Dosage regimens of Anti-LAG-3 antibodies and uses thereof

Abstract

To provide pharmaceutical compositions comprising antibody molecules that bind to Lymphocyte Activation Gene-3 (LAG-3) with high affinity and specificity.SOLUTION: A pharmaceutical composition comprises an anti-LAG-3 antibody molecule for use at a fixed dose of the anti-LAG-3 antibody molecule of 300-700 mg or 900-1300 mg once every 2, 3 or 4 weeks in treating a cancer in a subject, where the anti-LAG-3 antibody molecule comprises: a heavy chain variable region (VH) comprising VHCDR1, VHCDR2 and VHCDR3 of specific amino acid sequences; and a light chain variable region (VL) comprising VLCDR1, VLCDR2 and VLCDR3 of specific amino acid sequences.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 534,798, filed July 20, 2017, and U.S. Provisional Patent Application No. 62 / 643,992, filed March 16, 2018, the entire contents of which are hereby incorporated by reference herein.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created on July 17, 2018, is named C2160-7019WO_SL.txt and is 233,727 bytes in size. [Background technology]

[0003] Lymphocyte activation gene-3, or LAG-3 (also known as CD223), is a member of the immunoglobulin supergene family and is expressed on the surface of activated T cells [Huard et al. (1994) Immunogenetics 39:213], NK cells [Triebel et al. (1990) J. Exp. Med. 171:1393-1405], regulatory T cells [Huang et al. (2004) Immunity 21:503-513; Camisaschi et al. (2010) J Immunol. 184:6545-6551; Gagliani et al. (2013) Nat Med 19:739-746], and plasmacytoid dendritic cells (DCs) [Workman et al. (2009) J Immunol 182:1885-1891]. LAG-3 is a membrane protein encoded by a gene located on chromosome 12 and is structurally and genetically related to CD4.

[0004] Like CD4, LAG-3 can interact with MHC class II molecules on the cell surface [Baixeras et al. (1992) J. Exp. Med. 176:327-337; Huard et al. (1996) Eur. J. Immunol. 26:1180-1186]. Direct binding of LAG-3 to MHC class II mediates the expression of CD4 + It has been suggested to play a role in downregulating antigen-dependent stimulation of T lymphocytes [Huard et al. (1994) Eur. J. Immunol. 24:3216-3221], and LAG-3 blockade has also been shown to inhibit CD8 T cell proliferation in both tumor or self-antigen [Gross et al. (2007) J Clin Invest. 117:3383-3392] and viral models [Blackburn et al. (2009) Nat. Immunol. 10:29-37]. + It has been shown to reactivate lymphocytes. Furthermore, the cytoplasmic domain of LAG-3 can interact with LAP (LAG-3 associated protein), a signaling molecule involved in downregulation of the CD3 / TCR activation pathway [Iouzalen et al. (2001) Eur. J. Immunol. 31:2885-2891]. Furthermore, CD4 + CD25 + Regulatory T cells (T reg ) have been shown to express LAG-3 after activation, which suggests that T reg LAG-3 contributes to the suppressor activity of T cells by both T cell-dependent and -independent mechanisms [Huang, C. et al. (2004) Immunity 21:503-513]. reg It can also negatively regulate T cell homeostasis by cells [Workman, CJ and Vignali, DA (2005) J. Immunol. 174:688-695]. Summary of the Invention [Problem to be solved by the invention]

[0005] Thus, there is a need for novel therapeutic approaches that modulate LAG-3 function and the function of LAG-3-expressing cells, including dosage regimens and formulations for anti-LAG-3 antibody molecules to treat diseases, such as cancer. [Means for solving the problem]

[0006] Disclosed herein are antibody molecules (e.g., humanized antibody molecules) that bind to lymphocyte activation gene-3 (LAG-3) with high affinity and specificity, at least in part. Pharmaceutical compositions and dosage formulations comprising the anti-LAG-3 antibody molecules are also provided. The anti-LAG-3 antibody molecules disclosed herein can be used (alone or in combination with other therapeutic agents, procedures or modalities) to treat or prevent disorders such as cancerous disorders (e.g., solid tumors and hematological cancers) and infectious diseases (e.g., chronic infectious disorders or sepsis). Thus, disclosed herein are methods including dosage regimens for treating various disorders using the anti-LAG-3 antibody molecules. In certain embodiments, the anti-LAG-3 antibody molecules are administered or used at a constant or fixed dose.

[0007] Accordingly, in one aspect, the disclosure features a method of treating (e.g., inhibiting, reducing, ameliorating, or preventing) a disorder, e.g., a hyperproliferative condition or disorder (e.g., cancer), in a subject.

[0008] In certain embodiments, the methods include administering an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule described herein, to a subject once every three weeks or once every four weeks at a dose of about 300 mg to about 500 mg, about 500 mg to about 700 mg, or about 700 mg to about 900 mg.

[0009] In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg once every three weeks or once every four weeks. In other embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 500 mg to about 700 mg once every three weeks or once every four weeks. In other embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 700 mg to about 900 mg once every three weeks or once every four weeks. In other embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg, about 500 mg to about 700 mg, or about 700 mg to about 900 mg once every three weeks. In other embodiments, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 300 mg to about 500 mg, about 500 mg to about 700 mg, or about 700 mg to about 900 mg.

[0010] In one embodiment, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 500 mg, e.g., about 350 mg to about 450 mg, about 300 mg to about 400 mg, or about 400 mg to about 500 mg, e.g., about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. In a particular embodiment, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 350 mg to about 450 mg, e.g., about 400 mg.

[0011] In one embodiment, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 500 mg to about 700 mg, e.g., about 550 mg to about 650 mg, about 500 mg to about 600 mg, or about 600 mg to about 700 mg, e.g., about 500 mg, about 533 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg. In a particular embodiment, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 500 mg to about 650 mg, e.g., about 533 mg or about 600 mg.

[0012] In one embodiment, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 700 mg to about 900 mg, e.g., about 750 mg to about 850 mg, about 700 mg to about 800 mg, or about 800 mg to about 900 mg, e.g., about 700 mg, about 750 mg, about 800 mg, about 850 mg, or about 900 mg. In a particular embodiment, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 750 mg to about 850 mg, e.g., about 800 mg.

[0013] In one embodiment, the anti-LAG-3 antibody molecule comprises: (a) anti-LAG-3 antibody molecules bind to 50% or more (e.g., 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 99% or more) of the soluble LAG-3 in a subject (e.g., blood); or (b) the anti-LAG-3 antibody molecule binds to 50% or more (e.g., 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 99% or more) of the membrane-bound LAG-3 in a subject (e.g., a cancer). The therapeutic dose or dosage schedule is administered to provide one or both of the following:

[0014] In some embodiments, binding of the anti-LAG-3 antibody molecule to soluble LAG-3 is determined in a blood sample (e.g., a serum or plasma sample). In some embodiments, binding of the anti-LAG-3 antibody molecule to membrane-bound LAG-3 is determined in a cancer (e.g., a cancer sample).

[0015] In some embodiments, the binding of anti-LAG-3 antibody molecules to soluble LAG-3, the binding of anti-LAG-3 antibody molecules to membrane-bound LAG-3, or both, is determined when the subject has a steady-state trough level of anti-LAG-3 antibody molecules. In some embodiments, the trough level is the concentration of anti-LAG-3 antibody molecules about 24 weeks after administration, or the lowest concentration that anti-LAG-3 antibody molecules reach before the next dose is administered. In some embodiments, the binding of anti-LAG-3 antibody molecules to soluble LAG-3, the binding of anti-LAG-3 antibody molecules to membrane-bound LAG-3, or both, is determined, e.g., measured, in vitro (e.g., by ELISA or cell-based assay) or in vivo (e.g., by imaging), or predicted from a PK / PD model, e.g., a PK / PD model described herein.

[0016] In some embodiments, the anti-LAG-3 antibody molecule binds to 60% or more of the soluble LAG-3 in a serum sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 80% or more of the soluble LAG-3 in a serum sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 90% or more of the soluble LAG-3 in a serum sample from the subject.

[0017] In some embodiments, the anti-LAG-3 antibody molecule binds to 85% or more of the membrane-bound LAG-3 in the cancer or cancer sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 90% or more of the membrane-bound LAG-3 in the cancer or cancer sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 95% or more of the membrane-bound LAG-3 in the cancer or cancer sample from the subject.

[0018] In certain embodiments, the anti-LAG-3 antibody molecule binds to 70% or more, 80% or more or 90% or more of soluble LAG-3 in a serum sample from a subject, and the anti-LAG-3 antibody molecule binds to 85% or more, 90% or more or 95% or more of membrane-bound LAG-3 in a cancer or cancer sample from a subject.

[0019] In some embodiments, the anti-LAG-3 antibody molecule binds to 70% or more of the soluble LAG-3 in the serum sample from the subject, and the anti-LAG-3 antibody molecule binds to 90% or more of the membrane-bound LAG-3 in the cancer or cancer sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 80% or more of the soluble LAG-3 in the serum sample from the subject, and the anti-LAG-3 antibody molecule binds to 90% or more of the membrane-bound LAG-3 in the cancer or cancer sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 90% or more of the soluble LAG-3 in the serum sample from the subject, and the anti-LAG-3 antibody molecule binds to 90% or more of the membrane-bound LAG-3 in the cancer or cancer sample from the subject.

[0020] In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 800 mg, e.g., about 300 mg to about 500 mg (e.g., about 400 mg) or about 600 mg to about 800 mg (e.g., about 700 mg). In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg).

[0021] In other embodiments, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 600 mg to about 1600 mg, e.g., about 600 mg to about 1000 mg (e.g., about 800 mg) or about 1200 mg to about 1600 mg (e.g., about 1400 mg). In one embodiment, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 600 mg to about 1000 mg (e.g., about 800 mg).

[0022] In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosage schedule that reduces one or both of the following: (a) increasing the level of free soluble LAG-3 in a subject (e.g., blood), e.g., to 50% or less (e.g., 40% or less, 30% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less) of a reference level of free soluble LAG-3; or (b) reducing the level of free membrane-bound LAG-3 in a subject (e.g., cancer), for example, to 50% or less (e.g., 40% or less, 30% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less) of a reference level of membrane-bound LAG-3.

[0023] In some embodiments, the level of free soluble LAG-3 is determined in a blood sample (e.g., a serum sample or a plasma sample). In some embodiments, the reference level of free soluble LAG-3 is the baseline level of free soluble LAG-3 in a subject prior to administration of, e.g., an anti-LAG-3 antibody molecule, e.g., according to a dosage schedule.

[0024] In some embodiments, the level of free membrane-bound LAG-3 is determined in a cancer (e.g., a cancer sample). In some embodiments, the reference level of free membrane-bound LAG-3 is the baseline level of free membrane-bound LAG-3 in a subject prior to administration of, e.g., an anti-LAG-3 antibody molecule, e.g., according to a dosage schedule.

[0025] In some embodiments, the level of free soluble LAG-3, the level of free membrane-bound LAG-3, or both are determined when the subject has a steady-state trough level of anti-LAG-3 antibody molecules.In some embodiments, the trough level is the concentration of anti-LAG-3 antibody molecules about 24 weeks after administration, or the lowest concentration that anti-LAG-3 antibody molecules reach before the next dose is administered.In some embodiments, the level of free soluble LAG-3, the level of free membrane-bound LAG-3, or both are determined, e.g., measured, in vitro (e.g., by ELISA or cell-based assay) or in vivo (e.g., by imaging), or predicted from a PK / PD model, e.g., a PK / PD model described herein.

[0026] In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less of the reference level of free soluble LAG-3 in a serum sample from a subject.In some embodiments, the level of free soluble LAG-3 is reduced to 20% or less of the reference level of free soluble LAG-3 in a serum sample from a subject.In some embodiments, the level of free soluble LAG-3 is reduced to 10% or less of the reference level of free soluble LAG-3 in a serum sample from a subject.

[0027] In some embodiments, the level of free membrane-bound LAG-3 is reduced to 15% or less of the reference level of free membrane-bound LAG-3 in cancer or cancer sample from a subject. In some embodiments, the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer or cancer sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 5% or less of the reference level of free membrane-bound LAG-3 in cancer or cancer sample from a subject.

[0028] In certain embodiments, the level of free soluble LAG-3 is reduced to 30% or less, 20% or less, or 10% or less of the reference level of free soluble LAG-3 in a serum sample from the subject, and the level of free membrane-bound LAG-3 is reduced to 15% or less, 10% or less, or 5% or less of the reference level of free membrane-bound LAG-3 in a cancer or cancer sample from the subject.

[0029] In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less of the reference level of free soluble LAG-3 in serum sample from the subject, and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer or cancer sample from the subject.In some embodiments, the level of free soluble LAG-3 is reduced to 20% or less of the reference level of free soluble LAG-3 in serum sample from the subject, and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer or cancer sample from the subject.In some embodiments, the level of free soluble LAG-3 is reduced to 10% or less of the reference level of free soluble LAG-3 in serum sample from the subject, and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer or cancer sample from the subject.

[0030] In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 800 mg, e.g., about 300 mg to about 500 mg (e.g., about 400 mg) or about 600 mg to about 800 mg (e.g., about 700 mg). In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg).

[0031] In other embodiments, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 600 mg to about 1600 mg, e.g., about 600 mg to about 1000 mg (e.g., about 800 mg) or about 1200 mg to about 1600 mg (e.g., about 1400 mg). In one embodiment, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 600 mg to about 1000 mg (e.g., about 800 mg).

[0032] In some embodiments, the disorder is a cancer, e.g., a cancer described herein. In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a brain tumor, e.g., glioblastoma, gliosarcoma, or recurrent brain tumor. In some embodiments, the cancer is a pancreatic cancer, e.g., advanced pancreatic cancer. In some embodiments, the cancer is a skin cancer, e.g., a melanoma (e.g., stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma) or a Merkel cell carcinoma. In some embodiments, the cancer is a kidney cancer, e.g., a renal cell carcinoma (RCC) (e.g., metastatic renal cell carcinoma). In some embodiments, the cancer is a breast cancer, e.g., a metastatic breast cancer or a stage IV breast cancer, e.g., a triple negative breast cancer (TNBC). In some embodiments, the cancer is a virus-associated cancer. In some embodiments, the cancer is anal canal cancer (e.g., squamous cell carcinoma of the anal canal). In some embodiments, the cancer is cervical cancer (e.g., squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastric cancer (e.g., Epstein-Barr virus (EBV) positive gastric cancer, or gastric or gastroesophageal junction cancer). In some embodiments, the cancer is head and neck cancer (e.g., HPV positive and negative squamous cell carcinoma of the head and neck (SCCHN)). In some embodiments, the cancer is nasopharyngeal carcinoma (NPC). In some embodiments, the cancer is penile cancer (e.g., squamous cell carcinoma of the penis). In some embodiments, the cancer is vaginal or vulvar cancer (e.g., vaginal or vulvar squamous cell carcinoma). In some embodiments, the cancer is colorectal cancer, e.g., recurrent colorectal cancer or metastatic colorectal cancer, e.g., microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch repair proficient colorectal cancer or mismatch repair deficient colorectal cancer. In some embodiments, the cancer is lung cancer, e.g., non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is a leukemia. In some embodiments, the cancer is a lymphoma, e.g., Hodgkin's lymphoma (HL) or diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed or refractory HL or DLBCL). In some embodiments, the cancer is a myeloma.

[0033] In other embodiments, the cancer is an MSI-high cancer. In some embodiments, the cancer is a metastatic cancer. In other embodiments, the cancer is an advanced cancer. In other embodiments, the cancer is a recurrent or refractory cancer. In other embodiments, the cancer is a recurrent cancer.

[0034] In certain embodiments, the anti-LAG-3 antibody molecule is administered by injection (e.g., intravenously or subcutaneously) at a dose (e.g., fixed dose) of about 300 mg to about 500 mg (e.g., about 400 mg), about 500 mg to about 700 mg (e.g., about 533 mg or about 600 mg), or about 700 mg to about 900 mg (e.g., about 800 mg). The dosing schedule (e.g., fixed dosing schedule) can vary, for example, from once every three weeks to once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered intravenously at a dose of about 300 mg to 500 mg (e.g., about 400 mg) once every three weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered intravenously at a dose of about 500 mg to 700 mg (e.g., about 533 mg or about 600 mg) once every four weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered intravenously at a dose of about 700 mg to 900 mg (eg, about 800 mg) once every four weeks.

[0035] In some embodiments, the anti-LAG-3 antibody molecule is administered intravenously at a dose of about 400 mg once every three weeks to treat the cancers disclosed herein. In some embodiments, the anti-LAG-3 antibody molecule is administered intravenously at a dose of about 533 mg or 600 mg once every four weeks to treat the cancers disclosed herein. In some embodiments, the anti-LAG-3 antibody molecule is administered intravenously at a dose of about 800 mg once every four weeks to treat the cancers disclosed herein.

[0036] In certain embodiments, the method further includes administering to the subject a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein) or a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody molecule described herein). In certain embodiments, the PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein) is administered intravenously once every three weeks at a dose of about 200 mg to about 400 mg (e.g., about 300 mg). In certain embodiments, the subject is administered an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) together with the anti-PD-1 antibody molecule at a dose of about 200 mg to about 400 mg (e.g., about 300 mg) once every three weeks. In certain embodiments, the anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) is administered once every three weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) and the PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein) is administered once every three weeks at a dose of about 200 mg to about 400 mg (e.g., about 300 mg). In other embodiments, the subject is administered an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) once every four weeks along with an anti-PD-1 antibody molecule at a dose of about 300 mg to about 500 mg (e.g., about 400 mg). In certain embodiments, the anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) is administered at a dose of about 600 mg to about 1000 mg (e.g., about 800 mg) once every four weeks, and the PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein) is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every four weeks. In certain embodiments, the method includes administering to the subject an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) and a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or precursor analog (e.g., capecitabine)).In certain embodiments, a chemotherapeutic agent (e.g., a platinum agent, e.g., carboplatin) is administered intravenously once every three weeks at a dose that achieves an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (e.g., an AUC of about 6). In certain embodiments, an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) is administered once every three weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg), and a chemotherapeutic agent (e.g., a platinum agent, e.g., carboplatin) is administered once every three weeks at a dose that achieves an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (e.g., an AUC of about 6).

[0037] In one embodiment, the method includes administering to the subject an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein), a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein), and a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or precursor analog (e.g., capecitabine)). In certain embodiments, the anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) is administered once every three weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg), the PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein) is administered once every three weeks at a dose of about 200 mg to about 400 mg (e.g., about 300 mg), and the chemotherapeutic agent (e.g., a platinum agent, e.g., carboplatin) is administered once every three weeks at a dose that achieves an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (e.g., an AUC of about 6).

[0038] In certain embodiments, an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein), or a combination comprising an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule in combination with one or both of a PD-1 inhibitor or a chemotherapeutic agent), is used to treat breast cancer, e.g., triple-negative breast cancer (TNBC), e.g., according to a dosing schedule described herein.

[0039] In certain embodiments, the subject has not been treated with PD-1 or PD-L1 therapy prior to receiving the anti-LAG-3 antibody molecule, hi other embodiments, the subject has been treated with PD-1 or PD-L1 therapy prior to receiving the anti-LAG-3 antibody molecule.

[0040] In certain embodiments, the subject has not been treated with a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide or precursor analog (e.g., capecitabine)) prior to receiving the anti-LAG-3 antibody molecule. In other embodiments, the subject has been treated with a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide or precursor analog (e.g., capecitabine)) prior to receiving the anti-LAG-3 antibody molecule.

[0041] In other embodiments, the subject has or has been identified as having LAG-3 expression in tumor infiltrating lymphocytes (TILs).

[0042] In another aspect, the disclosure features a method of reducing the activity (e.g., growth, survival or viability, or all of the above) of a hyperproliferative (e.g., cancer) cell. The method includes contacting the cell with an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule described herein. The method can be performed in a subject, e.g., as part of a treatment protocol, e.g., at a dose of about 300 mg to about 500 mg (e.g., about 400 mg), about 500 mg to about 700 mg (e.g., about 533 mg or about 600 mg), or about 700 mg to about 900 mg (e.g., about 800 mg) of the anti-LAG-3 antibody molecule once every three weeks or once every four weeks. In certain embodiments, the dose is about 300 mg to about 500 mg (e.g., about 400 mg) of the anti-LAG-3 antibody molecule once every three weeks. In other embodiments, the dose is about 500 mg to about 700 mg (e.g., about 533 mg or about 600 mg) of the anti-LAG-3 antibody molecule once every four weeks. In other embodiments, the dose is about 700 mg to about 900 mg (e.g., about 800 mg) of the anti-LAG-3 antibody molecule once every four weeks.

[0043] The cancer cells may be, for example, a solid tumor or a hematological cancer, such as a brain tumor (e.g., glioblastoma, gliosarcoma, or recurrent brain tumor), pancreatic cancer (e.g., advanced pancreatic cancer), skin cancer (e.g., melanoma (e.g., stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma) or Merkel cell carcinoma), kidney cancer (e.g., renal cell carcinoma (RCC) (e.g., metastatic renal cell carcinoma)], breast cancer (e.g., metastatic breast cancer or stage IV breast cancer, e.g., triple negative breast cancer (TNBC)), virus-related cancer, anal canal cancer (e.g., squamous cell carcinoma of the anal canal), cervical cancer (e.g., squamous cell carcinoma of the cervix), gastric cancer (e.g., Epstein-Barr virus (EBV) positive gastric cancer, or gastric or gastroesophageal junction cancer), head and neck cancer (e.g., HPV positive and negative squamous cell carcinoma of the head and neck (SCCHN)], nasopharyngeal carcinoma (NPC), penile cancer (e.g., squamous cell carcinoma of the penis), vaginal or vulvar cancer (e.g., squamous cell carcinoma of the vagina or vulva), colorectal cancer (e.g., recurrent colorectal cancer or metastatic colorectal cancer, e.g., microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch repair competent colorectal cancer or mismatch repair deficient colorectal cancer), lung cancer [e.g., non-small cell lung cancer (NSCLC)], leukemia, lymphoma [e.g., Hodgkin's lymphoma (HL) or diffuse large B-cell lymphoma (DLBCL), e.g., relapsed or refractory HL or DLBCL], or myeloma, as described herein.

[0044] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a brain tumor, e.g., glioblastoma, gliosarcoma, or recurrent brain tumor. In certain embodiments, the cancer is a pancreatic cancer, e.g., advanced pancreatic cancer. In certain embodiments, the cancer is a skin cancer, e.g., a melanoma (e.g., stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma) or a Merkel cell carcinoma. In certain embodiments, the cancer is a kidney cancer, e.g., a renal cell carcinoma (RCC) (e.g., metastatic renal cell carcinoma). In certain embodiments, the cancer is a breast cancer, e.g., metastatic breast cancer or stage IV breast cancer, e.g., triple negative breast cancer (TNBC). In certain embodiments, the cancer is a virus-associated cancer. In certain embodiments, the cancer is anal canal cancer (e.g., squamous cell carcinoma of the anal canal). In certain embodiments, the cancer is cervical cancer (e.g., squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastric cancer (e.g., Epstein-Barr virus (EBV) positive gastric cancer, or gastric or gastroesophageal junction cancer). In some embodiments, the cancer is head and neck cancer (e.g., HPV positive and negative squamous cell carcinoma of the head and neck (SCCHN)). In some embodiments, the cancer is nasopharyngeal carcinoma (NPC). In some embodiments, the cancer is penile cancer (e.g., squamous cell carcinoma of the penis). In some embodiments, the cancer is vaginal or vulvar cancer (e.g., squamous cell carcinoma of the vagina or vulva). In some embodiments, the cancer is colorectal cancer, e.g., recurrent colorectal cancer or metastatic colorectal cancer, e.g., microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch repair competent colorectal cancer, or mismatch repair deficient colorectal cancer. In some embodiments, the cancer is lung cancer, e.g., non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is a leukemia. In some embodiments, the cancer is a lymphoma, e.g., Hodgkin's lymphoma (HL) or diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed or refractory HL or DLBCL). In some embodiments, the cancer is a myeloma.

[0045] In certain embodiments, the method further comprises contacting the cell with one or both of a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein) or a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide or precursor analog (e.g., capecitabine)). The method can be performed in a subject, e.g., as part of a treatment protocol, e.g., the anti-LAG-3 antibody molecule once every three weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) and the PD-1 inhibitor once every three weeks at a dose of about 200 mg to about 400 mg (e.g., about 300 mg). The method can be performed in a subject, e.g., as part of a treatment protocol, with, for example, an anti-LAG-3 antibody molecule once every four weeks at a dose of about 600 mg to about 1000 mg (e.g., about 800 mg), and a PD-1 inhibitor once every four weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg). The method can be performed in a subject, e.g., as part of a treatment protocol, with, for example, an anti-LAG-3 antibody molecule once every three weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) of the anti-LAG-3 antibody molecule, and a chemotherapeutic agent once every three weeks at a dose that achieves an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (e.g., an AUC of about 6). The method can be performed in a subject, e.g., as part of a treatment protocol, by administering, e.g., an anti-LAG-3 antibody molecule once every three weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg), a PD-1 inhibitor once every three weeks at a dose of about 200 mg to about 400 mg (e.g., about 300 mg), and a chemotherapeutic agent once every three weeks at a dose that achieves an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (e.g., an AUC of about 6). In certain embodiments, the cancer cells can be, e.g., breast cancer cells, e.g., TNBC cells. In certain embodiments of the methods disclosed herein, the method further includes determining the level of LAG-3 expression in tumor infiltrating lymphocytes (TILs) of the subject. In other embodiments, the level of LAG-3 expression is determined in a sample (e.g., a tumor biopsy) obtained from the subject (e.g., using immunohistochemistry).In certain embodiments, the anti-LAG-3 antibody molecule is administered when there is detectable or elevated levels of LAG-3 in the subject (e.g., the anti-LAG-3 antibody molecule is administered in response to detectable or elevated levels of LAG-3 in the subject).The detection step can also be used to monitor, for example, the effectiveness of the therapeutic agent described herein.For example, the detection step can be used to monitor the effectiveness of the anti-LAG-3 antibody molecule.

[0046] In another aspect, the disclosure features compositions (e.g., one or more compositions or dosage forms) that include an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein). Also described herein are formulations, e.g., dosage formulations, and kits, e.g., treatment kits, that include an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein). In certain embodiments, the composition or formulation includes about 300 mg to about 500 mg (e.g., about 400 mg), about 500 mg to about 700 mg (e.g., about 533 mg or about 600 mg), or about 700 mg to about 900 mg (e.g., about 800 mg) of an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein). In certain embodiments, the composition or formulation is administered or used once every three weeks or once every four weeks. In certain embodiments, the composition or formulation comprises about 400 mg of the anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) and is administered or used once every three weeks. In certain embodiments, the composition or formulation comprises about 533 mg or 600 mg of the anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) and is administered or used once every four weeks. In certain embodiments, the composition or formulation comprises about 800 mg of the anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) and is administered or used once every four weeks. In certain embodiments, the composition or formulation is used to treat cancer, e.g., a cancer disclosed herein.

[0047] Additional features or embodiments of the methods, compositions, dosage formulations, and kits described herein include one or more of the following.

[0048] Antibody molecule against LAG-3 In certain embodiments, the anti-LAG-3 antibody molecule comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or all the CDRs collectively) from heavy and light chain variable regions comprising the amino acid sequences shown in Table 5 or the amino acid sequences encoded by the nucleotide sequences shown in Table 5 (e.g., the heavy and light chain variable region sequences of BAP050-clone I or BAP050-clone J disclosed in Table 5). In certain embodiments, the CDRs follow the Kabat definition (e.g., as presented in Table 5). In certain embodiments, the CDRs follow the Chothia definition (e.g., as presented in Table 5). In certain embodiments, the CDRs follow a combined CDR definition of both Kabat and Chothia (e.g., as presented in Table 5). In certain embodiments, the combined Kabat and Chothia CDRs of VH CDR1 comprise the amino acid sequence GFTLTNYGMN (SEQ ID NO: 766). In one embodiment, one or more of the CDRs (or all of the CDRs together) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the amino acid sequence shown in Table 5 or the amino acid sequence encoded by the nucleotide sequence shown in Table 5.

[0049] In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:701, the VHCDR2 amino acid sequence of SEQ ID NO:702, and the VHCDR3 amino acid sequence of SEQ ID NO:703; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:710, the VLCDR2 amino acid sequence of SEQ ID NO:711, and the VLCDR3 amino acid sequence of SEQ ID NO:712, each of which is disclosed in Table 5.

[0050] In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO:736 or 737, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO:738 or 739, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO:740 or 741; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO:746 or 747, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO:748 or 749, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO:750 or 751, respectively, as disclosed in Table 5. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO:758 or 737, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO:759 or 739, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO:760 or 741; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO:746 or 747, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO:748 or 749, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO:750 or 751, respectively, as disclosed in Table 5.

[0051] In certain embodiments, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:706 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:706. In certain embodiments, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO:718 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:718. In certain embodiments, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:724 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:724. In certain embodiments, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO:730 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:730. In certain embodiments, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:706, and a VL comprising the amino acid sequence of SEQ ID NO:718. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:724, and a VL comprising the amino acid sequence of SEQ ID NO:730.

[0052] In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:707 or 708, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:707 or 708. In certain embodiments, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO:719 or 720, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:719 or 720. In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:725 or 726, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:725 or 726. In certain embodiments, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO:731 or 732, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:731 or 732. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 707 or 708, and a VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726, and a VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732.

[0053] In certain embodiments, the anti-LAG-3 antibody molecule comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:709 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:709. In certain embodiments, the anti-LAG-3 antibody molecule comprises a light chain comprising an amino acid sequence of SEQ ID NO:721 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:721. In certain embodiments, the anti-LAG-3 antibody molecule comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:727 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:727. In certain embodiments, the anti-LAG-3 antibody molecule comprises a light chain comprising an amino acid sequence of SEQ ID NO:733 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:733. In certain embodiments, the anti-LAG-3 antibody molecule comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:709, and a light chain comprising an amino acid sequence of SEQ ID NO:721. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:727, and a light chain comprising the amino acid sequence of SEQ ID NO:733.

[0054] In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:716 or 717, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:716 or 717. In certain embodiments, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO:722 or 723, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:722 or 723. In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:728 or 729, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:728 or 729. In certain embodiments, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO:734 or 735, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:734 or 735. In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717, and a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723. In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729, and a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735.

[0055] Other Exemplary LAG-3 Inhibitors In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO2015 / 116539 and US9,505,839, which are incorporated herein by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences taken together), heavy or light chain variable region sequences, or heavy or light chain sequences of BMS-986016, e.g., as disclosed in Table 6.

[0056] In some embodiments, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In some embodiments, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences collectively), the heavy or light chain variable region sequence, or the heavy or light chain sequence of TSR-033.

[0057] In some embodiments, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are disclosed in WO2008 / 132601 and US9,244,059, which are incorporated herein by reference in their entirety. In some embodiments, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences collectively), heavy or light chain variable region sequences, or heavy or light chain sequences of IMP731, e.g., as disclosed in Table 6. In some embodiments, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences collectively), heavy or light chain variable region sequences, or heavy or light chain sequences of GSK2831781.

[0058] In some embodiments, the anti-LAG-3 antibody molecule is IMP761 (Prima BioMed). In some embodiments, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences taken together), the heavy or light chain variable region sequence, or the heavy or light chain sequence of IMP761.

[0059] Further known anti-LAG-3 antibodies include, for example, the antibodies described in WO2008 / 132601, WO2010 / 019570, WO2014 / 140180, WO2015 / 116539, WO2015 / 200119, WO2016 / 028672, US9,244,059, US9,505,839, which are incorporated by reference in their entireties.

[0060] In one embodiment, the anti-LAG-3 antibody is an antibody that competes for binding with one of the anti-LAG-3 antibodies described herein and / or binds to the same epitope on LAG-3 as that antibody.

[0061] In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, e.g., IMP321 (Prima BioMed), as disclosed in WO2009 / 044273, the entire contents of which are incorporated herein by reference.

[0062] formulation The anti-LAG-3 antibody molecules described herein can be formulated into a formulation (e.g., a dosage formulation or dosage form) suitable for administration (e.g., intravenous administration) to a subject, as described herein. The formulations described herein can be liquid formulations, lyophilized formulations, or reconstituted formulations.

[0063] In certain embodiments, the formulation is a liquid formulation. In some embodiments, the formulation (e.g., a liquid formulation) comprises an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) and a buffer.

[0064] In some embodiments, the formulation (e.g., a liquid formulation) comprises an anti-LAG-3 antibody molecule present in a concentration of 25 mg / mL to 250 mg / mL, e.g., 50 mg / mL to 200 mg / mL, 60 mg / mL to 180 mg / mL, 70 mg / mL to 150 mg / mL, 80 mg / mL to 120 mg / mL, 90 mg / mL to 110 mg / mL, 50 mg / mL to 150 mg / mL, 50 mg / mL to 100 mg / mL, 150 mg / mL to 200 mg / mL, or 100 mg / mL to 200 mg / mL, e.g., 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL. In certain embodiments, the anti-LAG-3 antibody molecule is present at a concentration of 80 mg / mL to 120 mg / mL, for example, 100 mg / mL.

[0065] In some embodiments, the formulation (e.g., liquid formulation) includes a buffer containing histidine (e.g., a histidine buffer). In certain embodiments, the buffer (e.g., histidine buffer) is present at a concentration of 1 mM to 100 mM, e.g., 2 mM to 50 mM, 5 mM to 40 mM, 10 mM to 30 mM, 15 to 25 mM, 5 mM to 40 mM, 5 mM to 30 mM, 5 mM to 20 mM, 5 mM to 10 mM, 40 mM to 50 mM, 30 mM to 50 mM, 20 mM to 50 mM, 10 mM to 50 mM, or 5 mM to 50 mM, e.g., 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM. In certain embodiments, the buffer (e.g., histidine buffer) is present at a concentration of 15 mM to 25 mM, e.g., 20 mM. In other embodiments, the buffer (e.g., histidine buffer) or formulation has a pH of 4 to 7, e.g., 5 to 6, e.g., 5, 5.5 or 6. In certain embodiments, the buffer (e.g., histidine buffer) or formulation has a pH of 5 to 6, e.g., 5.5. In certain embodiments, the buffer comprises a histidine buffer at a concentration of 15 mM to 25 mM (e.g., 20 mM) and has a pH of 5 to 6 (e.g., 5.5). In certain embodiments, the buffer comprises histidine and histidine-HCl.

[0066] In one embodiment, the formulation (e.g., a liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80-120 mg / mL, e.g., 100 mg / mL, at a pH of 5-6 (e.g., 5.5); and a buffer comprising a histidine buffer at a concentration of 15 mM-25 mM (e.g., 20 mM).

[0067] In some embodiments, the formulation (e.g., a liquid formulation) further comprises a carbohydrate. In certain embodiments, the carbohydrate is sucrose. In one embodiment, the carbohydrate (e.g., sucrose) is present at a concentration of 50 mM to 500 mM, e.g., 100 mM to 400 mM, 150 mM to 300 mM, 180 mM to 250 mM, 200 mM to 240 mM, 210 mM to 230 mM, 100 mM to 300 mM, 100 mM to 250 mM, 100 mM to 200 mM, 100 mM to 150 mM, 300 mM to 400 mM, 200 mM to 400 mM, or 100 mM to 400 mM, e.g., 100 mM, 150 mM, 180 mM, 200 mM, 220 mM, 250 mM, 300 mM, 350 mM, or 400 mM. In some embodiments, the formulation comprises carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, e.g., 220 mM.

[0068] In one embodiment, the formulation (e.g., a liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80-120 mg / mL, e.g., 100 mg / mL, at a pH of 5-6 (e.g., 5.5); a buffer comprising a histidine buffer at a concentration of 15 mM-25 mM (e.g., 20 mM); and a carbohydrate or sucrose present at a concentration of 200 mM-250 mM, e.g., 220 mM.

[0069] In some embodiments, the formulation (e.g., a liquid formulation) further comprises a surfactant. In certain embodiments, the surfactant is polysorbate 20. In one embodiment, the surfactant or polysorbate 20 is present at a concentration of 0.005% to 0.1% (w / w), e.g., 0.01% to 0.08%, 0.02% to 0.06%, 0.03% to 0.05%, 0.01% to 0.06%, 0.01% to 0.05%, 0.01% to 0.03%, 0.06% to 0.08%, 0.04% to 0.08%, or 0.02% to 0.08% (w / w), e.g., 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1% (w / w). In some embodiments, the formulation comprises a surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, e.g., 0.04% (w / w).

[0070] In one embodiment, the formulation (e.g., a liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80-120 mg / mL, e.g., 100 mg / mL, at a pH of 5-6 (e.g., 5.5); a buffer comprising a histidine buffer at a concentration of 15 mM-25 mM (e.g., 20 mM); a carbohydrate or sucrose present at a concentration of 200 mM-250 mM, e.g., 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.03%-0.05%, e.g., 0.04% (w / w).

[0071] In one embodiment, the formulation (e.g., a liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 100 mg / mL, at a pH of 5 to 6 (e.g., 5.5); a buffer comprising a histidine buffer (e.g., histidine / histidine-HCL) at a concentration of 20 mM; a carbohydrate or sucrose present at a concentration of 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.04% (w / w).

[0072] The formulations described herein can be stored in a container. The container used for any of the formulations described herein can include, for example, a vial, and optionally a stopper, a cap, or both. In certain embodiments, the vial is a glass vial, for example, a 6R white glass vial. In other embodiments, the stopper is a rubber stopper, for example, a grey rubber stopper. In other embodiments, the cap is a flip-off cap, for example, an aluminum flip-off cap. In some embodiments, the container includes a 6R white glass vial, a grey rubber stopper, and an aluminum flip-off cap. In some embodiments, the container (e.g., a vial) is for a single-use container. In certain embodiments, 25 mg / mL to 250 mg / mL, e.g., 50 mg / mL to 200 mg / mL, 60 mg / mL to 180 mg / mL, 70 mg / mL to 150 mg / mL, 80 mg / mL to 120 mg / mL, 90 mg / mL to 110 mg / mL, 50 mg / mL to 150 mg / mL, 50 mg / mL to 100 mg / mL, 150 mg / mL to 200 mg / mL, or 100 mg / mL to 200 mg / mL, e.g., 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL, of the anti-LAG-3 antibody molecule is present in the container (e.g., a vial).

[0073] In another aspect, the disclosure features a therapeutic kit including an anti-LAG-3 antibody molecule, composition, or formulation described herein, and instructions for use, e.g., according to a dosage regimen described herein.

[0074] Therapeutic Use The anti-LAG-3 antibody molecules described herein can inhibit, reduce or neutralize one or more activities of LAG-3, resulting in blocking or reducing immune checkpoints. Thus, the anti-LAG-3 antibody molecules described herein can be used to treat or prevent disorders in which an enhanced immune response in a subject is desired (e.g., cancer).

[0075] Thus, in another aspect, a method of modulating an immune response in a subject is provided. The method comprises administering to the subject an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more therapeutic agents, procedures or modalities, according to the dosage regimen as described herein, such that the immune response in the subject is modulated. In an embodiment, the antibody molecule enhances, stimulates or increases the immune response in the subject. The subject can be a mammal, e.g., a primate, preferably a higher primate, e.g., a human (e.g., a patient having or at risk of having a disorder as described herein). In an embodiment, the subject is in need of an enhanced immune response. In an embodiment, the subject has or is at risk of having a disorder as described herein, e.g., a cancer or an infectious disorder as described herein. In certain embodiments, the subject is or is at risk of being immunocompromised. For example, the subject has or has undergone chemotherapy treatment and / or radiation therapy. Alternatively or in combination, the subject is or is at risk of being immunocompromised as a result of an infection.

[0076] In one aspect, a method of treating (e.g., reducing, inhibiting, or delaying progression of) a cancer or tumor in a subject is provided. The method comprises administering to the subject an anti-LAG-3 antibody molecule described herein, alone or in combination with one or more therapeutic agents, procedures, or modalities, according to a dosage regimen described herein.

[0077] In certain embodiments, the cancers treated by the anti-LAG-3 antibody molecules include, but are not limited to, solid tumors, hematological cancers (e.g., leukemia, lymphoma, myeloma, e.g., multiple myeloma) and metastatic lesions. In some embodiments, the cancer is a solid tumor. Examples of solid tumors include malignant lesions, such as sarcomas and carcinomas, including adenocarcinomas of various organ systems, such as those affecting the lung, breast, ovary, lymphatic system, gastrointestinal tract (e.g., colon), anus, genital and urogenital tract (e.g., kidney, urothelium, bladder cells, prostate), pharynx, CNS (e.g., brain, neural or glial cells), head and neck, skin (e.g., melanoma), and pancreas, as well as malignant lesions such as colon cancer, rectal cancer, kidney cancer (e.g., renal cell carcinoma (clear cell or non-clear cell renal cell carcinoma)), liver cancer, lung cancer (e.g., non-small cell lung cancer (squamous or non-squamous non-small cell lung cancer)), small intestine cancer, and esophageal cancer. The cancer can be of early, mid, late stage, or metastatic cancer.

[0078] In certain embodiments, the cancer is selected from the group consisting of lung cancer (e.g., non-small cell lung cancer (NSCLC) (e.g., NSCLC with squamous and / or non-squamous histology, or NSCLC adenocarcinoma) or small cell lung cancer (SCLC)], skin cancer (e.g., Merkel cell carcinoma or melanoma (e.g., advanced melanoma)], ovarian cancer, mesothelioma, bladder cancer, soft tissue sarcoma (e.g., hemangiopericytoma (HPC)], bone cancer (osteosarcoma), kidney cancer (e.g., renal carcinoma (e.g., renal cell carcinoma)], liver cancer (e.g., hepatocellular carcinoma), cholangiocarcinoma, sarcoma, myelodysplastic syndrome (MDS), prostate cancer, breast cancer (e.g., estrogen receptor, progesterone receptor, or Her2 / neu cysts), and / or sarcoma. The cancer is selected from breast cancer that does not express one, two or all of the above (e.g., triple-negative breast cancer), colorectal cancer, nasopharyngeal cancer, duodenal cancer, endometrial cancer, pancreatic cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSCC)), anal cancer, gastroesophageal cancer, thyroid cancer (e.g., histopathological thyroid carcinoma), cervical cancer, neuroendocrine tumors (NETs) (e.g., atypical pulmonary carcinoid tumors), lymphoproliferative disorders (e.g., post-transplant lymphoproliferative disorders), lymphomas (e.g., T-cell lymphoma, B-cell lymphoma, or non-Hodgkin's lymphoma), myelomas (e.g., multiple myeloma), or leukemias (e.g., myeloid leukemia or lymphoid leukemia).

[0079] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a brain tumor, e.g., glioblastoma, gliosarcoma, or recurrent brain tumor. In certain embodiments, the cancer is a pancreatic cancer, e.g., advanced pancreatic cancer. In certain embodiments, the cancer is a skin cancer, e.g., a melanoma (e.g., stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma) or a Merkel cell carcinoma. In certain embodiments, the cancer is a kidney cancer, e.g., a renal cell carcinoma (RCC) (e.g., metastatic renal cell carcinoma). In certain embodiments, the cancer is a breast cancer, e.g., metastatic breast cancer or stage IV breast cancer, e.g., triple negative breast cancer (TNBC). In certain embodiments, the cancer is a virus-associated cancer. In certain embodiments, the cancer is anal canal cancer (e.g., squamous cell carcinoma of the anal canal). In certain embodiments, the cancer is cervical cancer (e.g., squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastric cancer (e.g., Epstein-Barr virus (EBV) positive gastric cancer, or gastric or gastroesophageal junction cancer). In some embodiments, the cancer is head and neck cancer (e.g., HPV positive and negative squamous cell carcinoma of the head and neck (SCCHN)). In some embodiments, the cancer is nasopharyngeal carcinoma (NPC). In some embodiments, the cancer is penile cancer (e.g., squamous cell carcinoma of the penis). In some embodiments, the cancer is vaginal or vulvar cancer (e.g., squamous cell carcinoma of the vagina or vulva). In some embodiments, the cancer is colorectal cancer, e.g., recurrent colorectal cancer or metastatic colorectal cancer, e.g., microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch repair competent colorectal cancer, or mismatch repair deficient colorectal cancer. In some embodiments, the cancer is lung cancer, e.g., non-small cell lung cancer (NSCLC).

[0080] In certain embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is a leukemia. In some embodiments, the cancer is a lymphoma, such as Hodgkin's lymphoma (HL) or diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed or refractory HL or DLBCL). In some embodiments, the cancer is a myeloma.

[0081] In another embodiment, the cancer is selected from carcinoma (e.g., advanced or metastatic carcinoma), melanoma, or lung cancer, e.g., non-small cell lung cancer. In an embodiment, the cancer is lung cancer, e.g., non-small cell lung cancer, or small cell lung cancer. In an embodiment, the non-small cell lung cancer is stage I (e.g., stage Ia or Ib), stage II (e.g., stage IIa or IIb), stage III (e.g., stage IIIa or IIIb), or stage IV non-small cell lung cancer. In an embodiment, the cancer is melanoma, e.g., advanced melanoma. In an embodiment, the cancer is advanced or unresectable melanoma that does not respond to other therapies. In another embodiment, the cancer is melanoma with a BRAF mutation (e.g., BRAF V600 mutation). In another embodiment, the cancer is hepatocellular carcinoma, e.g., advanced hepatocellular carcinoma with or without viral infection, e.g., chronic viral hepatitis. In another embodiment, the cancer is prostate cancer, e.g., advanced prostate cancer. In another embodiment, the cancer is a myeloma, e.g., multiple myeloma. In yet another embodiment, the cancer is a renal cancer, e.g., renal cell carcinoma (RCC) (e.g., metastatic RCC, non-clear cell renal cell carcinoma (nccRCC) or clear cell renal cell carcinoma (CCRCC)).

[0082] In some embodiments, the cancer microenvironment has elevated levels of LAG-3 expression. In some embodiments, the cancer microenvironment has elevated levels of PD-L1 expression. Alternatively or in combination, the cancer microenvironment can have increased IFNγ and / or CD8 expression.

[0083] In certain embodiments, the subject has or is identified as having a tumor with one or more of high PD-L1 levels or expression, or being tumor-infiltrating lymphocyte (TIL)+ (e.g., having an increased number of TILs), or both. In certain embodiments, the subject has or is identified as having a tumor with high PD-L1 levels or expression and being TIL+. In certain embodiments, the methods described herein further include identifying the subject based on having a tumor with high PD-L1 levels or expression, or being TIL+, or both. In certain embodiments, the methods described herein further include identifying the subject based on having a tumor with high PD-L1 levels or expression and being TIL+. In certain embodiments, the tumor that is TIL+ is positive for CD8 and IFNγ. In certain embodiments, the subject has or is identified as having a high percentage of cells that are positive for one or more of PD-L1, CD8, and / or IFNγ. In certain embodiments, the subject has, or is identified as having, a high percentage of cells that are all positive for PD-L1, CD8, and IFNγ.

[0084] In certain embodiments, the methods described herein further include identifying the subject based on having a high percentage of cells positive for one or more of PD-L1, CD8, and / or IFNγ. In certain embodiments, the methods described herein further include identifying the subject based on having a high percentage of cells positive for all of PD-L1, CD8, and IFNγ. In certain embodiments, the subject has or is identified as having one or more of PD-L1, CD8, and / or IFNγ, and one or more of lung cancer, e.g., lung squamous cell carcinoma or lung adenocarcinoma (e.g., NSCLC); head and neck cancer; squamous cell cervical cancer; gastric cancer; esophageal cancer; thyroid cancer (e.g., histoplastic thyroid cancer); skin cancer (e.g., Merkel cell carcinoma or melanoma), breast cancer (e.g., TNBC), and / or nasopharyngeal carcinoma (NPC). In certain embodiments, the methods described herein further describe identifying a subject based on having one, two or more of PD-L1, CD8 and / or IFNγ, and one or more of lung cancer, e.g., lung squamous cell carcinoma or lung adenocarcinoma (e.g., NSCLC); head and neck cancer; squamous cell cervical cancer; gastric cancer; thyroid cancer (e.g., histopathogenic thyroid carcinoma); skin cancer (e.g., Merkel cell carcinoma or melanoma), neuroendocrine tumors, breast cancer (e.g., TNBC), and / or nasopharyngeal carcinoma.

[0085] The methods, compositions and formulations disclosed herein are useful for treating metastatic lesions associated with the above-mentioned cancers.

[0086] In a further aspect, the disclosure provides a method of treating an infectious disease in a subject (e.g., an infectious disease described herein), comprising administering to the subject an anti-LAG-3 antibody molecule described herein according to a dosage regimen described herein.

[0087] Still further, the present invention provides a method of enhancing an immune response to an antigen in a subject, comprising administering to the subject (i) an antigen; and (ii) an anti-LAG-3 antibody molecule as described herein, in accordance with a dosage regimen as described herein, such that the immune response to the antigen in the subject is enhanced. The antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen, or an antigen derived from a pathogen.

[0088] The anti-LAG-3 antibody molecules described herein can be administered to a subject systemically (e.g., orally, parenterally, subcutaneously, intravenously, rectally, intramuscularly, intraperitoneally, intranasally, transdermally, or by inhalation or intracavitary placement), topically, or by application to mucous membranes such as the nose, pharynx, and bronchi. In certain embodiments, the anti-LAG-3 antibody molecules are administered intravenously at a fixed dose as described herein.

[0089] Combination therapy The anti-LAG-3 antibody molecules described herein may be used in combination with other therapeutic agents, procedures or modalities.

[0090] In certain embodiments, the methods described herein include administering to a subject a combination comprising an anti-LAG-3 antibody molecule described herein in combination with a therapeutic agent, procedure or modality in an amount effective to treat or prevent the disorder. In certain embodiments, the anti-LAG-3 antibody molecule is administered or used according to a dosage regimen described herein. In other embodiments, the antibody molecule is administered or used as a composition or formulation described herein.

[0091] The anti-LAG-3 antibody molecule and the therapeutic agent, procedure or modality may be administered or used simultaneously or sequentially in any order. Any combination and order of the anti-LAG-3 antibody molecule and the therapeutic agent, procedure or modality (e.g., as described herein) may be used. The antibody molecule and / or the therapeutic agent, procedure or modality may be administered or used during periods of active disorder or during periods of remission or less active disease. The antibody molecule may be administered prior to, concurrently with, or after treatment with the therapeutic agent, procedure or modality.

[0092] In certain embodiments, the anti-LAG-3 antibody molecule described herein is administered in combination with one or more of other antibody molecules, chemotherapy, other anti-cancer therapies (e.g., targeted anti-cancer therapies, gene therapy, viral therapy, RNA therapy, bone marrow transplantation, nanotherapy or oncolytic drugs), cytotoxic agents, immune-based therapies (e.g., cytokines or cell-based immunotherapy), surgical procedures (e.g., lumpectomy or mastectomy) or radiation procedures, or any combination of the above. The additional therapy can be in the form of adjuvant or neoadjuvant therapy. In some embodiments, the additional therapy is an enzyme inhibitor (e.g., a small molecule enzyme inhibitor) or a metastasis inhibitor. Exemplary cytotoxic agents that may be administered in combination include microtubule inhibitors, topoisomerase inhibitors, antimetabolites, mitotic inhibitors, alkylating agents, anthracyclines, vinca alkaloids, intercalating agents, agents that can interfere with signal transduction pathways, agents that promote apoptosis, proteasome inhibitors, and radiation (e.g., local or total body irradiation (e.g., gamma irradiation). In other embodiments, the additional therapy is surgery or radiation or a combination thereof. In other embodiments, the additional therapy is a therapy that targets one or more of the PI3K / AKT / mTOR pathway, an HSP90 inhibitor, or a tubulin inhibitor.

[0093] Alternatively, or in combination with the aforementioned combinations, the anti-LAG-3 antibodies described herein can be administered or used in combination with one or more of the following: an immunomodulatory agent (e.g., an activator of a costimulatory molecule or an inhibitory molecule, e.g., an inhibitor of an immune checkpoint molecule); a vaccine, e.g., a therapeutic cancer vaccine; or other forms of cellular immunotherapy.

[0094] In certain embodiments, the anti-LAG-3 molecules described herein are administered or used in combination with costimulatory or inhibitory molecules, such as co-inhibitory ligands or receptor modulators.

[0095] In some embodiments, the anti-LAG-3 antibody molecules described herein are administered or used in combination with a modulator, e.g., an agonist, of a costimulatory molecule. In some embodiments, the costimulatory molecule agonist is selected from OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or a CD83 ligand agonist (e.g., an agonistic antibody or an antigen-binding fragment or soluble fusion thereof).

[0096] In another embodiment, the anti-LAG-3 antibody molecules described herein are administered or used in combination with a GITR agonist, such as an anti-GITR antibody molecule.

[0097] In certain embodiments, the anti-LAG-3 antibody molecules described herein are administered or used in combination with an inhibitor of an inhibitory (or immune checkpoint) molecule selected from PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, CEACAM-3 and / or CEACAM-5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGFRbeta. In certain embodiments, the inhibitor is a soluble ligand (e.g., CTLA-4-Ig) or an antibody or antibody fragment that binds to PD-1, LAG-3, PD-L1, PD-L2 or CTLA-4.

[0098] In another embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a PD-1 inhibitor, e.g., an anti-PD-1 antibody molecule. In another embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a TIM-3 inhibitor, e.g., an anti-TIM-3 antibody molecule. In another embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a PD-L1 inhibitor, e.g., an anti-PD-L1 antibody molecule.

[0099] In another embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a chemotherapeutic agent. In certain embodiments, the chemotherapeutic agent comprises a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin). In certain embodiments, the chemotherapeutic agent comprises cisplatin, permetrexed, or both. Cisplatin is also known as cisplatin, platamin, neoplatin, cismaplat, or cis-diamminedichlorido platinum(II) (CDDP). Permetrxed is also known as (S)-2-(4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzamido)pentanedioic acid. In certain embodiments, the chemotherapeutic agent comprises a nucleotide analog or precursor analog (e.g., capecitabine, azacitidine, azathioprine, cytarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or tioguanine / thioguanine). In certain embodiments, the chemotherapeutic agent comprises a hypomethylating agent (e.g., decitabine). In certain embodiments, the chemotherapeutic agent comprises nab-paclitaxel.

[0100] Other exemplary chemotherapeutic agents that can be used in combination with the anti-LAG-3 antibody molecule include alkylating agents [e.g., bifunctional alkylating agents (e.g., cyclophosphamide, mechlorethamine, chlorambucil, or melphalan)], monofunctional alkylating agents [e.g., dacarbazine (DTIC), nitrosoureas, or temozolomide (oral dacarbazine)], anthracyclines (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, or valrubicin), cytoskeletal disruptors or taxanes (e.g., paclitaxel, docetaxel, abraxane, or taxotere), epothilones, histone deacetylase inhibitors (e.g., bovine serum albumin, bromine, riboflavin, ribavirin ... nostat or romidepsin), inhibitors of topoisomerase I (e.g., irinotecan or topotecan), inhibitors of topoisomerase II [e.g., etoposide, teniposide or tafluposide], kinase inhibitors (e.g., bortezomib, erlotinib, gefitinib, imatinib, vemurafenib or vismodegib), peptide antibiotics (e.g., bleomycin or actinomycin), retinoids (e.g., tretinoin, alitretinoin or bexarotene), or vinca alkaloids or derivatives thereof (e.g., vinblastine, vincristine, vindesine or vinorelbine).

[0101] In another embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) and a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody molecule). In another embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) and a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody molecule). In another embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody molecule) and a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody molecule). In another embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) and a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or precursor analog (e.g., capecitabine)). In another embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a CEACAM inhibitor (e.g., a CEACAM-1, CEACAM-3 and / or CEACAM-5 inhibitor), e.g., an anti-CEACAM antibody molecule. In another embodiment, the anti-LAG-3 antibody molecule is administered or used in combination with a CEACAM-1 inhibitor, e.g., an anti-CEACAM-1 antibody molecule. In another embodiment, the anti-LAG-3 antibody molecule is administered or used in combination with a CEACAM-3 inhibitor, e.g., an anti-CEACAM-3 antibody molecule. In another embodiment, the anti-LAG-3 antibody molecule is administered or used in combination with a CEACAM-5 inhibitor, e.g., an anti-CEACAM-5 antibody molecule.

[0102] The antibody molecule combinations disclosed herein can be administered separately, e.g., as separate antibody molecules, or can be linked, e.g., as bispecific or trispecific antibody molecules. In certain embodiments, a bispecific antibody is administered that includes an anti-LAG-3 antibody molecule and an anti-PD-1, anti-CEACAM (e.g., anti-CEACAM-1, CEACAM-3 and / or anti-CEACAM-5), anti-PD-L1 or anti-TIM-3 antibody molecule. In certain embodiments, the antibody combinations disclosed herein are used to treat cancer, e.g., a cancer described herein (e.g., a solid tumor or a hematological malignancy).

[0103] In another embodiment, an anti-LAG-3 antibody molecule is administered or used in combination with an anti-PD-1 antibody molecule to treat, for example, brain cancer (e.g., glioblastoma), melanoma, renal cancer (e.g., renal cell carcinoma), virus-associated cancer (e.g., anal canal cancer, cervical cancer, gastric cancer, head and neck cancer, nasopharyngeal carcinoma (NPC), penile cancer, or vaginal or vulvar cancer), colorectal cancer, or lung cancer (e.g., non-small cell lung cancer (NSCLC)). In certain embodiments, an anti-LAG-3 antibody molecule is administered or used in combination with an anti-PD-1 antibody molecule to treat, for example, breast cancer, e.g., triple-negative breast cancer (TNBC).

[0104] In another embodiment, the anti-LAG-3 antibody molecule is administered or used in combination with a chemotherapeutic agent (eg, gemcitabine, paclitaxel) to treat, for example, pancreatic or breast cancer.

[0105] In another embodiment, the anti-LAG-3 antibody molecule is administered or used in combination with a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide or precursor analog (e.g., capecitabine) to treat, e.g., breast cancer, e.g., TNBC). In certain embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with an anti-PD-1 antibody molecule and a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide or precursor analog (e.g., capecitabine) to treat, e.g., breast cancer, e.g., TNBC). In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with a cytokine. The cytokine can be administered as a fusion molecule with the anti-LAG-3 antibody molecule or as a separate composition. In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with one, two, three or more cytokines, e.g., as a fusion molecule or as a separate composition. In certain embodiments, the cytokine is an interleukin (IL) selected from one, two, three or more of IL-1, IL-2, IL-12, IL-15, or IL-21. In certain embodiments, the bispecific antibody molecule has a first binding specificity for a first target (e.g., LAG-3) and a second binding specificity for a second target (e.g., PD-1, TIM-3, or PD-L1), and may be linked to an interleukin (e.g., IL-12) domain, e.g., full-length IL-12 or a portion thereof. In certain embodiments, the combination of anti-LAG-3 antibody molecules and cytokines described herein are used to treat cancer, e.g., a cancer described herein (e.g., a solid tumor).

[0106] In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with an antibody specific for HLA C, e.g., an antibody specific for a killer cell immunoglobulin-like receptor (also referred to herein as an "anti-KIR antibody"). In certain embodiments, a combination of an anti-LAG-3 antibody molecule and an anti-KIR antibody is used to treat a cancer, e.g., a cancer described herein (e.g., a solid tumor, e.g., an advanced solid tumor).

[0107] In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with a cellular immunotherapy (e.g., PROVENGE® (e.g., sipuleucel-T)) and, optionally, in combination with cyclophosphamide. In certain embodiments, the combination of the anti-LAG-3 antibody molecule, PROVENGE® and / or cyclophosphamide is used to treat cancer, e.g., a cancer described herein (e.g., prostate cancer, e.g., advanced prostate cancer).

[0108] In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with a vaccine, e.g., a cancer vaccine (e.g., a dendritic cell renal cancer (DC-RCC) vaccine). In certain embodiments, the vaccine is peptide-based, DNA-based, RNA-based, or antigen-based, or a combination thereof. In embodiments, the vaccine comprises one or more peptides, nucleic acids (e.g., DNA or RNA), antigens, or a combination thereof. In certain embodiments, the combination of the anti-TIM-3 antibody molecule and a DC-RCC vaccine is used to treat cancer, e.g., a cancer described herein (e.g., kidney cancer, e.g., metastatic renal cell carcinoma (RCC) or clear cell renal carcinoma (CCRCC)).

[0109] In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with an adjuvant.

[0110] In other embodiments, anti-LAG-3 antibody molecules are administered or used in combination with chemotherapy and / or immunotherapy.For example, anti-LAG-3 antibody molecules can be used alone or in combination with one or more of the following to treat myeloma: chemotherapy or other anti-cancer drugs (e.g., thalidomide analogs, e.g., lenalidomide), anti-PD-1 antibody molecules, tumor antigen-pulsed dendritic cells, tumor cell and dendritic cell fusions (e.g., electrofusions), or vaccination with immunoglobulin idiotypes produced by malignant plasma cells.In other embodiments, anti-LAG-3 antibody molecules are administered or used in combination with anti-PD-1 antibody molecules to treat myeloma, e.g., multiple myeloma.

[0111] In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with chemotherapy to treat lung cancer, e.g., non-small cell lung cancer. In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with standard lung, e.g., NSCLC, chemotherapy, e.g., platinum doublet therapy, to treat lung cancer. In other embodiments, in subjects with advanced or metastatic cancer (e.g., patients with metastatic and recurrent NSCL cancer), the anti-LAG-3 antibody molecule is administered or used in combination with an indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor {e.g., (4E)-4-[(3-chloro-4-fluoroanilino)-nitrosomethylidene]-1,2,5-oxadiazol-3-amine (also known as INCB24360), indoximod (1-methyl-D-tryptophan), α-cyclohexyl-5H-imidazo[5,1-a]isoindole-5-ethanol (also known as NLG919), and the like.

[0112] In yet other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with one or more of the following: immune-based strategies (e.g., interleukin-2 or interferon-α), targeted agents (e.g., VEGF inhibitors, such as monoclonal antibodies against VEGF); VEGF tyrosine kinase inhibitors, such as sunitinib, sorafenib, axitinib, and pazopanib; RNAi inhibitors; or inhibitors of downstream mediators of VEGF signaling, such as inhibitors of mammalian target of rapamycin (mTOR), such as everolimus and temsirolimus. Any of these combinations can be used to treat kidney cancer, such as renal cell carcinoma (RCC) [e.g., clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (nccRCC) or metastatic RCC], or liver cancer (e.g., hepatocellular carcinoma).

[0113] In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with a MEK inhibitor (e.g., a MEK inhibitor described herein). In some embodiments, the combination of the anti-LAG-3 antibody molecule and the MEK inhibitor is used to treat cancer (e.g., a cancer described herein). In some embodiments, the cancer treated by the combination is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematological malignancies, or renal cell carcinoma. In certain embodiments, the cancer comprises a BRAF mutation (e.g., a BRAF V600E mutation), a BRAF wild type, a KRAS wild type, or an activating KRAS mutation. The cancer can be of early, intermediate, or late stage.

[0114] In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with one, two or all of the following chemotherapeutic agents (e.g., platinum agents (e.g., carboplatin, oxaliplatin, cisplatin, or tetraplatin) or nucleotide or precursor analogs (e.g., capecitabine), leucovorin, or 5-FU (e.g., FOLFOX co-treatment). Alternatively or in combination, the combination further comprises a VEGF inhibitor (e.g., a VEGF inhibitor disclosed herein). In some embodiments, the combination of the anti-LAG-3 antibody molecule, FOLFOX co-treatment, and a VEGF inhibitor is used to treat cancer (e.g., a cancer described herein). In some embodiments, the cancer treated by the combination is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematological malignancies, or renal cell carcinoma. The cancer can be in early, mid, or late stage.

[0115] In other embodiments, the anti-LAG-3 antibody molecule is administered or used in conjunction with a tyrosine kinase inhibitor (eg, axitinib) to treat renal cell carcinoma and other solid tumors.

[0116] In other embodiments, the anti-LAG-3 antibody molecule is administered or used in conjunction with a 4-1BB receptor targeting agent (e.g., an antibody that stimulates signaling by 4-1BB (CD-137), e.g., PF-2566). In other embodiments, the anti-TIM-3 antibody molecule is administered or used in combination with a tyrosine kinase inhibitor (e.g., axitinib) and a 4-1BB receptor targeting agent.

[0117] The anti-LAG-3 antibody molecule can be conjugated to a substance, e.g., a cytotoxic agent or moiety (e.g., a therapeutic agent; a compound that emits radiation; a molecule of plant, fungal or bacterial origin; or a biological protein (e.g., a protein toxin) or particle (e.g., a recombinant viral particle, e.g., via a viral coat protein). For example, the antibody can be conjugated to a radioactive isotope, such as an α-, β- or γ-emitter, or a β- and γ-emitter.

[0118] Immunomodulatory drugs The anti-LAG-3 antibody molecules described herein may be used in combination with one or more immunomodulatory agents.

[0119] In certain embodiments, the immunomodulatory agent is an inhibitor of an immune checkpoint molecule. In some embodiments, the immunomodulatory agent is an inhibitor of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, CEACAM (e.g., CEACAM-1, -3 and / or -5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGF beta. In some embodiments, the inhibitor of an immune checkpoint molecule inhibits PD-1, PD-L1, TIM-3, CEACAM (e.g., CEACAM-1, -3 and / or -5), CTLA-4, or any combination thereof.

[0120] Inhibition of inhibitory molecules can be performed at DNA, RNA or protein level. In some embodiments, inhibitory nucleic acids (e.g., dsRNA, siRNA or shRNA) can be used to inhibit the expression of inhibitory molecules. In other embodiments, the inhibitor of inhibitory signals is a polypeptide, such as a soluble ligand (e.g., PD-1-Ig or CTLA-4 Ig), or an antibody molecule that binds to inhibitory molecules; for example, an antibody molecule that binds to PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3 and / or -5), CTLA-4, TIM-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGF beta, or a combination thereof.

[0121] In certain embodiments, the anti-LAG-3 antibody molecule is in the form of a bispecific or multispecific antibody molecule. In certain embodiments, the bispecific antibody molecule has a first binding specificity for LAG-3 and a second binding specificity, e.g., a second binding specificity for PD-1, PD-L1, CEACAM (e.g., CEACAM-1, -3 and / or -5), TIM-3 or PD-L2. In certain embodiments, the bispecific antibody molecule binds (i) PD-1 or PD-L1, and (ii) LAG-3. In other embodiments, the bispecific antibody molecule binds LAG-3 and TIM-3. In other embodiments, the bispecific antibody molecule binds LAG-3 and CEACAM (e.g., CEACAM-1, -3 and / or -5). In other embodiments, the bispecific antibody molecule binds LAG-3 and CEACAM-1. In yet other embodiments, the bispecific antibody molecule binds LAG-3 and CEACAM-3. In yet another embodiment, the bispecific antibody molecule binds to LAG-3 and CEACAM-5.

[0122] In other embodiments, the anti-LAG-3 antibody molecule is used in combination with a bispecific or multispecific antibody molecule. In another embodiment, the bispecific antibody molecule binds PD-1 or PD-L1. In yet another embodiment, the bispecific antibody molecule binds PD-1 and PD-L2. In another embodiment, the bispecific antibody molecule binds CEACAM (e.g., CEACAM-1, -3 and / or -5) and TIM-3.

[0123] Combinations of any of the foregoing molecules can be produced in a multispecific antibody molecule, e.g., a trispecific antibody that contains a first binding specificity for LAG-3, and second and third binding specificities for two or more of PD-1, PD-L1, CEACAM (e.g., CEACAM-1, -3 and / or -5), TIM-3, or PD-L2.

[0124] In certain embodiments, the immunomodulatory agent is an inhibitor of PD-1, e.g., human PD-1. In another embodiment, the immunomodulatory agent is an inhibitor of PD-L1, e.g., human PD-L1. In some embodiments, the PD-1 or PD-L1 inhibitor is an antibody molecule against PD-1 or PD-L1 (e.g., an anti-PD-1 or anti-PD-L1 antibody molecule described herein).

[0125] The combination of the anti-LAG-3 antibody molecule and a PD-1 or PD-L1 inhibitor can further include one or more additional immunomodulatory agents, e.g., in combination with an inhibitor of TIM-3, CEACAM (e.g., CEACAM-1, -3 and / or -5) or CTLA-4. In one embodiment, an inhibitor of PD-1 or PD-L1 (e.g., an anti-PD-1 or PD-L1 antibody molecule) is administered in combination with an anti-LAG-3 antibody molecule and a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody molecule). In another embodiment, an inhibitor of PD-1 or PD-L1 (e.g., an anti-PD-1 or PD-L1 antibody molecule) is administered in combination with an anti-LAG-3 antibody molecule and a CEACAM inhibitor (e.g., a CEACAM-1, -3 and / or -5 inhibitor), e.g., an anti-CEACAM antibody molecule. In another embodiment, a PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 or PD-L1 antibody molecule) is administered in combination with an anti-LAG-3 antibody molecule and a CEACAM-1 inhibitor (e.g., an anti-CEACAM-1 antibody molecule). In another embodiment, a PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 or PD-L1 antibody molecule) is administered in combination with an anti-LAG-3 antibody molecule and a CEACAM-5 inhibitor (e.g., an anti-CEACAM-5 antibody molecule). In yet another embodiment, a PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 or PD-L1 antibody molecule) is administered in combination with an anti-LAG-3 antibody molecule and a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody molecule). Other combinations of anti-LAG-3 antibody molecules and PD-1 inhibitors with immunomodulatory agents, including, for example, one or more of PD-L2, CTLA-4, LAG-3, CEACAM (e.g., CEACAM-1, -3 and / or -5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGFbeta, are also within the scope of the present invention. In the aforementioned combinations of inhibitors of checkpoint molecules, any of the antibody molecules known in the art or disclosed herein may be used.

[0126] In other embodiments, the immunomodulatory agent is an inhibitor of CEACAM (e.g., CEACAM-1, -3 and / or -5), e.g., human CEACAM (e.g., CEACAM-1, -3 and / or -5). In one embodiment, the immunomodulatory agent is an inhibitor of CEACAM-1, e.g., human CEACAM-1. In another embodiment, the immunomodulatory agent is an inhibitor of CEACAM-3, e.g., human CEACAM-3. In another embodiment, the immunomodulatory agent is an inhibitor of CEACAM-5, e.g., human CEACAM-5. In one embodiment, the inhibitor of CEACAM (e.g., CEACAM-1, -3 and / or -5) is an antibody molecule against CEACAM (e.g., CEACAM-1, -3 and / or -5). The combination of a CEACAM (e.g., CEACAM-1, -3 and / or -5) inhibitor and an anti-LAG-3 antibody molecule can further include one or more additional immunomodulatory agents, e.g., in combination with an inhibitor of TIM-3, PD-1, PD-L1 or CTLA-4.

[0127] In other embodiments, the immunomodulatory agent is an inhibitor of TIM-3, e.g., human TIM-3. In some embodiments, the inhibitor of TIM-3 is an antibody molecule against TIM-3. The combination of a TIM-3 inhibitor and an anti-LAG-3 antibody molecule can further include one or more additional immunomodulatory agents, e.g., in combination with an inhibitor of CEACAM (e.g., CEACAM-1, -3 and / or -5), PD-1, PD-L1 or CTLA-4.

[0128] In certain embodiments, the immunomodulatory agent used in the combinations disclosed herein (e.g., in combination with a therapeutic agent selected from an antigen-presenting combination) is an activator or agonist of a costimulatory molecule. In some embodiments, the agonist of a costimulatory molecule is selected from OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand agonist (e.g., agonistic antibody or its antigen-binding fragment, or soluble fusion).

[0129] In other embodiments, the immunomodulatory agent is a GITR agonist. In one embodiment, the GITR agonist is an antibody molecule against GITR. The anti-GITR antibody molecule and the anti-LAG-3 antibody molecule can be in the form of separate antibody compositions or as bispecific antibody molecules. The combination of the anti-LAG-3 antibody molecule and the GITR agonist can further include one or more additional immunomodulatory agents, for example, in combination with an inhibitor of PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and / or -5) or TIM-3. In one embodiment, the anti-GITR antibody molecule is a bispecific antibody that binds to GITR and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and / or -5) or TIM-3. In other embodiments, the GITR agonist can be administered in combination with one or more additional activators of costimulatory molecules, such as agonists of OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligand.

[0130] In other embodiments, the immunomodulatory agent is an OX40 agonist. In one embodiment, the OX40 agonist is an antibody molecule against OX40. The OX40 antibody molecule and the anti-LAG-3 antibody molecule can be in the form of separate antibody compositions or as bispecific antibody molecules. The combination of the anti-LAG-3 antibody molecule and the OX40 agonist can further include one or more additional immunomodulatory agents, for example, in combination with an inhibitor of PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and / or -5) or TIM-3. In one embodiment, the anti-OX40 antibody molecule is a bispecific antibody that binds to OX40 and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and / or -5) or TIM-3. In other embodiments, OX40 agonists can be administered in combination with agonists of other costimulatory molecules, such as GITR, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligand.

[0131] It is recognized that merely exemplary combinations of inhibitors of checkpoint inhibitors or agonists of costimulatory molecules are provided herein. Additional combinations of these agents are within the scope of the invention.

[0132] Biomarkers In certain aspects, any of the methods disclosed herein further include evaluating or monitoring the effectiveness of a therapy (e.g., a monotherapy or combination therapy) described herein in a subject (e.g., a subject having cancer, e.g., a cancer described herein). The method includes acquiring an efficacy value for the therapy, the value indicating the efficacy of the therapy.

[0133] In embodiments, the efficacy value for a treatment includes a measure of 1, 2, 3, 4, 5, 6, 7, 8, 9 or more (e.g., all) of the following: (i) Tumor infiltrating lymphocyte (TIL) phenotypic parameters; (ii) parameters of myeloid cell populations; (iii) parameters of surface-expressed markers; (iv) biomarker parameters of immune responses; (v) parameters of systemic cytokine modulation; (vi) circulating free DNA (cfDNA) parameters; (vii) parameters of systemic immune modulation; (viii) microbiome parameters; (ix) a parameter of a marker of activation in circulating immune cells; or (x) Circulating cytokine parameters.

[0134] In one aspect, TIL phenotypic parameters include the level or activity of one, two, three, four or more (e.g., all) of CD8, FOXP3, CD4 or CD3 in a subject, e.g., in a sample derived from a subject (e.g., a tumor sample), by hematoxylin and eosin (H&E) staining for TIL enumeration.

[0135] In certain embodiments, a parameter of a myeloid cell population includes the level or activity of one or both of CD68 or CD163 in a subject, e.g., in a sample derived from a subject (e.g., a tumor sample).

[0136] In some embodiments, the parameters of the surface-expressed markers include the level or activity of one, two, three or more (e.g., all) of TIM-3, PD-1, PD-L1 or LAG-3 in a subject, e.g., a sample (e.g., a tumor sample) derived from the subject. In certain embodiments, the level of TIM-3, PD-1, PD-L1 or LAG-3 is determined by immunohistochemistry (IHC). In certain embodiments, the level of TIM-3 is determined.

[0137] In certain embodiments, an immune response biomarker parameter comprises the level or sequence of one or more nucleic acid-based markers in a subject, e.g., in a sample derived from a subject (e.g., a tumor sample).

[0138] In one embodiment, parameters of systemic cytokine modulation include the level or activity of one, two, three, four, five, six, seven, eight or more (e.g., all) of IL-18, IFN-γ, ITAC (CXCL11), IL-6, IL-10, IL-4, IL-17, IL-15, or TGF-beta in a subject, e.g., in a sample from the subject (e.g., a blood sample, e.g., a plasma sample).

[0139] In an embodiment, a cfDNA parameter includes the sequence or level of one or more circulating tumor DNA (cfDNA) molecules in a subject, e.g., in a sample from the subject (e.g., a blood sample, e.g., a plasma sample).

[0140] In one embodiment, parameters of systemic immune modulation include phenotypic characterization of activated immune cells, e.g., CD3-expressing cells, CD8-expressing cells, or both, in a subject, e.g., a sample from a subject (e.g., a blood sample, e.g., a PBMC sample).

[0141] In one embodiment, a parameter of the microbiome includes the sequence or expression level of one or more genes in the microbiome of a subject, e.g., in a sample from the subject (e.g., a fecal sample).

[0142] In one embodiment, parameters of markers of activation in circulating immune cells include the level or activity of one, two, three, four, five or more (e.g., all) of circulating CD8+, HLA-DR+Ki67+, T cells, IFN-γ, IL-18, or CXCL11 (IFN-γ inducible CCK) expressing cells in a sample (e.g., a blood sample, e.g., a plasma sample).

[0143] In certain embodiments, a circulating cytokine parameter comprises IL-6 level or activity in a subject, e.g., in a sample from a subject (e.g., a blood sample, e.g., a plasma sample).

[0144] In certain embodiments of any of the methods disclosed herein, the treatment includes a combination of an anti-TIM-3 antibody molecule described herein and a second inhibitor of an immune checkpoint molecule, e.g., an inhibitor of PD-1 (e.g., an anti-PD-1 antibody molecule) or an inhibitor of PD-L1 (e.g., an anti-PD-L1 antibody molecule).

[0145] In certain embodiments of any of the methods disclosed herein, one or more of the measures (i)-(x) are obtained from a sample obtained from the subject. In certain embodiments, the sample is selected from a tumor sample, a blood sample (e.g., a plasma sample or a PBMC sample), or a fecal sample.

[0146] In certain aspects of any of the methods disclosed herein, the subject is evaluated before, during, or after receiving the therapy.

[0147] In certain embodiments of any of the methods disclosed herein, one or more of the measures (i)-(x) evaluate one or more of the profiles of gene expression, flow cytometry, or protein expression.

[0148] In certain embodiments of any of the methods disclosed herein, the presence in a subject or sample of increased levels or activity of one, two, three, four, five or more (e.g., all) of circulating CD8+, HLA-DR+Ki67+, T cells, IFN-γ, IL-18, or CXCL11 (IFN-γ inducible CCK) expressing cells, and / or the presence of decreased levels or activity of IL-6 is a positive predictor of efficacy of the treatment.

[0149] Alternatively, or in combination with the methods disclosed herein, in response to said value, do one, two, three, four or more (e.g., all) of the following: (i) administering a treatment to a subject; (ii) being administered a modified regimen of treatment; (iii) altering the schedule or time course of treatment; (iv) administering to the subject an additional agent (e.g., a therapeutic agent described herein) in combination with the therapy; or (v) administering an alternative treatment to a subject.

[0150] Additional Aspects In certain embodiments, any of the methods disclosed herein further include identifying the presence of LAG-3 in a subject or sample (e.g., a sample of a subject containing cancer cells and / or immune cells, such as TILs), thereby obtaining a value for LAG-3. The method can further include comparing the LAG-3 value to a reference value, e.g., a control value. If the LAG-3 value is greater than the reference value, e.g., the control value, administering to the subject a therapeutically effective amount of an anti-LAG-3 antibody molecule described herein, optionally in combination with a second therapeutic agent, procedure or modality described herein, thereby treating the cancer.

[0151] In other aspects, any of the methods disclosed herein further include identifying the presence of PD-L1 in a subject or sample (e.g., a sample of a subject containing cancer cells and / or immune cells, such as TILs), thereby obtaining a level of PD-L1. The method can further include comparing the PD-L1 level to a reference value, e.g., a control value. If the PD-L1 level is greater than the reference value, e.g., the control value, administering to the subject a therapeutically effective amount of an anti-LAG-3 antibody molecule described herein, optionally in combination with a second therapeutic agent, procedure or modality described herein, thereby treating the cancer.

[0152] In other aspects, any of the methods disclosed herein further include identifying the presence of one, two or all of PD-L1, CD8 or IFN-γ in a subject or sample (e.g., a sample from a subject containing cancer cells and optionally immune cells, such as TILs), thereby obtaining a value for one, two or all of PD-L1, CD8 and IFN-γ. The method can further include comparing the PD-L1, CD8 and / or IFN-γ value to a reference value, e.g., a control value. If the PD-L1, CD8 and / or IFN-γ value is greater than the reference value, e.g., a control value, administering to the subject a therapeutically effective amount of an anti-LAG-3 antibody molecule as described herein, optionally in combination with a second therapeutic agent, procedure or modality as described herein, thereby treating the cancer.

[0153] The subject may have a solid tumor or hematological cancer, such as a brain tumor (e.g., glioblastoma, gliosarcoma, or recurrent brain tumor), pancreatic cancer (e.g., advanced pancreatic cancer), skin cancer (e.g., melanoma (e.g., stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma) or Merkel cell carcinoma), kidney cancer (e.g., renal cell carcinoma (RCC) (e.g., metastatic renal cell carcinoma)], breast cancer (e.g., metastatic breast cancer or stage IV breast cancer, e.g., triple negative breast cancer (TNBC)), virus-related cancer, anal canal cancer (e.g., squamous cell carcinoma of the anal canal), cervical cancer (e.g., squamous cell carcinoma of the cervix), gastric cancer (e.g., Epstein-Barr virus (EBV) positive gastric cancer, or gastric or gastroesophageal junction cancer), head and neck cancer (e.g., HPV positive and negative The patient may have a cancer described herein, such as squamous cell carcinoma of the head and neck (SCCHN)], nasopharyngeal carcinoma (NPC), penile cancer (e.g., squamous cell carcinoma of the penis), vaginal or vulvar cancer (e.g., squamous cell carcinoma of the vagina or vulva), colorectal cancer (e.g., recurrent colorectal cancer or metastatic colorectal cancer, e.g., microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch repair competent colorectal cancer, or mismatch repair deficient colorectal cancer), lung cancer [e.g., non-small cell lung cancer (NSCLC)], leukemia, lymphoma [e.g., Hodgkin's lymphoma (HL) or diffuse large B-cell lymphoma (DLBCL), e.g., relapsed or refractory HL or DLBCL], myeloma, or a metastatic lesion of a cancer.

[0154] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0155] Other features, objects, and advantages of the invention will become apparent from the specification and drawings, and from the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0156] LAG-3 (CD223) is an immune checkpoint inhibitor that binds to MHC II, LSECtin, and galectin-3. LAG-3 is expressed on the surface of immune cells including CD4+ and CD8+ T effector cells, regulatory T cells (Tregs), natural killer (NK) cells, and plasmacytoid dendritic cells. LAG-3 engagement has been shown to negatively regulate T cell signaling and increase the suppressive function of Tregs, which is in turn predicted to reduce T cell activity against tumor cells. Blockade of LAG-3 has been shown to activate T cells by increasing T cell proliferation and cytokine secretion (IFN-γ).

[0157] Thus, at least in part, antibody molecules (e.g., humanized antibody molecules) that bind to LAG-3 with high affinity and specificity are disclosed herein. Pharmaceutical compositions and dosage formulations comprising the anti-LAG-3 antibody molecules are also provided. The anti-LAG-3 antibody molecules disclosed herein can be used (alone or in combination with other therapeutic agents, procedures or modalities) to treat or prevent disorders such as cancerous disorders (e.g., solid tumors and hematological cancers) and infectious diseases (e.g., chronic infectious disorders or sepsis). For example, the anti-LAG-3 antibody molecules described herein can be used in combination with other therapeutic agents {e.g., one or both of PD-1 inhibitors (e.g., anti-PD-1 antibody molecules described herein) or chemotherapeutic agents (e.g., platinum agents (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or nucleotide analogs or precursor analogs (e.g., capecitabine)} to treat or prevent, for example, cancer (e.g., cancers described herein), e.g., breast cancer, e.g., triple-negative breast cancer (TNBC). Thus, disclosed herein are methods including dosage regimens for treating various disorders using anti-LAG-3 antibody molecules. In certain embodiments, the anti-LAG-3 antibody molecules are administered or used in a constant or fixed dose.

[0158] definition Additional terms are defined below and throughout the application. The articles "a" and "an" are used herein to refer to one or to more than one (eg, to at least one) of the grammatical object of the article.

[0159] The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless context clearly indicates otherwise.

[0160] "About" and "approximately" generally refer to an acceptable degree of error for the measured content, taking into account the nature or accuracy of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0161] "Combination" or "in combination with" is not intended to imply that the therapies or therapeutic agents must be administered simultaneously and / or formulated for delivery together, although such delivery methods are within the scope described herein. The therapeutic agents in the combination can be administered concurrently with, prior to or following one or more other additional therapies or therapeutic agents. The therapeutic agents or treatment protocols can be administered in any order. Generally, each agent will be administered at a dose and / or time schedule determined for that agent. It will further be appreciated that the additional therapeutic agents utilized in the combination may be administered together in a single composition or separately in different compositions. In general, it is expected that the additional therapeutic agents utilized in the combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in the combination will be lower than the levels utilized individually.

[0162] In embodiments, the additional therapeutic agent is administered at a therapeutic dose or at a sub-therapeutic dose. In certain embodiments, the concentration of the second therapeutic agent required to achieve inhibition, e.g., growth inhibition, is lower when the second therapeutic agent is administered in combination with a first therapeutic agent, e.g., an anti-LAG-3 antibody molecule, than when the second therapeutic agent is administered individually. In certain embodiments, the concentration of the first therapeutic agent required to achieve inhibition, e.g., growth inhibition, is lower when the first therapeutic agent is administered in combination with a second therapeutic agent than when the first therapeutic agent is administered individually. In certain embodiments, the concentration of the second therapeutic agent required to achieve inhibition, e.g., growth inhibition, in combination therapy is lower than the therapeutic dose of the second therapeutic agent as a monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower. In certain embodiments, in a combination therapy, the concentration of the first therapeutic agent required to achieve inhibition, e.g., growth inhibition, is lower, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or 80-90% lower, than the therapeutic dose of the first therapeutic agent as a monotherapy.

[0163] The terms "inhibition," "inhibitor," or "antagonist" include the reduction of a certain parameter, e.g., activity, of a given molecule, e.g., an immune checkpoint inhibitor. For example, inhibition of at least 5%, 10%, 20%, 30%, 40% or more activity, e.g., PD-1 or PD-L1 activity, is included by this term. Thus, inhibition need not be 100%.

[0164] The terms "activation," "activator," or "agonist" include an increase in a particular parameter, e.g., activity, of a given molecule, e.g., a costimulatory molecule. For example, an increase in activity, e.g., costimulatory activity, of at least 5%, 10%, 25%, 50%, 75% or more is encompassed by this term.

[0165] The term "anti-cancer effect" refers to a biological effect that can be manifested by various means, including, but not limited to, a reduction in tumor volume, a reduction in the number of cancer cells, a reduction in the number of metastases, an increase in life expectancy, a reduction in cancer cell proliferation, a reduction in cancer cell survival, or the amelioration of various physiological symptoms associated with a cancerous condition. An "anti-cancer effect" can also be manifested by the ability of peptides, polynucleotides, cells and antibodies in preventing the development of cancer in the first place.

[0166] The term "anti-tumor effect" refers to a biological effect that can be manifested by various means, including, but not limited to, a reduction in tumor volume, a reduction in tumor cell number, a reduction in tumor cell proliferation, or a reduction in tumor cell survival.

[0167] The term "cancer" refers to a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein, including, but not limited to, solid tumors, such as lung cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer and brain cancer, and hematological malignancies, such as lymphoma and leukemia, among others. The terms "tumor" and "cancer" are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating tumors. As used herein, the term "cancer" or "tumor" includes pre-malignant as well as malignant cancers and tumors.

[0168] The term "antigen-presenting cell" or "APC" refers to a cell of the immune system, such as an accessory cell (e.g., B cell, dendritic cell, etc.), that displays on its surface a foreign antigen complexed with a major histocompatibility complex (MHC). T cells can recognize such complexes using their T cell receptor (TCR). APCs process antigens and present them to T cells.

[0169] The term "costimulatory molecule" refers to a cognate binding partner in a T cell that specifically binds to a costimulatory ligand, thereby mediating a costimulatory response by the T cell, including, but not limited to, proliferation. A costimulatory molecule is a cell surface molecule other than an antigen receptor or its ligand that is required for an efficient immune response. Costimulatory molecules include MHC class I molecules, TNF receptor proteins, immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocyte activation molecules (SLAM proteins), activating NK cell receptors, BTLA, Toll ligand receptors, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a / CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30 , NKp46, CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, IT GAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB 7, NKG2D, NKG2C, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, These include, but are not limited to, ligands that specifically bind to Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, CD19a, and CD83.

[0170] "Immune effector cell" or "effector cell", as the term is used herein, refers to a cell that is involved in an immune response, e.g., promoting an immune effector response. Examples of immune effector cells include T cells, e.g., alpha / beta T cells and gamma / delta T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, mast cells, and myeloid-derived phagocytes.

[0171] "Immune effector" or "effector" "function" or "response", as the term is used herein, refers to a function or response of an immune effector cell, for example, to enhance or promote immune attack of a target cell. For example, immune effector function or response refers to a property of a T or NK cell that promotes killing or inhibiting growth or proliferation of a target cell. In the case of T cells, primary stimulation and co-stimulation are examples of immune effector functions or responses.

[0172] The term "effector function" refers to a specialized function of a cell. For example, the effector function of a T cell can be cytolytic activity or helper activity, including cytokine secretion.

[0173] As used herein, the terms "treat", "treatment" and "treating" refer to the reduction or amelioration of the progression, severity and / or duration of a disorder, e.g., a proliferative disorder, or the amelioration of one or more symptoms (preferably one or more identifiable symptoms) of the disorder resulting from the administration of one or more therapeutic modalities. In a specific embodiment, the terms "treat", "treatment" and "treating" refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, such as tumor growth, which is not necessarily identifiable by the patient. In other embodiments, the terms "treat", "treatment" and "treating" refer to the inhibition of the progression of a proliferative disorder, either physically, e.g., by stabilization of an identifiable symptom, physiologically, e.g., by stabilization of a physical parameter, or both. In other embodiments, the terms "treat", "treatment" and "treating" refer to the reduction or stabilization of tumor size or cancerous cell number.

[0174] The compositions, formulations and methods of the present invention encompass polypeptides and nucleic acids having a specified sequence or a substantially identical or similar sequence thereto, for example, a sequence that is at least 85%, 90%, 95% or more identical to the specified sequence. In the context of amino acid sequences, the term "substantially identical" is used herein to refer to a first amino acid sequence that contains a sufficient or minimum number of amino acid residues that are i) identical to, or ii) conservative substitutions of, the aligned amino acid residues in the second amino acid sequence, such that the first and second amino acid sequences can have a common structural domain and / or a common functional activity. For example, an amino acid sequence that contains a common structural domain that has at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, for example, a sequence presented herein.

[0175] In the context of nucleotide sequences, the term "substantially identical" is used herein to refer to a first nucleic acid sequence that contains a sufficient or a minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having a common functional activity, or encode a common structural polypeptide domain or common functional polypeptide activity. For example, a nucleotide sequence having at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., a sequence presented herein.

[0176] The term "functional variant" refers to a polypeptide that has substantially the same amino acid sequence as a naturally occurring sequence, or is encoded by a substantially identical nucleotide sequence, and that is capable of one or more activities of the naturally occurring sequence.

[0177] Calculations of homology or sequence identity between sequences (the terms are used interchangeably herein) are performed as follows.

[0178] To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced into one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes). In a preferred embodiment, the length of the reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. If a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then both molecules are identical at that position (as used herein, amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology").

[0179] The percent identity between the two sequences is a function of the number of identical positions shared by both sequences, taking into account the number of gaps, and the length of each gap, that need to be introduced for optimal alignment of the two sequences.

[0180] Comparison of sequences and determination of percent identity between two sequences can be accomplished using mathematical algorithms. In a preferred embodiment, percent identity between two amino acid sequences is determined using the Needleman and Wunsch [(1970) J. Mol. Biol. 48:444-453] algorithm incorporated into the GAP program in the GCG software package (available at www.gcg.com) using either the Blossum62 matrix or the PAM250 matrix, and gap weights of 16, 14, 12, 10, 8, 6 or 4 and length weights of 1, 2, 3, 4, 5 or 6. In yet another preferred embodiment, percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at www.gcg.com) using the NWSgapdna.CMP matrix, and gap weights of 40, 50, 60, 70 or 80 and length weights of 1, 2, 3, 4, 5 or 6. A particularly preferred set of parameters (and the set that should be used unless otherwise specified) is a Blossum 62 scoring matrix, with a gap penalty of 12, a gap extend penalty of 4 and a frameshift gap penalty of 5.

[0181] The percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller [(1989) CABIOS, 4:11-17] incorporated into the ALIGN program (version 2.0), using a PAM120 weight-due table, a gap length penalty of 12, and a gap penalty of 4.

[0182] The nucleic acid and protein sequences described herein can be used as "query sequences" to perform searches against public databases, for example to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score=100, word length=12 to obtain nucleotide sequences homologous to the nucleic acid (SEQ ID NO:1) molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, word length=3 to obtain amino acid sequences homologous to the protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http: / / www.ncbi.nlm.nih.gov.

[0183] As used herein, the term "hybridize under low stringency, medium stringency, high stringency or very high stringency conditions" describes conditions for hybridization and washing. Guidance for performing hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, NY (1989), 6.3.1-6.3.6, which is incorporated herein by reference. Aqueous and non-aqueous methods are described in the references and either can be used. The specific hybridization conditions referred to herein are as follows: 1) low stringency hybridization conditions are 6× sodium chloride / sodium citrate (SSC), about 45° C., followed by two washes in 0.2× SSC, 0.1% SDS, at least 50° C. (the temperature of the washes can be increased to 55° C. for low stringency conditions); 2) medium stringency hybridization conditions are 6× SSC, about 45° C., followed by two washes in 0.2× SSC, 0.1% SDS, at least 50° C. (the temperature of the washes can be increased to 55° C. for low stringency conditions); 5° C. followed by one or more washes at 0.2×SSC, 0.1% SDS, 60° C.; 3) high stringency hybridization conditions are 6×SSC, about 45° C. followed by one or more washes at 0.2×SSC, 0.1% SDS, 65° C.; and preferably 4) very high stringency hybridization conditions are 0.5 M sodium phosphate, 7% SDS, 65° C. followed by one or more washes at 0.2×SSC, 1% SDS, 65° C. Very high stringency conditions (4) are the preferred conditions and are the conditions to be used unless otherwise specified.

[0184] It is understood that a molecule of the invention can have additional conservative or non-essential amino acid substitutions, which have no substantial effect on its function.

[0185] The term "amino acid" is intended to encompass any molecule, whether natural or synthetic, that can be included in a polymer of naturally occurring amino acids that contains both amino and acid functionality. Exemplary amino acids include naturally occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs with variant side chains; and any stereoisomers of any of the foregoing. As used herein, the term "amino acid" includes both D- or L-optical isomers and peptidomimetics.

[0186] "Conservative amino acid substitution" refers to a substitution in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. Such families include amino acids having basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0187] The terms "polypeptide", "peptide" and "protein" (if single chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymers may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. The term also encompasses amino acid polymers that have been modified; for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling moiety. Polypeptides can be isolated from natural sources, produced by recombinant techniques from eukaryotic or prokaryotic hosts, or can be the product of synthetic techniques.

[0188] The terms "nucleic acid", "nucleic acid sequence", "nucleotide sequence" or "polynucleotide sequence" and "polynucleotide" are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides or analogs thereof. A polynucleotide can be either single-stranded or double-stranded, and if single-stranded, can be the coding strand or the non-coding (antisense) strand. A polynucleotide can contain modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides can be interrupted by non-nucleotide components. A polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. A nucleic acid can be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic or synthetic origin, not occurring in nature or linked to another polynucleotide in a non-natural configuration.

[0189] The term "isolated" as used herein refers to a material that is removed from its original or native environment (e.g., the natural environment if it is of natural origin). For example, a polynucleotide or polypeptide of natural origin present in a living animal is not isolated, but the same polynucleotide or polypeptide separated by human intervention from some or all of the coexisting materials in a natural system is isolated. Such a polynucleotide can be part of a vector, and / or such a polynucleotide or polypeptide can be part of a composition, and such a vector or composition is still isolated in that it is not part of the environment in which it is found in nature.

[0190] Various aspects of the invention are described in further detail below. Additional definitions are presented throughout the specification.

[0191] Dosage Regimen The anti-LAG-3 antibody molecules described herein can be administered according to the dosage regimens described herein to treat (e.g., inhibit, reduce, ameliorate, or prevent) a disorder, e.g., a hyperproliferative condition or disorder (e.g., cancer) in a subject. In certain embodiments, the anti-LAG-3 antibody molecule is administered to a subject at a dose of about 200 mg to about 2000 mg, e.g., once every 2, 3, or 4 weeks.

[0192] In one aspect, the disclosure features a method of treating cancer in a subject, the method including administering to the subject an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) at a dose or dosage schedule described herein.

[0193] In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosage schedule that results in binding, e.g., saturation, of soluble LAG-3 in the subject. In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosage schedule that results in at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98% or 99% binding, e.g., saturation, of soluble LAG-3 in the subject, e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, 24, 36, or 48 weeks of administration.

[0194] In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosage schedule that results in at least 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% binding, e.g., occupancy, of LAG-3 in the tumor in the subject, e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36 or 48 weeks of administration.

[0195] In other embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosage schedule that results in at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98% or 99% binding, e.g., saturation, of soluble LAG-3 in the subject, and at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98% or 99% binding, e.g., occupancy, of LAG-3 in the tumor in the subject. In embodiments, the saturation and / or occupancy occurs, e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36 or 48 weeks of administration.

[0196] In one embodiment, the anti-LAG-3 antibody molecule comprises: (a) anti-LAG-3 antibody molecules bind to 40% or more (e.g., 50% or more, 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 99% or more) of the soluble LAG-3 in a subject (e.g., blood); or (b) the anti-LAG-3 antibody molecule binds to 50% or more (e.g., 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 99% or more) of the membrane-bound LAG-3 in a subject (e.g., a cancer). The therapeutic dose or dosage schedule is administered to provide one or both of the following:

[0197] In some embodiments, binding of the anti-LAG-3 antibody molecule to soluble LAG-3 is determined in a blood sample (e.g., a serum or plasma sample). In some embodiments, binding of the anti-LAG-3 antibody molecule to membrane-bound LAG-3 is determined in a cancer (e.g., a cancer sample).

[0198] In some embodiments, the binding of anti-LAG-3 antibody molecules to soluble LAG-3, the binding of anti-LAG-3 antibody molecules to membrane-bound LAG-3, or both, is determined when the subject has a steady-state trough level of anti-LAG-3 antibody molecules. In some embodiments, the trough level is the concentration of anti-LAG-3 antibody molecules about 24 weeks after administration, or the lowest concentration that the anti-LAG-3 antibody molecules reach before the next dose is administered. In some embodiments, the binding of anti-LAG-3 antibody molecules to soluble LAG-3, the binding of anti-LAG-3 antibody molecules to membrane-bound LAG-3, or both, is determined, e.g., measured, in vitro (e.g., by ELISA or cell-based assay) or in vivo (e.g., by imaging), or predicted from a PK / PD model, e.g., a PK / PD model described herein.

[0199] In some embodiments, the anti-LAG-3 antibody molecule binds to 50% or more of the soluble LAG-3 in the serum sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 60% or more of the soluble LAG-3 in the serum sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 70% or more of the soluble LAG-3 in the serum sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 80% or more of the soluble LAG-3 in the serum sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 90% or more of the soluble LAG-3 in the serum sample from the subject.

[0200] In some embodiments, the anti-LAG-3 antibody molecule binds to 85% or more of the membrane-bound LAG-3 in the cancer or cancer sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 90% or more of the membrane-bound LAG-3 in the cancer or cancer sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 95% or more of the membrane-bound LAG-3 in the cancer or cancer sample from the subject.

[0201] In one embodiment, the anti-LAG-3 antibody molecule binds to 50% or more, 60% or more, 70% or more, 80% or more or 90% or more of soluble LAG-3 in a serum sample from a subject, and the anti-LAG-3 antibody molecule binds to 85% or more, 90% or more or 95% or more of membrane-bound LAG-3 in a cancer or cancer sample from a subject.

[0202] In some embodiments, the anti-LAG-3 antibody molecule binds to 50% or more of the soluble LAG-3 in the serum sample from the subject, and the anti-LAG-3 antibody molecule binds to 90% or more of the membrane-bound LAG-3 in the cancer or cancer sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 60% or more of the soluble LAG-3 in the serum sample from the subject, and the anti-LAG-3 antibody molecule binds to 90% or more of the membrane-bound LAG-3 in the cancer or cancer sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 70% or more of the soluble LAG-3 in the serum sample from the subject, and the anti-LAG-3 antibody molecule binds to 90% or more of the membrane-bound LAG-3 in the cancer or cancer sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 80% or more of the soluble LAG-3 in a serum sample from the subject, and the anti-LAG-3 antibody molecule binds to 90% or more of the membrane-bound LAG-3 in a cancer or cancer sample from the subject. In some embodiments, the anti-LAG-3 antibody molecule binds to 90% or more of the soluble LAG-3 in a serum sample from the subject, and the anti-LAG-3 antibody molecule binds to 90% or more of the membrane-bound LAG-3 in a cancer or cancer sample from the subject.

[0203] In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosage schedule that reduces one or both of the following: (a) increasing the level of free soluble LAG-3 in the subject, e.g., to 40% or less (e.g., 50% or less, 40% or less, 30% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less) of a reference level of free soluble LAG-3; or (b) increasing the level of free membrane-bound LAG-3 in the subject, for example to 50% or less (e.g., 40% or less, 30% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less) of a reference level of membrane-bound LAG-3.

[0204] In some embodiments, the level of free soluble LAG-3 is determined in a blood sample (e.g., a serum sample or a plasma sample). In some embodiments, the reference level of free soluble LAG-3 is the baseline level of free soluble LAG-3 in a subject prior to administration of, e.g., an anti-LAG-3 antibody molecule, e.g., according to a dosage schedule.

[0205] In some embodiments, the level of free membrane-bound LAG-3 is determined in a cancer (e.g., a cancer sample). In some embodiments, the reference level of free membrane-bound LAG-3 is the baseline level of free membrane-bound LAG-3 in a subject prior to administration of, e.g., an anti-LAG-3 antibody molecule, e.g., according to a dosage schedule.

[0206] In some embodiments, the level of free soluble LAG-3, the level of free membrane-bound LAG-3, or both are determined when the subject has a steady-state trough level of anti-LAG-3 antibody molecules.In some embodiments, the trough level is the concentration of anti-LAG-3 antibody molecules about 24 weeks after administration, or the lowest concentration that anti-LAG-3 antibody molecules reach before the next dose is administered.In some embodiments, the level of free soluble LAG-3, the level of free membrane-bound LAG-3, or both are determined, e.g., measured, in vitro (e.g., by ELISA or cell-based assay) or in vivo (e.g., by imaging), or predicted from a PK / PD model, e.g., a PK / PD model described herein.

[0207] In some embodiments, the level of free soluble LAG-3 is reduced to 50% or less of the reference level of free soluble LAG-3 in a serum sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 40% or less of the reference level of free soluble LAG-3 in a serum sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less of the reference level of free soluble LAG-3 in a serum sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 20% or less of the reference level of free soluble LAG-3 in a serum sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 10% or less of the reference level of free soluble LAG-3 in a serum sample from a subject.

[0208] In some embodiments, the level of free membrane-bound LAG-3 is reduced to 15% or less of the reference level of free membrane-bound LAG-3 in cancer or cancer sample from a subject. In some embodiments, the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer or cancer sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 5% or less of the reference level of free membrane-bound LAG-3 in cancer or cancer sample from a subject.

[0209] In certain embodiments, the level of free soluble LAG-3 is reduced to 50% or less, 40% or less, 30% or less, 20% or less or 10% or less of the reference level of free soluble LAG-3 in a serum sample from the subject, and the level of free membrane-bound LAG-3 is reduced to 15% or less, 10% or less or 5% or less of the reference level of free membrane-bound LAG-3 in a cancer or cancer sample from the subject.

[0210] In some embodiments, the level of free soluble LAG-3 is reduced to 50% or less of the reference level of free soluble LAG-3 in serum sample from the subject, and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer or cancer sample from the subject.In some embodiments, the level of free soluble LAG-3 is reduced to 40% or less of the reference level of free soluble LAG-3 in serum sample from the subject, and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer or cancer sample from the subject.In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less of the reference level of free soluble LAG-3 in serum sample from the subject, and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane-bound LAG-3 in cancer or cancer sample from the subject. In some embodiments, the level of free soluble LAG-3 is reduced to 20% or less of the reference level of free soluble LAG-3 in a serum sample from the subject, and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane-bound LAG-3 in a cancer or cancer sample from the subject. In some embodiments, the level of free soluble LAG-3 is reduced to 10% or less of the reference level of free soluble LAG-3 in a serum sample from the subject, and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane-bound LAG-3 in a cancer or cancer sample from the subject.

[0211] In certain embodiments, the dose or dosage schedule is crit In one embodiment, the method provides a trough level (e.g., a steady-state trough level) of an anti-LAG-3 antibody molecule that is greater than or equal to 100 mg / mL (e.g., as described in Example 1). crit is the concentration below which non-linear PK is observed. crit is approximately 60 nM.

[0212] In certain embodiments, the anti-LAG-3 antibody molecule is administered in a dosage regimen disclosed herein.

[0213] In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of, for example, about 200 mg to about 1600 mg, about 300 mg to about 1500 mg, about 400 mg to about 1400 mg, about 500 mg to about 1300 mg, about 600 mg to about 1200 mg, about 700 mg to about 1100 mg, about 800 mg to about 1000 mg, about 200 mg to about 1400 mg, about 200 mg to about 1200 mg, about 200 mg to about 1000 mg, about 200 mg to about 800 mg, about 200 mg to about 600 mg, about 200 mg to about 400 mg, about 1400 mg to about 1600 mg, once every two weeks, once every three weeks, or once every four weeks. , about 1200 mg to about 1600 mg, about 1000 mg to about 1600 mg, about 800 mg to about 1600 mg, about 600 mg to about 1600 mg, about 400 mg to about 1600 mg, about 200 mg to about 600 mg, about 300 mg to about 700 mg, about 400 mg to about 800 mg, about 500 mg to about 900 mg, about 600 mg to about 1000 mg, about 700 mg to about 1100 mg, about 800 mg to about 1200 mg, about 900 mg to about 1300 mg, about 1000 mg to about 1400 mg, about 1100 mg to about 1500 mg, or about 1200 mg to about 1600 mg.

[0214] In one embodiment, the anti-LAG-3 antibody molecule is administered, for example, once every three weeks or once every four weeks, at a dose of about 200 mg to about 600 mg, about 250 mg to about 550 mg, about 300 mg to about 500 mg, about 350 mg to about 450 mg, about 200 mg to about 400 mg, about 400 mg to about 600 mg, e.g., about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 500 mg, e.g., about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, or about 500 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 350 mg to about 450 mg, e.g., about 400 mg.

[0215] In one embodiment, the anti-LAG-3 antibody molecule is administered, for example, once every three weeks or once every four weeks, at a dose of about 600 mg to about 1000 mg, about 650 mg to about 950 mg, about 700 mg to about 900 mg, about 750 mg to about 950 mg, about 600 mg to about 800 mg, about 800 mg to about 1000 mg, for example, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 900 mg to about 1100 mg, e.g., about 900 mg, about 920 mg, about 940 mg, about 960 mg, about 980 mg, about 900 mg, about 920 mg, about 940 mg, about 960 mg, about 980 mg, or about 1000 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 950 mg to about 1050 mg, e.g., about 1000 mg.

[0216] In certain embodiments, the anti-LAG-3 antibody molecule is administered, for example, once every three weeks or once every four weeks, at a dose of about 500 mg to about 900 mg, about 550 mg to about 850 mg, about 600 mg to about 800 mg, about 650 mg to about 750 mg, for example, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered, for example, once every three weeks, at a dose of about 600 mg to about 800 mg, for example, about 600 mg, about 620 mg, about 640 mg, about 660 mg, about 680 mg, about 700 mg, about 720 mg, about 740 mg, about 760 mg, about 780 mg, or about 800 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 650 mg to about 750 mg, for example, about 700 mg, once every three weeks.

[0217] In one embodiment, the anti-LAG-3 antibody molecule is administered, for example, once every three weeks or once every four weeks, at a dose of about 1200 mg to about 1600 mg, about 1250 mg to about 1550 mg, about 1300 mg to about 1500 mg, or about 1350 mg to about 1450 mg, e.g., about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, or about 1600 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 1300 mg to about 1500 mg, e.g., about 1300 mg, about 1320 mg, about 1340 mg, about 1360 mg, about 1380 mg, about 1400 mg, about 1420 mg, about 1440 mg, about 1460 mg, about 1480 mg, or about 1500 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 1350 mg to about 1450 mg, e.g., about 1400 mg.

[0218] In one embodiment, the anti-LAG-3 antibody molecule is administered, for example, once every four weeks at a dose of about 400 mg to about 700 mg, about 450 mg to about 650 mg, about 500 mg to about 600 mg, about 450 mg to about 550 mg, about 500 mg to about 600 mg, about 550 mg to about 650 mg, about 600 mg to about 700 mg, about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, e.g., about 400 mg, about 450 mg, about 500 mg, about 533 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 450 mg to about 650 mg, e.g., about 450 mg, about 500 mg, about 533 mg, about 550 mg, about 600 mg, or about 650 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 500 mg to about 650 mg, e.g., about 533 mg or about 600 mg.

[0219] In certain embodiments, the anti-LAG-3 antibody molecule is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 2000 mg or less, about 1900 mg or less, about 1800 mg or less, about 1700 mg or less, about 1600 mg or less, about 1500 mg or less, about 1400 mg or less, about 1300 mg or less, about 1200 mg or less, about 1100 mg or less, about 1000 mg or less, about 900 mg or less, about 800 mg or less, about 700 mg or less, about 600 mg or less, about 533 mg or less, about 500 mg or less, about 400 mg or less, about 300 mg or less, about 250 mg or less, or about 200 mg or less.

[0220] In some embodiments, the disorder is a cancer, e.g., a cancer described herein. In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a brain tumor, e.g., glioblastoma, gliosarcoma, or recurrent brain tumor. In some embodiments, the cancer is a pancreatic cancer, e.g., advanced pancreatic cancer. In some embodiments, the cancer is a skin cancer, e.g., a melanoma (e.g., stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma) or a Merkel cell carcinoma. In some embodiments, the cancer is a kidney cancer, e.g., a renal cell carcinoma (RCC) (e.g., metastatic renal cell carcinoma). In some embodiments, the cancer is a breast cancer, e.g., a metastatic breast cancer or a stage IV breast cancer, e.g., a triple negative breast cancer (TNBC). In some embodiments, the cancer is a virus-associated cancer. In some embodiments, the cancer is anal canal cancer (e.g., squamous cell carcinoma of the anal canal). In some embodiments, the cancer is cervical cancer (e.g., squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastric cancer (e.g., Epstein-Barr virus (EBV) positive gastric cancer, or gastric or gastroesophageal junction cancer). In some embodiments, the cancer is head and neck cancer (e.g., HPV positive and negative squamous cell carcinoma of the head and neck (SCCHN)). In some embodiments, the cancer is nasopharyngeal carcinoma (NPC). In some embodiments, the cancer is penile cancer (e.g., squamous cell carcinoma of the penis). In some embodiments, the cancer is vaginal or vulvar cancer (e.g., vaginal or vulvar squamous cell carcinoma). In some embodiments, the cancer is colorectal cancer, e.g., recurrent colorectal cancer or metastatic colorectal cancer, e.g., microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, mismatch repair competent colorectal cancer or mismatch repair deficient colorectal cancer. In some embodiments, the cancer is lung cancer, e.g., non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is a leukemia. In some embodiments, the cancer is a lymphoma, e.g., Hodgkin's lymphoma (HL) or diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed or refractory HL or DLBCL). In some embodiments, the cancer is a myeloma.

[0221] In other embodiments, the cancer is an MSI-high cancer. In some embodiments, the cancer is a metastatic cancer. In other embodiments, the cancer is an advanced cancer. In other embodiments, the cancer is a recurrent or refractory cancer. In other embodiments, the cancer is an unresectable cancer.

[0222] In some embodiments, the cancer is Merkel cell carcinoma. In other embodiments, the cancer is melanoma. In other embodiments, the cancer is breast cancer, e.g., triple-negative breast cancer (TNBC) or HER2-negative breast cancer. In other embodiments, the cancer is renal cell carcinoma (e.g., clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (nccRCC)). In other embodiments, the cancer is thyroid cancer, e.g., histopathologic thyroid carcinoma (ATC). In other embodiments, the cancer is a neuroendocrine tumor (NET), e.g., an atypical pulmonary carcinoid tumor, or a NET in the pancreas, gastrointestinal (GI) tract, or lung. In certain embodiments, the cancer is non-small cell lung cancer (NSCLC) (e.g., squamous NSCLC or non-squamous NSCLC). In certain embodiments, the cancer is fallopian tube cancer. In certain embodiments, the cancer is microsatellite instability-high colorectal cancer (MSI-high CRC) or microsatellite-stable colorectal cancer (MSS CRC).

[0223] In some embodiments, the anti-LAG-3 antibody molecule is administered in combination with an anti-PD-1 antibody molecule (e.g., an anti-PD-1 antibody molecule described herein). Without wishing to be bound by theory, it is believed that, as observed in mice [Woo et al. Cancer Research 72: 917-927 (2012)], in some embodiments, the anti-LAG-3 therapy is expected to have an additive effect in combination with the anti-PD-1 therapy. The anti-PD-1 antibody molecule can be administered with or without a chemotherapeutic agent [e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or precursor analog (e.g., capecitabine)]. Without wishing to be bound by theory, it is believed that in some embodiments, the addition of a chemotherapeutic agent will further enhance the efficacy of the anti-LAG-3 immunotherapy, alone or in combination with the anti-PD-1 immunotherapy, by making the tumor more immunoresponsive and / or by modifying the tumor microenvironment to achieve an optimal anti-tumor immune response.

[0224] In certain embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every four weeks, or about 200 mg to about 400 mg (e.g., about 300 mg) once every three weeks. In some embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every four weeks. In some embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 200 mg to about 400 mg (e.g., about 300 mg) once every three weeks.

[0225] In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every three weeks, and the anti-PD-1 antibody molecule is administered at a dose of about 200 mg to about 400 mg (e.g., about 300 mg) once every three weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every three weeks, and the anti-PD-1 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 700 mg to about 900 mg (e.g., about 800 mg) once every four weeks, and the anti-PD-1 antibody molecule is administered at a dose of about 200 mg to about 400 mg (e.g., about 300 mg) once every three weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 700 mg to about 900 mg (e.g., about 800 mg) once every four weeks, and the anti-PD-1 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 500 mg to about 650 mg (e.g., about 533 mg or about 600 mg) once every four weeks, and the anti-PD-1 antibody molecule is administered at a dose of about 200 mg to about 400 mg (e.g., about 300 mg) once every three weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 500 mg to about 650 mg (e.g., about 533 mg or about 600 mg) once every four weeks, and the anti-PD-1 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every four weeks.

[0226] In certain embodiments, the anti-TIM-3 antibody molecule is administered in combination with a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or precursor analog (e.g., capecitabine)). In certain embodiments, the chemotherapeutic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments, the platinum agent is oxaliplatin. In certain embodiments, the platinum agent is tetraplatin.

[0227] In certain embodiments, the chemotherapeutic agent is a nucleotide analog or precursor analog. In certain embodiments, the nucleotide analog or precursor analog is capecitabine.

[0228] In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to 500 mg (e.g., about 400 mg) once every three weeks, and the chemotherapeutic agent (e.g., a platinum agent, e.g., carboplatin) is administered once every three weeks at a dose to achieve an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (e.g., an AUC of about 6).

[0229] In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to about 500 mg (e.g., about 400 mg), the anti-PD-1 antibody molecule is administered once every three weeks at a dose of about 200 mg to about 400 mg (e.g., about 300 mg), and the chemotherapeutic agent (e.g., a platinum agent, e.g., carboplatin) is administered once every three weeks at a dose to achieve an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (e.g., an AUC of about 6).

[0230] In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the anti-PD-1 antibody molecule is PDR001 (spartalizumab).

[0231] In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the chemotherapeutic agent is a platinum agent. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the platinum agent is carboplatin. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the platinum agent is cisplatin. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the platinum agent is oxaliplatin. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the platinum agent is tetraplatin.

[0232] In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the chemotherapeutic agent is a platinum agent, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the platinum agent is carboplatin, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the platinum agent is cisplatin, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the platinum agent is oxaliplatin, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the platinum agent is tetraplatin, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab).

[0233] In some embodiments, the anti-LAG-3 antibody molecule is LAG525 and the chemotherapeutic agent is a nucleotide analog or precursor analog. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the nucleotide analog or precursor analog is capecitabine.

[0234] In one embodiment, the anti-LAG-3 antibody molecule is LAG525, the chemotherapeutic agent is a nucleotide analog or precursor analog, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In one particular embodiment, the anti-LAG-3 antibody molecule is LAG525, the nucleotide analog or precursor analog is capecitabine, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab).

[0235] Any of the doses disclosed herein can be repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times.

[0236] antibody molecule Disclosed herein are methods, compositions and formulations that include antibody molecules that bind to mammalian, e.g., human, LAG-3. For example, the antibody molecules specifically bind to an epitope, e.g., a linear or conformational epitope (e.g., an epitope described herein), on LAG-3.

[0237] As used herein, the term "antibody molecule" refers to a protein, e.g., an immunoglobulin chain or fragment thereof, that comprises at least one immunoglobulin variable domain sequence. The term "antibody molecule" includes, for example, monoclonal antibodies (including full-length antibodies having an immunoglobulin Fc region). In embodiments, an antibody molecule comprises a full-length antibody or a full-length immunoglobulin chain. In embodiments, an antibody molecule comprises an antigen-binding or functional fragment of a full-length antibody or a full-length immunoglobulin chain. In an embodiment, an antibody molecule is a multispecific antibody molecule, e.g., it comprises a plurality of immunoglobulin variable domain sequences, a first immunoglobulin variable domain sequence of the plurality having binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality having binding specificity for a second epitope. In an embodiment, a multispecific antibody molecule is a bispecific antibody molecule.

[0238] In aspects, the antibody molecule is a monospecific antibody molecule and binds to a single epitope. For example, a monospecific antibody molecule can have multiple immunoglobulin variable domain sequences that each bind to the same epitope.

[0239] In embodiments, the antibody molecule is a multispecific antibody molecule, e.g., comprising a plurality of immunoglobulin variable domain sequences, a first immunoglobulin variable domain sequence of the plurality having binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality having binding specificity for a second epitope. In embodiments, the first and second epitopes are present on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In embodiments, the first and second epitopes overlap. In embodiments, the first and second epitopes do not overlap. In embodiments, the first and second epitopes are present on different antigens, e.g., different proteins (or different subunits of a multimeric protein). In embodiments, the multispecific antibody molecule comprises a third, fourth or fifth immunoglobulin variable domain. In embodiments, the multispecific antibody molecule is a bispecific antibody molecule, a trispecific antibody molecule or a tetraspecific antibody molecule.

[0240] In an embodiment, the multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody has specificity for no more than two antigens. A bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence having binding specificity for a first epitope and a second immunoglobulin variable domain sequence having binding specificity for a second epitope. In an embodiment, the first and second epitopes are present on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In an embodiment, the first and second epitopes overlap. In an embodiment, the first and second epitopes do not overlap. In an embodiment, the first and second epitopes are present on different antigens, e.g., different proteins (or different subunits of a multimeric protein). In embodiments, a bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence that have binding specificity for a first epitope, and a heavy chain variable domain sequence and a light chain variable domain sequence that have binding specificity for a second epitope. In embodiments, a bispecific antibody molecule comprises a half antibody that has binding specificity for a first epitope, and a half antibody that has binding specificity for a second epitope. In embodiments, a bispecific antibody molecule comprises a half antibody or a fragment thereof that has binding specificity for a first epitope, and a half antibody or a fragment thereof that has binding specificity for a second epitope. In embodiments, a bispecific antibody molecule comprises an scFv or a fragment thereof that has binding specificity for a first epitope, and an scFv or a fragment thereof that has binding specificity for a second epitope. In embodiments, the first epitope is located in LAG-3 and the second epitope is located in PD-1, TIM-3, CEACAM (e.g., CEACAM-1 and / or CEACAM-5), PD-1 or PD-L2.

[0241] Protocols for generating multispecific (e.g., bispecific or trispecific), polyspecific or heterodimeric antibody molecules are known in the art; for example, but are not limited to, the "knobs and holes" approach, as described, for example, in US5731168; electrostatic steering Fc pairing, as described, for example, in WO09 / 089004, WO06 / 106905 and WO2010 / 129304; strand-exchange engineered domain (SEED) heterodimerization, as described, for example, in WO07 / 110205. Fab arm exchange, as described, for example, in WO08 / 119353, WO2011 / 131746 and WO2013 / 060867; double antibody conjugates, for example, by cross-linking antibodies to create bispecific structures using heterobifunctional reagents with amine-reactive and sulfhydryl-reactive groups, as described, for example, in US4433059; by recombining half-antibodies (heavy-light chain pairs or Fabs) from different antibodies by cycles of reduction and oxidation of the disulfide bond between the two heavy chains, as described, for example, in US4444878. bispecific antibody determinants made by synthesis of antibodies against different binding specificities; trifunctional antibodies, e.g., three Fab' fragments cross-linked by sulfhydryl-reactive groups, as described, for example, in US5273743; biosynthetic binding proteins, e.g., pairs of scFv cross-linked by their C-terminal tails, preferably by disulfide or amine-reactive chemical bridges, as described, for example, in US5534254; bifunctional antibodies, e.g., Fab fragments with different binding specificities dimerized by leucine zippers replacing the constant domains, as described, for example, in US5582996. (e.g. c-fos and c-jun); bispecific and oligospecific monovalent and oligovalent receptors, e.g. the VH-CH1 regions of two antibodies (two Fab fragments) linked by a polypeptide spacer between the CH1 region of one antibody and the VH region of the other antibody, typically with the associated light chain, e.g. as described in US5591828; bispecific DNA-antibody conjugates, e.g. cross-linking of an antibody or Fab fragment with a double-stranded piece of DNA, e.g. as described in US5635602;Bispecific fusion proteins, e.g. expression constructs containing two scFvs and complete constant regions with a hydrophilic helical peptide linker between them; multivalent and multispecific binding proteins, e.g. dimers of polypeptides having a first domain with a binding region of an Ig heavy chain variable region and a second domain with a binding region of an Ig light chain variable region, commonly referred to as diabodies [higher order structures creating bispecific, trispecific or tetraspecific molecules are also disclosed], e.g. minibody constructs with linked VL and VH chains further connected by a peptide spacer to the antibody hinge and CH3 regions, which can dimerize to form bispecific / multivalent molecules ... diabodies, as described e.g. trimers and tetramers, e.g., as described in US5844094; strings of VH domains (or VL domains in family members) connected by peptide bonds with a crosslinkable chemical group at the C-terminus, which further associate with the VL domain to form a series of FVs (or scFvs), e.g., as described in US5864019; and single-chain binding polypeptides with both VH and VL domains linked by peptide linkers, which are combined into multivalent structures by non-covalent or chemical crosslinking to form homo-bivalent, hetero-bivalent, trivalent and tetravalent structures, e.g., using both scFV or diabody-type formats, e.g., as described in US5869620. Additional exemplary multispecific and bispecific molecules, as well as methods of making the same, can be found in, e.g., US5910573, US5932448, US5959083, US5989830, US6005079, US6239259, US6294353, US6333396, US6476198, US6511663, US6670453, US6743896, US6809185, US6833441, US7129330, US7183076, US7521056, US7527787,US7534866、US7612181、US2002 / 004587A1、US2002 / 076406A1、US2002 / 103345A1、US2003 / 207346A1、US2003 / 211078A1、US2004 / 219643A1、US2004 / 220388A1、US2004 / 242847A1、US2005 / 003403A1、US2005 / 004352A1、US2005 / 069552A1、US2005 / 079170A1、US2005 / 100543A1、US2005 / 136049A1、US2005 / 136051A1、US2005 / 163782A1、US2005 / 266425A1、US2006 / 083747A1、US2006 / 120960A1、US2006 / 204493A1、US2006 / 263367A1、US2007 / 004909A1、US2007 / 087381A1、US2007 / 128150A1、US2007 / 141049A1、US2007 / 154901A1、US2007 / 274985A1、US2008 / 050370A1、US2008 / 069820A1、US2008 / 152645A1、US2008 / 171855A1、US2008 / 241884A1、US2008 / 254512A1、US2008 / 260738A1、US2009 / 130106A1、US2009 / 148905A1、US2009 / 155275A1、US2009 / 162359A1、US2009 / 162360A1、US2009 / 175851A1、US2009 / 175867A1、US2009 / 232811A1、US2009 / 234105A1、US2009 / 263392A1、US2009 / 274649A1、EP346087A2、WO00 / 06605A2、WO02 / 072635A2、WO04 / 081051A1、WO06 / 020258A2、WO2007 / 044887A2、WO2007 / 095338A2、WO2007 / 137760A2、WO2008 / 119353A1、WO2009 / 021754A2、WO2009 / 068630A1、WO91 / 03493A1、WO93 / 23537A1、WO94 / 09131A1、WO94 / 12625A2、WO95 / 09917A1、WO96 / 37621A2、WO99 / 64460A1, the contents of which are incorporated herein by reference in their entirety.

[0242] In other embodiments, the anti-LAG-3 antibody molecule (e.g., a monospecific, bispecific or multispecific antibody molecule) is covalently linked, e.g., fused, e.g., as a fusion molecule, e.g., a fusion protein, to another partner, e.g., a protein, e.g., one or more cytokines. In other embodiments, the fusion molecule comprises one or more proteins, e.g., one or more cytokines. In some embodiments, the cytokine is an interleukin (IL) selected from one, two or more of IL-1, IL-2, IL-12, IL-15 or IL-21. In some embodiments, the bispecific antibody molecule has a first binding specificity for a first target (e.g., LAG-3) and a second binding specificity for a second target (e.g., PD-1 or TIM-3), and may be linked to an interleukin (e.g., IL-12) domain, e.g., full-length IL-12 or a portion thereof.

[0243] "Fusion protein" and "fusion polypeptide" refer to a polypeptide having at least two moieties covalently linked together, each of which is a polypeptide having a distinct property. The property can be a biological property, such as activity in vitro or in vivo. The property can also be a simple chemical or physical property, such as binding to a target molecule, catalysis of a reaction, etc. The two moieties can be linked directly by a single peptide bond or through a peptide linker, but are in reading frame with each other.

[0244] In embodiments, antibody molecules include diabodies and single chain molecules, as well as antigen-binding fragments of antibodies (e.g., Fab, F(ab')2, and Fv). For example, an antibody molecule can include a heavy (H) chain variable domain sequence (abbreviated herein as VH) and a light (L) chain variable domain sequence (abbreviated herein as VL). In embodiments, an antibody molecule includes or consists of one heavy chain and one light chain (referred to herein as a half antibody). In another example, an antibody molecule includes two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequences, thereby forming two antigen-binding sites, and includes Fab, Fab', F(ab')2, Fc, Fd, Fd', Fv, single chain antibodies (e.g., scFv), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific), and chimeric (e.g., humanized) antibodies, etc., which can be produced by modification of a whole antibody or synthesized de novo using recombinant DNA technology. These functional antibody fragments retain the ability to selectively bind to their respective antigens or receptors. The antibodies and antibody fragments can be from any class of antibody, including but not limited to IgG, IgA, IgM, IgD and IgE, and can be from any subclass of antibody (e.g., IgG1, IgG2, IgG3 and IgG4). Preparations of antibody molecules can be monoclonal or polyclonal. The antibody molecules can also be human, humanized, CDR-grafted or in vitro generated antibodies. The antibody can have a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3 or IgG4. The antibody can have a light chain selected from, for example, kappa or lambda. The term "immunoglobulin" (Ig) is used interchangeably herein with the term "antibody."

[0245] Examples of antigen-binding fragments of antibody molecules include (i) a Fab fragment; a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) an F(ab')2 fragment; a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a diabody (dAb) fragment consisting of the VH domain; (vi) a camelid or camelized variable domain; (vii) a single chain Fv (scFv), see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883); (viii) a single domain antibody. These antibody fragments are obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.

[0246] The term "antibody" includes intact molecules as well as functional fragments thereof. The constant region of an antibody can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, the number of cysteine ​​residues, effector cell function, or complement function).

[0247] The antibody molecule can also be a single domain antibody. A single domain antibody can include an antibody whose complementary determining region is part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies naturally devoid of light chains, single domain antibodies derived from conventional four-chain antibodies, genetically engineered antibodies, and single domain scaffolds other than those derived from antibodies. A single domain antibody can be any or any future single domain antibody in the art. A single domain antibody can be derived from any species, including, but not limited to, mouse, human, camel, llama, fish, shark, goat, rabbit, and cow. In another aspect of the invention, a single domain antibody is a naturally occurring single domain antibody known as a heavy chain antibody devoid of light chains. Such single domain antibodies are disclosed, for example, in WO94 / 04678. For clarity, this variable domain derived from a heavy chain antibody naturally devoid of light chains is known herein as a VHH or nanobody, to distinguish it from the conventional VH of four-chain immunoglobulins. Such VHH molecules can be derived from antibodies produced in Camelidae species, such as camel, llama, dromedary, alpaca and guanaco. Other species outside of Camelidae can also produce heavy chain antibodies that are naturally devoid of light chains; such VHHs are within the scope of the present invention.

[0248] The VH and VL regions can be subdivided into regions of hypervariability, termed "complementarity determining regions" (CDRs), interspersed with more conserved regions, termed "framework regions" (FR or FW).

[0249] The extent of framework regions and CDRs have been precisely defined in a number of ways [see Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and the AbM definitions used by Oxford Molecular's AbM antibody modeling software]. See generally, e.g., in Protein Sequence and Structure Analysis of Antibody Variable Domains.:Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg).

[0250] The terms "complementarity determining region" and "CDR" refer to the amino acid sequence in the antibody variable region that confers antigen specificity and binding affinity. Generally, there are three CDRs in each heavy chain variable region (HCDR1, HCDR2 and HCDR3), and three CDRs in each light chain variable region (LCDR1, LCDR2 and LCDR3).

[0251] The exact amino acid sequence boundaries of a given CDR can be determined using any of a number of well-known schemes, including those described in Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (the "Kabat" numbering scheme); Al-Lazikani et al., (1997) JMB 273,927-948 (the "Chothia" numbering scheme). As used herein, CDRs defined according to the "Chothia" numbering scheme are sometimes referred to as "hypervariable loops."

[0252] For example, in Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3); the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3). In Chothia, the CDR amino acids in the VH are numbered 26-32 (HCDR1), 52-56 (HCDR2) and 95-102 (HCDR3); the amino acid residues in the VL are numbered 26-32 (LCDR1), 50-52 (LCDR2) and 91-96 (LCDR3). Combining the Kabat and Chothia CDR definitions, the CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3) in human VH, and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3) in human VL.

[0253] Generally, unless otherwise indicated, anti-LAG-3 antibody molecules may contain any combination of one or more Kabat CDRs and / or Chothia hypervariable loops. In some embodiments, the following definitions are used for anti-LAG-3 antibody molecules: HCDR1 according to the combined Kabat and Chothia CDR definitions, and HCCDR2-3 and LCCDR1-3 according to the Kabat CDR definitions. In all definitions, each VH and VL typically contains three CDRs and four FRs arranged in the following order from amino-terminus to carboxy-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0254] As used herein, "immunoglobulin variable domain sequence" refers to an amino acid sequence capable of forming the structure of an immunoglobulin variable domain. For example, the sequence may include the entire or part of the amino acid sequence of a naturally occurring variable domain. For example, the sequence may or may not include one, two or more N- or C-terminal amino acids, or may include other modifications compatible with forming a protein structure.

[0255] The term "antigen-binding site" refers to the portion of an antibody molecule that contains determinants that form an interface that binds to a LAG-3 polypeptide or an epitope thereof. For proteins (or protein mimetics), the antigen-binding site typically includes one or more loops (of at least four amino acids or amino acid mimetics) that form an interface that binds to the LAG-3 polypeptide. Typically, the antigen-binding site of an antibody molecule includes at least one or two CDRs and / or hypervariable loops, or more typically, at least three, four, five or six CDRs and / or hypervariable loops.

[0256] The terms "compete" or "cross-compete" are used interchangeably herein to refer to the ability of an antibody molecule to interfere with the binding of an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule provided herein, to a target, such as human LAG-3. The interference with binding can be direct or indirect (e.g., via allosteric modulation of the antibody molecule or the target). The extent to which an antibody molecule can interfere with the binding of another antibody molecule to a target, and therefore whether it can be said to compete, can be determined using a competitive binding assay, such as a FACS assay, an ELISA, or a BIACORE assay. In some embodiments, the competitive binding assay is a quantitative competitive assay. In certain aspects, a first anti-LAG-3 antibody molecule is said to compete with a second anti-LAG-3 antibody molecule for binding to a target if binding of the first antibody molecule to the target is reduced by 10% or more, e.g., 20% or more, 30% or more, 40% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more in a competitive binding assay (e.g., a competitive assay described herein).

[0257] The terms "monoclonal antibody" or "monoclonal antibody composition" as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope. Monoclonal antibodies can be made by hybridoma technology or by methods that do not use hybridoma technology (e.g., recombinant methods).

[0258] A "effectively human" protein is one that does not elicit a neutralizing antibody response, such as a human anti-mouse antibody (HAMA) response. HAMA can be problematic in many situations, for example, when antibody molecules are administered repeatedly, for example, in the treatment of chronic or recurrent disease states. HAMA responses can potentially render repeated antibody administration ineffective due to increased clearance of antibodies from serum [see, e.g., Saleh et al., Cancer Immunol. Immunother., 32:180-190 (1990)] and due to potential allergic reactions [see, e.g., LoBuglio et al., Hybridoma, 5:5117-5123 (1986)].

[0259] The antibody molecule can be a polyclonal or monoclonal antibody. In other embodiments, the antibody can be recombinantly produced, for example, by phage display or combinatorial methods.

[0260] Phage display and combinatorial methods for generating antibodies are known in the art [see, e.g., Ladner et al. U.S. Pat. No. 5,223,409; Kang et al. International Publication No. WO 92 / 18619; Dower et al. International Publication No. WO 91 / 17271; Winter et al. International Publication No. WO 92 / 20791; Markland et al. International Publication No. WO 92 / 15679; Breitling et al. International Publication No. WO 93 / 01288; McCafferty et al. International Publication No. WO 92 / 01047; Garrard et al. International Publication No. WO 92 / 09690; Ladner et al. International Publication No. WO 90 / 02809; Fuchs et al. (1991) Bio / Technology 9:1370-1372; Hay et al. (1992) Hum Antibody Hybridomas 3:81-85;Huse et al. (1989) Science 246:1275-1281;Griffths et al. (1993) EMBO J 12:725-734;Hawkins et al. (1992) J Mol Biol 226:889-896;Clackson et al. (1991) Nature 352:624-628; Gram et al. (1992) PNAS 89:3576-3580; Garrad et al. (1991) Bio / Technology 9:1373-1377; Hoogenboom et al. (1991) Nuc Acid Res 19:4133-4137; and Barbas et al. (1991) PNAS 88:7978-7982].

[0261] In certain embodiments, the antibody is a fully human antibody (e.g., an antibody made in a mouse genetically engineered to produce antibodies from human immunoglobulin sequences) or a non-human antibody, e.g., a rodent (mouse or rat), goat, primate (e.g., monkey), camel antibody. Preferably, the non-human antibody is a rodent (mouse or rat antibody). Methods for producing rodent antibodies are known in the art.

[0262] Human monoclonal antibodies can be made using transgenic mice carrying the human immunoglobulin genes rather than the mouse system. Spleen cells from such transgenic mice immunized with an antigen of interest are used to produce hybridomas secreting human mAbs with specific affinity for epitopes derived from human proteins (see, e.g., Wood et al. International Application WO 91 / 00906; Kucherlapati et al. PCT Publication WO 91 / 10741; Lonberg et al. International Application WO 92 / 03918; Kay et al. International Application 92 / 03917; Lonberg, N. et al. 1994 Nature 368:856-859; Green, LL et al. 1994 Nature Genet. 7:13-21; Morrison, SL et al. 1994 Proc. Natl. Acad. Sci. USA 81:6851-6855; Bruggeman et al. 1993 Year Immunol 7:33-40; Tuaillon et al. al. 1993 PNAS 90:3720-3724; Bruggeman et al. 1991 Eur J Immunol 21:1323-1326).

[0263] The antibody can be an antibody whose variable region or part thereof, for example, CDR, is made in a non-human organism, for example, rat or mouse. Chimeric, CDR-grafted and humanized antibodies are within the scope of the present invention. Antibodies made in a non-human organism, for example, rat or mouse, and then modified in variable framework or constant region, for example, to reduce antigenicity in humans, are within the scope of the present invention.

[0264] Chimeric antibodies can be produced by recombinant DNA techniques known in the art [Robinson et al., International Patent Publication No. PCT / US86 / 02269; Akira, et al., European Patent Application No. 184,187; Taniguchi, M., European Patent Application No. 171,496; Morrison et al., European Patent Application No. 173,494; Neuberger et al., International Application WO86 / 01533; Cabilly et al., U.S. Patent No. 4,816,567; Cabilly et al., European Patent Application No. 125,023; Better et al. (1988 Science 240:1041-1043); Liu et al. (1987) PNAS 84:3439-3443; Liu et al., 1987, J. Immunol. 139:3521-3526; Sun et al. (1987) PNAS 84:214-218; Nishimura et al., 1987, Canc. Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; and Shaw et al., 1988, J. Natl Cancer Inst. 80:1553-1559].

[0265] A humanized or CDR-grafted antibody will have at least one or two, but typically all three, recipient CDRs (of the heavy and / or light immunoglobulin chains) replaced by donor CDRs. The antibody can be replaced with at least a portion of the non-human CDRs, or only a small portion of the CDRs can be replaced with non-human CDRs. It is only necessary to replace the number of CDRs required for binding of the humanized antibody to PD-1. Preferably, the donor will be a rodent antibody, e.g., a rat or mouse antibody, and the recipient will be a human framework or human consensus framework. Typically, the immunoglobulin providing the CDRs is referred to as the "donor" and the immunoglobulin providing the framework is referred to as the "acceptor." In some embodiments, the donor immunoglobulin is non-human (e.g., rodent). The acceptor framework is a naturally occurring (eg, human) framework or a consensus framework, or a sequence that is about 85% or more, preferably 90%, 95%, 99% or more identical thereto.

[0266] As used herein, the term "consensus sequence" refers to a sequence formed from the amino acids (or nucleotides) that occur most frequently in a family of related sequences [see, e.g., Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987)]. In a family of proteins, each position in the consensus sequence is occupied by the amino acid that occurs most frequently at that position in the family. If two amino acids occur equally frequently, either may be included in the consensus sequence. "Consensus framework" refers to the framework region in the consensus immunoglobulin sequence.

[0267] Antibodies can be humanized by methods known in the art (see, e.g., Morrison, SL, 1985, Science 229:1202-1207; Oi et al., 1986, BioTechniques 4:214; and US 5,585,089, US 5,693,761, and US 5,693,762 by Queen et al., the entire contents of which are hereby incorporated by reference).

[0268] Humanized or CDR-grafted antibodies can be produced by CDR-grafting or CDR-replacement, whereby one, two or all CDRs of an immunoglobulin chain can be replaced. See, for example, U.S. Patent No. 5,225,539; Jones et al. 1986 Nature 321:552-525; Verhoeyan et al. 1988 Science 239:1534; Beidler et al. 1988 J. Immunol. 141:4053-4060; Winter, U.S. Patent No. 5,225,539, the contents of all of which are hereby expressly incorporated by reference. Winter describes a CDR-grafting method that can be used to prepare the humanized antibodies of the present invention [UK Patent Application GB2188638(A), filed March 26, 1987; Winter, U.S. Patent No. 5,225,539], the contents of which are hereby expressly incorporated by reference.

[0269] Humanized antibodies in which specific amino acids have been substituted, deleted or added are also within the scope of the present invention. Criteria for selecting amino acids from the donor are described in US 5,585,089, e.g., columns 12-16 of US 5,585,089, the contents of which are hereby incorporated by reference. Other techniques for humanizing antibodies are described in Padlan et al., EP 519596 (A1), published December 23, 1992.

[0270] The antibody molecule can be a single chain antibody. Single chain antibodies (scFV) can be genetically engineered (see, for example, Colcher, D. et al. (1999) Ann NY Acad Sci 880:263-80; and Reiter, Y. (1996) Clin Cancer Res 2:245-52). Single chain antibodies can dimerize or multimerize to form multivalent antibodies with specificity for different epitopes of the same target protein.

[0271] In still other embodiments, the antibody molecule has a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE; in particular, for example, from IgG1, IgG2, IgG3 and IgG4 (e.g., human) heavy chain constant regions. In another embodiment, the antibody molecule has a light chain constant region selected from, for example, kappa or lambda (e.g., human) light chain constant regions. The constant region can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, number of cysteine ​​residues, effector cell function and / or complement function). In some embodiments, the antibody has effector function and can fix complement. In other embodiments, the antibody does not recruit effector cells or does not fix complement. In another embodiment, the antibody has a reduced or no ability to bind to Fc receptors. For example, it may be an isotype or subtype, fragment or other mutant that does not support binding to an Fc receptor, eg, having an Fc receptor binding region mutagenized or deleted.

[0272] Methods for modifying antibody constant regions are known in the art. Antibodies with modified functions, such as modified affinity for effector ligands, such as FcR in cells or the C1 component of complement, can be produced by replacing at least one amino acid residue in the constant portion of the antibody with a different residue (see, for example, EP388,151(A1), U.S. Pat. No. 5,624,821 and U.S. Pat. No. 5,648,260, the entire contents of which are hereby incorporated by reference). Similar types of modifications can be described that, when applied to mouse or other species of immunoglobulins, would reduce or eliminate these functions.

[0273] An antibody molecule can be derivatized or linked to another functional molecule (e.g., another peptide or protein). As used herein, a "derivatized" antibody molecule is an antibody molecule that has been modified. Methods of derivatization include, but are not limited to, the addition of a fluorescent moiety, a radioactive nucleotide, a toxin, an enzyme, or an affinity ligand such as biotin. Thus, the antibody molecule of the present invention is intended to include derivatized and otherwise modified forms of the antibodies described herein, including immunoadhesion molecules. For example, an antibody molecule can be functionally linked (by chemical coupling, genetic fusion, non-covalent binding, or otherwise) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or diabody), a detectable agent, a cytotoxic agent, a pharmaceutical agent, and / or a protein or peptide that can mediate the association of an antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).

[0274] One type of derivatized antibody molecule is produced by crosslinking two or more antibodies (of the same or different types, e.g., to create bispecific antibodies). Suitable crosslinkers include those that are heterobifunctional (e.g., m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (e.g., disuccinimidyl suberate), having two separate reactive groups separated by an appropriate spacer. Such linkers are available from Pierce Chemical Company, Rockford, Ill.

[0275] Useful detectable agents with which the antibody molecules of the present invention may be derivatized (or labeled) include fluorescent compounds, various enzymes, prosthetic groups, luminescent materials, bioluminescent materials, fluorescence-emitting metal atoms, e.g., europium (Eu) and other lanthanides, and radioactive materials (discussed below). Exemplary fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5 dimethylamine-1-naphthalenesulfonyl chloride, phycoerythrin, and others. Antibodies may also be derivatized with detectable enzymes, such as alkaline phosphatase, horseradish peroxidase, β-galactosidase, acetylcholinesterase, glucose oxidase, and others. When an antibody is derivatized with a detectable enzyme, it is detected by adding additional reagents that the enzyme uses to produce a detectable reaction product. For example, when the detectable agent horseradish peroxidase is present, the addition of hydrogen peroxide and diaminobenzidine results in a colored reaction product that is detectable. Antibody molecules can also be derivatized with prosthetic groups (e.g., streptavidin / biotin and avidin / biotin). For example, an antibody can be derivatized with biotin and detected through indirect measurement of avidin or streptavidin binding. Examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin.

[0276] Labeled antibody molecules can be used, for example, diagnostically and / or experimentally in a number of contexts, including: (i) to isolate a given antigen by standard techniques, such as affinity chromatography or immunoprecipitation; (ii) to detect a given antigen (e.g., in a cell lysate or cell supernatant) to assess protein abundance and expression patterns; (iii) to monitor protein levels in tissues as part of a clinical laboratory procedure, e.g., to determine the effectiveness of a given treatment regimen.

[0277] The antibody molecule can be conjugated to another molecular entity, typically a labeling or therapeutic (e.g., cytotoxic or cytostatic) agent or moiety. Radioisotopes can be used in diagnostic or therapeutic applications.

[0278] The present invention provides radiolabeled antibody molecules and methods for labeling the same. In one aspect, a method for labeling an antibody molecule is disclosed. The method comprises contacting the antibody molecule with a chelating agent, thereby producing a conjugated antibody.

[0279] As mentioned above, the antibody molecule can be conjugated to a therapeutic agent. Therapeutically active radioisotopes have already been mentioned. Examples of other therapeutic agents include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, maytansinoids, such as maytansinol (see, e.g., U.S. Pat. No. 5,208,020), CC-1065 (see, e.g., U.S. Pat. Nos. 5,475,092, 5,585,499, and 5,846,545), and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil dacarbazine), alkylating agents (e.g., mechlorethamine, thiotepa chlorambucil, CC-1065, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C and cis-dichlorodiamineplatinum(II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin and anthramycin (AMC)] and antimitotic agents (e.g., vincristine, vinblastine, taxol and maytansinoids).

[0280] In one aspect, the disclosure provides a method of preparing a target binding molecule that specifically binds to a target disclosed herein, e.g., LAG-3. For example, the target binding molecule is an antibody molecule. The method includes: preparing a target protein that includes at least a portion of a non-human protein that is homologous (at least 70, 75, 80, 85, 87, 90, 92, 94, 95, 96, 97, 98% identical) to a corresponding portion of a human target protein, but differs by at least one amino acid (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acids); obtaining an antibody molecule that specifically binds to the antigen; and evaluating the effectiveness of a binding agent in modulating the activity of the target protein. The method can further include administering the binding agent (e.g., antibody molecule) or derivative (e.g., humanized antibody molecule) to a human subject.

[0281] The present disclosure provides isolated nucleic acid molecules encoding the above-mentioned antibody molecules, vectors and host cells thereof. Nucleic acid molecules include, but are not limited to, RNA, genomic DNA and cDNA.

[0282] Exemplary Anti-LAG-3 Antibody Molecules In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule disclosed in US2015 / 0259420, published September 17, 2015, entitled "Antibody Molecules to LAG-3 and Uses Thereof," which is incorporated by reference in its entirety.

[0283] In certain embodiments, the anti-LAG-3 antibody molecule comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or all the CDRs collectively) from heavy and light chain variable regions comprising the amino acid sequences shown in Table 5 or the amino acid sequences encoded by the nucleotide sequences shown in Table 5 (e.g., the heavy and light chain variable region sequences of BAP050-clone I or BAP050-clone J disclosed in Table 5). In certain embodiments, the CDRs follow the Kabat definition (e.g., as presented in Table 5). In certain embodiments, the CDRs follow the Chothia definition (e.g., as presented in Table 5). In certain embodiments, the CDRs follow a combined CDR definition of both Kabat and Chothia (e.g., as presented in Table 5). In certain embodiments, the combined Kabat and Chothia CDRs of VH CDR1 comprise the amino acid sequence GFTLTNYGMN (SEQ ID NO: 766). In one embodiment, one or more of the CDRs (or all of the CDRs together) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the amino acid sequence shown in Table 5 or the amino acid sequence encoded by the nucleotide sequence shown in Table 5.

[0284] In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:701, the VHCDR2 amino acid sequence of SEQ ID NO:702, and the VHCDR3 amino acid sequence of SEQ ID NO:703; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:710, the VLCDR2 amino acid sequence of SEQ ID NO:711, and the VLCDR3 amino acid sequence of SEQ ID NO:712, each of which is disclosed in Table 5.

[0285] In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO:736 or 737, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO:738 or 739, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO:740 or 741; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO:746 or 747, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO:748 or 749, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO:750 or 751, respectively, as disclosed in Table 5. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO:758 or 737, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO:759 or 739, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO:760 or 741; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO:746 or 747, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO:748 or 749, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO:750 or 751, respectively, as disclosed in Table 5.

[0286] In certain embodiments, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:706 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:706. In certain embodiments, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO:718 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:718. In certain embodiments, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:724 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:724. In certain embodiments, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO:730 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:730. In certain embodiments, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:706, and a VL comprising the amino acid sequence of SEQ ID NO:718. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:724, and a VL comprising the amino acid sequence of SEQ ID NO:730.

[0287] In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:707 or 708, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:707 or 708. In certain embodiments, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO:719 or 720, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:719 or 720. In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:725 or 726, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:725 or 726. In certain embodiments, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO:731 or 732, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:731 or 732. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 707 or 708, and a VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726, and a VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732.

[0288] In certain embodiments, the anti-LAG-3 antibody molecule comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:709 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:709. In certain embodiments, the anti-LAG-3 antibody molecule comprises a light chain comprising an amino acid sequence of SEQ ID NO:721 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:721. In certain embodiments, the anti-LAG-3 antibody molecule comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:727 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:727. In certain embodiments, the anti-LAG-3 antibody molecule comprises a light chain comprising an amino acid sequence of SEQ ID NO:733 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:733. In certain embodiments, the anti-LAG-3 antibody molecule comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:709, and a light chain comprising an amino acid sequence of SEQ ID NO:721. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:727, and a light chain comprising the amino acid sequence of SEQ ID NO:733.

[0289] In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:716 or 717, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:716 or 717. In certain embodiments, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO:722 or 723, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:722 or 723. In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:728 or 729, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:728 or 729. In certain embodiments, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO:734 or 735, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:734 or 735. In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717, and a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723. In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729, and a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735.

[0290] The antibody molecules described herein can be produced by the vectors, host cells and methods described in US2015 / 0259420, which is incorporated herein by reference in its entirety.

[0291] Table 5. Amino acid and nucleotide sequences of exemplary anti-LAG-3 antibody molecules [Table 1] [Table 2]

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

[0292] In certain embodiments, the anti-LAG-3 antibody molecule is selected from the group consisting of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum 16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g. BAP050-hum01-Ser, BAP050-hum02-Ser, BAP05 0-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser , BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-clone-F, BAP050-clone-G, BAP050-clone-H, BAP050-clone-I, or BAP050-clone-J. at least one or two heavy chain variable domains (which may include constant regions), at least one or two light chain variable domains (which may include constant regions), or both, comprising the amino acid sequence of any of Lone-J, or a sequence set forth in Table 1 of US2015 / 0259420, or a sequence encoded by the nucleotide sequence of Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the foregoing sequences.

[0293] In yet another embodiment, the anti-LAG-3 antibody molecule is an antibody described herein, e.g., BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP 050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser, B AP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum0 8-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-clone-F, BAP050-clone-G, BAP050-clone-H, An antibody selected from either BAP050-clone-I, or BAP050-clone-J, or a sequence set forth in Table 1 of US2015 / 0259420, or a sequence encoded by the nucleotide sequence of Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the aforementioned sequences.

[0294] In yet another embodiment, the anti-LAG-3 antibody molecule comprises at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising the amino acid sequence set forth in Table 1 of US2015 / 0259420 or the amino acid sequence encoded by the nucleotide sequence of Table 1. In certain embodiments, one or more CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, compared to the amino acid sequence set forth in Table 1 or the amino acid sequence encoded by the nucleotide sequence set forth in Table 1.

[0295] In yet another embodiment, the anti-LAG-3 antibody molecule comprises at least one, two or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising the amino acid sequence set forth in Table 1 of US2015 / 0259420, or the amino acid sequence encoded by the nucleotide sequence of Table 1. In certain embodiments, one or more CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more alterations, e.g., amino acid substitutions or deletions, compared to the amino acid sequence set forth in Table 1 or the amino acid sequence encoded by the nucleotide sequence set forth in Table 1. In certain embodiments, the anti-PD-L1 antibody molecule comprises a substitution in a light chain CDR, e.g., one or more substitutions in CDR1, CDR2 and / or CDR3 of the light chain.

[0296] In another embodiment, the anti-LAG-3 antibody molecule comprises at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence set forth in Table 1 of US2015 / 0259420 or an amino acid sequence encoded by a nucleotide sequence of Table 1 of US2015 / 0259420. In certain embodiments, one or more CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, compared to the amino acid sequence set forth in Table 1 or the amino acid sequence encoded by the nucleotide sequence set forth in Table 1.

[0297] Other Exemplary Anti-LAG-3 Antibody Molecules In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO2015 / 116539 and US9,505,839, which are incorporated herein by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences taken together), heavy or light chain variable region sequences, or heavy or light chain sequences of BMS-986016, e.g., as disclosed in Table 6.

[0298] In some embodiments, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In some embodiments, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences collectively), the heavy or light chain variable region sequence, or the heavy or light chain sequence of TSR-033.

[0299] In some embodiments, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are disclosed in WO2008 / 132601 and US9,244,059, which are incorporated herein by reference in their entirety. In some embodiments, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences collectively), heavy or light chain variable region sequences, or heavy or light chain sequences of IMP731, e.g., as disclosed in Table 6. In some embodiments, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences collectively), heavy or light chain variable region sequences, or heavy or light chain sequences of GSK2831781.

[0300] In some embodiments, the anti-LAG-3 antibody molecule is IMP761 (Prima BioMed). In some embodiments, the anti-LAG-3 antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences taken together), the heavy or light chain variable region sequence, or the heavy or light chain sequence of IMP761.

[0301] Further known anti-LAG-3 antibodies include, for example, the antibodies described in WO2008 / 132601, WO2010 / 019570, WO2014 / 140180, WO2015 / 116539, WO2015 / 200119, WO2016 / 028672, US9,244,059, US9,505,839, which are incorporated by reference in their entireties.

[0302] In one embodiment, the anti-LAG-3 antibody is an antibody that competes for binding with one of the anti-LAG-3 antibodies described herein and / or binds to the same epitope on LAG-3 as that antibody.

[0303] In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, e.g., IMP321 (Prima BioMed), as disclosed in WO2009 / 044273, the entire contents of which are incorporated herein by reference.

[0304] Table 6. Amino acid sequences of other exemplary anti-LAG-3 antibody molecules [Table 18]

[0305] PD-1 inhibitors In certain embodiments, the anti-LAG-3 antibody molecules described herein are administered in combination with a PD-1 inhibitor. In certain embodiments, the PD-1 inhibitor is selected from PDR001 or spartalizumab (Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck&Co), pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).

[0306] Exemplary PD-1 Inhibitors In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule described in US2015 / 0210769, published July 30, 2015, entitled "Antibody Molecules to PD-1 and Uses Thereof," which is incorporated by reference in its entirety.

[0307] In certain embodiments, the anti-PD-1 antibody molecule comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from heavy and light chain variable regions comprising the amino acid sequences set forth in Table 1 or the amino acid sequences encoded by the nucleotide sequences set forth in Table 1 (e.g., the heavy and light chain variable region sequences of BAP049-clone-E or BAP049-clone-B disclosed in Table 1). In certain embodiments, the CDRs follow the Kabat definition (e.g., as presented in Table 1). In certain embodiments, the CDRs follow the Chothia definition (e.g., as presented in Table 1). In certain embodiments, the CDRs follow a combined CDR definition of both Kabat and Chothia (e.g., as presented in Table 1). In certain embodiments, the combined Kabat and Chothia CDRs of VH CDR1 comprise the amino acid sequence GYTFTTYWMH (SEQ ID NO:541). In one embodiment, one or more of the CDRs (or all of the CDRs together) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the amino acid sequence shown in Table 1 or the amino acid sequence encoded by the nucleotide sequence shown in Table 1.

[0308] In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO:501, a VHCDR2 amino acid sequence of SEQ ID NO:502, and a VHCDR3 amino acid sequence of SEQ ID NO:503; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO:510, a VLCDR2 amino acid sequence of SEQ ID NO:511, and a VLCDR3 amino acid sequence of SEQ ID NO:512, respectively, as disclosed in Table 1.

[0309] In one embodiment, the antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO:524, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO:525, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO:526; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO:529, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO:530, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO:531, each of which are disclosed in Table 1.

[0310] In certain embodiments, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:506, or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:506. In certain embodiments, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO:520, or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:520. In certain embodiments, the anti-PD-1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO:516, or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:516. In certain embodiments, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:506, and a VL comprising the amino acid sequence of SEQ ID NO:520. In certain embodiments, the anti-PD-1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:506, and a VL comprising the amino acid sequence of SEQ ID NO:516.

[0311] In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:507, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:507. In certain embodiments, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO:521 or 517, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:521 or 517. In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:507, and a VL encoded by the nucleotide sequence of SEQ ID NO:521 or 517.

[0312] In certain embodiments, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:508, or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:508. In certain embodiments, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO:522, or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:522. In certain embodiments, the anti-PD-1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO:518, or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:518. In certain embodiments, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:508, and a light chain comprising the amino acid sequence of SEQ ID NO:522. In certain embodiments, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:508, and a light chain comprising the amino acid sequence of SEQ ID NO:518.

[0313] In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:509, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:509. In certain embodiments, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO:523 or 519, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:523 or 519. In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:509, and a light chain encoded by the nucleotide sequence of SEQ ID NO:523 or 519.

[0314] The antibody molecules described herein can be produced by the vectors, host cells and methods described in US2015 / 0210769, which is incorporated herein by reference in its entirety.

[0315] Table 1. Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules [Table 19]

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

[0316] Other Exemplary PD-1 Inhibitors In some embodiments, the anti-PD-1 antibody molecule is nivolumab (Bristol-Myers Squibb), also known as MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or OPDIVO®. Nivolumab (clone 5C4) and other anti-PD-1 antibodies are disclosed in US8,008,449 and WO2006 / 121168, which are incorporated by reference in their entireties. In some embodiments, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), heavy or light chain variable region sequences, or heavy or light chain sequences of nivolumab, e.g., as disclosed in Table 2.

[0317] In one embodiment, the anti-PD-1 antibody molecule is pembrolizumab (Merck&Co), also known as lambrolizumab, MK-3475, MK03475, SCH-900475, or KEYTRUDA®. Pembrolizumab and other anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, US8,354,509, and WO2009 / 114335, which are incorporated by reference in their entireties. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), a heavy or light chain variable region sequence, or a heavy or light chain sequence of pembrolizumab, e.g., as disclosed in Table 2.

[0318] In one embodiment, the anti-PD-1 antibody molecule is pidilizumab (CureTech), also known as CT-011. Pidilizumab and other anti-PD-1 antibodies are disclosed in Rosenblatt, J. et al. (2011) J Immunotherapy 34(5): 409-18, US7,695,715, US7,332,582, and US8,686,119, which are incorporated by reference in their entireties. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), a heavy or light chain variable region sequence, or a heavy or light chain sequence of pidilizumab, e.g., as disclosed in Table 2.

[0319] In one embodiment, the anti-PD-1 antibody molecule is MEDI0680 (Medimmune), also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US9,205,148 and WO2012 / 145493, which are incorporated by reference in their entireties. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy or light chain variable region sequence, or the heavy or light chain sequences of MEDI0680.

[0320] In some embodiments, the anti-PD-1 antibody molecule is REGN2810 (Regeneron). In some embodiments, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy or light chain variable region sequence, or the heavy or light chain sequences of REGN2810.

[0321] In some embodiments, the anti-PD-1 antibody molecule is PF-06801591 (Pfizer). In some embodiments, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), a heavy or light chain variable region sequence, or a heavy or light chain sequence of PF-06801591.

[0322] In some embodiments, the anti-PD-1 antibody molecule is BGB-A317 or BGB-108 (Beigene). In some embodiments, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy or light chain variable region sequence, or the heavy or light chain sequences of BGB-A317 or BGB-108.

[0323] In some embodiments, the anti-PD-1 antibody molecule is INCSHR1210 (Incyte), also known as INCSHR01210 or SHR-1210. In some embodiments, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy or light chain variable region sequence, or the heavy or light chain sequences of INCSHR1210.

[0324] In some embodiments, the anti-PD-1 antibody molecule is TSR-042 (Tesaro), also known as ANB011. In some embodiments, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences together), the heavy or light chain variable region sequence, or the heavy or light chain sequences of TSR-042.

[0325] Further known anti-PD-1 antibodies include those described in, e.g., WO2015 / 112800, WO2016 / 092419, WO2015 / 085847, WO2014 / 179664, WO2014 / 194302, WO2014 / 209804, WO2015 / 200119, US8,735,553, US7,488,802, US8,927,697, US8,993,731, and US9,102,727, which are incorporated by reference in their entireties.

[0326] In certain embodiments, the anti-PD-1 antibody is an antibody that competes for binding with and / or binds to the same epitope on PD-1 as one of the anti-PD-1 antibodies described herein.

[0327] In some embodiments, the PD-1 inhibitor is a peptide that inhibits the PD-1 signaling pathway, e.g., as described in US8,907,053, which is incorporated herein by reference in its entirety. In some embodiments, the PD-1 inhibitor is an immunoadhesin (an immunoadhesin that includes an extracellular or PD-1 binding portion of PD-L1 or PD-L2), e.g., fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the PD-1 inhibitor is AMP-224 (e.g., B7-DCIg (Amplimmune), as disclosed in WO2010 / 027827 and WO2011 / 066342, which are incorporated herein by reference in their entirety).

[0328] Table 2. Amino acid sequences of other exemplary anti-PD-1 antibody molecules [Table 30] [Table 31]

[0329] PD-L1 inhibitors In certain embodiments, the anti-LAG-3 antibody molecules described herein are administered in combination with a PD-L1 inhibitor. In certain embodiments, the PD-L1 inhibitor is selected from FAZ053 (Novartis), atezolizumab (Genentech / Roche), avelumab (Merck Serono and Pfizer), durvalumab (Medimmune / AstraZeneca) or BMS-936559 (Bristol-Myers Squibb).

[0330] Exemplary PD-L1 Inhibitors In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule as disclosed in US2016 / 0108123, published April 21, 2016, entitled "Antibody Molecules to PD-L1 and Uses Thereof," which is incorporated by reference in its entirety.

[0331] In some embodiments, the anti-PD-L1 antibody molecule comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or collectively all the CDRs) from a heavy and light chain variable region comprising an amino acid sequence set forth in Table 3, or an amino acid sequence encoded by a nucleotide sequence set forth in Table 3 (e.g., the heavy and light chain variable region sequences of BAP058-Clone O or BAP058-Clone N disclosed in Table 3). In some embodiments, the CDRs follow the Kabat definition (e.g., as presented in Table 3). In some embodiments, the CDRs follow the Chothia definition (e.g., as presented in Table 3). In some embodiments, the CDRs follow a combined CDR definition of both Kabat and Chothia (e.g., as presented in Table 3). In some embodiments, the combined Kabat and Chothia CDRs of VH CDR1 comprises the amino acid sequence GYTFTSYWMY (SEQ ID NO:647). In one embodiment, one or more of the CDRs (or all of the CDRs together) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the amino acid sequence shown in Table 3 or the amino acid sequence encoded by the nucleotide sequence shown in Table 3.

[0332] In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:601, the VHCDR2 amino acid sequence of SEQ ID NO:602, and the VHCDR3 amino acid sequence of SEQ ID NO:603; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:609, the VLCDR2 amino acid sequence of SEQ ID NO:610, and the VLCDR3 amino acid sequence of SEQ ID NO:611, respectively, as disclosed in Table 3.

[0333] In one embodiment, the anti-PD-L1 antibody molecule comprises a VH that comprises a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO:628, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO:629, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO:630; and a VL that comprises a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO:633, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO:634, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO:635, each of which are disclosed in Table 3.

[0334] In some embodiments, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:606, or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:606. In some embodiments, the anti-PD-L1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO:616, or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:616. In some embodiments, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:620, or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:620. In some embodiments, the anti-PD-L1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO:624, or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:624. In some embodiments, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:606, and a VL comprising the amino acid sequence of SEQ ID NO:616. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:620, and a VL comprising the amino acid sequence of SEQ ID NO:624.

[0335] In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:607 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:607. In certain embodiments, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO:617 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:617. In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:621 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:621. In certain embodiments, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO:625 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:625. In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:607, and a VL encoded by the nucleotide sequence of SEQ ID NO:617. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:621, and a VL encoded by the nucleotide sequence of SEQ ID NO:625.

[0336] In some embodiments, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:608, or an amino acid sequence at least 85%, 90%, 95% or more identical to SEQ ID NO:608. In some embodiments, the anti-PD-L1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO:618, or an amino acid sequence at least 85%, 90%, 95% or more identical to SEQ ID NO:618. In some embodiments, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:622, or an amino acid sequence at least 85%, 90%, 95% or more identical to SEQ ID NO:622. In some embodiments, the anti-PD-L1 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO:626, or an amino acid sequence at least 85%, 90%, 95% or more identical to SEQ ID NO:626. In some embodiments, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:608, and a light chain comprising the amino acid sequence of SEQ ID NO:618. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:622, and a light chain comprising the amino acid sequence of SEQ ID NO:626.

[0337] In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:615 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:615. In certain embodiments, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO:619 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:619. In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:623 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:623. In certain embodiments, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO:627 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:627. In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:615, and a light chain encoded by the nucleotide sequence of SEQ ID NO:619. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:623 and a light chain encoded by the nucleotide sequence of SEQ ID NO:627.

[0338] The antibody molecules described herein can be produced by the vectors, host cells and methods described in US2016 / 0108123, which is incorporated herein by reference in its entirety.

[0339] Table 3. Amino acid and nucleotide sequences of exemplary anti-PD-L1 antibody molecules [Table 32] [Table 33] [Table 34] [Table 35] [Table 36] [Table 37] [Table 38] [Table 39] [Table 40]

[0340] Other Exemplary PD-L1 Inhibitors In one embodiment, the anti-PD-L1 antibody molecule is atezolizumab (Genentech / Roche), also known as MPDL3280A, RG7446, RO5541267, YW243.55.S70, or TECENTRIQ™. Atezolizumab and other anti-PD-L1 antibodies are disclosed in US8,217,149, the entire contents of which are incorporated herein by reference. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), a heavy or light chain variable region sequence, or a heavy or light chain sequence of atezolizumab, e.g., as disclosed in Table 4.

[0341] In one embodiment, the anti-PD-L1 antibody molecule is avelumab (Merck Serono and Pfizer), also known as MSB0010718C. Avelumab and other anti-PD-L1 antibodies are disclosed in WO2013 / 079174, which is incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), a heavy or light chain variable region sequence, or a heavy or light chain sequence of avelumab, e.g., as disclosed in Table 4.

[0342] In one embodiment, the anti-PD-L1 antibody molecule is durvalumab (Medimmune / AstraZeneca), also known as MEDI4736. Durvalumab and other anti-PD-L1 antibodies are disclosed in US 8,779,108, which is incorporated herein by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), a heavy or light chain variable region sequence, or a heavy or light chain sequence of durvalumab, e.g., as disclosed in Table 4.

[0343] In one embodiment, the anti-PD-L1 antibody molecule is BMS-936559 (Bristol-Myers Squibb), also known as MDX-1105 or 12A4. BMS-936559 and other anti-PD-L1 antibodies are disclosed in US 7,943,743 and WO 2015 / 081158, which are incorporated by reference in their entireties. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), a heavy or light chain variable region sequence, or a heavy or light chain sequence of BMS-936559, e.g., as disclosed in Table 4.

[0344] Further known anti-PD-L1 antibodies include those described in, for example, WO2015 / 181342, WO2014 / 100079, WO2016 / 000619, WO2014 / 022758, WO2014 / 055897, WO2015 / 061668, WO2013 / 079174, WO2012 / 145493, WO2015 / 112805, WO2015 / 109124, WO2015 / 195163, US8,168,179, US8,552,154, US8,460,927, and US9,175,082, which are incorporated by reference in their entireties.

[0345] In one embodiment, the anti-PD-L1 antibody is an antibody that competes for binding with and / or binds to the same epitope on PD-L1 as one of the anti-PD-L1 antibodies described herein.

[0346] Table 4. Amino acid sequences of other exemplary anti-PD-L1 antibody molecules [Table 41] [Table 42]

[0347] TIM-3 inhibitors In certain embodiments, the anti-LAG-3 antibody molecules described herein are administered in combination with a TIM-3 inhibitor. In certain embodiments, the TIM-3 inhibitor is MGB453 (Novartis) or TSR-022 (Tesaro).

[0348] Exemplary TIM-3 Inhibitors In some embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule as disclosed in US2015 / 0218274, published Aug. 6, 2015, entitled "Antibody Molecules to TIM-3 and Uses Thereof," which is incorporated herein by reference in its entirety.

[0349] In certain embodiments, the anti-TIM-3 antibody molecule comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence set forth in Table 7 or an amino acid sequence encoded by a nucleotide sequence set forth in Table 7 (e.g., the heavy and light chain variable region sequences of ABTIM3-hum11 or ABTIM3-hum03 disclosed in Table 7). In certain embodiments, the CDRs follow the Kabat definition (e.g., as presented in Table 7). In certain embodiments, the CDRs follow the Chothia definition (e.g., as presented in Table 7). In certain embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the amino acid sequence set forth in Table 7 or the amino acid sequence encoded by the nucleotide sequence set forth in Table 7.

[0350] In certain embodiments, an anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:801, the VHCDR2 amino acid sequence of SEQ ID NO:802, and the VHCDR3 amino acid sequence of SEQ ID NO:803; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:810, the VLCDR2 amino acid sequence of SEQ ID NO:811, and the VLCDR3 amino acid sequence of SEQ ID NO:812, respectively, as disclosed in Table 7. In certain embodiments, an anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO:801, the VHCDR2 amino acid sequence of SEQ ID NO:820, and the VHCDR3 amino acid sequence of SEQ ID NO:803; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:810, the VLCDR2 amino acid sequence of SEQ ID NO:811, and the VLCDR3 amino acid sequence of SEQ ID NO:812, respectively, as disclosed in Table 7.

[0351] In certain embodiments, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:806 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:806. In certain embodiments, the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO:816 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:816. In certain embodiments, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:822 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:822. In certain embodiments, the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO:826 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:826. In certain embodiments, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:806, and a VL comprising the amino acid sequence of SEQ ID NO:816. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:822, and a VL comprising the amino acid sequence of SEQ ID NO:826.

[0352] In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:807 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:807. In certain embodiments, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO:817 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:817. In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:823 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:823. In certain embodiments, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO:827 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:827. In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:807, and a VL encoded by the nucleotide sequence of SEQ ID NO:817. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:823, and a VL encoded by the nucleotide sequence of SEQ ID NO:827.

[0353] In certain embodiments, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:808 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:808. In certain embodiments, the anti-TIM-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO:818 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:818. In certain embodiments, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:824 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:824. In certain embodiments, the anti-TIM-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO:828 or an amino acid sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:828. In certain embodiments, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:808, and a light chain comprising the amino acid sequence of SEQ ID NO:818. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:824 and a light chain comprising the amino acid sequence of SEQ ID NO:828.

[0354] In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:809 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:809. In certain embodiments, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO:819 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:819. In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:825 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:825. In certain embodiments, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO:829 or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:829. In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:809, and a light chain encoded by the nucleotide sequence of SEQ ID NO:819. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:825 and a light chain encoded by the nucleotide sequence of SEQ ID NO:829.

[0355] The antibody molecules described herein can be produced by the vectors, host cells and methods described in US2015 / 0218274, which is incorporated herein by reference in its entirety.

[0356] Table 7. Amino acid and nucleotide sequences of exemplary anti-TIM-3 antibody molecules [Table 43] [Table 44] [Table 45] [Table 46] [Table 47] [Table 48] [Table 49] [Table 50]

[0357] Other Exemplary TIM-3 Inhibitors In some embodiments, the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio / Tesaro). In some embodiments, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), heavy or light chain variable region sequences, or heavy or light chain sequences of TSR-022. In some embodiments, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), heavy or light chain variable region sequences, or heavy or light chain sequences of APE5137 or APE5121, e.g., as disclosed in Table 8. APE5137, APE5121, and other anti-TIM-3 antibodies are disclosed in WO2016 / 161270, the entire contents of which are incorporated herein by reference.

[0358] In some embodiments, the anti-TIM-3 antibody molecule is antibody clone F38-2E2. In some embodiments, the anti-TIM-3 antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences together), the heavy or light chain variable region sequence, or the heavy or light chain sequences of F38-2E2.

[0359] Further known anti-TIM-3 antibodies include, for example, the antibodies described in WO2016 / 111947, WO2016 / 071448, WO2016 / 144803, US8,552,156, US8,841,418 and US9,163,087, which are incorporated by reference in their entireties.

[0360] In certain embodiments, the anti-TIM-3 antibody is an antibody that competes for binding with and / or binds to the same epitope on TIM-3 as one of the anti-TIM-3 antibodies described herein.

[0361] Table 8. Amino acid sequences of other exemplary anti-TIM-3 antibody molecules [Table 51]

[0362] GITR agonists In certain embodiments, the anti-LAG-3 antibody molecule described herein is administered in combination with a GITR agonist. In some embodiments, the GITR agonist is GWN323 (NVS), BMS-986156, MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte / Agenus), AMG 228 (Amgen) or INBRX-110 (Inhibrx).

[0363] Exemplary GITR Agonists In one embodiment, the GITR agonist is an anti-GITR antibody molecule. In one embodiment, the GITR agonist is an anti-GITR antibody molecule described in WO2016 / 057846, published April 14, 2016, entitled "Compositions and Methods of Use for Augmented Immune Response and Cancer Therapy," which is incorporated herein by reference in its entirety.

[0364] In certain embodiments, the anti-GITR antibody molecule comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from heavy and light chain variable regions comprising an amino acid sequence set forth in Table 9 or an amino acid sequence encoded by a nucleotide sequence set forth in Table 9 (e.g., the heavy and light chain variable region sequences of MAB7 disclosed in Table 9). In certain embodiments, the CDRs follow the Kabat definition (e.g., as presented in Table 9). In certain embodiments, the CDRs follow the Chothia definition (e.g., as presented in Table 9). In certain embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the amino acid sequence set forth in Table 9 or the amino acid sequence encoded by the nucleotide sequence set forth in Table 9.

[0365] In one embodiment, the anti-GITR antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO:909, a VHCDR2 amino acid sequence of SEQ ID NO:911, and a VHCDR3 amino acid sequence of SEQ ID NO:913; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO:914, a VLCDR2 amino acid sequence of SEQ ID NO:916, and a VLCDR3 amino acid sequence of SEQ ID NO:918, each of which are disclosed in Table 9.

[0366] In certain embodiments, an anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:901, or an amino acid sequence at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO:901. In certain embodiments, an anti-GITR antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO:902, or an amino acid sequence at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO:902. In certain embodiments, an anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO:901, and a VL comprising the amino acid sequence of SEQ ID NO:902.

[0367] In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:905, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:905. In certain embodiments, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO:906, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:906. In certain embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:905, and a VL encoded by the nucleotide sequence of SEQ ID NO:906.

[0368] In certain embodiments, the anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:903, or an amino acid sequence at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO:903. In certain embodiments, the anti-GITR antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO:904, or an amino acid sequence at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO:904. In certain embodiments, the anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:903, and a light chain comprising the amino acid sequence of SEQ ID NO:904.

[0369] In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:907, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:907. In certain embodiments, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO:908, or a nucleotide sequence at least 85%, 90%, 95% or 99% or more identical to SEQ ID NO:908. In certain embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:907, and a light chain encoded by the nucleotide sequence of SEQ ID NO:908.

[0370] The antibody molecules described herein can be produced by the vectors, host cells and methods described in WO2016 / 057846, which is incorporated herein by reference in its entirety.

[0371] Table 9: Amino acid and nucleotide sequences of exemplary anti-GITR antibody molecules [Table 52] [Table 53] [Table 54]

[0372] Other Exemplary GITR Agonists In one embodiment, the anti-GITR antibody molecule is BMS-986156 (Bristol-Myers Squibb), also known as BMS 986156 or BMS986156. BMS-986156 and other anti-GITR antibodies are disclosed, for example, in US9,228,016 and WO2016 / 196792, which are incorporated herein by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), heavy or light chain variable region sequences, or heavy or light chain sequences of BMS-986156, for example, as disclosed in Table 10.

[0373] In some embodiments, the anti-GITR antibody molecule is MK-4166 or MK-1248 (Merck). MK-4166, MK-1248 and other anti-GITR antibodies are disclosed, for example, in US8,709,424, WO2011 / 028683, WO2015 / 026684 and Mahne et al. Cancer Res. 2017; 77(5):1108-1118, which are incorporated herein by reference in their entirety. In some embodiments, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), heavy or light chain variable region sequences, or heavy or light chain sequences of MK-4166 or MK-1248.

[0374] In one embodiment, the anti-GITR antibody molecule is TRX518 (Leap Therapeutics). TRX518 and other anti-GITR antibodies are disclosed, for example, in US7,812,135, US8,388,967, US9,028,823, WO2006 / 105021 and Ponte J et al. (2010) Clinical Immunology; 135:S96, which are incorporated herein by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences taken together), heavy or light chain variable region sequences, or heavy or light chain sequences of TRX518.

[0375] In one embodiment, the anti-GITR antibody molecule is INCAGN1876 (Incyte / Agenus). INCAGN1876 and other anti-GITR antibodies are disclosed, for example, in US2015 / 0368349 and WO2015 / 184099, which are incorporated herein by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences taken together), the heavy or light chain variable region sequence, or the heavy or light chain sequence of INCAGN1876.

[0376] In one embodiment, the anti-GITR antibody molecule is AMG 228 (Amgen). AMG 228 and other anti-GITR antibodies are disclosed, for example, in US9,464,139 and WO2015 / 031667, which are incorporated by reference in their entireties. In one embodiment, the anti-GITR antibody molecule comprises one or more of the CDR sequences (or all of the CDR sequences collectively), the heavy or light chain variable region sequence, or the heavy or light chain sequence of AMG 228.

[0377] In one embodiment, the anti-GITR antibody molecule is INBRX-110 (Inhibrx). INBRX-110 and other anti-GITR antibodies are disclosed, for example, in US2017 / 0022284 and WO2017 / 015623, which are incorporated herein by reference in their entirety. In one embodiment, the GITR agonist comprises one or more of the CDR sequences (or all of the CDR sequences taken together), heavy or light chain variable region sequences, or heavy or light chain sequences of INBRX-110.

[0378] In some embodiments, the GITR agonist (e.g., fusion protein) is MEDI 1873 (Medimmune), also known as MEDI1873. MEDI 1873 and other GITR agonists are disclosed, for example, in US2017 / 0073386, WO2017 / 025610, and Ross et al. Cancer Res 2016; 76(14 Suppl): Abstract nr 561, which are incorporated herein by reference in their entireties. In some embodiments, the GITR agonist comprises one or more of the IgG Fc domain, functional multimerization domain, and receptor binding domain of the glucocorticoid-induced TNF receptor ligand (GITRL) of MEDI 1873.

[0379] Further known GITR agonists (e.g., anti-GITR antibodies) include, for example, those described in WO2016 / 054638, the entire contents of which are incorporated herein by reference.

[0380] In certain embodiments, the anti-GITR antibody is an antibody that competes for binding with and / or binds to the same epitope on GITR as one of the anti-GITR antibodies described herein.

[0381] In some embodiments, the GITR agonist is a peptide that activates the GITR signaling pathway. In some embodiments, the GITR agonist is an immunoadhesin binding fragment (e.g., an immunoadhesin binding fragment that includes an extracellular or GITR binding portion of GITRL) fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).

[0382] Table 10: Amino acid sequences of other exemplary anti-GITR antibody molecules [Table 55]

[0383] IL15 / IL-15Ra complex In certain embodiments, the anti-LAG-3 antibody molecules described herein are administered in combination with an IL-15 / IL-15Ra complex. In certain embodiments, the IL-15 / IL-15Ra complex is selected from NIZ985 (Novartis), ATL-803 (Altor) or CYP0150 (Cytune).

[0384] Exemplary IL-15 / IL-15Ra Complexes In one embodiment, the IL-15 / IL-15Ra complex comprises human IL-15 complexed with a soluble form of human IL-15Ra. The complex may comprise IL-15 covalently or non-covalently bound to a soluble form of IL-15Ra. In a particular embodiment, the human IL-15 is non-covalently bound to a soluble form of IL-15Ra. In a particular embodiment, the human IL-15 of the composition comprises the amino acid sequence of SEQ ID NO: 1001 in Table 11, and the soluble form of human IL-15Ra comprises the amino acid sequence of SEQ ID NO: 1002 in Table 11, as described in WO2014 / 066527, which is incorporated herein by reference in its entirety. The molecules described herein can be produced by the vectors, host cells and methods described in WO2007 / 084342, which is incorporated herein by reference in its entirety.

[0385] Table 11. Amino acid and nucleotide sequences of exemplary IL-15 / IL-15Ra complexes [Table 56]

[0386] Other Exemplary IL-15 / IL-15Ra Complexes In one embodiment, the IL-15 / IL-15Ra complex is ALT-803, which is an IL-15 / IL-15Ra Fc fusion protein (IL-15N72D:IL-15RaSu / Fc soluble complex). ALT-803 is disclosed in WO2008 / 143794, which is incorporated herein by reference in its entirety. In one embodiment, the IL-15 / IL-15Ra Fc fusion protein comprises a sequence disclosed in Table 12.

[0387] In one embodiment, the IL-15 / IL-15Ra complex comprises IL-15 (CYP0150, Cytune) fused to the IL-15Ra sushi domain. The IL-15Ra sushi domain refers to the domain that begins with the first cysteine ​​residue after the signal peptide of IL-15Ra and ends with the fourth cysteine ​​residue after said signal peptide. Complexes of IL-15 fused to the IL-15Ra sushi domain are disclosed in WO2007 / 04606 and WO2012 / 175222, which are incorporated herein by reference in their entirety. In one embodiment, the IL-15 / IL-15Ra sushi domain fusion comprises a sequence disclosed in Table 12.

[0388] Table 12. Amino acid sequences of other exemplary IL-15 / IL-15Ra complexes [Table 57]

[0389] Pharmaceutical Compositions, Formulations, and Kits In another aspect, the present disclosure provides compositions, e.g., pharma- ceutically acceptable compositions, comprising the anti-LAG-3 antibody molecules described herein, formulated together with a pharma- ceutically acceptable carrier. As used herein, a "pharma- ceutically acceptable carrier" includes any and all solvents, dispersion media, isotonic and absorption delaying agents, etc. that are physiologically compatible. The carrier can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion).

[0390] The compositions described herein can be in various forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes and suppositories. The preferred form depends on the intended administration mechanism and therapeutic application. A typical preferred composition is in the form of an injectable or infusible solution. A preferred administration mechanism is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In a preferred embodiment, the antibody is administered by intravenous infusion or injection. In another preferred embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0391] The phrases "parenteral administration" and "administered parenterally", as used herein, mean mechanisms of administration other than enteral and topical administration, usually by injection, including, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion.

[0392] Therapeutic compositions should typically be sterile and stable under the conditions of manufacture and storage. The compositions should be formulated as solutions, microemulsions, dispersions, liposomes or other ordered structures suitable for high antibody concentrations. Sterile injectable solutions can be prepared by incorporating the active compound (e.g., antibody or antibody moiety) in the required amount in an appropriate solvent with one or a combination of ingredients listed above, as required, followed by sterile filtration. In general, dispersions are prepared by incorporating the active compound in a sterile vehicle containing a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredients from a previously sterile-filtered solution thereof. The proper fluidity of the solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

[0393] The anti-LAG-3 antibody molecules or compositions described herein can be formulated into a formulation (e.g., a dosage formulation or dosage form) suitable for administration (e.g., intravenous administration) to a subject as described herein. The formulations described herein can be liquid formulations, lyophilized formulations, or reconstituted formulations.

[0394] In certain embodiments, the formulation is a liquid formulation. In some embodiments, the formulation (e.g., a liquid formulation) comprises an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) and a buffer.

[0395] In some embodiments, the formulation (e.g., a liquid formulation) comprises an anti-LAG-3 antibody molecule present in a concentration of 25 mg / mL to 250 mg / mL, e.g., 50 mg / mL to 200 mg / mL, 60 mg / mL to 180 mg / mL, 70 mg / mL to 150 mg / mL, 80 mg / mL to 120 mg / mL, 90 mg / mL to 110 mg / mL, 50 mg / mL to 150 mg / mL, 50 mg / mL to 100 mg / mL, 150 mg / mL to 200 mg / mL, or 100 mg / mL to 200 mg / mL, e.g., 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL. In certain embodiments, the anti-LAG-3 antibody molecule is present at a concentration of 80 mg / mL to 120 mg / mL, for example, 100 mg / mL.

[0396] In some embodiments, the formulation (e.g., liquid formulation) includes a buffer containing histidine (e.g., a histidine buffer). In certain embodiments, the buffer (e.g., histidine buffer) is present at a concentration of 1 mM to 100 mM, e.g., 2 mM to 50 mM, 5 mM to 40 mM, 10 mM to 30 mM, 15 to 25 mM, 5 mM to 40 mM, 5 mM to 30 mM, 5 mM to 20 mM, 5 mM to 10 mM, 40 mM to 50 mM, 30 mM to 50 mM, 20 mM to 50 mM, 10 mM to 50 mM, or 5 mM to 50 mM, e.g., 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM. In certain embodiments, the buffer (e.g., histidine buffer) is present at a concentration of 15 mM to 25 mM, e.g., 20 mM. In other embodiments, the buffer (e.g., histidine buffer) has a pH of 4 to 7, e.g., 5 to 6, e.g., 5, 5.5 or 6. In certain embodiments, the buffer (e.g., histidine buffer) has a pH of 5 to 6, e.g., 5.5. In certain embodiments, the buffer comprises a histidine buffer at a concentration of 15 mM to 25 mM (e.g., 20 mM) and has a pH of 5 to 6 (e.g., 5.5). In certain embodiments, the buffer comprises histidine and histidine-HCl.

[0397] In one embodiment, the formulation (e.g., a liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80-120 mg / mL, e.g., 100 mg / mL; and a buffer comprising a histidine buffer at a concentration of 15 mM-25 mM (e.g., 20 mM), and has a pH of 5-6 (e.g., 5.5).

[0398] In some embodiments, the formulation (e.g., a liquid formulation) further comprises a carbohydrate. In certain embodiments, the carbohydrate is sucrose. In one embodiment, the carbohydrate (e.g., sucrose) is present at a concentration of 50 mM to 500 mM, e.g., 100 mM to 400 mM, 150 mM to 300 mM, 180 mM to 250 mM, 200 mM to 240 mM, 210 mM to 230 mM, 100 mM to 300 mM, 100 mM to 250 mM, 100 mM to 200 mM, 100 mM to 150 mM, 300 mM to 400 mM, 200 mM to 400 mM, or 100 mM to 400 mM, e.g., 100 mM, 150 mM, 180 mM, 200 mM, 220 mM, 250 mM, 300 mM, 350 mM, or 400 mM. In some embodiments, the formulation comprises carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, e.g., 220 mM.

[0399] In one embodiment, the formulation (e.g., a liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80-120 mg / mL, e.g., 100 mg / mL; a buffering agent comprising a histidine buffer at a concentration of 15 mM-25 mM (e.g., 20 mM) and having a pH of 5-6 (e.g., 5.5); and a carbohydrate or sucrose present at a concentration of 200 mM-250 mM, e.g., 220 mM.

[0400] In some embodiments, the formulation (e.g., a liquid formulation) further comprises a surfactant. In certain embodiments, the surfactant is polysorbate 20. In one embodiment, the surfactant or polysorbate 20 is present at a concentration of 0.005% to 0.1% (w / w), e.g., 0.01% to 0.08%, 0.02% to 0.06%, 0.03% to 0.05%, 0.01% to 0.06%, 0.01% to 0.05%, 0.01% to 0.03%, 0.06% to 0.08%, 0.04% to 0.08%, or 0.02% to 0.08% (w / w), e.g., 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1% (w / w). In some embodiments, the formulation comprises a surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, e.g., 0.04% (w / w).

[0401] In one embodiment, the formulation (e.g., a liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80-120 mg / mL, e.g., 100 mg / mL; a buffering agent comprising a histidine buffer at a concentration of 15 mM-25 mM (e.g., 20 mM) and having a pH of 5-6 (e.g., 5.5); a carbohydrate or sucrose present at a concentration of 200 mM-250 mM, e.g., 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.03%-0.05%, e.g., 0.04% (w / w).

[0402] In one embodiment, the formulation (e.g., a liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 100 mg / mL; a buffer comprising a histidine buffer (e.g., histidine / histidine-HCL) at a concentration of 20 mM and having a pH of 5.5; a carbohydrate or sucrose present at a concentration of 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.04% (w / w).

[0403] In certain embodiments, the liquid formulation is prepared by diluting a formulation comprising an anti-LAG-3 antibody molecule described herein. For example, the drug substance formulation can be diluted with a solution comprising one or more excipients (e.g., concentrated excipients). In certain embodiments, the solution comprises one, two or all of histidine, sucrose or polysorbate 20. In certain embodiments, the solution comprises the same excipient(s) as the drug substance formulation. Exemplary excipients include, but are not limited to, amino acids (e.g., histidine), carbohydrates (e.g., sucrose) or surfactants (e.g., polysorbate 20). In certain embodiments, the liquid formulation is not a reconstituted lyophilized formulation. In other embodiments, the liquid formulation is a reconstituted lyophilized formulation. In certain embodiments, the formulation is stored as a liquid. In other embodiments, the formulation is prepared as a liquid and then dried, for example, by lyophilization or spray drying, prior to storage.

[0404] In certain embodiments, 0.5 mL to 10 mL (e.g., 0.5 mL to 8 mL, 1 mL to 6 mL, or 2 mL to 5 mL, e.g., 1 mL, 1.2 mL, 1.5 mL, 2 mL, 3 mL, 4 mL, 4.5 mL, or 5 mL) of the liquid formulation is filled per container (e.g., vial). In other embodiments, the liquid formulation is filled into the container (e.g., vial) such that an extractable volume of at least 1 mL (e.g., at least 1.2 mL, at least 1.5 mL, at least 2 mL, at least 3 mL, at least 4 mL, or at least 5 mL) of the liquid formulation can be removed per container (e.g., vial). In certain embodiments, the liquid formulation is extracted from the container (e.g., vial) without dilution at the clinical site. In certain embodiments, the liquid formulation is diluted from the drug substance formulation and extracted from the container (e.g., vial) at the clinical site. In certain embodiments, the formulation (eg, a liquid formulation) is injected into the infusion bag, for example, within one hour (eg, within 45 minutes, 30 minutes, or 15 minutes) prior to beginning the infusion into the patient.

[0405] The formulations described herein can be stored in a container. The container used for any of the formulations described herein can include, for example, a vial, and optionally a stopper, a cap, or both. In certain embodiments, the vial is a glass vial, for example, a 6R white glass vial. In other embodiments, the stopper is a rubber stopper, for example, a gray rubber stopper. In other embodiments, the cap is a flip-off cap, for example, an aluminum flip-off cap. In some embodiments, the container includes a 6R white glass vial, a gray rubber stopper, and an aluminum flip-off cap. In some embodiments, the container (e.g., a vial) is for single-use containers. In certain embodiments, 25 mg / mL to 250 mg / mL, e.g., 50 mg / mL to 200 mg / mL, 60 mg / mL to 180 mg / mL, 70 mg / mL to 150 mg / mL, 80 mg / mL to 120 mg / mL, 90 mg / mL to 110 mg / mL, 50 mg / mL to 150 mg / mL, 50 mg / mL to 100 mg / mL, 150 mg / mL to 200 mg / mL, or 100 mg / mL to 200 mg / mL, e.g., 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL, of the anti-LAG-3 antibody molecule is present in the container (e.g., a vial).

[0406] In some embodiments, the formulation is a lyophilized formulation. In certain embodiments, the lyophilized formulation is lyophilized or dried from a liquid formulation comprising the anti-LAG-3 antibody molecule described herein. For example, 1-5 mL, e.g., 1-2 mL of the liquid formulation can be filled into each container (e.g., vial) and lyophilized.

[0407] In certain embodiments, the formulation is a reconstituted formulation. In certain embodiments, the reconstituted formulation is reconstituted from a lyophilized formulation comprising an anti-LAG-3 antibody molecule as described herein. For example, the reconstituted formulation can be prepared by dissolving the lyophilized formulation in a diluent such that the protein is dispersed in the reconstituted formulation. In certain embodiments, the lyophilized formulation is reconstituted with 1 mL to 5 mL, e.g., 1 mL to 2 mL, e.g., 1.2 mL, of water for injection or buffer. In certain embodiments, the lyophilized formulation is reconstituted with 1 mL to 2 mL of water for injection, e.g., at a clinical site.

[0408] In certain embodiments, the reconstituted formulation comprises an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule described herein) and a buffer.

[0409] In certain embodiments, the reconstituted formulation comprises anti-LAG-3 antibody molecules present in a concentration of 25 mg / mL to 250 mg / mL, e.g., 50 mg / mL to 200 mg / mL, 60 mg / mL to 180 mg / mL, 70 mg / mL to 150 mg / mL, 80 mg / mL to 120 mg / mL, 90 mg / mL to 110 mg / mL, 50 mg / mL to 150 mg / mL, 50 mg / mL to 100 mg / mL, 150 mg / mL to 200 mg / mL, or 100 mg / mL to 200 mg / mL, e.g., 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, or 150 mg / mL. In certain embodiments, the anti-LAG-3 antibody molecule is present at a concentration of 80 mg / mL to 120 mg / mL, for example, 100 mg / mL.

[0410] In certain embodiments, the reconstituted formulation comprises a buffer comprising histidine (e.g., a histidine buffer). In certain embodiments, the buffer (e.g., a histidine buffer) is present at a concentration of 1 mM to 100 mM, e.g., 2 mM to 50 mM, 5 mM to 40 mM, 10 mM to 30 mM, 15 to 25 mM, 5 mM to 40 mM, 5 mM to 30 mM, 5 mM to 20 mM, 5 mM to 10 mM, 40 mM to 50 mM, 30 mM to 50 mM, 20 mM to 50 mM, 10 mM to 50 mM, or 5 mM to 50 mM, e.g., 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM. In certain embodiments, the buffer (e.g., histidine buffer) is present at a concentration of 15 mM to 25 mM, e.g., 20 mM. In other embodiments, the buffer (e.g., histidine buffer) has a pH of 4 to 7, e.g., 5 to 6, e.g., 5, 5.5 or 6. In certain embodiments, the buffer (e.g., histidine buffer) has a pH of 5 to 6, e.g., 5.5. In certain embodiments, the buffer comprises a histidine buffer at a concentration of 15 mM to 25 mM (e.g., 20 mM) and has a pH of 5 to 6 (e.g., 5.5). In certain embodiments, the buffer comprises histidine and histidine-HCl.

[0411] In one embodiment, the reconstituted formulation comprises anti-LAG-3 antibody molecules present at a concentration of 80-120 mg / mL, e.g., 100 mg / mL; and a histidine buffer at a concentration of 15 mM-25 mM (e.g., 20 mM) and having a pH of 5-6 (e.g., 5.5).

[0412] In certain embodiments, the reconstituted formulation further comprises a carbohydrate, hi certain embodiments, the carbohydrate is sucrose. In one embodiment, the carbohydrate (e.g., sucrose) is present at a concentration of 50 mM to 500 mM, e.g., 100 mM to 400 mM, 150 mM to 300 mM, 180 mM to 250 mM, 200 mM to 240 mM, 210 mM to 230 mM, 100 mM to 300 mM, 100 mM to 250 mM, 100 mM to 200 mM, 100 mM to 150 mM, 300 mM to 400 mM, 200 mM to 400 mM, or 100 mM to 400 mM, e.g., 100 mM, 150 mM, 180 mM, 200 mM, 220 mM, 250 mM, 300 mM, 350 mM, or 400 mM. In some embodiments, the formulation comprises carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, e.g., 220 mM.

[0413] In one embodiment, the reconstituted formulation comprises anti-LAG-3 antibody molecules present at a concentration of 80-120 mg / mL, e.g., 100 mg / mL; a buffering agent comprising a histidine buffer at a concentration of 15 mM-25 mM (e.g., 20 mM) and having a pH of 5-6 (e.g., 5.5); and a carbohydrate or sucrose present at a concentration of 200 mM-250 mM, e.g., 220 mM.

[0414] In certain embodiments, the reconstituted formulation further comprises a surfactant. In certain embodiments, the surfactant is polysorbate 20. In one embodiment, the surfactant or polysorbate 20 is present at a concentration of 0.005% to 0.1% (w / w), e.g., 0.01% to 0.08%, 0.02% to 0.06%, 0.03% to 0.05%, 0.01% to 0.06%, 0.01% to 0.05%, 0.01% to 0.03%, 0.06% to 0.08%, 0.04% to 0.08%, or 0.02% to 0.08% (w / w), e.g., 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1% (w / w). In some embodiments, the formulation comprises a surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, e.g., 0.04% (w / w).

[0415] In one embodiment, the reconstituted formulation comprises anti-LAG-3 antibody molecules present at a concentration of 80-120 mg / mL, e.g., 100 mg / mL; a buffering agent comprising a histidine buffer at a concentration of 15 mM-25 mM (e.g., 20 mM) and having a pH of 5-6 (e.g., 5.5); a carbohydrate or sucrose present at a concentration of 200 mM-250 mM, e.g., 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.03%-0.05%, e.g., 0.04% (w / w).

[0416] In one embodiment, the reconstituted formulation comprises an anti-LAG-3 antibody molecule present at a concentration of 100 mg / mL; a buffer comprising a histidine buffer (e.g., histidine / histidine-HCL) at a concentration of 20 mM and having a pH of 5.5; a carbohydrate or sucrose present at a concentration of 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.04% (w / w).

[0417] In certain embodiments, the formulation is reconstituted such that an extractable volume of at least 1 mL (e.g., at least 1.2 mL, 1.5 mL, 2 mL, 2.5 mL, or 3 mL) of the reconstituted formulation can be removed from the container (e.g., vial) containing the reconstituted formulation. In certain embodiments, the formulation is reconstituted and / or extracted from the container (e.g., vial) at the clinical site. In certain embodiments, the formulation (e.g., the reconstituted formulation) is injected into an infusion bag, for example, within 1 hour (e.g., within 45 minutes, 30 minutes, or 15 minutes) prior to the start of the infusion into the patient.

[0418] Other exemplary buffers that can be used in the formulations described herein include, but are not limited to, arginine buffer, citrate buffer or phosphate buffer.Other exemplary carbohydrates that can be used in the formulations described herein include, but are not limited to, trehalose, mannitol, sorbitol or combinations thereof.The formulations described herein can also contain an agent for osmotic pressure, such as sodium chloride, and / or a stabilizer, such as an amino acid (e.g., glycine, arginine, methionine or combinations thereof).

[0419] The antibody molecule can be administered by a variety of methods known in the art, but for many therapeutic applications, the preferred route / mechanism of administration is intravenous injection or infusion. For example, the antibody molecule can be administered at a dose of about 35-440 mg / m 2 , typically about 70 to 310 mg / m 2 , more typically about 110-130 mg / m 2 In one embodiment, the antibody molecule can be administered by intravenous infusion at a rate of greater than 20 mg / min, e.g., 20-40 mg / min, typically 40 mg / min or more, to reach a dose of about 1-100 mg / m. 2 , preferably about 5 to 50 mg / m 2 , about 7~25mg / m 2 , more preferably about 10 mg / m 2The drug may be administered by intravenous infusion at a rate of less than 10 mg / min; preferably 5 mg / min or less, to reach a dose of 10 mg / min. As recognized by those skilled in the art, the route and / or mechanism of administration will vary depending on the desired results. In certain embodiments, the active compound can be prepared with a carrier that will protect the compound from rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, for example, Sustained and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978.

[0420] In certain embodiments, the antibody molecule can be orally administered, for example, with an inert diluent or an assimilable edible carrier. The compound (and other ingredients, if desired) can also be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or directly incorporated into the subject's diet. For oral therapeutic administration, the compound can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. To administer the compounds of the present invention by other than parenteral administration, it may be necessary to coat or co-administer the compound with a material to prevent its inactivation. Therapeutic compositions can also be administered by medical devices known in the art.

[0421] The dosage regimen is adjusted to provide the optimum desired response (e.g., therapeutic response). For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. For ease of administration and uniformity of dosage, it is particularly advantageous to formulate parenteral compositions in dosage unit form. Dosage unit form herein refers to physically discrete units suitable as unitary dosages for the subject to be treated; each unit contains a predetermined content of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit form of the present invention are dictated by and directly depend on (a) the unique characteristics of the active compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the technical field of compounding such active compound for the treatment of susceptibility in an individual.

[0422] An exemplary non-limiting range of a therapeutically or prophylactically effective amount of an antibody molecule is 50 mg to 1500 mg, typically 80 mg to 1200 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered by injection (e.g., subcutaneously or intravenously) at a dose (e.g., fixed dose) of about 60 mg to about 100 mg (e.g., about 80 mg), about 200 mg to about 300 mg (e.g., about 240 mg), or about 1000 mg to about 1500 mg (e.g., about 1200 mg). The dosing schedule (e.g., fixed dosing schedule) can vary, for example, from once a week to once every 2, 3, 4, 5, or 6 weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 60 mg to 100 mg (e.g., about 80 mg) once every two weeks or once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 200 mg to about 300 mg (e.g., about 240 mg) once every two weeks or once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 1000 mg to about 1500 mg (e.g., about 1200 mg) once every two weeks or once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 80 mg once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 240 mg once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 1200 mg once every four weeks. Without wishing to be bound by theory, in certain embodiments, a constant or fixed dosing may be beneficial to the patient, for example, to conserve drug supply and reduce pharmaceutical errors.

[0423] The antibody molecule is approximately 35-440 mg / m 2 , typically about 70 to 310 mg / m 2 , more typically about 110-130 mg / m 2 The drug may be administered by intravenous infusion at a rate of greater than 20 mg / min, e.g., 20-40 mg / min, typically 40 mg / min or greater, to reach a dose of about 110-130 mg / m. 2 In another embodiment, the antibody molecule is administered at a dose of about 1 to 100 mg / m 2 , for example, about 5 to 50 mg / m 2, about 7~25mg / m 2 or about 10 mg / m 2 The antibody can be administered by intravenous infusion at a rate of less than 10 mg / min, for example, 5 mg / min or less, to reach a dose of 10 mg / min. In some embodiments, the antibody is infused over a period of about 30 minutes. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated. It should be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and that the dosage ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0424] The pharmaceutical compositions of the present invention may include a "therapeutically effective amount" or a "prophylactically effective amount" of the antibody or antibody portion of the present invention. A "therapeutically effective amount" refers to an amount effective at the dosage and duration necessary to achieve the desired therapeutic result. The therapeutically effective amount of the modified antibody or antibody fragment may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit a desired response in the individual. A therapeutically effective amount is also an amount in which any toxic or detrimental effects of the modified antibody or antibody fragment are outweighed by the therapeutically beneficial effects. A "therapeutically effective dosage" preferably inhibits a measurable parameter, such as tumor growth rate, by at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and even more preferably at least about 80% compared to untreated subjects. The ability of the compound to inhibit a measurable parameter, such as cancer, can be evaluated in an animal model system predictive of efficacy in human tumors. Alternatively, this property of the composition can be evaluated by testing the ability of the compound to inhibit and assess such inhibition in vitro by assays known to those skilled in the art.

[0425] A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0426] Kits that include the anti-LAG-3 antibody molecules, compositions or formulations described herein are also within the scope of this disclosure.Kits can include one or more other elements, including: instructions for use (e.g., according to the dosage regimen described herein); other reagents, such as labels, therapeutic agents, or agents useful for chelating or otherwise coupling antibodies to labels or therapeutic agents, or radioprotective compositions; equipment or other materials for preparing antibodies for administration; pharma-ceutically acceptable carriers; and equipment or other materials for administration to subjects.

[0427] Uses of anti-LAG-3 antibody molecules The anti-LAG-3 antibody molecules described herein can be used to modify immune responses in subjects. In some embodiments, immune responses are enhanced, stimulated, or upregulated. In certain embodiments, immune responses are inhibited, reduced, or downregulated. For example, such antibody molecules can be administered to cells in culture, e.g., in vitro or ex vivo, or to cells in a subject, e.g., in vivo, to treat, prevent, and / or diagnose various disorders, such as cancer, immune disorders, and infectious diseases.

[0428] As used herein, the term "subject" is intended to include humans and non-human animals. In certain embodiments, the subject is a human subject, e.g., a human patient, having a disorder or condition characterized by abnormal LAG-3 function. Generally, the subject has at least some LAG-3 protein that contains the LAG-3 epitope to which the antibody molecule binds, e.g., a sufficiently high level of the protein and epitope to support antibody binding to LAG-3. The term "non-human animal" includes mammals and non-mammals, such as non-human primates. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human patient in need of an enhanced immune response. The methods and compositions described herein are suitable for treating human patients with disorders that can be treated by modulating (e.g., increasing or inhibiting) the immune response. In certain embodiments, the patient has or is at risk of having a disorder described herein, e.g., breast cancer, e.g., triple-negative breast cancer (TNBC). In certain embodiments, patients with TNBC are more immunogenic than other breast cancer subtypes, have higher expression of PD-L1, and / or have increased infiltration by tumor-infiltrating lymphocytes (TILs) [Loi et al. (2014) Ann Oncol; 25: 1544-50; Mittendorf et al. (2014) Cancer Immunol Res; 2:361-70]. In certain embodiments, patients do not exhibit liver metastases.

[0429] Combination immunotherapy approaches suggest that synergistic blockade of co-inhibitory receptors demonstrates superior antitumor activity than single agents [Wolchok et al. (2013) New Engl J Med; 369: 122-33]. LAG-3 is a co-inhibitory receptor that may cooperate with PD-1 to inhibit immune responses (Anderson et al. (2016) Immunity; 44: 989-1004). Combined inhibition of PD-1 and LAG-3 checkpoints synergistically enhances antitumor responses more than inhibition of either checkpoint alone [Woo et al. (2012) Cancer Res; 72: 917-27].

[0430] There is also growing evidence that cytotoxic agents can affect the tumor-host environment to make it more favorable for an immune response, and as a result, the combination of cytotoxic agents and immunotherapy can synergize to increase therapeutic efficacy [Zitvogel et al. (2013) Immunity; 39: 74-88]. Importantly, chemotherapy can induce immunogenic cell death, which has been shown to facilitate efficient antigen presentation and elicit strong T cell responses in preclinical models [Kroemer et al. (2013) Immunol; 31:51-72;Pfirschke et al. (2016) Immunity; 44:343-54;Lu et al. (2017) Biomedical Res; 28:828-34]. Without wishing to be bound by theory, it is believed that in certain embodiments, chemotherapy (e.g., platinum agents) creates an early T cell activation environment (e.g., increased antigen concentration and / or antigen availability) that would favor the generation of LAG-3+CD8+T cells, which would require only LAG3 inhibition to differentiate into tumor antigen-specific effector cells. The primary mechanism of action of platinum agents is believed to be the induction of cancer cell apoptosis in response to their covalent binding to DNA, but recent studies have shown that cellular molecules other than DNA can potentially act as targets, and that part of the antitumor effect of platinum drugs occurs via modulation of the immune system [Hato et al. (2014) Clin Cancer Res; 20: 2831-7].Such immunogenic effects include modulation of STAT signaling [Lesterhuis et al. (2011) J Clin Invest; 121:3100-08]; induction of immunogenic forms of cancer cell death via exposure of calreticulin and release of ATP and high mobility group protein box-1 (HMGB-1) [Kroemer et al. (2013) Immunol; 31:51-72;Tesniere et al. (2010) Oncogenel; 29: 482-91]; and enhancement of effector immune responses via modulation of programmed death receptor 1-ligand and mannose-6-phosphate receptor expression [Liu et al. (2010) Br J Cancer; 102:115-23]. Without wishing to be bound by theory, it is believed that in certain embodiments, the combination of immune checkpoint blockade with platinum will enhance immunotherapy in that platinum may result in immunogenic cell death, sensitize tumor cells to CTL lysis, and down-regulate PD-L.

[0431] In some embodiments, the subject has not been treated with a therapeutic agent, procedure or modality prior to receiving the anti-LAG-3 antibody molecule, hi other embodiments, the subject has been treated with a therapeutic agent, procedure or modality prior to receiving the anti-LAG-3 antibody molecule.

[0432] In certain embodiments, the subject has not been treated with an anti-LAG-3 therapy prior to receiving the anti-LAG-3 antibody molecule, hi other embodiments, the subject has been treated with an anti-LAG-3 therapy prior to receiving the anti-LAG-3 antibody molecule.

[0433] In certain embodiments, the subject has not been treated with PD-1 / PD-L1 therapy prior to receiving the anti-LAG-3 antibody molecule, hi other embodiments, the subject has been treated with PD-1 / PD-L1 therapy prior to receiving the anti-LAG-3 antibody molecule.

[0434] In certain embodiments, the subject has not been treated with a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide or precursor analog (e.g., capecitabine)) prior to receiving the anti-LAG-3 antibody molecule. In other embodiments, the subject has been treated with a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide or precursor analog (e.g., capecitabine)) prior to receiving the anti-LAG-3 antibody molecule.

[0435] In certain embodiments, the subject has been identified as having LAG-3 expression in tumor-infiltrating lymphocytes, hi other embodiments, the subject does not have detectable levels of LAG-3 expression in tumor-infiltrating lymphocytes.

[0436] Methods of Treating Cancer In one aspect, the disclosure relates to treating a subject in vivo with an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) or a composition or formulation comprising an anti-LAG-3 antibody molecule (e.g., a composition or formulation described herein), such that the growth of a cancerous tumor is inhibited or reduced.

[0437] In certain embodiments, the anti-LAG-3 antibody molecule is administered in an amount effective for treating cancer or a metastatic lesion thereof. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 100 mg to about 2000 mg. For example, the anti-LAG-3 antibody molecule can be administered once every three weeks or once every four weeks at a dose of about 200 mg to about 1000 mg, about 300 mg to about 900 mg, about 200 mg to about 600 mg, about 300 mg to about 500 mg, about 600 mg to about 1000 mg, about 700 mg to about 900 mg, or about 400 mg to about 800 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered once every three weeks at a dose of about 300 mg to 500 mg (e.g., about 400 mg). In some embodiments, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 700 mg to about 900 mg (e.g., about 800 mg). In some embodiments, the anti-LAG-3 antibody molecule is administered once every four weeks at a dose of about 500 mg to about 700 mg (e.g., about 533 mg or about 600 mg).

[0438] The anti-LAG-3 antibody or the composition or formulation comprising the anti-LAG-3 antibody molecule can be used alone to inhibit the growth of cancerous tumors. Alternatively, the anti-LAG-3 antibody or the composition or formulation comprising the anti-LAG-3 antibody molecule can be used in combination with one or more of the following: standard therapeutic treatment (e.g., for cancer or infectious disease), another antibody or its antigen-binding fragment, an immunomodulator (e.g., an activator of a costimulatory molecule or an inhibitor of an inhibitory molecule); a vaccine, e.g., a therapeutic cancer vaccine; or other forms of cellular immunotherapy as described herein.

[0439] Thus, in certain aspects, the disclosure provides a method of inhibiting the growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of an anti-LAG-3 antibody molecule described herein, e.g., according to a dosage regimen described herein. In certain aspects, the anti-LAG-3 antibody molecule is administered in the form of a composition or formulation described herein.

[0440] In some embodiments, the method is suitable for treating cancer in vivo.To achieve antigen-specific enhancement of immunity, anti-LAG-3 antibody molecule can be administered together with the antigen of interest.When anti-LAG-3 antibody is administered in combination with one or more agents, the combination can be administered in any order or simultaneously.

[0441] In another aspect, a method of treating a subject, e.g., reducing or ameliorating a hyperproliferative condition or disorder (e.g., cancer), e.g., a solid tumor, a hematological cancer, a soft tissue tumor, or a metastatic lesion, in a subject is provided. The method comprises administering to the subject an anti-LAG-3 antibody molecule disclosed herein, or a composition or formulation comprising an anti-LAG-3 antibody molecule, according to the dosage regimen disclosed herein.

[0442] As used herein, the term "cancer" is meant to include any type of cancerous growth or oncogenic process, metastatic tissue, or malignantly transformed cell, tissue, or organ, regardless of histopathological type or invasive stage. Examples of cancerous disorders include, but are not limited to, solid tumors, hematological cancers, soft tissue tumors, and metastatic lesions. Examples of solid tumors include malignant lesions of various organ systems, such as those affecting the liver, lung, breast, lymphatic system, gastrointestinal tract (e.g., colon), genitourinary tract (e.g., kidney, urothelium, bladder cells), prostate, CNS (e.g., brain, neural or glial cells), skin, pancreas, and pharynx, including sarcomas and carcinomas (including adenocarcinomas and squamous cell carcinomas). Adenocarcinomas include malignant lesions such as most colon cancers, rectal cancers, renal cell carcinomas, liver cancers, non-small cell carcinomas of the lung, cancers of the small intestine, and cancers of the esophagus. Squamous cell carcinomas include, for example, malignant lesions in the lung, esophagus, skin, head and neck region, oral cavity, anus and cervix. In some embodiments, the cancer is melanoma, for example, advanced stage melanoma. The methods and compositions of the present invention can also be used to treat or prevent metastatic lesions of the above-mentioned cancers.

[0443] Exemplary cancers that can be inhibited by using the antibody molecules, compositions or preparations disclosed herein include cancers that typically respond to immunotherapy.Non-limiting examples of typical cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), breast cancer, colon cancer and lung cancer (e.g., non-small cell lung cancer).In addition, the antibody molecules described herein can be used to treat refractory or recurrent malignant lesions.

[0444] Examples of other cancers that may be treated include basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and CNS cancer; primary CNS lymphoma; neoplasms of the central nervous system (CNS); breast cancer; cervical cancer; choriocarcinoma; colon and rectal cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer; intraepithelial neoplasia; kidney cancer; laryngeal cancer; leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic or acute leukemi...

Claims

1. A pharmaceutical composition comprising an anti-LAG-3 antibody molecule for use in the treatment of cancer in a subject, at doses of approximately 300 mg to approximately 700 mg or approximately 900 mg to approximately 1300 mg, once every two weeks, once every three weeks, or once every four weeks, A pharmaceutical composition comprising an anti-LAG-3 antibody molecule comprising a heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO: 701, the VHCDR2 amino acid sequence of SEQ ID NO: 702, and the VHCDR3 amino acid sequence of SEQ ID NO: 703; and a light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO: 710, the VLCDR2 amino acid sequence of SEQ ID NO: 711, and the VLCDR3 amino acid sequence of SEQ ID NO:

712.

2. The anti-LAG-3 antibody molecule (a) Approximately 300 mg to 700 mg once every two weeks; (b) Approximately 300 mg to 700 mg once every three weeks; or (c) Approximately 300 mg to 700 mg or 900 mg to 1300 mg once every four weeks The pharmaceutical composition according to claim 1, used in the specified dosage.

3. The pharmaceutical composition according to claim 1, wherein the anti-LAG-3 antibody molecule is used in doses of approximately 300 mg, approximately 400 mg, approximately 600 mg, or approximately 1000 mg once every two weeks, once every three weeks, or once every four weeks.

4. Antibody molecules, (a) VH containing the amino acid sequence of SEQ ID NO: 706 and VL containing the amino acid sequence of SEQ ID NO: 718; or (b) VH containing the amino acid sequence of SEQ ID NO: 724 and VL containing the amino acid sequence of SEQ ID NO: 730 A pharmaceutical composition according to claim 1, comprising:

5. Antibody molecules, (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 709 and a light chain containing the amino acid sequence of SEQ ID NO: 721; or (b) Heavy chain containing the amino acid sequence of SEQ ID NO: 727 and light chain containing the amino acid sequence of SEQ ID NO: 733 A pharmaceutical composition according to claim 1, comprising:

6. The pharmaceutical composition according to claim 1, wherein the cancer is a solid tumor or a hematological cancer.

7. The pharmaceutical composition according to claim 1, wherein the cancer is brain cancer, pancreatic cancer, skin cancer, kidney cancer, breast cancer, virus-related cancer, anal canal cancer, cervical cancer, stomach cancer, head and neck cancer, nasopharyngeal cancer (NPC), penile cancer, vaginal or vulvar cancer, colorectal cancer, lung cancer, leukemia, lymphoma, myeloma, or metastatic lesions of cancer.

8. (a) The cancer is a brain cancer which is glioblastoma or gliosarcoma. (b) The cancer is a skin cancer that is melanoma or Merkel cell carcinoma. (c) The cancer is renal cell carcinoma (RCC), (d) The cancer is breast cancer or triple-negative breast cancer (TNBC), (e) The cancer is a virus-associated cancer which is anal canal cancer, cervical cancer, stomach cancer, head and neck cancer, nasopharyngeal cancer (NPC), penile cancer, or vaginal or vulvar cancer. (f) The cancer is a colorectal cancer that is microsatellite unstable colorectal cancer, microsatellite stable colorectal cancer, colorectal cancer with mismatch repair ability, or mismatch repair deficient colorectal cancer. (g) The cancer is a lung cancer that is non-small cell lung cancer (NSCLC), or (h) The cancer is a lymphoma, which is Hodgkin lymphoma (HL) or diffuse large B-cell lymphoma (DLBCL). The pharmaceutical composition according to claim 7.

9. The pharmaceutical composition according to claim 1, wherein the cancer is advanced cancer, metastatic cancer, recurrent cancer, recurrent cancer, or unresectable cancer.

10. The pharmaceutical composition according to claim 1, wherein an anti-LAG-3 antibody molecule is used in combination with a second therapeutic agent or modality.

11. The anti-LAG-3 antibody molecule (a) PD-1 inhibitors; (b) PD-L1 inhibitors; and / or (c) Chemotherapy agents The pharmaceutical composition according to claim 1, used in combination with the above.

12. (a) an anti-LAG-3 antibody molecule used in combination with a PD-1 inhibitor, wherein the PD-1 inhibitor is PDR001, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, PF-06801591, BGB-A317, INCHR1210, TSR-042, or AMP-224; (b) The anti-LAG-3 antibody molecule is used in combination with a PD-L1 inhibitor, the PD-L1 inhibitor being FAZ053, atezolizumab, avelumab, durvalumab or BMS-936559; and / or (c) The anti-LAG-3 antibody molecule is used in combination with a chemotherapeutic agent, and the chemotherapeutic agent is a platinum compound, or a nucleotide analog or precursor analog. The pharmaceutical composition according to claim 11.

13. The pharmaceutical composition according to claim 11, wherein the PD-1 inhibitor is used in a dose of approximately 300 mg once every three weeks or approximately 400 mg once every four weeks.

14. (a) The chemotherapeutic agent is a platinum agent, and the platinum agent is carboplatin, cisplatin, oxaliplatin or tetraplatin; or (b) The chemotherapeutic agent is a nucleotide analog or precursor analog, and the nucleotide analog or precursor analog contains capecitabine. The pharmaceutical composition according to claim 12.

15. The pharmaceutical composition according to claim 1, wherein an anti-LAG-3 antibody molecule is used in combination with an anti-PD-1 antibody molecule for the treatment of NSCLC, melanoma, renal cancer, glioblastoma, virus-associated cancer, or colorectal cancer.

16. The pharmaceutical composition according to claim 1, wherein an anti-LAG-3 antibody molecule is used in combination with an anti-PD-1 antibody molecule and / or a chemotherapeutic agent for the treatment of pancreatic cancer or breast cancer.

17. The target is, (a) LAG-3 expression in tumor-infiltrating lymphocytes (TILs); and / or (b) Cancers that express PD-L1 A pharmaceutical composition according to claim 1, having or being identified as having the same.

18. A dosage formulation containing an anti-LAG-3 antibody molecule, formulated for use in the treatment of cancer in the target population, at doses of approximately 300 mg to approximately 700 mg or approximately 900 mg to approximately 1300 mg, once every two weeks, once every three weeks, or once every four weeks. A dose formulation comprising an anti-LAG-3 antibody molecule comprising a heavy chain variable region (VH) containing the VHCDR1 amino acid sequence of SEQ ID NO: 701, the VHCDR2 amino acid sequence of SEQ ID NO: 702, and the VHCDR3 amino acid sequence of SEQ ID NO: 703; and a light chain variable region (VL) containing the VLCDR1 amino acid sequence of SEQ ID NO: 710, the VLCDR2 amino acid sequence of SEQ ID NO: 711, and the VLCDR3 amino acid sequence of SEQ ID NO:

712.

19. A pharmaceutical composition for use in the treatment of cancer in a subject, in a dose or dosing schedule that results in either or both of the following: (a) the binding of the anti-LAG-3 antibody molecule to 50% or more of the soluble LAG-3 in serum or serum samples derived from the subject; or (b) the binding of the anti-LAG-3 antibody molecule to 90% or more of the membrane-bound LAG-3 in cancer or cancer samples derived from the subject.

20. The pharmaceutical composition according to claim 19, wherein the anti-LAG-3 antibody molecule comprises a heavy chain variable region (VH) including the VHCDR1 amino acid sequence of SEQ ID NO: 701, the VHCDR2 amino acid sequence of SEQ ID NO: 702, and the VHCDR3 amino acid sequence of SEQ ID NO: 703; and a light chain variable region (VL) including the VLCDR1 amino acid sequence of SEQ ID NO: 710, the VLCDR2 amino acid sequence of SEQ ID NO: 711, and the VLCDR3 amino acid sequence of SEQ ID NO:

712.

21. Antibody molecules, (a) VH containing the amino acid sequence of SEQ ID NO: 706 and VL containing the amino acid sequence of SEQ ID NO: 718; or (b) VH containing the amino acid sequence of SEQ ID NO: 724 and VL containing the amino acid sequence of SEQ ID NO: 730 The pharmaceutical composition according to claim 19, comprising:

22. Antibody molecules, (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 709 and a light chain containing the amino acid sequence of SEQ ID NO: 721; or (b) Heavy chain containing the amino acid sequence of SEQ ID NO: 727 and light chain containing the amino acid sequence of SEQ ID NO: 733 The pharmaceutical composition according to claim 19, comprising:

23. The pharmaceutical composition according to claim 19, wherein the anti-LAG-3 antibody molecule is used in a dose of approximately 80 mg to approximately 1200 mg once every two weeks, once every three weeks, or once every four weeks.