) targeted therapy, including monoclonal antibodies and angiogenesis inhibitors. In some aspects, the methods of the present disclosure further include administering a standard care therapy for the treatment of colon cancer.

[0129] There are five stages of rectal cancer: stage 0 (intraepithelial carcinoma), stage I, stage II, stage III, and stage IV. Standard care treatments for rectal cancer include: 1) surgery, including polypectomy, local excision, excision, radiofrequency ablation, cryosurgery, and pelvic exenteration; 2) radiation therapy; 3) chemotherapy; and 4) targeted therapy, including monoclonal antibody therapy. In some embodiments, the methods of the present disclosure further include administering a standard care therapy for the treatment of rectal cancer.

[0130] In some embodiments, the method is a first line (1L) therapy.

[0131] In some aspects, the method is a second line (2L) therapy.

[0132] In some aspects, the method is a third line (3L) therapy.

[0133] In some aspects, the subject has progressed on or is intolerant to prior therapy (e.g., standard of care therapy, including standard of care 1L or 2L therapy).

[0134] The predominant first-line treatment options for patients with metastatic CRC (mCRC) are 5-fluorouracil (5-FU)-containing regimens in combination with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), for example with a biologic agent such as bevacizumab. Combinations with the epidermal growth factor receptor (EGFR) inhibitors cetuximab and panitumumab are also options when Kirsten rat sarcoma viral oncogene homolog (KRAS) status is non-mutated.

[0135] FOLFIRI is used in the second-line setting for patients whose first-line therapy was FOLFOX or another 5-FU-containing regimen. Bevacizumab, ramucirumab, and ziv-aflibercept are also used in second-line treatment in combination with chemotherapy.

[0136] Regorafenib (also known as STIVARGA®), an oral multikinase inhibitor, and TAS-102 (also known as LONSURF®), an oral combination therapy of trifluridine and tipiracil hydrochloride, are used as subsequent line of therapy in patients previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-vascular endothelial growth factor (VEGF) therapy, and in cases of KRAS WT, anti-epidermal growth factor receptor (EGFR) therapy.

[0137] In some aspects, the prior therapy includes a fluoropyrimidine, oxaliplatin, irinotecan, anti-vascular endothelial growth factor (VEGF) therapy, anti-epidermal growth factor receptor (EGFR) therapy for CRC containing a Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (e.g., cetuximab or panitumumab), regorafenib, TAS-102, or any combination thereof.

[0138] In some aspects, the subject has undergone one, two, three, four or more prior therapies.

[0139] In some aspects, the subject has not received prior systemic therapy for advanced and / or metastatic CRC.

[0140] In some embodiments, the subject has no prior immuno-oncology (IO) therapy. In some embodiments, the subject has never received IO therapy, has received IO therapy for a cancer other than CRC, or has received IO therapy for a past CRC but not for the current CRC. In some embodiments, the subject has no prior IO therapy, the subject has no prior IO therapy for CRC, or the CRC has no prior IO therapy. In some embodiments, the prior IO therapy is an antibody. In some embodiments, the antibody is bound to a checkpoint inhibitor. In some embodiments, the prior IO therapy is an anti-PD-1 antibody and / or a combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody.

[0141] In some aspects, the methods of the present disclosure result in increased progression-free survival (PFS), objective response rate (ORR), overall survival (OS), or any combination thereof, when compared to standard of care and / or prior therapies, such as those disclosed herein.

[0142] In some aspects, the methods of the disclosure reduce tumor size, inhibit tumor growth, eliminate a tumor from a subject, prevent recurrence of CRC, induce remission of CRC, provide a complete or partial response, or any combination thereof.

[0143] In some embodiments, the CRC comprises adenocarcinoma histology.

[0144] In some aspects, the CRC is unresectable, advanced and / or metastatic.

[0145] Approximately 4% of CRCs are associated with microsatellite instability-high (MSI-H), a genetic hypermutable state caused by deficient DNA mismatch repair (dMMR). The presence of MSI-H represents phenotypic evidence of dMMR. In most cases, the genetic basis of MSI-H CRC is an inherited germline alteration in any one or more of the five human MMR genes: MLH1, MSH2, MSH6, PMS1, or PMS2.

[0146] In contrast to MSI-H, microsatellite stability (MSS) is a molecular fingerprint of the mismatch repair-competent (pMMR) system. The term MSS is widely accepted as a surrogate term for pMMR tumors. Approximately 85% of CRCs exhibit MSS without novel microsatellite alleles.

[0147] In colorectal cancer, MSI-H is associated with immune infiltration and increased expression of immune checkpoint regulators, whereas MSS is typically associated with an immunosuppressive tumor microenvironment that blunts activation of antitumor immune responses. However, some MSS CRC patients display an MSI-like tumor immune architecture characterized by high T cell activation and LAG-3 upregulation.

[0148] Patients with MSI-H mCRC are less likely to benefit from conventional chemotherapy than those with MSS mCRC, but studies have confirmed that identification of MSS may have prognostic value in that MSS CRC has a poorer prognosis compared with MSI-H CRC.

[0149] There are several well-established methods to distinguish MSS from MSI-H. One is immunohistochemistry (IHC) for MMR. IHC MMR testing consists of staining tumor tissue for loss of expression of four mismatch repair proteins known to be mutated in Lynch syndrome: MLH1, MSH2, MSH6 and PMS2. If at least one of these is not normally expressed, the test indicates a dMMR (MSI-H) phenotype. MSI can also be determined by polymerase chain reaction (PCR) amplification of a set of mono- and / or dinucleotide repeats on tumor and normal DNA, followed by comparison of peak patterns by capillary electrophoresis, in three categories: MSI-H, MSI-low and MSS. Clinicopathological features and many molecular features in MSI-low tumors do not appear to differ from MSS tumors. Therefore, unless otherwise noted, MSS CRC in the methods disclosed herein includes MSI-low CRC.

[0150] In some aspects, the CRC is an MSS CRC.

[0151] In some aspects, MSS CRC comprises high T cell activation and LAG-3 upregulation.

[0152] In some aspects, the MSS CRC does not include the MSI low CRC (i.e., the MSS CRC excludes the MSI low CRC).

[0153] In some aspects, the CRC comprises normal expression of an MMR protein (e.g., when compared to a reference expressing the corresponding wild-type MMR protein). In some aspects, the MMR proteins are MLH1, MSH2, MSH6, and PMS2. In some aspects, the MMR proteins are MLH1, MSH2, MSH6, PMS1, and PMS2.

[0154] In some aspects, the CRC is an MSI-H CRC.

[0155] In some aspects, the CRC comprises reduced expression of an MMR protein (e.g., when compared to a reference expressing the corresponding wild-type MMR protein). In some aspects, the MMR protein is MLH1, MSH2, MSH6, PMS2, or a combination thereof. In some aspects, the MMR protein is MLH1, MSH2, MSH6, PMS1, PMS2, or a combination thereof.

[0156] In some aspects, the CRC comprises a KRAS mutation, an NRAS mutation, a B-rapid fibrosarcoma proto-oncogene (BRAF) mutation, or a combination thereof.

[0157] In some aspects, the CRC comprises wild-type KRAS, wild-type NRAS, wild-type BRAF, or a combination thereof.

[0158] In some aspects, the methods of the disclosure include administering an anti-LAG-3 antibody and an anti-PD-1 or anti-PD-L1 antibody to a subject based on the subject's performance status. The performance status may be indicated by any one or more systems in the art. In some aspects, the system is Eastern Cooperative Oncology Group Performance Status (ECOG PS). In some aspects, the subject has an ECOG PS of 0 or 1. In some aspects, the subject has an ECOG PS of 0, 1 or 2. In some aspects, the subject has an ECOG PS of 0, 1, 2 or 3. In some aspects, the subject has an ECOG PS of 0, 1, 2, 3 or 4.

[0159] In some aspects, one or more immune cells in the tumor tissue from the subject express LAG-3 (i.e., the tumor tissue from the subject is LAG-3 positive) and / or one or more cells in the tumor tissue from the subject express PD-L1 (i.e., the tumor tissue from the subject is PD-L1 positive). In some aspects, one or more immune cells in the tumor tissue from the subject express LAG-3. In some aspects, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the immune cells express LAG-3. In some embodiments, at least about 1% of the immune cells express LAG-3. In some embodiments, more than about 1% of the immune cells express LAG-3. In some embodiments, at least about 5% of the immune cells express LAG-3. In some embodiments, the immune cells are tumor infiltrating lymphocytes. In some embodiments, the tumor infiltrating lymphocytes are CD8 +In some embodiments, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of nucleated cells in tumor tissue from the subject express LAG-3 (i.e., immune cells that express LAG-3 as a percentage of total nucleated cells). In some embodiments, at least about 1% of nucleated cells express LAG-3. In some embodiments, more than about 1% of nucleated cells express LAG-3. In some embodiments, at least about 5% of nucleated cells express LAG-3. In some embodiments, one or more cells in tumor tissue from the subject express PD-L1. In some aspects, tumor tissue from the subject has a PD-L1 Tumor Percentage Score (TPS) as defined herein and / or a Combined Positive Score (CPS) as defined herein of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100%. In some aspects, tumor tissue from the subject has a PD-L1 TPS and / or CPS of at least about 1%. In some aspects, tumor tissue from the subject has a PD-L1 TPS and / or CPS of greater than about 1%. In some aspects, tumor tissue from the subject has a PD-L1 TPS and / or CPS of at least about 5%.In some aspects, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of nucleated cells in tumor tissue from a subject express PD-L1 (i.e., tumor cells that express PD-L1 as a percentage of total nucleated cells). In some aspects, at least about 1% of nucleated cells in tumor tissue from a subject express PD-L1. In some aspects, at least about 1% of nucleated cells in tumor tissue from a subject express PD-L1. In some aspects, more than about 1% of nucleated cells in tumor tissue from a subject express PD-L1. In some embodiments, at least about 5% of nucleated cells in a tumor tissue from a subject express PD-L1. In some embodiments, any of the values ​​of "at least about X%" are "≧X%."

[0160] In some embodiments, one or more immune cells in a tumor tissue from a patient do not express LAG-3 (i.e., the tumor tissue from a patient is LAG-3 negative). In some embodiments, the tumor tissue is LAG-3 negative when less than about 1% of immune cells express LAG-3. In some embodiments, the tumor tissue is LAG-3 negative when less than about 1% of nucleated cells express LAG-3.

[0161] In some aspects, one or more cells in a tumor tissue from a patient do not express PD-L1 (i.e., the tumor tissue from a patient is PD-L1 negative). In some aspects, a tumor tissue is PD-L1 negative when it has less than about 1% TPS and / or CPS. In some aspects, a tumor tissue is PD-L1 negative when less than about 1% of nucleated cells express PD-L1.

[0162] In some embodiments, LAG-3 and / or PD-L1 expression in a subject's tumor tissue is determined from a test tissue sample. In some embodiments, the test tissue sample includes any clinically relevant tissue sample, such as, but not limited to, a tumor biopsy, a core biopsy, an incisional biopsy, an excision biopsy, a surgical specimen, a fine needle aspirate, or a sample of bodily fluid, such as blood, plasma, serum, lymph, ascites, cyst fluid, or urine. In some embodiments, the test tissue sample is from a primary tumor. In some embodiments, the test tissue sample is from a metastasis. In some embodiments, the test tissue sample is from multiple time points, such as before, during, and / or after treatment. In some embodiments, the test tissue sample is from different locations of a subject, such as from a primary tumor and from a metastasis.

[0163] In some aspects, the tissue sample tested is a paraffin-embedded fixed tissue sample. In some aspects, the tissue sample tested is a formalin-fixed paraffin-embedded (FFPE) tissue sample. In some aspects, the tissue sample tested is a fresh tissue (e.g., tumor) sample. In some aspects, the tissue sample tested is a frozen tissue sample. In some aspects, the tissue sample tested is a fresh frozen (FF) tissue (e.g., tumor) sample. In some aspects, the tissue sample tested is a cell isolated from a bodily fluid. In some aspects, the tissue sample tested comprises circulating tumor cells (CTCs). In some aspects, the tissue sample tested comprises tumor infiltrating lymphocytes (TILs). In some aspects, the tissue sample tested comprises tumor cells and tumor infiltrating lymphocytes (TILs). In some aspects, the tissue sample tested comprises circulating lymphocytes. In some aspects, the tissue sample tested is an archival tissue sample. In some aspects, the tissue sample tested is an archival tissue sample with a known diagnosis, treatment and / or outcome history. In some aspects, the sample is a tissue block. In some embodiments, the test tissue sample is a dispersed cell. In some embodiments, the sample size is from about 1 cell to about 1 x 10 6 In some embodiments, the sample size is between about 1 cell and about 1 x 10 5In some embodiments, the sample size is about 1 cell to about 10,000 cells. In some embodiments, the sample size is about 1 cell to about 1,000 cells. In some embodiments, the sample size is about 1 cell to about 100 cells. In some embodiments, the sample size is about 1 cell to about 10 cells. In some embodiments, the sample size is a single cell.

[0164] In some embodiments, LAG-3 and / or PD-L1 expression is determined by performing an assay to detect the presence of LAG-3 and / or PD-L1 RNA, respectively, hi some embodiments, the presence of LAG-3 and / or PD-L1 RNA is detected by RT-PCR, in situ hybridization, or RNase protection.

[0165] In some aspects, LAG-3 and / or PD-L1 expression is determined by performing an assay that detects the presence of LAG-3 and / or PD-L1 polypeptides, respectively. In some aspects, the presence of LAG-3 and / or PD-L1 polypeptides is detected by immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), in vivo imaging, or flow cytometry.

[0166] In some aspects, the subject has progressed on or is intolerant to prior therapy, the CRC is MSS mCRC with adenocarcinoma histology and wild-type KRAS, and the tumor tissue from the subject contains at least about 1% PD-L1 TPS and / or CPS.

[0167] In some aspects, the subject has progressed on or is intolerant to prior therapy, the CRC is MSS mCRC with adenocarcinoma histology and a KRAS mutation, and the tumor tissue from the subject contains at least about 1% PD-L1 TPS and / or CPS.

[0168] In some aspects, the subject has progressed on or is intolerant to prior therapy, the CRC is MSS mCRC with adenocarcinoma histology and wild-type KRAS, and the tumor tissue from the subject contains less than about 1% PD-L1 TPS and / or CPS.

[0169] In some aspects, the subject has progressed on or is intolerant to prior therapy, the CRC is MSS mCRC with adenocarcinoma histology and a KRAS mutation, and the tumor tissue from the subject contains less than about 1% PD-L1 TPS and / or CPS.

[0170] II.A. Anti-LAG-3 antibody Antibodies that bind to LAG-3 are disclosed, for example, in WO 2015 / 042246 and U.S. Patent Application Publication Nos. 2014 / 0093511 and 2011 / 0150892, each of which is incorporated by reference in its entirety.

[0171] An exemplary LAG-3 antibody useful in the present disclosure is 25F7 (described in U.S. Patent Application Publication No. 2011 / 0150892). An additional exemplary LAG-3 antibody useful in the present disclosure is BMS-986016 (relatolimab). In some aspects, an anti-LAG-3 antibody useful in the present disclosure cross-competes with 25F7 or BMS-986016. In some aspects, an anti-LAG-3 antibody useful in the present disclosure binds to the same epitope as 25F7 or BMS-986016. In some aspects, an anti-LAG-3 antibody comprises the six CDRs of 25F7 or BMS-986016.

[0172] Other art-recognized anti-LAG-3 antibodies that can be used in the methods of the present disclosure include IMP731 (H5L7BW), described in U.S. Patent Application Publication No. 2011 / 007023; MK-4280 (28G-10, favezelimab), described in WO 2016028672 and U.S. Patent Application Publication No. 2020 / 0055938; Burova E, et al. al., J. Immunother. Cancer (2016); 4 (Supp. 1): P195 and REGN3767 (fianlimab) described in U.S. Pat. No. 10,358,495, humanized BAP050 described in International Publication No. WO 2017 / 019894, GSK2831781, IMP-701 (LAG-525; yelamirimab) described in U.S. Pat. No. 10,711,060 and U.S. Patent Application Publication No. 2020 / 0172617, aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (formerly XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P 13B02-30, AVA-017, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007 and ABL501.These and other anti-LAG-3 antibodies useful in the claimed invention are described, for example, in U.S. Pat. No. 10,188,730, WO 2016 / 028672, WO 2017 / 106129, WO 2017 / 062888, WO 2009 / 044273, WO 2018 / 069500, WO 2016 / 126858, WO 2014 / 179664, and the like. brochure, International Publication No. 2016 / 200782 pamphlet, International Publication No. 2015 / 200119 pamphlet, International Publication No. 2017 / 019846 pamphlet, International Publication No. 2017 / 198741 pamphlet, International Publication No. 2017 / 220555 pamphlet, International Publication No. 2017 / 220569 pamphlet, International Publication No. 2018 / 071500 pamphlet, International Publication No. 2017 / 015560 pamphlet, International Publication No. 2017 / 025498 pamphlet, International Publication No. WO 2017 / 087589, International Publication No. WO 2017 / 087901, International Publication No. WO 2018 / 083087, International Publication No. WO 2017 / 149143, International Publication No. WO 2017 / 219995, U.S. Patent Application Publication No. WO 2017 / 0260271, International Publication No. WO 2017 / 086367, International Publication No. WO 2017 / 086419, International Publication No. WO 2018 / 034227, International Publication Reference may be made to International Publication No. WO 2018 / 185046, International Publication No. WO 2018 / 185043, International Publication No. WO 2018 / 217940, International Publication No. WO 19 / 011306, International Publication No. WO 2018 / 208868, International Publication No. WO 2014 / 140180, International Publication No. WO 2018 / 201096, International Publication No. WO 2018 / 204374 and International Publication No. WO 2019 / 018730. The contents of each of these references are incorporated by reference in their entirety.

[0173] Anti-LAG-3 antibodies that can be used in the methods of the disclosure also include isolated antibodies that specifically bind to human LAG-3 and cross-compete with any of the anti-LAG-3 antibodies disclosed herein, such as relatolimab, for binding to human LAG-3. In some embodiments, the anti-LAG-3 antibody binds to the same epitope as any of the anti-LAG-3 antibodies described herein, such as relatolimab.

[0174] In some aspects, any of the anti-LAG-3 antibodies disclosed herein, such as antibodies that cross-compete with relatolimab for binding to human LAG-3 or that bind to the same epitopic region as relatolimab, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric, engineered, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0175] The ability of an antibody to cross-compete for binding to an antigen indicates that such an antibody binds to the same epitope region of the antigen and sterically prevents other cross-competing antibodies from binding to that particular epitope region. These cross-competing antibodies are likely to have very similar functional properties to a reference antibody, such as relatolimab, because they bind to the same epitope region. Cross-competing antibodies can be easily identified based on their ability to cross-compete in standard binding assays, such as Biacore analysis, ELISA assays or flow cytometry (see, for example, WO2013 / 173223).

[0176] Anti-LAG-3 antibodies that can be used in the methods of the present disclosure also include antigen-binding portions of any of the full-length antibodies described above. It is well-documented that fragments of full-length antibodies can perform the antigen-binding function of an antibody.

[0177] In some embodiments, the anti-LAG-3 antibody is a full-length antibody.

[0178] In some aspects, the anti-LAG-3 antibody is a monoclonal, human, humanized, chimeric or multispecific antibody. In some aspects, the multispecific antibody is a dual affinity retargeting antibody (DART), DVD-Ig or bispecific antibody.

[0179] In some aspects, the anti-LAG-3 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.

[0180] In some embodiments, the anti-LAG-3 antibody is selected from the group consisting of BMS-986016 (leratolimab), IMP731 (H5L7BW), MK4280 (28G-10, favezelimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, yelamirimab), aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P 13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501 or an antigen-binding portion thereof.

[0181] In some embodiments, the anti-LAG-3 antibody is leratolimab. In some embodiments, leratolimab is administered intravenously at about 80 mg, about 120 mg, about 240 mg, about 360 mg, about 480 mg, or about 960 mg about once every 2, 3, or 4 weeks.

[0182] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:3, and CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:4.

[0183] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:5; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:6; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:7; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:8; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:9; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:10.

[0184] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 3 and 4, respectively.

[0185] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 1 and 2, respectively.

[0186] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs:21 and 2, respectively.

[0187] In some embodiments, the anti-LAG-3 antibody is MGD013 (tebotelimab), which is a bispecific PD-1 x LAG-3 DART. In some embodiments, tebotelimab is administered intravenously at about 300 mg or about 600 mg about once every 2, 3, or 4 weeks. In some embodiments, tebotelimab is administered intravenously at about 300 mg about once every 2 weeks. In some embodiments, tebotelimab is administered intravenously at about 600 mg about once every 3 weeks.

[0188] In some embodiments, the anti-LAG-3 antibody is REGN3767 (fianlimab). In some embodiments, fianlimab is administered intravenously at about 1 mg / kg, about 3 mg / kg, about 10 mg / kg, or about 20 mg / kg about once every three weeks. In some embodiments, fianlimab is administered intravenously at about 1600 mg about once every three weeks.

[0189] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 25, and CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 26.

[0190] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:27; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:28; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:29; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:30; (e) a light chain variable region CDR2 comprising the sequence DAS; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:32.

[0191] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 25 and 26, respectively.

[0192] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs:23 and 24, respectively.

[0193] In some embodiments, the anti-LAG-3 antibody is LAG525 (Yelamirimab). In some embodiments, Yelamirimab is administered intravenously at 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, or about 1300 mg about once every 2, 3, or 4 weeks.

[0194] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 47, and CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 49.

[0195] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 48, and CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 50.

[0196] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:51; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:52; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:53; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:54; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:55; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:56.

[0197] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 47 and 49, respectively.

[0198] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 48 and 50, respectively.

[0199] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 43 and 45, respectively.

[0200] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 44 and 46, respectively.

[0201] In some embodiments, the anti-LAG-3 antibody is MK4280 (fabezelimab). In some embodiments, favezelimab is administered intravenously at about 7 mg, about 21 mg, about 70 mg, about 210 mg, about 700 mg, or about 800 mg about once every 3 weeks or about once every 6 weeks. In some embodiments, favezelimab is administered intravenously at about 200 mg about once every 3 weeks. In some embodiments, favezelimab is administered intravenously at about 800 mg about once every 6 weeks. In some embodiments, favezelimab is administered intravenously at about 800 mg on day 1, then about once every 3 weeks. In some embodiments, favezelimab is administered for up to 35 cycles. In some embodiments, favezelimab is administered intravenously at about 800 mg for about 30 minutes on day 1 of a 3-week cycle for up to 35 cycles.

[0202] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:69, and CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:70.

[0203] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 71; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 72; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 73; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 74; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 75; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 76.

[0204] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 69 and 70, respectively.

[0205] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 67 and 68, respectively.

[0206] In some aspects, LAG-3 expression is determined using an anti-LAG-3 antibody. In some aspects, the anti-LAG-3 antibody is selected for its ability to bind to LAG-3 in formalin-fixed paraffin-embedded (FFPE) tissue specimens. In some aspects, the anti-LAG-3 antibody has the ability to bind to LAG-3 in frozen tissue. In some aspects, the anti-LAG-3 antibody has the ability to distinguish between membrane-bound, cytoplasmic and / or soluble forms of LAG-3.

[0207] In some aspects, an anti-LAG-3 antibody useful for assaying, detecting and / or quantifying LAG-3 expression according to the methods disclosed herein is the 17B4 mouse IgG1 anti-human LAG-3 monoclonal antibody. See, e.g., Matsuzaki, J et al., PNAS (2010); 107: 7875.

[0208] In some aspects, the anti-LAG-3 antibodies as disclosed herein are formulated for intravenous administration.

[0209] In some aspects, the anti-LAG-3 antibodies as disclosed herein are administered in a fixed dose.

[0210] In some embodiments, an anti-LAG-3 antibody as disclosed herein is at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400mg, about 20mg to about 100mg, about 100mg to about 2000mg, about 100mg to about 1800mg, about 100mg to about 1600mg, about 100mg to about 1400mg, about 100mg to about 1200mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 100mg to about 400mg, about 400mg to about 2000mg, about 400mg to about 1800mg, about 400mg to about 1600mg, about 400mg to about 1400mg, about 400mg to about 1200mg, or about 400mg to about 1000mg.

[0211] In some embodiments, an anti-LAG-3 antibody as disclosed herein is administered at a concentration of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg , about 4.5mg, about 4.75mg, about 5mg, about 5.25mg, about 5.5mg, about 5.75mg, about 6mg, about 6.25mg, about 6.5mg, about 6.75mg, about 7m g, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 3 50mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, About 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg , about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 10 80 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0212] In some aspects, the anti-LAG-3 antibodies as disclosed herein are administered in weight-based doses.

[0213] In some embodiments, an anti-LAG-3 antibody as disclosed herein has a concentration of at least about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, about 0.003mg / kg~about 0.8mg / kg, about 0.003mg / kg~about 0.7mg / kg, about 0.003mg / kg~about 0.6mg / kg, about 0.003mg / kg~about 0.5mg / kg, about 0.00 3mg / kg~about 0.4mg / kg, about 0.003mg / kg~about 0.3mg / kg, about 0.003mg / kg~about 0.2mg / kg, about 0.003mg / kg~about 0.1mg / kg, about 0.1mg / kg~ Approximately 25mg / kg, approximately 0.1mg / kg to approximately 20mg / kg, approximately 0.1mg / kg to approximately 15mg / kg, approximately 0.1mg / kg to approximately 10mg / kg, approximately 0.1mg / kg to approximately 5mg / kg, approximately 0.1mg / k g ~ about 1 mg / kg, about 1 mg / kg - about 25 mg / kg, about 1 mg / kg - about 20 mg / kg, about 1 mg / kg - about 15 mg / kg, about 1 mg / kg - about 10 mg / kg, about 1 mg / kg - about 5 mg / k g, about 5 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

[0214] In some embodiments, an anti-LAG-3 antibody as disclosed herein has a concentration of about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0. ... The compound is administered at about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg or about 25.0 mg / kg.

[0215] In some aspects, the dose of an anti-LAG-3 antibody as disclosed herein is administered in a fixed amount.

[0216] In some embodiments, the dose of anti-LAG-3 antibody as disclosed herein is administered in variable amounts. For example, in some embodiments, the maintenance (or subsequent) dose of anti-LAG-3 antibody as disclosed herein can be higher than or the same as the loading dose administered initially. In some embodiments, the maintenance dose of anti-LAG-3 antibody as disclosed herein can be lower than or the same as the loading dose.

[0217] In some aspects, an anti-LAG-3 antibody as disclosed herein is administered about once every week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, about once every 10 weeks, about once every 11 weeks, or about once every 12 weeks.

[0218] II.B. Anti-PD-1 and Anti-PD-L1 Antibodies II.B.1. Anti-PD-1 antibody In the methods of the present disclosure, anti-PD-1 antibodies known in the art can be used. Various human monoclonal antibodies that specifically bind to PD-1 with high affinity are disclosed in U.S. Pat. No. 8,008,449. The anti-PD-1 human antibodies disclosed in U.S. Pat. No. 8,008,449 have been demonstrated to exhibit one or more of the following characteristics: (a) 1×10 binding to human PD-1 as determined by surface plasmon resonance using a Biacore biosensor system; -7 K below M D (b) does not substantially bind to human CD28, CTLA-4, or ICOS; (c) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay; (d) increases interferon-γ production in an MLR assay; (e) increases IL-2 secretion in an MLR assay; (f) binds to human PD-1 and cynomolgus PD-1; (g) inhibits the binding of PD-L1 and / or PD-L2 to PD-1; (h) stimulates an antigen-specific memory response; (i) stimulates an antibody response; and (j) inhibits tumor cell growth in vivo. Anti-PD-1 antibodies that can be used in the present disclosure include monoclonal antibodies that specifically bind to human PD-1 and exhibit at least one, and in some embodiments at least five, of the foregoing characteristics.

[0219] Other anti-PD-1 monoclonal antibodies that can be used in the methods of the disclosure are described in, e.g., U.S. Pat. Nos. 6,808,710, 7,488,802, 8,168,757, and 8,354,509, U.S. Patent Application Publication No. 2016 / 0272708, and WO 2012 / 145493, WO 2008 / 156712, WO 2015 / 0272713, WO 2016 / 0272714, WO 2015 / 0272715, WO 2015 / 0272716, and WO 2015 / 0272717. Brochure No. 112900, Brochure No. 2012 / 145493, Brochure No. 2015 / 112800, Brochure No. 2014 / 206107, Brochure No. 2015 / 35606, Brochure No. 2015 / 085847, Brochure No. 2014 / 179664, Brochure No. 2017 / 020291, Brochure No. 2017 / 020858, Brochure No. 2016 / 19 Brochure No. 7367, Brochure No. 2017 / 024515, Brochure No. 2017 / 025051, Brochure No. 2017 / 123557, Brochure No. 2016 / 106159, Brochure No. 2014 / 194302, Brochure No. 2017 / 040790, Brochure No. 2017 / 133540, Brochure No. 2017 / 132827, Brochure No. 2017 / 024 Nos. 465, 2017 / 025016, 2017 / 106061, 2017 / 19846, 2017 / 024465, 2017 / 025016, 2017 / 132825 and 2017 / 133540 (each of which is incorporated by reference in its entirety).

[0220] Anti-PD-1 antibodies that can be used in the methods of the disclosure include nivolumab (also known as OPDIVO®, 5C4, BMS-936558, MDX-1106, and ONO-4538), pembrolizumab (Merck; also known as KEYTRUDA®, lambrolizumab, and MK3475; see WO 2008 / 156712), PDR001 (Novartis; also known as spartalizumab; see WO 2015 / 112900 and U.S. Pat. No. 9,683,048), MEDI-0680 (AstraZeneca; also known as AMP-514; see WO 2012 / 145493), TSR-042 (Tesaro Biopharmaceutical; also known as ANB011 or dostallimab; see WO 2014 / 179664), cemiplimab (Regeneron; also known as LIBTAYO® ORREGN2810; see WO 2015 / 112800 and U.S. Pat. No. 9,987,500), JS001 (TAIZHOU JUNSHI PHARMA; also known as toripalimab; Si-Yang Liu et al. al., J. Hematol. Oncol. 10:136 (2017)), PF-06801591 (Pfizer; also known as Sasanlimab; U.S. Patent Application Publication No. 2016 / 0159905), BGB-A317 (Beigene; also known as Tislelizumab; see WO 2015 / 35606 and U.S. Patent Application Publication No. 2015 / 0079109), BI 754091 (Boehringer Ingelheim; see Zettl M et al., Cancer. Res. (2018); 78(13 Suppl):Abstract 4558), INCSHR1210 (Jiangsu Hengrui Medicine; also known as SHR-1210 or camrelizumab; International Publication No. WO 2015 / 085847; Si-Yang Liu et al., J. Hematol. Oncol.10:136 (2017)), GLS-010 (Wuxi / Harbin Gloria Pharmaceuticals; aka WBP3055; see Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), AM-0001 (Armo), STI-1110 (Sorrento Therapeutics; see WO 2014 / 194302), AGEN2034 (Agenus; see WO 2017 / 040790), MGA012 (Macrogenics, see WO 2017 / 19846), BCD-100 (Biocad; Kaplon et al., mAbs 10(2):183-203 (2018), IBI308 (Innovent; also known as sintilimab; see WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825, and WO 2017 / 133540), and SSI-361 (Lyvgen Biopharma Holdings Limited, U.S. Patent Application Publication No. 2018 / 0346569).

[0221] Anti-PD-1 antibodies that can be used in the methods of the disclosure can also include isolated antibodies that specifically bind to human PD-1 and cross-compete for binding to human PD-1 with any of the anti-PD-1 antibodies disclosed herein, such as nivolumab (see, e.g., U.S. Pat. Nos. 8,008,449 and 8,779,105; WO 2013 / 173223). In some aspects, the anti-PD-1 antibody binds to the same epitope as any of the anti-PD-1 antibodies described herein, such as nivolumab.

[0222] In some aspects, any of the anti-PD-1 antibodies disclosed herein, such as antibodies that cross-compete with nivolumab for binding to human PD-1 or that bind to the same epitopic region as nivolumab, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric, engineered, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0223] Anti-PD-1 antibodies that can be used in the methods of the disclosure also include antigen-binding portions of any of the full-length antibodies listed above.

[0224] Anti-PD-1 antibodies that can be used in the methods of the disclosure are those that bind to PD-1 with high specificity and affinity, that block binding of PD-L1 and / or PD-L2, and that inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-1 "antibody" includes an antigen-binding portion or fragment that exhibits functional properties similar to a whole antibody in binding to the PD-1 receptor and inhibiting ligand binding and upregulating the immune system. In certain embodiments, the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1.

[0225] In some aspects, the anti-PD-1 antibody is a full-length antibody. In some aspects, the anti-PD-1 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. In some aspects, the multispecific antibody is a DART, DVD-Ig, or bispecific antibody.

[0226] In some aspects, the anti-PD-1 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0227] In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, cemiplimab, JS001, PF-06801591, BGB-A317, BI 754091, INCSHR1210, GLS-010, AM-001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, SSI-361, or comprises an antigen-binding portion thereof.

[0228] In some aspects, the anti-PD-1 antibody is nivolumab, a fully human IgG4(S228P)PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking downregulation of anti-tumor T cell function (U.S. Pat. No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9):846-56).

[0229] In some embodiments, nivolumab is administered at about 240 mg, about 360 mg, or about 480 mg about once every 2, 3, or 4 weeks.

[0230] In some embodiments, nivolumab is administered intravenously over about 30 minutes at about 240 mg on day 1 of a two-week cycle.

[0231] In some embodiments, nivolumab is administered intravenously over about 30 minutes at about 480 mg on day 1 of a 4 week cycle.

[0232] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:13, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:14.

[0233] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 15; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 16; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 17; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 18; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 19; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 20.

[0234] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively.

[0235] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs:11 and 12, respectively.

[0236] In some aspects, the methods of the disclosure include a combination of leratolimab and nivolumab.

[0237] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:3, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:4; and (b) an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:13, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:14.

[0238] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10, respectively, and (b) an anti-PD-1 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:15, SEQ ID NO:16, and SEQ ID NO:17, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:18, SEQ ID NO:19, and SEQ ID NO:20, respectively.

[0239] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 3 and 4, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively.

[0240] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs: 1 and 2, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs: 11 and 12, respectively.

[0241] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs:21 and 2, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs:11 and 12, respectively.

[0242] In some embodiments, the anti-PD-1 antibody is pembrolizumab, which is a humanized monoclonal IgG4 (S228P) antibody directed against the human cell surface receptor PD-1. Pembrolizumab is described, for example, in U.S. Patent Nos. 8,354,509 and 8,900,587.

[0243] In some embodiments, pembrolizumab is administered at about 200 mg once about every 2 weeks. In some embodiments, pembrolizumab is administered at about 200 mg once about every 3 weeks. In some embodiments, pembrolizumab is administered at about 400 mg once about every 4 weeks. In some embodiments, pembrolizumab is administered at about 400 mg once about every 6 weeks. In some embodiments, pembrolizumab is administered at about 300 mg once about every 4-5 weeks.

[0244] In some embodiments, pembrolizumab is administered intravenously at about 200 mg on day 1, then about once every 3 weeks. In some embodiments, pembrolizumab is administered for up to 35 cycles. In some embodiments, pembrolizumab is administered intravenously at about 200 mg for about 30 minutes on day 1 of a 3-week cycle, for up to 35 cycles.

[0245] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:79, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:80.

[0246] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:81; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:82; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:83; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:84; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:85; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:86.

[0247] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:79 and 80, respectively.

[0248] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs:77 and 78, respectively.

[0249] In some embodiments, the disclosed method includes a combination of favezelimab and pembrolizumab. In some embodiments, 200mg or 700mg of favezelimab and 200mg of pembrolizumab are administered intravenously on day 1, and then about once every 3 weeks. In some embodiments, the combination of favezelimab and pembrolizumab is administered for up to 35 cycles. In some embodiments, 200mg or 700mg of favezelimab and 200mg of pembrolizumab are administered intravenously for about 30 minutes on day 1 of a 3-week cycle, for up to 35 cycles.

[0250] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:69, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:70; and (b) an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:79, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:80.

[0251] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively, and (b) an anti-PD-1 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively.

[0252] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 69 and 70, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 79 and 80, respectively.

[0253] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs: 67 and 68, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs: 77 and 78, respectively.

[0254] In some aspects, the anti-PD-1 antibody is cemiplimab (REGN2810), which is described, for example, in WO 2015 / 112800 and U.S. Patent No. 9,987,500.

[0255] In some aspects, cemiplimab is administered intravenously at about 3 mg / kg or about 350 mg about once every three weeks.

[0256] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:35, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:36.

[0257] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:37; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:38; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:39; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:40; (e) a light chain variable region CDR2 comprising the sequence AAS; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:42.

[0258] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 35 and 36, respectively.

[0259] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 33 and 34, respectively.

[0260] In some aspects, the methods of the disclosure include a combination of fianlimab and cemiplimab.

[0261] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:25, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:26; and (b) an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:35, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:36.

[0262] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:27, SEQ ID NO:28, and SEQ ID NO:29, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:30, sequence DAS, and the sequence set forth in SEQ ID NO:32, respectively; and (b) an anti-PD-1 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:37, SEQ ID NO:38, and SEQ ID NO:39, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:40, sequence AAS, and the sequence set forth in SEQ ID NO:42, respectively.

[0263] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:25 and 26, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:35 and 36, respectively.

[0264] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs: 23 and 24, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs: 33 and 34, respectively.

[0265] In some aspects, the anti-PD-1 antibody is spartalizumab (PDR001), which is described, for example, in WO 2015 / 112900 and U.S. Patent No. 9,683,048.

[0266] In some embodiments, spartalizumab is administered intravenously at about 300 mg about once every three weeks or about 400 mg about once every four weeks.

[0267] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:59, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:60.

[0268] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:61; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:62; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:63; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:64; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:65; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:66.

[0269] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:59 and 60, respectively.

[0270] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs:57 and 58, respectively.

[0271] In some embodiments, the method of the present disclosure includes a combination of yelamirimab and spartalizumab. In some embodiments, yelamirimab is administered intravenously at about 400 mg once about every 3 weeks, and spartalizumab is administered intravenously at about 300 mg once about every 3 weeks. In some embodiments, yelamirimab is administered intravenously at about 600 mg once about every 4 weeks, and spartalizumab is administered intravenously at about 400 mg once about every 4 weeks.

[0272] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:47, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:49; and (b) an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:59, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:60.

[0273] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 48, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 50; and (b) an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 59, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 60.

[0274] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively, and (b) an anti-PD-1 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:61, SEQ ID NO:62, and SEQ ID NO:63, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively.

[0275] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 47 and 49, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 59 and 60, respectively.

[0276] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 48 and 50, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 59 and 60, respectively.

[0277] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs: 43 and 45, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs: 57 and 58, respectively.

[0278] In some aspects, the methods of the disclosure include (a) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs: 44 and 46, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs: 57 and 58, respectively.

[0279] II.B.2. Anti-PD-L1 antibody Anti-PD-L1 antibodies known in the art may be used in the methods of the disclosure. Examples of anti-PD-L1 antibodies useful in the compositions and methods of the disclosure include those disclosed in U.S. Patent No. 9,580,507. The anti-PD-L1 human monoclonal antibody disclosed in U.S. Patent No. 9,580,507 has been demonstrated to exhibit one or more of the following characteristics: (a) a PD-L1 affinity of 1×10 as determined by surface plasmon resonance using a Biacore biosensor system; -7 K below M D (b) bind to human PD-L1 in a mixed lymphocyte reaction (MLR) assay; (c) increase interferon-γ production in an MLR assay; (d) increase IL-2 secretion in an MLR assay; (e) stimulate antibody responses; and (f) reverse the effects of regulatory T cells on T cell effector cells and / or dendritic cells. Anti-PD-L1 antibodies that can be used in the present disclosure include monoclonal antibodies that specifically bind to human PD-L1 and exhibit at least one, and in some embodiments at least five, of the foregoing characteristics.

[0280] Anti-PD-L1 antibodies that can be used in the methods of the disclosure include BMS-936559 (also known as 12A4, MDX-1105; see, e.g., U.S. Pat. No. 7,943,743 and WO 2013 / 173223), atezolizumab (Roche; also known as TECENTRIQ®; MPDL3280A, RG7446; see, U.S. Pat. No. 8,217,149; see also Herbst et al. (2013) J Clin Oncol 31(suppl):3000), durvalumab (AstraZeneca; also known as IMFINZI™, MEDI-4736; see WO 2011 / 066389), avelumab (Pfizer; also known as BAVENCIO®, MSB-0010718C; see WO 2013 / 079174), STI-1014 (Sorrento; see WO 2013 / 181634), CX-072 (Cytomx; see WO 2016 / 149201), KN035 (3D Med / Alphamab; see Zhang et al., Cell Discov. 7:3 (March 2017), LY3300054 (Eli Lilly Co.; see, e.g., WO 2017 / 034916), BGB-A333 (BeiGene; see, Desai et al., JCO 36(15suppl):TPS3113(2018)), ICO 36, FAZ053 (Novartis), and CK-301 (Checkpoint Therapeutics; see, Gorelik et al., AACR:Abstract 4606(Apr 2016)).

[0281] Anti-PD-L1 antibodies that can be used in the methods of the disclosure can also include isolated antibodies that specifically bind human PD-L1 and cross-compete with any of the anti-PD-L1 antibodies disclosed herein, such as atezolizumab, durvalumab, and / or avelumab, for binding to human PD-L1. In some embodiments, the anti-PD-L1 antibodies bind to the same epitope as any of the anti-PD-L1 antibodies described herein, such as atezolizumab, durvalumab, and / or avelumab. In certain embodiments, the antibodies that cross-compete with any of the anti-PD-L1 antibodies disclosed herein, such as atezolizumab, durvalumab, and / or avelumab, for binding to human PD-L1 or bind to the same epitopic region as any of the anti-PD-L1 antibodies disclosed herein, such as atezolizumab, durvalumab, and / or avelumab, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric, engineered, or humanized or human antibodies. Such chimeric, modified, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0282] Anti-PD-L1 antibodies that can be used in the methods of the disclosure also include antigen-binding portions of any of the full-length antibodies listed above.

[0283] Anti-PD-L1 antibodies that can be used in the methods of the disclosure are those that bind to PD-L1 with high specificity and affinity, that block the binding of PD-1, and that inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-L1 "antibody" includes an antigen-binding portion or fragment that binds to PD-L1 and exhibits functional properties similar to a whole antibody in inhibiting receptor binding and upregulating the immune system. In certain embodiments, the anti-PD-L1 antibody or antigen-binding portion thereof cross-competes with atezolizumab, durvalumab, and / or avelumab for binding to human PD-L1.

[0284] In some aspects, an anti-PD-L1 antibody is substituted for the anti-PD-1 antibody in any of the methods disclosed herein.

[0285] In some aspects, the anti-PD-L1 antibody is a full-length antibody.

[0286] In some aspects, the anti-PD-L1 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody, hi some aspects, the multispecific antibody is a DART, DVD-Ig, or a bispecific antibody.

[0287] In some aspects, the anti-PD-L1 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0288] In some aspects, the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301, or comprises an antigen-binding portion thereof.

[0289] In some embodiments, the PD-L1 antibody is atezolizumab. Atezolizumab is a fully humanized IgG1 monoclonal anti-PD-L1 antibody. In some embodiments, atezolizumab is administered at about 800 mg about once every two weeks. In some embodiments, atezolizumab is administered at about 840 mg about once every two weeks.

[0290] In some embodiments, atezolizumab is administered intravenously at about 1,200 mg on day 1 of a 3-week cycle.

[0291] In some embodiments, atezolizumab is administered intravenously at about 1,200 mg on day 1 of a 3 week cycle and bevacizumab is administered at about 15 mg / kg on day 1 of each cycle.

[0292] In some embodiments, the PD-L1 antibody is durvalumab. Durvalumab is a human IgG1κ monoclonal anti-PD-L1 antibody. In some embodiments, durvalumab is administered at about 10 mg / kg about once every two weeks. In some embodiments, durvalumab is administered at about 10 mg / kg about once every two weeks for up to 12 months. In some embodiments, durvalumab is administered at about 800 mg / kg about once every two weeks. In some embodiments, durvalumab is administered at about 1200 mg / kg about once every three weeks.

[0293] In some embodiments, the PD-L1 antibody is avelumab. Avelumab is a human IgG1 lambda monoclonal anti-PD-L1 antibody. In some embodiments, avelumab is administered at about 800 mg about once every two weeks.

[0294] II.B.3. Antibody Administration In some aspects, the anti-PD-1 or anti-PD-L1 antibodies as disclosed herein are formulated for intravenous administration.

[0295] In some aspects, the anti-PD-1 or anti-PD-L1 antibodies as disclosed herein are administered in a fixed dose.

[0296] In some embodiments, an anti-PD-1 or anti-PD-L1 antibody as disclosed herein is administered at a concentration of at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 5 ... The present invention is administered at a dose of from about 100 mg to about 400 mg, from about 20 mg to about 100 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1800 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1400 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 400 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1800 mg, from about 400 mg to about 1600 mg, from about 400 mg to about 1400 mg, from about 400 mg to about 1200 mg, or from about 400 mg to about 1000 mg.

[0297] In some aspects, an anti-PD-1 or anti-PD-L1 antibody as disclosed herein is administered at a concentration of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.2 5mg, about 4.5mg, about 4.75mg, about 5mg, about 5.25mg, about 5.5mg, about 5.75mg, about 6mg, about 6.25mg, about 6.5mg, about 6.75mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 3 50mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, About 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg , about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 10 80 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0298] In some aspects, an anti-PD-1 or anti-PD-L1 antibody as disclosed herein is administered in a weight-based dose.

[0299] In some embodiments, an anti-PD-1 or anti-PD-L1 antibody as disclosed herein is administered at a dose of at least about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, / kg, about 0.003mg / kg to about 0.8mg / kg, about 0.003mg / kg to about 0.7mg / kg, about 0.003mg / kg to about 0.6mg / kg, about 0.003mg / kg to about 0.5mg / kg, about 0.003mg / kg~about 0.4mg / kg, about 0.003mg / kg~about 0.3mg / kg, about 0.003mg / kg~about 0.2mg / kg, about 0.003mg / kg~about 0.1mg / kg, about 0.1mg / kg~about 25mg / kg, about 0.1mg / kg~about 20mg / kg, about 0.1mg / kg~about 15mg / kg, about 0.1mg / kg~about 10mg / kg, about 0.1mg / kg~about 5mg / kg, about 0.1m g / kg~about 1mg / kg, about 1mg / kg~about 25mg / kg, about 1mg / kg~about 20mg / kg, about 1mg / kg~about 15mg / kg, about 1mg / kg~about 10mg / kg, about 1mg / kg~about 5mg / kg, about 5 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

[0300] In some aspects, an anti-PD-1 or anti-PD-L1 antibody as disclosed herein may be administered at a dose of about 0.003mg / kg, about 0.004mg / kg, about 0.005mg / kg, about 0.006mg / kg, about 0.007mg / kg, about 0.008mg / kg, about 0.009mg / kg, about 0.01mg / kg, about 0.02mg / kg, about 0.03mg / kg, about 0.04mg / kg, about 0.05mg / kg, about 0.06mg / kg, about 0.07mg / kg, about 0.08mg / kg, about 0.09mg / kg, about 0.1mg / kg, about 0.2mg / kg, about 0.3mg / kg, about 0.4mg / kg, about 0.5mg / kg, about 0.6mg / kg, about 0.7mg / kg, The compound is administered at about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg or about 25.0 mg / kg.

[0301] In some aspects, the dose of an anti-PD-1 or anti-PD-L1 antibody as disclosed herein is administered at a constant rate.

[0302] In some aspects, the dose of an anti-PD-1 or anti-PD-L1 antibody as disclosed herein is administered in varying amounts. For example, in some aspects, the maintenance (or subsequent) dose of an anti-PD-1 or anti-PD-L1 antibody as disclosed herein may be higher than or the same as the loading dose initially administered. In some aspects, the maintenance dose of an anti-PD-1 or anti-PD-L1 antibody as disclosed herein may be lower than or the same as the loading dose.

[0303] In some aspects, an anti-PD-1 or anti-PD-L1 antibody as disclosed herein is administered about once every week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, about once every 10 weeks, about once every 11 weeks, or about once every 12 weeks.

[0304] Any amount of an anti-PD-1 or anti-PD-L1 antibody as described herein can be administered in combination with any amount of an anti-LAG-3 antibody as described herein.

[0305] In some embodiments, the amount of anti-LAG-3 antibody is about 80 mg.

[0306] In some embodiments, the amount of anti-LAG-3 antibody is about 160 mg.

[0307] In some embodiments, the amount of anti-LAG-3 antibody is about 360 mg.

[0308] In some embodiments, the amount of anti-LAG-3 antibody is about 480 mg.

[0309] In some embodiments, the amount of anti-LAG-3 antibody is about 720 mg.

[0310] In some embodiments, the amount of anti-LAG-3 antibody is about 800 mg.

[0311] In some embodiments, the amount of anti-LAG-3 antibody is about 960 mg.

[0312] In some aspects, the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 200 mg.

[0313] In some aspects, the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 240 mg.

[0314] In some aspects, the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 360 mg.

[0315] In some aspects, the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 480 mg.

[0316] In some embodiments, the amount of anti-LAG-3 antibody is about 80 mg and the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 240 mg.

[0317] In some embodiments, the amount of anti-LAG-3 antibody is about 80 mg and the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 480 mg.

[0318] In some embodiments, the amount of anti-LAG-3 antibody is about 160 mg and the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 480 mg.

[0319] In some embodiments, the amount of anti-LAG-3 antibody is about 360 mg and the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 360 mg.

[0320] In some embodiments, the amount of anti-LAG-3 antibody is about 480 mg and the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 480 mg.

[0321] In some embodiments, the amount of anti-LAG-3 antibody is about 720 mg and the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 360 mg.

[0322] In some embodiments, the amount of anti-LAG-3 antibody is about 800 mg and the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 200 mg.

[0323] In some embodiments, the amount of anti-LAG-3 antibody is about 960 mg and the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 480 mg.

[0324] In some aspects, the amount of anti-LAG-3 antibody is about 2 mg / kg and the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 6 mg / kg.

[0325] In some aspects, the amount of anti-LAG-3 antibody is about 1 mg / kg and the amount of anti-PD-1 antibody or anti-PD-L1 antibody is about 6 mg / kg.

[0326] Provided herein is a method of treating a human subject suffering from CRC, the method comprising administering to the subject (a) about 480 mg of an anti-LAG-3 antibody, and (b) about 480 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0327] Provided herein is a method of treating a human subject suffering from CRC, comprising administering to the subject (a) about 480 mg of an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:3, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:4, and (b) about 480 mg of an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:13, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:14.

[0328] In some aspects, the anti-LAG-3 antibody and / or anti-PD-1 antibody or anti-PD-L1 antibody is formulated for intravenous administration.

[0329] In some aspects, the anti-LAG-3 antibody and / or anti-PD-1 antibody or anti-PD-L1 antibody is administered about once every week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, about once every 10 weeks, about once every 11 weeks, or about once every 12 weeks.

[0330] In some aspects, the anti-PD-1 antibody or the anti-PD-L1 antibody is administered prior to the anti-LAG-3 antibody.

[0331] In some aspects, the anti-LAG-3 antibody is administered prior to the anti-PD-1 antibody or the anti-PD-L1 antibody.

[0332] In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody or anti-PD-L1 antibody are administered simultaneously.

[0333] In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody or anti-PD-L1 antibody are formulated separately.

[0334] In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody or anti-PD-L1 antibody are formulated together.

[0335] II.C. Additional Medications and Therapies In some aspects, the methods of the present disclosure further comprise administering to the subject an additional therapeutic agent and / or anti-cancer therapy.

[0336] The additional anti-cancer therapy may include any therapy known in the art for treating the subject's tumor and / or any standard of care therapy as disclosed herein. In some aspects, the additional anti-cancer therapy includes surgery, radiation therapy, chemotherapy, immunotherapy, or any combination thereof. In some aspects, the additional anti-cancer therapy includes chemotherapy including any chemotherapeutic agent disclosed herein. In some aspects, the chemotherapy includes platinum doublet chemotherapy.

[0337] In some aspects, the additional therapeutic agent comprises an anti-cancer agent, hi some aspects, the anti-cancer agent comprises a tyrosine kinase inhibitor, an anti-angiogenic agent, a checkpoint inhibitor, a checkpoint stimulator, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topoisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof.

[0338] In some embodiments, the tyrosine kinase inhibitor is sorafenib (e.g., sorafenib tosylate, also known as NEXAVAR®), lenvatinib (e.g., lenvatinib mesylate, also known as LENVIMA®), regorafenib (e.g., STIVARGA®), cabozantinib (e.g., cabozantinib S-malate, also known as CABOMETYX®), sunitinib (e.g., sunitinib malate, also known as SUTENT®), brivanib, linifanib, pemigatinib (also known as PEMAZYRE®), )), everolimus (also known as AFINITOR® or ZORTRESS®), gefitinib (IRESSA®, a small molecule TKI for EGFR), imatinib (e.g., imatinib mesylate), lapatinib (e.g., lapatinib ditosylate, also known as TYKERB®), nilotinib (e.g., nilotinib hydrochloride, also known as TASIGNA®), pazopanib (e.g., pazopanib hydrochloride, also known as VOTRIENT®), temsirolimus (also known as TORISEL®), erlotinib (e.g., erlotinib Rulotinib hydrochloride, also known as TARCEVA®, a small molecule TKI for EGFR), afatinib (GILOTRIF®, a small molecule TKI for EGFR), dacomitinib (VIZIMPRO®, a small molecule TKI for EGFR), osimertinib (TAGRISSO®, a small molecule TKI for EGFR), alectinib (ALECENSA®, a small molecule TKI for ALK), ceritinib (ZYKADIA®, a small molecule TKI for ALK and ROS-1), brigatinib (ALUNBRIG®, a small molecule TKI for ALK) small molecule TKI), crizotinib (XALKORI®, a small molecule TKI for ALK and ROS-1), lorlatinib (LORBRENA®, a small molecule TKI for ALK and ROS-1), entrectinib (ROZLYTREK®, a small molecule TKI for ROS-1 and NTRK), dabrafenib (TAFINLAR®, a small molecule TKI for BRAF), trametinib (MEKINIST®, a small molecule TKI for BRAF), vemurafenib (ZELBORAF®, a small molecule TKI for BRAF),larotrectinib (ROZLYTREK®, a small molecule TKI of NTRK), or any combination thereof.

[0339] In some aspects, the anti-angiogenic agent comprises an inhibitor of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase containing Ig-like and EGF-like domains (Tie) receptor, hepatocyte growth factor (HGF), tyrosine protein kinase Met (c-MET), C-type lectin family 14 member A (CLEC14A), multimerin 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), EGFR, or any combination thereof. In some aspects, the antiangiogenic agent comprises bevacizumab (also known as AVASTIN®), ranibizumab (also known as LUCENTIS®), ramucirumab (also known as CYRAMZA®), aflibercept (also known as EYLEA® or ZALTRAP®), tanibirumab, olaratumab (also known as LARTRUVO™), nesvacumab, AMG780, MEDI3617, vanucizumab, rilotumumab, ficlatuzumab, TAK-701, onartuzumab, emibetuzumab, or any combination thereof.

[0340] In some aspects, checkpoint stimulators include agonists of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, GITR, inducible T cell costimulator (ICOS), ICOS-L, OX40, OX40L, CD70, CD27, CD40, death receptor 3 (DR3), CD28H, or any combination thereof.

[0341] In some aspects, the chemotherapeutic agent comprises an alkylating agent, antimetabolite, antineoplastic antibiotic, a mitotic inhibitor, a hormone or hormone modulating agent, a protein tyrosine kinase inhibitor, an epidermal growth factor inhibitor, a proteasome inhibitor, another neoplastic agent, or any combination thereof.

[0342] In some aspects, the immunotherapeutic agent comprises an antibody that specifically binds to EGFR (e.g., cetuximab (ERBITUX®)), ALK, ROS-1, NTRK, BRAF, ICOS, CD137 (4-1BB), CD134 (OX40), NKG2A, CD27, CD96, GITR, herpes virus entry mediator (HVEM), PD-1, PD-L1, CTLA-4, BTLA, TIM-3, A2aR, killer cell lectin-like receptor G1 (KLRG-1), natural killer cell receptor 2B4 (CD244), CD160, TIGIT, VISTA, KIR, TGFβ, IL-10, IL-8, B7-H4, Fas ligand, CSF1R, CXCR4, mesothelin, CEACAM-1, CD52, HER2, MICA, MICB, or any combination thereof.

[0343] In some aspects, the platinum agent comprises cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin (eg, triplatin tetranitrate), lipoplatin, phenanthriplatin, or any combination thereof.

[0344] In some aspects, the alkylating agent comprises altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, procarbazine, streptozocin, temozolomide, thiotepa, or any combination thereof.

[0345] In some aspects, the taxane comprises paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel, or any combination thereof.

[0346] In some aspects, the nucleoside analog comprises cytarabine, gemcitabine, lamivudine, entecavir, telbivudine, or any combination thereof.

[0347] In some aspects, the antimetabolite comprises capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, thioguanine, or any combination thereof.

[0348] In some embodiments, the topoisomerase inhibitor comprises etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, camptothecin, or any combination thereof.

[0349] In some aspects, the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, or any combination thereof.

[0350] In some aspects, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vineridine, vinbrunin, or any combination thereof.

[0351] II.C.1. Checkpoint inhibitors In some aspects, the anti-cancer agent administered as an additional therapeutic agent in the methods of the present disclosure is a checkpoint inhibitor.

[0352] In some aspects, the checkpoint inhibitors are selected from the group consisting of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, T-cell immunoglobulin and ITIM domain (TIGIT) inhibitors, T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B- and T-cell lymphocyte attenuator (BTLA) inhibitors, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitors, killer cell immunoglobulin-like receptor (KIR) inhibitors, adenosine A2a receptor (A2aR) inhibitors, transforming These include transforming growth factor beta (TGF-β) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, CD47 inhibitors, CD48 inhibitors, CD73 inhibitors, CD113 inhibitors, sialic acid-binding immunoglobulin-like lectin 7 (SIGLEC-7) inhibitors, SIGLEC-9 inhibitors, SIGLEC-15 inhibitors, glucocorticoid-inducible TNFR-related protein (GITR) inhibitors, galectin-1 inhibitors, galectin-9 inhibitors, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) inhibitors, G protein-coupled receptor 56 (GPR56) inhibitors, glycoprotein A repeat dominant (GARP) inhibitors, 2B4 inhibitors, programmed death 1 homolog (PD1H) inhibitors, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitors, or any combination thereof.

[0353] In some aspects, the checkpoint inhibitor is formulated for intravenous administration.

[0354] In some aspects, the checkpoint inhibitor is administered in a fixed dose.

[0355] In some embodiments, the checkpoint inhibitor is at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg , about 20 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

[0356] In some embodiments, the checkpoint inhibitor is administered at a concentration of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 3 50mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, About 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg , about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 10 80 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0357] In some aspects, the checkpoint inhibitor is administered as a weight-based dose.

[0358] In some embodiments, the checkpoint inhibitor is at least about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, about 0.003 mg / kg to about 10 ... kg~about 0.8mg / kg, about 0.003mg / kg~about 0.7mg / kg, about 0.003mg / kg~about 0.6mg / kg, about 0.003mg / kg~about 0.5mg / kg, about 0.003mg / kg~ Approximately 0.4mg / kg, approximately 0.003mg / kg to approximately 0.3mg / kg, approximately 0.003mg / kg to approximately 0.2mg / kg, approximately 0.003mg / kg to approximately 0.1mg / kg, approximately 0.1mg / kg to approximately 25mg / kg, about 0.1mg / kg to about 20mg / kg, about 0.1mg / kg to about 15mg / kg, about 0.1mg / kg to about 10mg / kg, about 0.1mg / kg to about 5mg / kg, about 0.1mg / kg to about 1 mg / kg, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about It is administered at 5 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

[0359] In some embodiments, the checkpoint inhibitor is about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg , about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg or about 25.0 mg / kg.

[0360] In some aspects, the dose of the checkpoint inhibitor is administered at a constant rate.

[0361] In some embodiments, the dose of the checkpoint inhibitor is administered in variable amounts. For example, in some embodiments, the maintenance (or subsequent) dose of the checkpoint inhibitor can be higher than or the same as the loading dose administered initially. In some embodiments, the maintenance dose of the checkpoint inhibitor can be lower than or the same as the loading dose.

[0362] In some aspects, the checkpoint inhibitor is administered every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, or every 12 weeks.

[0363] II.C.1.a.CTLA-4 inhibitors In some embodiments, a checkpoint inhibitor as disclosed herein comprises a CTLA-4 inhibitor. In some embodiments, the CTLA-4 inhibitor is an anti-CTLA-4 antibody.

[0364] Anti-CTLA-4 antibodies that can be used in the methods of the present disclosure bind to human CTLA-4 and disrupt the interaction of CTLA-4 with the human B7 receptor, and disruption of this interaction effectively induces, enhances or prolongs activation of T cells bearing the CTLA-4 receptor, thereby effectively inducing, enhancing or prolongs activation of such T cells and thus effectively inducing, enhancing or prolongs immune responses.

[0365] A human monoclonal antibody that specifically binds to CTLA-4 with high affinity is disclosed in U.S. Patent No. 6,984,720. Other anti-CTLA-4 monoclonal antibodies are described, for example, in U.S. Patent Nos. 5,977,318, 6,051,227, 6,682,736 and 7,034,121 and WO 2012 / 122444, 2007 / 113648, 2016 / 196237 and 2000 / 037504, each of which is incorporated herein by reference in its entirety. The anti-CTLA-4 human monoclonal antibody disclosed in U.S. Patent No. 6,984,720 has been demonstrated to exhibit one or more of the following characteristics: (a) a specific binding affinity of at least about 10 to human CTLA-4 as determined by Biacore analysis; 7 M -1 , or about 10 9 M -1 , or about 10 10 M -1 ~10 11 M -1 or greater equilibrium binding constant (K a (b) specifically binds with a binding affinity reflected by at least about 10 3, about 10 4 Or about 10 5 m -1 s -1 The kinetic binding constant (k a );(c) at least about 10 3 , about 10 4 Or about 10 5 m -1 s -1 The kinetic dissociation constant (k d and (d) inhibit the binding of CTLA-4 to B7-1 (CD80) and B7-2 (CD86). Anti-CTLA-4 antibodies useful in the present disclosure include monoclonal antibodies that specifically bind to human CTLA-4 and exhibit at least one, at least two, or at least three of the aforementioned characteristics.

[0366] Anti-CTLA-4 antibodies that can be used in the methods of the disclosure include ipilimumab (also known as YERVOY®, MDX-010, 10D1; see U.S. Pat. No. 6,984,720), MK-1308 (Merck), AGEN-1884 (Agenus Inc.; see WO 2016 / 196237), and tremelimumab (AstraZeneca; also known as ticilimumab, CP-675,206; see WO 2000 / 037504 and Ribas, Update Cancer Ther. 2(3):133-39 (2007)).

[0367] In some aspects, the anti-CTLA-4 antibody specifically binds to human CTLA-4 and cross-competes with any of the anti-CTLA-4 antibodies disclosed herein, e.g., ipilimumab and / or tremelimumab, for binding to human CTLA-4. In some aspects, the anti-CTLA-4 antibody binds to the same epitope as any of the anti-CTLA-4 antibodies described herein, e.g., ipilimumab and / or tremelimumab.

[0368] In some aspects, any of the anti-CTLA-4 antibodies disclosed herein, such as antibodies that cross-compete with ipilimumab and / or tremelimumab for binding to human CTLA-4 or that bind to the same epitopic region as ipilimumab and / or tremelimumab, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric, engineered, or humanized or human antibodies.

[0369] Anti-CTLA-4 antibodies that can be used in the methods of the disclosure also include antigen-binding portions of any of the full-length antibodies described above.

[0370] In some aspects, the anti-CTLA-4 antibody is a full-length antibody. In some aspects, the anti-CTLA-4 antibody is a monoclonal, human, humanized, chimeric or multispecific antibody. In some aspects, the multispecific antibody is a DART, DVD-Ig or bispecific antibody.

[0371] In some aspects, the anti-CTLA-4 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.

[0372] In some aspects, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, MK-1308, AGEN-1884, or comprises an antigen-binding portion thereof.

[0373] In some embodiments, the anti-CTLA-4 antibody is ipilimumab. Ipilimumab is a fully human IgG1 monoclonal antibody that stimulates T cell activation by blocking the binding of CTLA-4 to its B7 ligand. In some embodiments, ipilimumab is administered at about 3 mg / kg once about every 3 weeks. In some embodiments, ipilimumab is administered at about 10 mg / kg once about every 3 weeks. In some embodiments, ipilimumab is administered at about 10 mg / kg once about every 12 weeks. In some embodiments, ipilimumab is administered over 4 doses. In some embodiments, ipilimumab is administered on day 1 of each cycle.

[0374] III. Pharmaceutical Compositions The therapeutic agents of the present disclosure may be components of compositions, e.g., pharmaceutical compositions, that contain an inhibitor, antibody and / or agent as disclosed herein and a pharma- ceutically acceptable carrier. As used herein, "pharma-ceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.

[0375] In some aspects, the carrier for the composition containing the inhibitors, antibodies and / or agents as disclosed herein is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). In some aspects, the carrier is suitable for non-parenteral administration, such as oral administration. In some aspects, subcutaneous injection is based on Halozyme Therapeutics' ENHANZE® drug delivery technology (see U.S. Pat. No. 7,767,429, which is incorporated herein by reference in its entirety). ENHANZE® uses a co-formulation of antibodies with recombinant human hyaluronidase enzyme (rHuPH20), which removes the traditional limitations imposed by the extracellular matrix on the volume of biologics and drugs that can be delivered subcutaneously (see U.S. Pat. No. 7,767,429). Pharmaceutical compositions of the disclosure may include one or more pharma- ceutically acceptable salts, antioxidants, aqueous and non-aqueous carriers and / or adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents, etc. In some aspects, pharmaceutical compositions of the disclosure may further include a recombinant human hyaluronidase enzyme, such as rHuPH20.

[0376] Treatment is continued as long as clinical benefit is observed or until unacceptable toxicity or disease progression occurs. Dosage and frequency vary depending on the half-life of the inhibitor, antibody and / or agent in the subject. In general, human antibodies exhibit the longest half-life, followed by humanized antibodies, chimeric antibodies and non-human antibodies. Dosage and frequency of administration may vary depending on whether the treatment is preventive or therapeutic. In preventive applications, typically, relatively low dosages are administered less frequently and over a long period of time. Some patients continue to receive treatment for life. In therapeutic applications, relatively high dosages at relatively short intervals may sometimes be required until disease progression is reduced or ceased, preferably until the patient shows partial or complete improvement of the symptoms of the disease. The patient can then be administered a preventive regime.

[0377] The actual dosage level of the active ingredient (i.e., inhibitor, antibody and / or drug) in the pharmaceutical composition of the present disclosure can be varied to achieve an amount of active ingredient effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration without excessive toxicity to the patient. The dosage level selected will depend on various pharmacokinetic factors including the activity of the particular composition of the present disclosure used, the route of administration, the timing of administration, the rate of excretion of the particular compound used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular composition used, the age, sex, weight, condition, general health and medical history of the patient under treatment, and similar factors well known in the medical art. The compositions of the present disclosure can be administered by one or more routes of administration using one or more of a variety of methods well known in the art. As one of ordinary skill in the art will understand, the route and / or mode of administration will vary depending on the desired results.

[0378] Provided herein are pharmaceutical compositions comprising any amount of an anti-LAG-3 antibody and any amount of an anti-PD-1 antibody or an anti-PD-L1 antibody as described herein.

[0379] In some aspects, the pharmaceutical composition is for the treatment of a human subject having CRC as described herein, including unresectable or metastatic CRC.

[0380] In some aspects, the method of treating a human subject having CRC as described herein comprises administering a pharmaceutical composition as described herein.

[0381] In some aspects, the pharmaceutical composition comprises relatolimab and an anti-PD-1 antibody or an anti-PD-L1 antibody as described herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, or spartalizumab. In some aspects, the anti-PD-1 antibody is nivolumab. In some aspects, the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, or CK-301.

[0382] In some aspects, the pharmaceutical composition comprises favezelimab and an anti-PD-1 antibody or an anti-PD-L1 antibody as described herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, or spartalizumab. In some aspects, the anti-PD-1 antibody is pembrolizumab. In some aspects, the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, or CK-301.

[0383] In some embodiments, the pharmaceutical composition comprises fianlimab and an anti-PD-1 antibody or an anti-PD-L1 antibody as described herein. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, or spartalizumab. In some embodiments, the anti-PD-1 antibody is cemiplimab. In some embodiments, the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, or CK-301.

[0384] In some embodiments, the pharmaceutical composition comprises yelamirimab and an anti-PD-1 antibody or an anti-PD-L1 antibody as described herein. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, or spartalizumab. In some embodiments, the anti-PD-1 antibody is spartalizumab. In some embodiments, the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, or CK-301.

[0385] In some embodiments, the pharmaceutical composition comprises about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, The anti-LAG-3 antibody may be an anti-PD-1 antibody or an anti-PD-L1 antibody in a ratio of about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1 or about 2:1.

[0386] In some aspects, the pharmaceutical composition comprises an anti-LAG-3 antibody and an anti-PD-1 antibody or an anti-PD-L1 antibody in a ratio of about 1:6.

[0387] In some aspects, the pharmaceutical composition comprises an anti-LAG-3 antibody and an anti-PD-1 antibody or an anti-PD-L1 antibody in a ratio of about 1:3.

[0388] In some aspects, the pharmaceutical composition comprises about a 1:1 ratio of anti-LAG-3 antibody to anti-PD-1 antibody or anti-PD-L1 antibody.

[0389] In some aspects, the pharmaceutical composition comprises an about 2:1 ratio of anti-LAG-3 antibody to anti-PD-1 antibody or anti-PD-L1 antibody.

[0390] In some aspects, the pharmaceutical composition comprises an anti-LAG-3 antibody to anti-PD-1 antibody or anti-PD-L1 antibody ratio of about 4:1.

[0391] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, about 110 mg / mL, about 115 mg / mL, about 120 mg / mL, about 125 mg / mL, About 130mg / mL, about 135mg / mL, about 140mg / mL, about 145mg / mL, about 150mg / mL, about 155mg / mL, about 160mg / mL, about 165mg / mL, about 170mg / mL, about 175mg / mL, about 180mg / mL, about 185mg / mL, about 190 mg / mL, approximately 195 mg / mL, approximately 200 mg / mL, approximately 205 mg / mL, approximately 210 mg / mL, approximately 215 mg / mL, approximately 220 mg / mL, approximately 225 mg / mL, approximately 230 mg / mL, approximately 235 mg / mL, approximately 240 mg / mL, approximately 245 mg / mL, approximately 250 mg / mL , about 255 mg / mL, about 260 mg / mL, about 265 mg / mL, about 270 mg / mL, about 275 mg / mL, about 280 mg / mL, about 285 mg / mL, about 290 mg / mL, about 295 mg / mL, about 300 mg / mL, about 305 mg / mL, about 310 mg / mL, about 31 5mg / mL, approximately 320mg / mL, approximately 325mg / mL, approximately 330mg / mL, approximately 335mg / mL, approximately 340mg / mL, approximately 345mg / mL, approximately 350mg / mL, approximately 355mg / mL, approximately 360mg / mL, approximately 365mg / mL, approximately 370mg / mL, approximately 375mg / m L, approx. 380 mg / mL, approx. 385 mg / mL, approx. 390 mg / mL, approx. 395 mg / mL, approx. 400 mg / mL, approx. 50 mg, approx. 60 mg, approx. 70 mg, approx. 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg,about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050mg, about 1060mg, about 1070mg, about 1080mg, about 1090mg, about 1100mg, about 1110mg, about 1120mg, about 1130mg, about 1140mg, about 1150mg, about 1160mg, about 1170mg, about 1180mg, about 1190mg, about 1200mg, about 1210mg, about 1220mg, about 1230mg, about 1240mg, about 1250mg, about 1260mg, about 1270mg, about 1280mg, about 1290mg, about 1300mg, about 1310mg, about 1320mg, about 1330mg, about 1340mg, about 1350mg g, about 1360mg, about 1370mg, about 1380mg, about 1390mg, about 1400mg, about 1410mg, about 1420mg, about 1430mg, about 1440mg, about 1450mg, about 1460mg, about 1470mg, about 1480mg, about 1490mg, about 1500mg, about 1510mg, about 1520mg, about 1530mg, about 1540mg, about 1550mg, about 1560mg, about 1570mg, about 1580mg, about 1590mg, about 1600mg, about 1610mg, about 1620mg, about 1630mg, about 1640mg, about 1650mg, about 1660mg,About 1670 mg, about 1680 mg, about 1690 mg, about 1700 mg, about 1710 mg, about 1720 mg, about 1730 mg, about 1740 mg, about 1750 mg, about 1760 mg, about 1770 mg, or about 1780 mg.

[0392] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 25 mg / mL.

[0393] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 50 mg / mL.

[0394] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 150 mg / mL.

[0395] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 50 mg.

[0396] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 320 mg.

[0397] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 480 mg.

[0398] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 560 mg.

[0399] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 640 mg.

[0400] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 720 mg.

[0401] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 960 mg.

[0402] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 1000 mg.

[0403] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 1080 mg.

[0404] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the pharmaceutical composition is about 1440 mg.

[0405] In some embodiments, the pharmaceutical composition comprises about 10 mg / mL, about 12.5 mg / mL, about 15 mg / mL, about 17.5 mg / mL, about 20 mg / mL, about 22.5 mg / mL, about 25 mg / mL, about 27.5 mg / mL, about 30 mg / mL, about 32.5 mg / mL, about 35 mg / mL, about 37.5 mg / mL, about 40 mg / mL, about 42.5 mg / mL, about 45 mg / mL, about 50 mg / mL, about 52 mg / mL, about 54 mg / mL, about 56 mg / mL, about 58 mg / mL, about 59 mg / mL, about 60 mg / mL, about 61 mg / mL, about 62 mg / mL, about 63 mg / mL, about 64 mg / mL, about 65 mg / mL, about 66 mg / mL, about 67 mg / mL, about 68 mg / mL, about 69 mg / mL, about 70 mg / mL, about 72 mg / mL, about 75 mg / mL, about 76 mg / mL, about 77 mg / mL, about 78 mg / mL, about 79 mg / mL, about 80 mg / mL, about 82 mg / mL, about 85 mg / mL, about 86 mg / mL, about 87 mg / mL, about 88 mg / mL, about 89 mg / mL, about 90 mg / mL, about 91 mg / mL, about 92 mg / mL, about 93 mg / mL, about 94 mg / mL, about 95 mg / mL, about 96 mg / mL, about 97 mg / mL, about 98 mg / mL, about 99 mg / mL, about 100 mg / mL, about 100 mg / mL, about 101 mg / mL, about 102 mg / mL, about 103 mg / mL, about 10 / mL, approximately 47.5mg / mL, approximately 50mg / mL, approximately 55mg / mL, approximately 60mg / mL, approximately 65mg / mL, approximately 70mg / mL, approximately 75mg / mL, approximately 80mg / mL, approximately 8 5mg / mL, approx. 90mg / mL, approx. 95mg / mL, approx. 100mg / mL, approx. 105mg / mL, approx. 110mg / mL, approx. 115mg / mL, approx. 120mg / mL, approx. 125m g / mL, 130mg / mL, approx. 135mg / mL, approx. 140mg / mL, approx. 145mg / mL, approx. 150mg / mL, approx. 155mg / mL, approx. 160mg / mL, approx. 165mg / mL, about 170mg / mL, about 175mg / mL, about 180mg / mL, about 185mg / mL, about 190mg / mL, about 195mg / mL, about 200mg / mL, about 7mg, about 21 mg, about 70 mg, about 80 mg, about 120 mg, about 160 mg, about 200 mg, about 210 mg, about 300 mg, about 360 mg, about 400 mg, about 480 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 960 mg, about 1000 mg, about 1100 mg, about 1200 mg or about 1300 mg of anti-LAG-3 antibody.

[0406] In some embodiments, the pharmaceutical composition comprises about 10 mg / mL, about 12.5 mg / mL, about 15 mg / mL, about 17.5 mg / mL, about 20 mg / mL, about 22.5 mg / mL, about 25 mg / mL, about 27.5 mg / mL, about 30 mg / mL, about 32.5 mg / mL, about 35 mg / mL, about 37.5 mg / mL, about 40 mg / mL, about 42.5 mg / mL, about 45 mg / mL, about 47.5 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 ... The composition comprises about 100 mg, about 200 mg, about 240 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, or about 480 mg of an anti-PD-1 antibody or anti-PD-L1 antibody.

[0407] In some aspects, the pharmaceutical composition comprises about 12.5 mg / mL of anti-LAG-3 antibody and about 37.5 mg / mL of anti-PD-1 antibody or anti-PD-L1 antibody.

[0408] In some aspects, the pharmaceutical composition comprises about 20 mg / mL of an anti-LAG-3 antibody and about 5 mg / mL of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0409] In some aspects, the pharmaceutical composition comprises about 75 mg / mL of an anti-LAG-3 antibody and about 75 mg / mL of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0410] In some aspects, the pharmaceutical composition comprises about 100 mg / mL of an anti-LAG-3 antibody and about 50 mg / mL of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0411] In some aspects, the pharmaceutical composition comprises about 80 mg of an anti-LAG-3 antibody and about 240 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0412] In some aspects, the pharmaceutical composition comprises about 80 mg of an anti-LAG-3 antibody and about 480 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0413] In some aspects, the pharmaceutical composition comprises about 120 mg of an anti-LAG-3 antibody and about 360 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0414] In some aspects, the pharmaceutical composition comprises about 160 mg of anti-LAG-3 antibody and about 480 mg of anti-PD-1 antibody or anti-PD-L1 antibody.

[0415] In some aspects, the pharmaceutical composition comprises about 360 mg of an anti-LAG-3 antibody and about 360 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0416] In some aspects, the pharmaceutical composition comprises about 480 mg of an anti-LAG-3 antibody and about 480 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0417] In some aspects, the pharmaceutical composition comprises about 720 mg of an anti-LAG-3 antibody and about 360 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0418] In some aspects, the pharmaceutical composition comprises about 800 mg of an anti-LAG-3 antibody and about 200 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0419] In some aspects, the pharmaceutical composition comprises about 960 mg of anti-LAG-3 antibody and about 480 mg of anti-PD-1 antibody or anti-PD-L1 antibody.

[0420] In some embodiments, the pharmaceutical composition comprises about 5 mM to about 50 mM histidine, about 50 mM to about 300 mM sucrose, about 5 μM to about 1 mM diethylenetriaminepentaacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA), and about 0.001% to about 1% (w / v) polysorbate or poloxamer (e.g., polysorbate 80 (PS80), polysorbate 20 (PS20), poloxamer 188 (PX188), or any combination thereof).

[0421] In some embodiments, the pharmaceutical composition comprises about 20 mM histidine, about 250 mM sucrose, about 50 μM DTPA, and 0.05% PS80.

[0422] In some embodiments, the pH of the pharmaceutical composition is about 5 to about 6.5. In some embodiments, the pH is about 5.3 to about 6.3. In some embodiments, the pH is 5.8. In some embodiments, the pH is 5.7.

[0423] Provided herein is a vial, syringe, or intravenous bag comprising a pharmaceutical composition as described herein. In some aspects, the present disclosure includes an autoinjector comprising a pharmaceutical composition as described herein.

[0424] In some embodiments, the vial comprises a pharmaceutical composition as described herein, and the vial further comprises a stopper and a seal. In some embodiments, the total volume within the vial is about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL.

[0425] IV. Kit Also within the scope of the invention are kits for treating a human subject having CRC as described herein, including unresectable or metastatic CRC, comprising any of the antibodies, therapeutic agents and / or anti-cancer therapies described herein.

[0426] Kits typically include labeling and instructions directing the intended use of the contents of the kit. The term "labeling" includes any written or recorded material supplied on or with the kit, or which otherwise accompanies the kit.

[0427] Provided herein is a kit for treating a human subject with CRC, the kit comprising: (a) an anti-LAG-3 antibody; and (b) an anti-PD-1 antibody or an anti-PD-L1 antibody; and (c) instructions for using the anti-LAG-3 antibody and the anti-PD-1 antibody or the anti-PD-L1 antibody in the method of treating a human subject with CRC.

[0428] The anti-LAG-3 antibody and the anti-PD-1 antibody or anti-PD-L1 antibody may be provided in any of the amounts or combinations of amounts described herein.

[0429] In some embodiments, the kit comprises relatolimab and an anti-PD-1 antibody or an anti-PD-L1 antibody as described herein. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, or spartalizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, or CK-301.

[0430] In some aspects, the kit comprises favezelimab and an anti-PD-1 antibody or an anti-PD-L1 antibody as described herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, or spartalizumab. In some aspects, the anti-PD-1 antibody is pembrolizumab. In some aspects, the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, or CK-301.

[0431] In some embodiments, the kit comprises fianlimab and an anti-PD-1 antibody or an anti-PD-L1 antibody as described herein. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, or spartalizumab. In some embodiments, the anti-PD-1 antibody is cemiplimab. In some embodiments, the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, or CK-301.

[0432] In some embodiments, the kit comprises yelamirimab and an anti-PD-1 antibody or an anti-PD-L1 antibody as described herein. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, or spartalizumab. In some embodiments, the anti-PD-1 antibody is spartalizumab. In some embodiments, the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, or CK-301.

[0433] In some embodiments, the kit comprises about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about The anti-LAG-3 antibody may be an anti-PD-1 antibody or an anti-PD-L1 antibody in a ratio of about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1 or about 2:1.

[0434] In some aspects, the kit comprises an anti-LAG-3 antibody and an anti-PD-1 antibody or an anti-PD-L1 antibody in a ratio of about 1:6.

[0435] In some aspects, the kit comprises an anti-LAG-3 antibody and an anti-PD-1 antibody or an anti-PD-L1 antibody in a ratio of about 1:3.

[0436] In some aspects, the kit comprises about a 1:1 ratio of an anti-LAG-3 antibody to an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0437] In some aspects, the kit comprises an anti-LAG-3 antibody and an anti-PD-1 antibody or an anti-PD-L1 antibody in a ratio of about 2:1.

[0438] In some aspects, the kit comprises an anti-LAG-3 antibody and an anti-PD-1 antibody or an anti-PD-L1 antibody in a ratio of about 4:1.

[0439] In some embodiments, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, about 110 mg / mL, about 115 mg / mL, about 120 mg / mL, about 125 mg / mL, About 130mg / mL, about 135mg / mL, about 140mg / mL, about 145mg / mL, about 150mg / mL, about 155mg / mL, about 160mg / mL, about 165mg / mL, about 170mg / mL, about 175mg / mL, about 180mg / mL, about 185mg / mL, about 190 mg / mL, approximately 195 mg / mL, approximately 200 mg / mL, approximately 205 mg / mL, approximately 210 mg / mL, approximately 215 mg / mL, approximately 220 mg / mL, approximately 225 mg / mL, approximately 230 mg / mL, approximately 235 mg / mL, approximately 240 mg / mL, approximately 245 mg / mL, approximately 250 mg / mL , about 255 mg / mL, about 260 mg / mL, about 265 mg / mL, about 270 mg / mL, about 275 mg / mL, about 280 mg / mL, about 285 mg / mL, about 290 mg / mL, about 295 mg / mL, about 300 mg / mL, about 305 mg / mL, about 310 mg / mL, about 31 5mg / mL, approximately 320mg / mL, approximately 325mg / mL, approximately 330mg / mL, approximately 335mg / mL, approximately 340mg / mL, approximately 345mg / mL, approximately 350mg / mL, approximately 355mg / mL, approximately 360mg / mL, approximately 365mg / mL, approximately 370mg / mL, approximately 375mg / m L, approx. 380 mg / mL, approx. 385 mg / mL, approx. 390 mg / mL, approx. 395 mg / mL, approx. 400 mg / mL, approx. 50 mg, approx. 60 mg, approx. 70 mg, approx. 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg,about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050mg, about 1060mg, about 1070mg, about 1080mg, about 1090mg, about 1100mg, about 1110mg, about 1120mg, about 1130mg, about 1140mg, about 1150mg, about 1160mg, about 1170mg, about 1180mg, about 1190mg, about 1200mg, about 1210mg, about 1220mg, about 1230mg, about 1240mg, about 1250mg, about 1260mg, about 1270mg, about 1280mg, about 1290mg, about 1300mg, about 1310mg, about 1320mg, about 1330mg, about 1340mg, about 1350mg g, about 1360mg, about 1370mg, about 1380mg, about 1390mg, about 1400mg, about 1410mg, about 1420mg, about 1430mg, about 1440mg, about 1450mg, about 1460mg, about 1470mg, about 1480mg, about 1490mg, about 1500mg, about 1510mg, about 1520mg, about 1530mg, about 1540mg, about 1550mg, about 1560mg, about 1570mg, about 1580mg, about 1590mg, about 1600mg, about 1610mg, about 1620mg, about 1630mg, about 1640mg, about 1650mg, about 1660mg,About 1670 mg, about 1680 mg, about 1690 mg, about 1700 mg, about 1710 mg, about 1720 mg, about 1730 mg, about 1740 mg, about 1750 mg, about 1760 mg, about 1770 mg, or about 1780 mg.

[0440] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 25 mg / mL.

[0441] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 50 mg / mL.

[0442] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 150 mg / mL.

[0443] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 50 mg.

[0444] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 320 mg.

[0445] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 480 mg.

[0446] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 560 mg.

[0447] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 640 mg.

[0448] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 720 mg.

[0449] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 960 mg.

[0450] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 1000 mg.

[0451] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 1080 mg.

[0452] In some aspects, the total amount of anti-LAG-3 and anti-PD-1 antibody or anti-PD-L1 antibody in the kit is about 1440 mg.

[0453] In some embodiments, the kit comprises about 10 mg / mL, about 12.5 mg / mL, about 15 mg / mL, about 17.5 mg / mL, about 20 mg / mL, about 22.5 mg / mL, about 25 mg / mL, about 27.5 mg / mL, about 30 mg / mL, about 32.5 mg / mL, about 35 mg / mL, about 37.5 mg / mL, about 40 mg / mL, about 42.5 mg / mL, about 45 mg / mL mL, approximately 47.5 mg / mL, approximately 50 mg / mL, approximately 55 mg / mL, approximately 60 mg / mL, approximately 65 mg / mL, approximately 70 mg / mL, approximately 75 mg / mL, approximately 80 mg / mL, approximately 85 mg / mL, approx. 90 mg / mL, approx. 95 mg / mL, approx. 100 mg / mL, approx. 105 mg / mL, approx. 110 mg / mL, approx. 115 mg / mL, approx. 120 mg / mL, approx. 125 mg / mL, approx. 130mg / mL, approx. 135mg / mL, approx. 140mg / mL, approx. 145mg / mL, approx. 150mg / mL, approx. 155mg / mL, approx. 160mg / mL, approx. 165mg / mL, about 170mg / mL, about 175mg / mL, about 180mg / mL, about 185mg / mL, about 190mg / mL, about 195mg / mL, about 200mg / mL, about 7mg, about 21 mg, about 70 mg, about 80 mg, about 120 mg, about 160 mg, about 200 mg, about 210 mg, about 300 mg, about 360 mg, about 400 mg, about 480 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 960 mg, about 1000 mg, about 1100 mg, about 1200 mg or about 1300 mg of anti-LAG-3 antibody.

[0454] In some embodiments, the kit comprises about 10 mg / mL, about 12.5 mg / mL, about 15 mg / mL, about 17.5 mg / mL, about 20 mg / mL, about 22.5 mg / mL, about 25 mg / mL, about 27.5 mg / mL, about 30 mg / mL, about 32.5 mg / mL, about 35 mg / mL, about 37.5 mg / mL, about 40 mg / mL, about 42.5 mg / mL, about 45 mg / mL, about 47.5 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 ... 100 mg / mL, about 110 mg / mL, about 115 mg / mL, about 120 mg / mL, about 125 mg / mL, 130 mg / mL, about 135 mg / mL, about 140 mg / mL, about 145 mg / mL, about 150 mg / mL, about 155 mg / mL, about 160 mg / mL, about 165 mg / mL, about 170 mg / mL, about 175 mg / mL, about 180 mg / mL, about 185 mg / mL, about 190 mg / mL, about 195 mg / mL, about 200 mg / mL, about 40 mg, about 100 mg, about 200 mg, about 240 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg or about 480 mg of the anti-PD-1 antibody or anti-PD-L1 antibody.

[0455] In some aspects, the kit comprises about 12.5 mg / mL of an anti-LAG-3 antibody and about 37.5 mg / mL of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0456] In some aspects, the kit comprises about 20 mg / mL of an anti-LAG-3 antibody and about 5 mg / mL of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0457] In some aspects, the kit comprises about 75 mg / mL of an anti-LAG-3 antibody and about 75 mg / mL of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0458] In some aspects, the kit comprises about 100 mg / mL of an anti-LAG-3 antibody and about 50 mg / mL of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0459] In some aspects, the kit comprises about 80 mg of an anti-LAG-3 antibody and about 240 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0460] In some aspects, the kit comprises about 80 mg of an anti-LAG-3 antibody and about 480 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0461] In some aspects, the kit comprises about 120 mg of an anti-LAG-3 antibody and about 360 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0462] In some aspects, the kit comprises about 160 mg of an anti-LAG-3 antibody and about 480 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0463] In some aspects, the kit comprises about 360 mg of an anti-LAG-3 antibody and about 360 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0464] In some aspects, the kit comprises about 480 mg of an anti-LAG-3 antibody and about 480 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0465] In some aspects, the kit comprises about 720 mg of an anti-LAG-3 antibody and about 360 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0466] In some aspects, the kit comprises about 800 mg of an anti-LAG-3 antibody and about 200 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0467] In some aspects, the kit comprises about 960 mg of an anti-LAG-3 antibody and about 480 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0468] Provided herein is a kit for treating a human subject with CRC, the kit comprising: (a) about 480 mg of an anti-LAG-3 antibody; (b) about 480 mg of an anti-PD-1 antibody or an anti-PD-L1 antibody; and (c) instructions for using the anti-LAG-3 antibody and the anti-PD-1 antibody or the anti-PD-L1 antibody in the method of treating a human subject with CRC.

[0469] In some aspects, the anti-LAG-3 and the anti-PD-1 antibody or anti-PD-L1 antibody are co-packaged in a single unit dosage form.

[0470] In some aspects, the anti-LAG-3 and the anti-PD-1 antibody or anti-PD-L1 antibody are packaged as separate unit dosage forms.

[0471] In some embodiments, about 80 mg of anti-LAG-3 antibody is provided in a unit dosage form.

[0472] In some embodiments, about 120 mg of anti-LAG-3 antibody is provided in a unit dosage form.

[0473] In some embodiments, about 160 mg of anti-LAG-3 antibody is provided in a unit dosage form.

[0474] In some embodiments, about 360 mg of anti-LAG-3 antibody is provided in a unit dosage form.

[0475] In some embodiments, about 480 mg of anti-LAG-3 antibody is provided in a unit dosage form.

[0476] In some embodiments, about 960 mg of anti-LAG-3 antibody is provided in a unit dosage form.

[0477] In some embodiments, about 50 mg / mL of anti-LAG-3 antibody is provided in the unit dosage form.

[0478] In some embodiments, about 100 mg / mL of anti-LAG-3 antibody is provided in the unit dosage form.

[0479] In some embodiments, about 130 mg / mL of anti-LAG-3 antibody is provided in the unit dosage form.

[0480] In some embodiments, about 150 mg / mL of anti-LAG-3 antibody is provided in the unit dosage form.

[0481] In some embodiments, about 175 mg / mL of anti-LAG-3 antibody is provided in the unit dosage form.

[0482] In some embodiments, about 200 mg / mL of anti-LAG-3 antibody is provided in the unit dosage form.

[0483] In some aspects, about 40 mg of the anti-PD-1 antibody or anti-PD-L1 antibody is provided in a unit dosage form.

[0484] In some embodiments, about 100 mg of the anti-PD-1 antibody or anti-PD-L1 antibody is provided in a unit dosage form.

[0485] In some embodiments, about 240 mg of the anti-PD-1 antibody or anti-PD-L1 antibody is provided in a unit dosage form.

[0486] In some embodiments, about 360 mg of the anti-PD-1 antibody or anti-PD-L1 antibody is provided in a unit dosage form.

[0487] In some embodiments, about 480 mg of the anti-PD-1 antibody or anti-PD-L1 antibody is provided in a unit dosage form.

[0488] In some aspects, about 10 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody is provided in the unit dosage form.

[0489] In some aspects, about 50 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody is provided in a unit dosage form.

[0490] In some aspects, about 100 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody is provided in the unit dosage form.

[0491] In some aspects, about 150 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody is provided in the unit dosage form.

[0492] In some aspects, about 175 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody is provided in the unit dosage form.

[0493] In some aspects, about 200 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody is provided in a unit dosage form.

[0494] In some embodiments, the unit dosage form comprises about 5 mM to about 50 mM histidine, about 50 mM to about 300 mM sucrose, about 5 μM to about 1 mM diethylenetriaminepentaacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA), and about 0.001% to about 1% (w / v) polysorbate or poloxamer (e.g., polysorbate 80 (PS80), polysorbate 20 (PS20), poloxamer 188 (PX188), or any combination thereof).

[0495] In some embodiments, the unit dosage form comprises about 20 mM histidine, about 250 mM sucrose, about 50 μM DTPA, and 0.05% PS80.

[0496] In some embodiments, the unit dosage form comprises a pH of about 5 to about 6.5. In some embodiments, the pH is about 5.3 to about 6.3. In some embodiments, the pH is 5.8. In some embodiments, the pH is 5.7.

[0497] In some embodiments, the unit dosage form is a vial, a syringe, or an intravenous bag. In some embodiments, the unit dosage form is an autoinjector. In some embodiments, the unit dosage form is a vial that includes a stopper and a seal. In some embodiments, the total volume in the vial is about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL.

[0498] In some aspects, the kit provides instructions for administering the anti-LAG-3 antibody and / or anti-PD-1 antibody or anti-PD-L1 antibody intravenously in about 30 minutes.

[0499] All of the references cited above and all of the references cited herein are hereby incorporated by reference in their entirety.

[0500] The following examples are offered by way of illustration and not by way of limitation. EXAMPLES

[0501] Example 1 Safety and efficacy of anti-LAG-3 antibodies in combination with anti-PD-1 antibodies in the treatment of colorectal cancer The open-label, sponsor-blinded, multicenter, Phase 3 study will evaluate the safety and efficacy of a fixed-dose combination of leratolimab and nivolumab compared with regorafenib or trifluridine / tipiracil (TAS-102) standard of care therapy in the treatment of mismatch repair proficient (pMMR) / microsatellite stable (MSS) metastatic colorectal cancer (mCRC).

[0502] Patients will be aged 18 years or older or of local adult age and will be selected based on eligibility criteria including: (1) histologically confirmed previously treated CRC with adenocarcinoma histology and metastatic or recurrent unresectable disease at the time of study entry; (2) confirmed tumor MSS / pMMR status as per local standard testing and acceptable MSS / pMMR results from initial diagnosis; (3) treatment with fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF therapy, and anti-EGFR therapy (if KRAS wild-type), if approved in the respective country. Progression approximately 3 months or within 3 months of the last dose of approved standard therapy (≥1 and ≤4 prior lines of therapy) that should be considered refractory to that therapy; i) participants treated in the adjuvant / neoadjuvant setting must have progression ≥6 months or within 6 months of completion of adjuvant therapy to be considered refractory to that therapy; ii) adjuvant / neoadjuvant or maintenance therapy should not be considered a line of prior therapy for the purposes of study enrollment unless disease progression occurs ≥6 months or within 6 months of completion of that adjuvant therapy. (iii) participants with KRAS mutant tumors and who received FOLFOXIRI with anti-VEGF therapy as first-line treatment will be eligible to participate in the study; iv) participants who have been intolerant to prior systemic chemotherapy regimens will be eligible if there is documentation of clinically significant intolerance despite appropriate supportive measures; (4) there must be documentation of KRAS mutation status available as part of medical history or based on local laboratory testing prior to study enrollment; (5) NRAS (expanded RAS) and BRAF mutation status as part of medical history is strongly encouraged if testing is available from local or local results prior to study treatment; (6) evaluable PD-L1 expression during the screening period and prior to randomization; (7) measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; participants with a previously irradiated area as the only site of measurable disease will be permitted to enroll if one or more of their lesions have demonstrated clear progression and can be accurately measured; and (8) Eastern Cooperative Oncology Group PS. 0 or 1.

[0503] Patients will not be eligible for the study if they have had previous treatment with immunotherapy (anti-LAG-3, anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibodies or any other antibodies or drugs that specifically target T cell costimulatory or checkpoint pathways), with regorafenib, or with TAS-102.

[0504] Approximately 700 patients will be randomized 1:1 to arms A and B, respectively.

[0505] Patients in Arm A will receive a fixed-dose combination of 480 mg leratolimab and 480 mg nivolumab on day 1 of every 4-week cycle (Q4W).

[0506] Patients in arm B received 160 mg regorafenib daily for 21 days of a 28-day cycle or 35 mg / m twice daily. 2 Patients will receive either regorafenib or TAS-102 on days 1-5 and days 8-12 of each 28-day cycle. The study is designed to allow investigators to choose whether to administer regorafenib or TAS-102, taking into account the patient's medical condition and drug availability, given the differences in toxicity profiles of the two agents.

[0507] Stratification factors at randomization were PD-L1 combined positive score (CPS) expression level (≥1 vs <1 [including undetermined expression]), region (Asia vs US / Canada / Western Europe / Australia vs other countries) and KRAS status (wild-type vs mutant / amplified).

[0508] PD-L1 expression on tumor and immune cells will be measured using analytically validated immunohistochemistry (IHC) assays. PD-L1 expression will be determined primarily based on CPS, defined as the number of PD-L1 stained cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells multiplied by 100. PD-L1 positivity will be defined by CPS > 1. PD-L1 may also be determined by tumor proportion score (TPS), which reflects the proportion of tumor cells positive for PD-L1 expression. IHC analysis will also be used to evaluate the association between tumor LAG-3 status (defined as the proportion of LAG-3+ cells in tumor specimens) and treatment efficacy and / or safety. The effect of LAG-3 positivity using a 1% threshold and possibly other cut-off levels will be examined retrospectively.

[0509] Administration of the relatolimab-nivolumab FDC will continue until progression, toxicity, withdrawal of consent, or for up to two years, whichever occurs first. Ongoing safety assessments and tumor evaluations will guide the decision to treat participants with additional cycles of study therapy if they demonstrate clinical benefit.

[0510] Regorafenib or TAS-102 administration will continue until progression, toxicity, or withdrawal of consent, whichever occurs first.

[0511] array SEQ ID NO: 1 Heavy chain amino acid sequence; anti-LAG-3 mAb (BMS-986016) [ka] SEQ ID NO:2 Light chain amino acid sequence; anti-LAG-3 mAb (BMS-986016) [ka] SEQ ID NO: 3 Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (BMS-986016) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSS SEQ ID NO: 4: Light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (BMS-986016) EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIK SEQ ID NO: 5 Heavy chain CDR1 amino acid sequence; anti-LAG-3 mAb (BMS-986016) DYYWN SEQ ID NO:6 Heavy chain CDR2 amino acid sequence; anti-LAG-3 mAb (BMS-986016) EINHRGSTNSNPSLKS SEQ ID NO: 7 Heavy chain CDR3 amino acid sequence; anti-LAG-3 mAb (BMS-986016) GYSDYEYNWFDP SEQ ID NO:8 Light chain CDR1 amino acid sequence; anti-LAG-3 mAb (BMS-986016) RASQSISSYLA SEQ ID NO: 9 Light chain CDR2 amino acid sequence; anti-LAG-3 mAb (BMS-986016) DASNRAT SEQ ID NO: 10 Light chain CDR3 amino acid sequence; anti-LAG-3 mAb (BMS-986016) QQRSNWPLT SEQ ID NO:11 Heavy chain amino acid sequence; anti-PD-1 mAb (BMS-936558) [ka] SEQ ID NO:12 Light chain amino acid sequence; anti-PD-1 mAb (BMS-936558) [ka] SEQ ID NO:13 Heavy chain variable region (VH) amino acid sequence; anti-PD-1 mAb (BMS-936558) QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS SEQ ID NO: 14: Light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (BMS-936558) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK SEQ ID NO: 15 Heavy chain CDR1 amino acid sequence; anti-PD-1 mAb (BMS-936558) NSGMH SEQ ID NO: 16 Heavy chain CDR2 amino acid sequence; anti-PD-1 mAb (BMS-936558) VIWYDGSKRYYADSVKG SEQ ID NO: 17 Heavy chain CDR3 amino acid sequence; anti-PD-1 mAb (BMS-936558) NDDY SEQ ID NO: 18 Light chain CDR1 amino acid sequence; anti-PD-1 mAb (BMS-936558) RASQSVSSYLA SEQ ID NO: 19 Light chain CDR2 amino acid sequence; anti-PD-1 mAb (BMS-936558) DASNRAT SEQ ID NO: 20 Light chain CDR3 amino acid sequence; anti-PD-1 mAb (BMS-936558) QQSSNWPRT SEQ ID NO:21 Heavy chain amino acid sequence; anti-LAG-3 mAb (BMS-986016) without terminal lysine [ka] SEQ ID NO: 22 Lymphocyte activation gene 3 protein amino acid sequence (Homo Sapiens, NP_002277) [ka] SEQ ID NO: 23 Heavy chain amino acid sequence; anti-LAG-3 mAb (REGN3767) [ka] SEQ ID NO: 24 Light chain amino acid sequence; anti-LAG-3 mAb (REGN3767) [ka] SEQ ID NO: 25 Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (REGN3767) [ka] SEQ ID NO: 26: Light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (REGN3767) EIVLTQSPATLSLSPGERTTLSCRASQRISTYLAWYQQKPGQAPRLLIYDASKRATGIPARFSGSGSGTGFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK SEQ ID NO: 27 Heavy chain CDR1 amino acid sequence; anti-LAG-3 mAb (REGN3767) GFTFSSYG SEQ ID NO: 28 Heavy chain CDR2 amino acid sequence; anti-LAG-3 mAb (REGN3767) IWYDGSNK SEQ ID NO: 29 Heavy chain CDR3 amino acid sequence; anti-LAG-3 mAb (REGN3767) ASVATSGDFDYYGMDV SEQ ID NO: 30 Light chain CDR1 amino acid sequence; anti-LAG-3 mAb (REGN3767) QRISTY Light chain CDR2 amino acid sequence; anti-LAG-3 mAb (REGN3767) DAS SEQ ID NO: 32 Light chain CDR3 amino acid sequence; anti-LAG-3 mAb (REGN3767) QQRSNWPLT SEQ ID NO: 33 Heavy chain amino acid sequence; anti-PD-1 mAb (REGN2810) [ka] SEQ ID NO: 34 Light chain amino acid sequence; anti-PD-1 mAb (REGN2810) [ka] SEQ ID NO: 35: Heavy chain variable region (VH) amino acid sequence; anti-PD-1 mAb (REGN2810) EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDTYFADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSS SEQ ID NO: 36: Light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (REGN2810) DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAASSLHGGVPSRFSGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFGPGTVVDFR SEQ ID NO: 37 Heavy chain CDR1 amino acid sequence; anti-PD-1 mAb (REGN2810) GFTFSNFG SEQ ID NO: 38 Heavy chain CDR2 amino acid sequence; anti-PD-1 mAb (REGN2810) ISGGGRDT SEQ ID NO: 39 Heavy chain CDR3 amino acid sequence; anti-PD-1 mAb (REGN2810) VKWGNIYFDY SEQ ID NO: 40 Light chain CDR1 amino acid sequence; anti-PD-1 mAb (REGN2810) LSINTF Light chain CDR2 amino acid sequence; Anti-PD-1 mAb (REGN2810) AAS SEQ ID NO: 42 Light chain CDR3 amino acid sequence; anti-PD-1 mAb (REGN2810) QQSSNTPFT SEQ ID NO: 43 Heavy chain amino acid sequence; anti-LAG-3 mAb (LAG525) [ka] SEQ ID NO: 44 Heavy chain amino acid sequence; anti-LAG-3 mAb (LAG525) [ka] SEQ ID NO: 45 Light chain amino acid sequence; anti-LAG-3 mAb (LAG525) [ka] SEQ ID NO: 46 Light chain amino acid sequence; anti-LAG-3 mAb (LAG525) [ka] SEQ ID NO: 47 Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (LAG525) [ka] SEQ ID NO: 48 Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (LAG525) [ka] SEQ ID NO: 49 Light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (LAG525) DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 50 Light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (LAG525) DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO:51 Heavy chain CDR1 amino acid sequence; anti-LAG-3 mAb (LAG525) NYGMN SEQ ID NO:52 Heavy chain CDR2 amino acid sequence; anti-LAG-3 mAb (LAG525) WINTDTGEPTYADDFKG SEQ ID NO:53 Heavy chain CDR3 amino acid sequence; anti-LAG-3 mAb (LAG525) NPPYYYGTNNAEAMDY SEQ ID NO:54 Light chain CDR1 amino acid sequence; anti-LAG-3 mAb (LAG525) SSSQDISNYLN SEQ ID NO: 55 Light chain CDR2 amino acid sequence; anti-LAG-3 mAb (LAG525) YTSTLHL SEQ ID NO:56 Light chain CDR3 amino acid sequence; anti-LAG-3 mAb (LAG525) QQYYNLPWT SEQ ID NO:57 Heavy chain amino acid sequence; anti-PD-1 mAb (PDR001) [ka] SEQ ID NO:58 Light chain amino acid sequence; anti-PD-1 mAb (PDR001) [ka] SEQ ID NO:59 Heavy chain variable region (VH) amino acid sequence; anti-PD-1 mAb (PDR001) EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 60 Light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (PDR001) EIVLTQSPATLLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 61 Heavy chain CDR1 amino acid sequence; anti-PD-1 mAb (PDR001) TYWMH SEQ ID NO: 62 Heavy chain CDR2 amino acid sequence; Anti-PD-1 mAb (PDR001) NIYPGTGGSNFDEKFKN SEQ ID NO: 63 Heavy chain CDR3 amino acid sequence; anti-PD-1 mAb (PDR001) WTTTGAY SEQ ID NO:64 Light chain CDR1 amino acid sequence; anti-PD-1 mAb (PDR001) KSSQSLLDSGNQKNFLT SEQ ID NO: 65 Light chain CDR2 amino acid sequence; anti-PD-1 mAb (PDR001) WASTRES SEQ ID NO: 66 Light chain CDR3 amino acid sequence; Anti-PD-1 mAb (PDR001) QNDYSYPYT SEQ ID NO: 67 Heavy chain amino acid sequence; anti-LAG-3 mAb (MK4280) [ka] SEQ ID NO:68 Light chain amino acid sequence; anti-LAG-3 mAb (MK4280) [ka] SEQ ID NO: 69 Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (MK4280) QMQLVQSGPEVKKPGTSVKVSCKASGYTFTDYNVDWVRQARGQRLEWIGDINPNDGGTIYAQKFQERVTITVDKSTSTAYMELSSLRSEDTAVYYCARNYRWFGAMDHWGQGTTVTVSS SEQ ID NO: 70 Light chain variable region (VL) amino acid sequence; anti-LAG-3 Anti-LAG-3 mAb (MK4280) DIVMTQTPLSLSVTPGQPASISCKASQSLDYEGDSDMNWYLQKPGQPPQLLIYGASNLESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQSTEDPRTFGGGTKVEIK SEQ ID NO: 71 Heavy chain CDR1 amino acid sequence; anti-LAG-3 mAb (MK4280) DYNVD SEQ ID NO: 72 Heavy chain CDR2 amino acid sequence; anti-LAG-3 mAb (MK4280) DINPNDGGTIYAQKFQE SEQ ID NO: 73 Heavy chain CDR3 amino acid sequence; anti-LAG-3 mAb (MK4280) NYRWFGAMDH SEQ ID NO: 74 Light chain CDR1 amino acid sequence; anti-LAG-3 mAb (MK4280) KASQSLDYEGDSDMN SEQ ID NO: 75 Light chain CDR2 amino acid sequence; anti-LAG-3 mAb (MK4280) GASNLES SEQ ID NO: 76 Light chain CDR3 amino acid sequence; anti-LAG-3 mAb (MK4280) QQSTEDPRT SEQ ID NO: 77 Heavy chain amino acid sequence; anti-PD-1 mAb (MK3475) [ka] SEQ ID NO:78 Light chain amino acid sequence; anti-PD-1 mAb (MK3475) [ka] SEQ ID NO: 79 Heavy chain variable region (VH) amino acid sequence; anti-PD-1 mAb (MK3475) QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS SEQ ID NO:80 Light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (MK3475) EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGGTKVEIK SEQ ID NO: 81 Heavy chain CDR1 amino acid sequence; anti-PD-1 mAb (MK3475) NYYMY SEQ ID NO: 82 Heavy chain CDR2 amino acid sequence; Anti-PD-1 mAb (MK3475) GINPSNGGTNFNEKFKN SEQ ID NO: 83 Heavy chain CDR3 amino acid sequence; anti-PD-1 mAb (MK3475) RDYRFDMGFDY SEQ ID NO: 84 Light chain CDR1 amino acid sequence; anti-PD-1 mAb (MK3475) RASKGVSTSGYSYLH SEQ ID NO: 85 Light chain CDR2 amino acid sequence; anti-PD-1 mAb (MK3475) LASYLES SEQ ID NO: 86 Light chain CDR3 amino acid sequence; Anti-PD-1 mAb (MK3475) QHSRDLPLT

Claims

1. A pharmaceutical composition comprising an anti-LAG-3 antibody for use in combination with an anti-PD-1 antibody or an anti-PD-L1 antibody in treating colorectal cancer (CRC) in a human subject, comprising: (a) an anti-LAG-3 antibody is administered to the subject at a dose of about 480 mg; and (b) the anti-PD-1 antibody or anti-PD-L1 antibody is administered to the subject at a dose of about 480 mg; Pharmaceutical compositions.

2. The anti-LAG-3 antibody and / or anti-PD-1 or anti-PD-L1 antibody is (a) is a full-length antibody; (b) is a monoclonal, human, humanized, chimeric, or multispecific antibody; (c) a dual affinity retargeting antibody, a dual variable domain immunoglobulin, or a bispecific antibody; or (d) F(ab') ２ a fragment, a Fab' fragment, a Fab fragment, an Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment or a single chain binding polypeptide, The pharmaceutical composition of claim 1. (a) the anti-LAG-3 antibody is (1) BMS-986016 (relatolimab), IMP731 (H5L7BW), MK4280 (28G-10, favezelimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, yelamilimab), aLAG3 (0414), aLAG3 (0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P 13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or an antigen-binding portion thereof; (2) A heavy chain variable region CDR1, CDR2, and CDR3 domains having the sequence shown in SEQ ID NO: 3, and a light chain variable region CDR1, CDR2, and CDR3 domains having the sequence shown in SEQ ID NO: 4; (3) Heavy chain variable regions CDR1, CDR2 and CDR3 comprising the sequences shown in SEQ ID NOs: 5, 6 and 7, respectively, and light chain variable regions CDR1, CDR2 and CDR3 comprising the sequences shown in SEQ ID NOs: 8, 9 and 10, respectively; (4) The heavy chain and light chain variable regions comprise the sequences set forth in SEQ ID NOs: 3 and 4, respectively; (5) comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 1 and 2, respectively; or (6) comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 21 and 2, respectively; and / or (b) the anti-PD-1 antibody (1) Nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, cemiplimab, JS001, PF-06801591, BGB-A317, BI 754091, INCSHR1210, GLS-010, AM-001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, SSI-361, or an antigen-binding portion thereof; (2) A heavy chain variable region CDR1, CDR2, and CDR3 domains having the sequence set forth in SEQ ID NO: 13, and a light chain variable region CDR1, CDR2, and CDR3 domains having the sequence set forth in SEQ ID NO: 14; (3) Heavy chain variable regions CDR1, CDR2 and CDR3 comprising the sequences shown in SEQ ID NOs: 15, 16 and 17, respectively, and light chain variable regions CDR1, CDR2 and CDR3 comprising the sequences shown in SEQ ID NOs: 18, 19 and 20, respectively; (4) comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively; or (5) A heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively; or (c) the anti-PD-L1 antibody comprises BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301, or an antigen-binding portion thereof; The pharmaceutical composition of claim 1.

4. A pharmaceutical composition comprising an anti-LAG-3 antibody for use in combination with an anti-PD-1 antibody, (a) the anti-LAG-3 antibody comprises leratolimab and the anti-PD-1 antibody comprises nivolumab; (b) the anti-LAG-3 antibody comprises CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 3, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 4; and the anti-PD-1 antibody comprises CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 13, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 14; (c) the anti-LAG-3 antibody comprises heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NOs: 5, 6, and 7, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NOs: 8, 9, and 10, respectively; and the anti-PD-1 antibody comprises heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NOs: 15, 16, and 17, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NOs: 18, 19, and 20, respectively; (d) the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 3 and 4, respectively, and the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively; (e) the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 1 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively; or (f) the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 21 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively; The pharmaceutical composition of claim 1.

5. the anti-LAG-3 antibody is formulated for intravenous administration, and / or the anti-PD-1 antibody or anti-PD-L1 antibody is formulated for intravenous administration, and / or (a) the anti-PD-1 antibody or anti-PD-L1 antibody is administered before the anti-LAG-3 antibody; (b) the anti-LAG-3 antibody is administered before the anti-PD-1 antibody or anti-PD-L1 antibody; (c) the anti-LAG-3 antibody and the anti-PD-1 antibody or anti-PD-L1 antibody are administered simultaneously; (d) the anti-LAG-3 antibody and the anti-PD-1 antibody or anti-PD-L1 antibody are formulated separately; or (e) the anti-LAG-3 antibody and the anti-PD-1 antibody or anti-PD-L1 antibody are formulated together; The pharmaceutical composition according to any one of claims 1 to 4.

6. (a)(1) The treatment is a first-line therapy. (2) the treatment is a second-line therapy; (3) the treatment is a third-line therapy; (4) the subject has progressed on or is intolerant to prior therapy; (5) the subject has not received prior systemic therapy for advanced and / or metastatic CRC, or (6) The subject has no prior immuno-oncology therapy, the subject has no prior immuno-oncology therapy for CRC, or the CRC has no prior immuno-oncology therapy, and / or (b) the CRC is (1) Including adenocarcinoma histology, (2) unresectable, advanced, and / or metastatic; (3) microsatellite stable (MSS) CRC or microsatellite instability-high (MSI-H) CRC, and / or (4) containing a KRAS mutation or wild-type KRAS; and / or (c) the CRC is colon cancer or rectal cancer; The pharmaceutical composition according to any one of claims 1 to 4.

7. one or more immune cells in tumor tissue from the subject express LAG-3, and / or one or more tumor cells in tumor tissue from the subject express PD-L1, and / or (a) at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of said immune cells in tumor tissue from said subject express LAG-3; and / or (b) tumor tissue from the subject comprises a PD-L1 tumor proportion score (TPS) and / or combined positive score (CPS) of at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100%, wherein the TPS is the proportion of tumor cells in the tumor tissue that express PD-L1, and the CPS is the number of tumor and immune cells in the tumor tissue that express PD-L1 as a proportion of the total number of viable tumor cells. The pharmaceutical composition according to any one of claims 1 to 4.

8. A pharmaceutical composition described in any one of claims 1 to 4, further used in combination with an additional therapeutic agent.

9. 9. The pharmaceutical composition of claim 8, wherein the additional therapeutic agent comprises a tyrosine kinase inhibitor, an anti-angiogenic agent, a checkpoint inhibitor, a checkpoint stimulator, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topoisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof.

10. The checkpoint inhibitors include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, T-cell immunoglobulin and ITIM domain (TIGIT) inhibitors, T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B- and T-cell lymphocyte attenuator (BTLA) inhibitors, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitors, killer cell immunoglobulin-like receptor (KIR) inhibitors, adenosine A2a receptor (A2aR) inhibitors, transforming growth factor beta (TG 10. The pharmaceutical composition of claim 9, comprising a phosphoinositide 3-kinase (PI3K) inhibitor, a CD47 inhibitor, a CD48 inhibitor, a CD73 inhibitor, a CD113 inhibitor, a sialic acid-binding immunoglobulin-like lectin 7 (SIGLEC-7) inhibitor, a SIGLEC-9 inhibitor, a SIGLEC-15 inhibitor, a glucocorticoid-inducible TNFR-related protein (GITR) inhibitor, a galectin-1 inhibitor, a galectin-9 inhibitor, a carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) inhibitor, a G protein-coupled receptor 56 (GPR56) inhibitor, a glycoprotein A repeat-dominant (GARP) inhibitor, a 2B4 inhibitor, a programmed death 1 homolog (PD1H) inhibitor, a leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitor, or any combination thereof.

11. The pharmaceutical composition of claim 10, wherein the checkpoint inhibitor comprises a CTLA-4 inhibitor.

12. The pharmaceutical composition of claim 11, wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody.

13. The anti-CTLA-4 antibody (a) is a full-length antibody; (b) is a monoclonal, human, humanized, chimeric, or multispecific antibody; (c) a dual affinity retargeting antibody, a dual variable domain immunoglobulin, or a bispecific antibody; or (d) F(ab') ２ a fragment, a Fab' fragment, a Fab fragment, an Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment or a single chain binding polypeptide, The pharmaceutical composition of claim 12.

14. 13. The pharmaceutical composition of claim 12, wherein the anti-CTLA-4 antibody comprises ipilimumab, tremelimumab, MK-1308, AGEN-1884, or an antigen-binding portion thereof.