Combination of PD-1 inhibitors and LAG-3 inhibitors for enhanced efficacy in treating cancer

Abstract

To provide a combination of PD-1 inhibitors and LAG-3 inhibitors for enhanced efficacy in treating cancer.SOLUTION: The present disclosure provides methods for treating cancer or inhibiting the growth of cancer, comprising selecting a patient with cancer and administering a therapeutically effective amount of a LAG-3 inhibitor in combination with a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody or antigen-binding fragment thereof). In certain embodiments, the administration of the PD-1 inhibitor enhances the efficacy of a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody or antigen-binding fragment thereof) in inhibiting the growth of cancer.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] This disclosure provides, in part, compositions comprising inhibitors of LAG-3 and PD-1, and methods of treating cancer.

[0002] Sequence Listing A public copy of the Sequence Listing has been submitted contemporaneously herewith electronically via EFS-Web as an ASCII formatted Sequence Listing, with a filename of "10568WO01_SEQ_LIST_ST25", a creation date of May 12, 2020, and a size of approximately 20 kilobytes. The Sequence Listing contained in this ASCII formatted document is a part of the present specification and is incorporated herein by reference in its entirety. [Background technology]

[0003] Programmed death-1 (PD-1) receptor signaling in the tumor microenvironment plays a key role in allowing tumor cells to escape immunosurveillance by the host immune system. The PD-1 receptor has two ligands, PD-ligand-1 (PD-L1) and PD-L2. Blockade of the PD-1 signaling pathway has shown clinical activity in patients with multiple tumor types, and antibody therapeutics that block PD-1 / PDL1 signaling (e.g., nivolumab, pembrolizumab, atezolizumab, durvalumab, and cemiplimab) have been approved for the treatment of various cancers, including metastatic melanoma and metastatic squamous non-small cell lung cancer.

[0004] Similar to PD-1, lymphocyte activation gene-3 (LAG-3) negatively regulates T cell activity. Lag-3 (also called CD223) is a 503 amino acid transmembrane protein receptor expressed on activated CD4 and CD8 T cells, γδ T cells, natural killer T cells, B cells, natural killer cells, plasmacytoid dendritic cells, and regulatory T cells. LAG-3 is a member of the immunoglobulin (Ig) superfamily. The main function of LAG-3 is to attenuate immune responses. LAG-3 binding to MHC class II molecules results in the delivery of a negative signal to LAG-3-expressing cells, downregulating antigen-dependent CD4 and CD8 T cell responses. Lag-3 also negatively regulates the ability of T cells to proliferate, produce cytokines, and lyse target cells, a process known as T cell "exhaustion." Lag-3 has also been reported to play a role in enhancing T regulatory (Treg) cell function (Pardoll 2012, Nature Reviews Cancer 12:252-264). Both PD-1 and LAG-3 play important roles in tumor immunity, making them ideal targets for immunotherapy. Targeting both LAG-3 and PD-1, including in anti-PD-1 resistant tumors, can result in objective responses in patients across several tumor types. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Pardoll 2012, Nature Reviews Cancer 12:252-264 Summary of the Invention

[0006] The present disclosure relates to methods of treating cancer and inhibiting tumor growth.

[0007] Provided herein are methods of treating, ameliorating, or inhibiting the growth of at least one symptom or sign of cancer in a subject. The method according to this aspect of the disclosure includes administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to programmed death 1 (PD-1), in combination with a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to LAG-3.

[0008] In certain embodiments, a method of treating cancer or inhibiting tumor growth in a subject in need thereof is provided. The method according to this aspect of the disclosure includes administering to the subject a therapeutically effective amount of each of (a) an antibody or antigen-binding fragment thereof that specifically binds to programmed death 1 (PD-1); and (b) an antibody or antigen-binding fragment thereof that specifically binds to lymphocyte activation gene-3 (LAG-3). In some aspects, one or more doses of an anti-LAG-3 antibody are administered in combination with one or more doses of an anti-PD-1 antibody.

[0009] In some embodiments, the treatment produces a therapeutic effect selected from the group consisting of delayed tumor growth, reduced tumor cell count, tumor regression, increased survival, partial response, and complete response. In some embodiments, tumor growth is delayed by at least 10 days compared to untreated subjects. In some embodiments, tumor growth is inhibited by at least 50% compared to untreated subjects. In some embodiments, tumor growth is inhibited by at least 20% compared to subjects administered either antibody as monotherapy.

[0010] In some aspects, the inhibition is more effective than administration of either antibody as monotherapy.

[0011] In certain embodiments, methods of treating, ameliorating, or inhibiting the growth of cancer in a subject are provided. In certain embodiments, methods of slowing tumor growth or preventing tumor recurrence are provided. The method according to this aspect includes sequentially administering to a subject in need thereof one or more therapeutically effective doses of an antibody or antigen-binding fragment thereof that specifically binds PD-1 in combination with one or more therapeutically effective doses of an antibody or antigen-binding fragment thereof that specifically binds LAG-3.

[0012] In one embodiment, the anti-PD-1 antibody and the anti-LAG-3 antibody are administered as a first ("front-line") line of treatment (e.g., initial or first treatment). In another embodiment, the anti-PD-1 antibody and the anti-LAG-3 antibody are administered as a second line of treatment (e.g., after initial treatment with the same or a different therapy, including after relapse and / or if the first treatment has failed).

[0013] In certain embodiments, a method for treating cancer or inhibiting tumor growth is provided. The method according to this aspect includes: (1) selecting a patient with a tumor, the selected patient having undergone a previous treatment including a PD-1 inhibitor or a PD-L1 inhibitor; and (2) administering to the patient: (a) 350 mg of an anti-PD-1 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:1 / 2; and (b) 1, 3, 10, 20, or 40 mg / kg or 1600 mg of an anti-LAG-3 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:11 / 12. In some aspects, the administration of step (2) occurs once every 3 weeks or once every 6 weeks. In some embodiments, the selection in step (1) is based on the following criteria: (i) platinum-based therapy ineligible or tumor progression or recurrence within 6 months of the last dose of platinum therapy; (ii) confirmed diagnosis of malignancy; (iii) presentation of tumor progression with no available therapy likely to provide clinical benefit; (iv) disease progression / recurrence after one platinum-containing regimen; (v) anti-PD-1 / PD-L1 experienced stage IIIB, IIIC, or IV disease with 2 or fewer prior therapies for metastatic disease. Further identifying patients who meet one or more of the following criteria: NSCLC; (vi) anti-PD-1 / PD-L1-experienced advanced ccRCC or metastatic ccRCC with clear cell component that has received ≤2 prior regimens of antiangiogenic therapy; (vii) anti-PD-1 / PD-L1-experienced advanced non-uveal melanoma or metastatic non-uveal melanoma that has received ≤2 prior regimens for metastatic disease; (xiii) anti-PD-1 / PD-L1-experienced relapsed / refractory DLBCL that has progressed after autologous stem cell transplant or is not a candidate for autologous stem cell transplant; (ix) anti-PD-1 / PD-L1-experienced recurrent and / or metastatic HNSCC (irrespective of HPV status) with no curative options; (x) anti-PD-1 / PD-L1-experienced locally advanced CSCC or metastatic CSCC where surgery is not appropriate; and (xi) ≥1% LAG-3 expression in tumor tissue. The tumor tissue may include tumor cells and / or tumor-infiltrating immune cells.

[0014] In certain embodiments, a method for treating cancer or inhibiting tumor growth is provided. The method according to this aspect includes: (1) selecting a patient with a tumor, the selected patient having no prior treatment with a PD-1 inhibitor or a PD-L1 inhibitor; and (2) administering to the patient: (a) 350 mg of an anti-PD-1 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:1 / 2; and (b) 1, 3, 10, 20, or 40 mg / kg or 1600 mg of an anti-LAG-3 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:11 / 12. In some embodiments, the administration of step (2) occurs once every three weeks or once every six weeks. In some embodiments, the selection in step (1) is based on the following criteria: (i) ineligible for platinum-based therapy or having tumor progression or recurrence within 6 months of the last dose of platinum therapy; (ii) a confirmed diagnosis of malignancy; (iii) presentation of tumor progression with no available therapy likely to provide clinical benefit; (iv) anti-PD-1 / PD-L1 naive stage IIIB, IIIC, or IV without prior therapy for metastatic disease. (v) disease progression / recurrence after one platinum-containing regimen; (vi) anti-PD-1 / PD-L1 naive advanced ccRCC or metastatic ccRCC with a clear cell component that has received ≤2 prior regimens of antiangiogenic therapy; (vii) anti-PD-1 / PD-L1 naive metastatic TNBC (estrogen, progesterone, and human epidermal growth factor receptor 2 negative) that has received ≤5 prior lines of therapy; (viii) anti-PD-1 / PD-L1 naive advanced non-uveal melanoma or metastatic non-uveal melanoma that has received ≤2 prior regimens for metastatic disease; (ix) anti-PD-1 / PD-L1 naive relapsed / refractory DLBCL that has progressed after or is not a candidate for autologous stem cell transplant; (x) anti-PD-1 / PD-L1 naive relapsed HNSCC and / or metastatic HNSCC with no curative options (xi) anti-PD-1 / PD-L1 naive locally advanced or metastatic CSCC for which surgery is not appropriate; and (xii) the patient has >= 1% LAG-3 expression in tumor tissue. The tumor tissue may include tumor cells and / or tumor-infiltrating immune cells.

[0015] In certain embodiments, a method of treating cancer or inhibiting tumor growth is provided. The method according to this aspect includes: (1) selecting a patient having a tumor; and (2) administering to the patient (a) 1, 3, 10, 20, or 40 mg / kg or 1600 mg of an anti-LAG-3 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:11 / 12 as monotherapy for about 1 month to about 12 months; and then further administering to the patient (b) 350 mg of an anti-PD-1 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:1 / 2 in combination with (a). In some aspects, the administration of step (2) occurs once every 3 weeks or once every 6 weeks.

[0016] In certain embodiments, methods of treating cancer or inhibiting tumor growth are provided. The methods according to this aspect include administering to a patient in need thereof: (1) a loading dose comprising an anti-PD-1 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:1 / 2; and an anti-LAG-3 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:11 / 12; and (2) one or more secondary doses, the one or more secondary doses occurring 1-4 weeks after the immediately preceding dose. In some aspects, the methods further include administering to a patient in need thereof: (3) one or more tertiary doses, the one or more tertiary doses occurring 3-12 weeks after the immediately preceding dose. In some aspects, the one or more secondary doses occurring 3 weeks after the immediately preceding dose. In some aspects, the one or more tertiary doses occurring 3 weeks or 6 weeks after the immediately preceding dose. In some embodiments, the initial loading dose comprises (a) 500 mg to 1500 mg of anti-PD-1 antibody and (b) 20 or 40 mg / kg of anti-LAG-3 antibody. In some embodiments, the one or more secondary doses comprise (a) 350 mg of anti-PD-1 antibody and (b) 1, 3, 10, 20, or 40 mg / kg of anti-LAG-3 antibody. In some embodiments, the one or more tertiary doses comprise (a) 350 mg of anti-PD-1 antibody and (b) 1, 3, 10, 20, or 40 mg / kg of anti-LAG-3 antibody. In some embodiments, the initial loading dose comprises (a) 500 mg to 1500 mg of anti-PD-1 antibody and (b) 50 mg to 8000 mg of anti-LAG-3 antibody. In some embodiments, the one or more secondary doses comprise (a) 350 mg of an anti-PD-1 antibody and (b) 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, or 2000 mg of an anti-LAG-3 antibody. In some embodiments, the one or more tertiary doses comprise (a) 350 mg of an anti-PD-1 antibody and (b) 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, or 2000 mg of an anti-LAG-3 antibody.

[0017] In certain embodiments, the cancer or tumor is selected from the group consisting of renal cancer, lung cancer, breast cancer, endometrial cancer, squamous cell carcinoma, melanoma, and lymphoma.

[0018] In certain embodiments, the cancer or tumor is selected from the group consisting of astrocytoma, bladder cancer, blood cancer, blood cancer, bone cancer, brain cancer, breast cancer, cervical cancer, renal clear cell carcinoma, colorectal cancer, microsatellite-intermediate colorectal cancer, cutaneous squamous cell carcinoma, diffuse large B-cell lymphoma, endometrial cancer, esophageal cancer, fibrosarcoma, gastric cancer, glioblastoma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, leukemia, liver cancer, leiomyosarcoma, lung cancer, lymphoma, melanoma, mesothelioma, myeloma, nasopharyngeal carcinoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, primary and / or recurrent cancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, squamous cell carcinoma, synovial sarcoma, thyroid cancer, triple-negative breast cancer, uterine cancer, and Wilms' tumor. In some aspects, the cancer is a primary cancer. In some embodiments, the cancer is a metastatic and / or recurrent cancer.

[0019] In certain embodiments, each dose of anti-PD-1 antibody comprises 0.1-20 mg / kg of subject body weight. In certain embodiments, each dose of anti-PD-1 antibody comprises 0.3, 1, 3, or 10 mg / kg of subject body weight. In certain embodiments, each dose of anti-PD-1 antibody comprises 50-1500 mg, e.g., 350 mg. In some aspects, each dose of anti-PD-1 antibody comprises 350 mg. In some aspects, the therapeutically effective amount of anti-PD-1 antibody comprises 50-1500 mg.

[0020] In certain embodiments, each dose of anti-LAG-3 antibody comprises 0.1 mg / kg to 50 mg / kg of subject body weight, e.g., 1, 3, 10, 20, 30, or 40 mg / kg of subject body weight. In certain embodiments, each dose of anti-LAG-3 antibody comprises 50 to 8000 mg, e.g., 1600 mg. In some aspects, the therapeutically effective amount of anti-LAG-3 antibody comprises 50 to 8000 mg.

[0021] In certain embodiments, each dose of anti-PD-1 antibody comprises 0.3, 1, 3, or 10 mg / kg of subject body weight and each dose of anti-LAG-3 antibody comprises 50 mg to 8000 mg. In certain embodiments, each dose of anti-PD-1 antibody comprises 1, 3, or 10 mg / kg of subject body weight and each dose of LAG-3 antibody comprises 100, 300, 1000, 1600, or 3000 mg. In certain embodiments, each dose of anti-PD-1 antibody comprises 50-1500 mg, e.g., 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg, and each dose of anti-LAG-3 antibody comprises 100, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, or 3000 mg. In certain embodiments, each dose of anti-PD-1 antibody comprises 1, 3, or 10 mg / kg, and each dose of anti-LAG-3 antibody comprises 1, 3, 10, 20, 30, or 40 mg / kg of subject body weight. In certain embodiments, each dose of the anti-PD-1 antibody comprises 200 mg, 250 mg, or 350 mg, and each dose of the anti-LAG-3 antibody comprises 800 mg, 1000 mg, 1400 mg, or 1600 mg.

[0022] In certain embodiments, the antibody is administered intravenously, subcutaneously, or intraperitoneally.

[0023] In certain embodiments, the method includes administering a therapeutically effective amount of an anti-PD-1 antibody, or an anti-PD-L1 antibody, before, simultaneously, or after an anti-LAG-3 antibody. In certain embodiments, the method includes administering a therapeutically effective amount of an anti-LAG-3 antibody before, simultaneously, or after an anti-PD-1 or anti-PD-L1 antibody. In one embodiment, the method includes administering the anti-LAG-3 antibody before the anti-PD-1 antibody. In some aspects, the anti-LAG-3 antibody can be administered as a first therapy, e.g., one to four doses over a period of several weeks or months, and then the anti-PD-1 antibody is administered as a combination therapy. In one embodiment, the method includes administering the anti-PD-1 antibody before the anti-LAG-3 antibody. In one embodiment, the method includes administering the anti-PD-1 antibody on the same day as the anti-LAG-3 antibody. In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are administered on the same day, but consecutively, with the anti-LAG3 antibody being administered first.

[0024] In certain embodiments, the method involves administering multiple therapeutic doses of each of the anti-PD-1 antibody and the anti-LAG-3 antibody over a period of months to years. The treatment interval (whether monotherapy or combination therapy) can be about 0.5 weeks to about 12 weeks, i.e., the treatments are administered about 0.5 weeks to about 12 weeks apart, e.g., about 18 days apart. In other words, the treatments are administered 0.5 weeks to 12 weeks after the immediately preceding dose. For example, in some aspects, each dose of the anti-PD-1 antibody is administered 0.5 weeks to 12 weeks after the immediately preceding dose. In some aspects, each dose of the anti-LAG-3 antibody is administered 0.5 weeks to 12 weeks after the immediately preceding dose. In certain embodiments, each dose of anti-PD-1 antibody is administered once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks, and each dose of anti-LAG-3 antibody is administered once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks. In one embodiment, each dose of anti-PD-1 antibody is administered once every three weeks, and each dose of anti-LAG-3 antibody is administered once every three weeks. In certain embodiments, patients can receive treatment once every three weeks for several months to several years, and then every six weeks for several months to several years. In some embodiments, one or both of the anti-PD-1 antibody and the anti-LAG-3 antibody are administered until disease progression. In some embodiments, one or both of the anti-PD-1 antibody and the anti-LAG-3 antibody are administered until toxicity due to treatment becomes unacceptable.

[0025] In certain embodiments, the anti-PD-1 antibody and the anti-LAG-3 antibody are administered in combination with a third therapeutic agent or therapy.

[0026] In some embodiments, the additional therapeutic agent or therapy is selected from the group consisting of radiation, surgery, chemotherapy, cancer vaccines, PD-L1 inhibitors, CTLA-4 inhibitors, TIM3 inhibitors, BTLA inhibitors, TIGIT inhibitors, CD47 inhibitors, CD28 agonists, CD38 inhibitors, indoleamine-2,3-dioxygenase (IDO) inhibitors, vascular endothelial growth factor (VEGF) antagonists, angiopoietin-2 (Ang2) inhibitors, transforming growth factor beta (TGFβ) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, antibodies against tumor-specific antigens, CD28 agonists, GITR agonists, 4-1BB agonists, CD20×CD3 bispecific antibodies (e.g., REGN1979), MUC16×CD3 bispecific antibodies, Bacillus Calmette-Guerin vaccine, granulocyte-macrophage colony-stimulating factor, oncolytic virus, cytotoxin, interleukin 6 receptor (IL-6R) inhibitor, interleukin 4 receptor (IL-4R) inhibitor, IL-10 inhibitor, IL-2, IL-7, IL-21, Il-12, IL-15, antibody drug conjugates (ADC) (e.g., anti-CD19-DM4 ADC, and anti-DS6-DM4 ADC), chimeric antigen receptor T cells (e.g., CD19-targeted T cells) or other cellular therapies, and anti-inflammatory drugs.

[0027] According to certain embodiments, the anti-PD-1 antibody or antigen binding protein comprises a heavy chain complementarity determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain CDR of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. One such type of antigen binding protein that may be used in the context of the methods provided herein is an anti-PD-1 antibody, such as REGN2810 (also known as cemiplimab, LIBTAYO®).

[0028] According to certain embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) of a heavy chain variable region (HCVR) and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) of a light chain variable region (LCVR), where HCDR1 comprises the amino acid sequence of SEQ ID NO:3, HCDR2 comprises the amino acid sequence of SEQ ID NO:4, HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, LCDR2 comprises the amino acid sequence of SEQ ID NO:7, and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0029] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a HCVR having the amino acid sequence of SEQ ID NO:1 and a LCVR having the amino acid sequence of SEQ ID NO:2.

[0030] In some embodiments, the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0031] According to certain embodiments, an anti-LAG-3 antibody or antigen binding protein comprises a heavy chain complementarity determining region (HCDR) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 11 and a light chain CDR (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) of SEQ ID NO: 12. One such type of antigen binding protein that may be used in the context of the methods provided herein is an anti-LAG-3 antibody, such as REGN3767.

[0032] According to certain embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the three heavy chain CDRs of HCVR (HCDR1, HCDR2 and HCDR3) and the three light chain CDRs of LCVR (LCDR1, LCDR2 and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 13, HCDR2 comprises the amino acid sequence of SEQ ID NO: 14, HCDR3 comprises the amino acid sequence of SEQ ID NO: 15, LCDR1 comprises the amino acid sequence of SEQ ID NO: 16, LCDR2 comprises the amino acid sequence of SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 18.

[0033] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a HCVR having the amino acid sequence of SEQ ID NO:11 and a LCVR having the amino acid sequence of SEQ ID NO:12.

[0034] In some embodiments, the anti-LAG-3 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:19 and a light chain comprising the amino acid sequence of SEQ ID NO:20.

[0035] Further provided is a combination comprising a PD-1 inhibitor in association with a LAG-3 inhibitor and optionally a pharma- ceutically acceptable carrier. For example, such a combination may comprise a co-formulation, or the inhibitors may be in separate compositions. In some embodiments, the PD-1 inhibitor and / or the LAG-3 inhibitor are antibodies or antigen-binding fragments thereof that specifically bind to PD-1 and / or LAG-3, respectively. In some embodiments, the PD-1 inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to PD-1, and includes REGN2810. In some embodiments, the LAG-3 inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to LAG-3, and includes REGN3767.

[0036] In certain embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof and the anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated separately or in combination. Thus, the anti-PD1 antibody or antigen-binding fragment thereof and the anti-LAG-3 antibody or antigen-binding fragment thereof can be combined and used in the manufacture of a medicament for treating or inhibiting the growth of cancer in a subject, including a human.

[0037] In certain embodiments, the cancer is astrocytoma, bladder cancer, blood cancer, blood cancer, bone cancer, brain cancer, breast cancer, cervical cancer, renal clear cell carcinoma, colorectal cancer, microsatellite-intermediate colorectal cancer, cutaneous squamous cell carcinoma, diffuse large B-cell lymphoma, endometrial cancer, esophageal cancer, fibrosarcoma, gastric cancer, glioblastoma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, leukemia, liver cancer, leiomyosarcoma, lung cancer, lymphoma, melanoma, mesothelioma, myeloma, nasopharyngeal carcinoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, primary and / or recurrent cancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, squamous cell carcinoma, synovial sarcoma, thyroid cancer, triple-negative breast cancer, uterine cancer, or Wilms' tumor. In some aspects, the cancer is a primary cancer. In some embodiments, the cancer is a metastatic and / or recurrent cancer.

[0038] In certain embodiments, the subject or patient has undergone a previous anti-cancer therapy comprising one or more of a PD-1 inhibitor, a PD-L1 inhibitor, surgery, radiation therapy, or chemotherapy. In some aspects, the previous anti-cancer therapy comprises a PD-1 inhibitor or a PD-L1 inhibitor. In certain embodiments, the subject is resistant or inadequately responsive to the previous therapy, or has relapsed after the previous therapy.

[0039] In certain embodiments, the subject has not undergone previous anti-cancer therapy.

[0040] Such combinations optionally include one or more additional therapeutic agents or therapies.

[0041] Also provided herein are injection devices (eg, hypodermic needle and syringe, autoinjector or pre-filled syringe) or containers (eg, vials) containing the antibody combination (eg, REGN2810 / REGN3767).

[0042] Further provided is a method of administering a combination of the present disclosure to a subject (e.g., a human suffering from cancer) comprising introducing the components of the combination into the subject's body, e.g., parenterally, e.g., by injection using an injection device according to the present disclosure.

[0043] Other embodiments will be apparent from consideration of the detailed description that follows. [Brief description of the drawings]

[0044] [Figure 1] Figure 1 shows the study flow diagram for an individual patient.

[0045] [Diagram 2] FIG. 2 shows the study design illustrating the dose escalation scheme and cohorts.

[0046] [Figure 3A] Figures 3A and 3B provide an analysis of T cell subset expansion following initiation of REGN3767 monotherapy or REGN3767 plus cemiplimab. [Figure 3B] Same as above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] It is to be understood that the invention is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure is limited only by the appended claims.

[0048] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.As used herein, the term "about" when used in relation to a specific referenced numerical value means that the value can vary from the referenced value by 1% or less.For example, as used herein, the expression "about 100" includes 99 and 101, and all values ​​therebetween (for example, 99.1, 99.2, 99.3, 99.4, etc.).

[0049] As used herein, the term "antibody" includes immunoglobulin molecules that contain four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, and multimers thereof (e.g., IgM). In a typical antibody, each heavy chain contains a heavy chain variable region (herein referred to as HCVR or V H The heavy chain constant region comprises a C H 1. C H 2, and C H Each light chain contains three domains: a light chain variable region (herein LCVR or V L The light chain constant region comprises one domain (C L 1) is included. H Area and V L The regions can be further subdivided into regions of hypervariability, called complementarity determining regions (CDRs), interspersed with regions that are more conserved, called framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the present disclosure, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to the human germline sequence or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on the parallel analysis of two or more CDRs.

[0050] As used herein, the term "antibody" also includes antigen-binding fragments of a complete antibody molecule. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc., include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies may be derived from complete antibody molecules using any suitable standard method, such as, for example, proteolytic or recombinant genetic engineering techniques, involving the manipulation and expression of DNA encoding the antibody variable regions and, optionally, the constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or may be synthesized. The DNA can be sequenced and manipulated chemically or by using molecular biology techniques, for example, to place one or more variable and / or constant domains in a suitable configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids, etc.

[0051] Non-limiting examples of antigen-binding fragments include (i) Fab fragments, (ii) F(ab')2 fragments, (iii) Fd fragments, (iv) Fv fragments, (v) single chain Fv (scFv) molecules, (vi) dAb fragments, and (vii) minimal recognition units consisting of amino acid residues mimicking a hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and other engineered molecules such as shark variable IgNAR domains are also encompassed by the term "antigen-binding fragment" as used herein.

[0052] Antigen-binding fragments of antibodies typically contain at least one variable domain. A variable domain may be of any size or amino acid composition and generally contains at least one CDR adjacent to or in frame with one or more framework sequences. L V bound to the domain H In an antigen-binding fragment having a domain, H Domains and V L The domains may be arranged relative to one another in any suitable configuration. For example, the variable region may be a dimer, with the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of the antibody may contain a dimer of monomeric V H or V L It may contain domains.

[0053] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found in an antigen-binding fragment of an antibody of the present disclosure include: (i) a V H -C H 1, (ii) V H -C H 2. (iii) V H -C H 3. (iv) V H -C H 1-C H 2. (v) V H -C H 1-C H 2-C H 3. (vi) V H -C H 2-C H 3. (vii) V H -C L、 (viii) V L -C H 1, (ix) V L -C H 2. (x)V L -C H3. (xi) V L -C H 1-C H 2. (xii) V L -C H 1-C H 2-C H 3. (xiii) V L -C H 2-C H 3, and (xiv) V L -C L In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or may be linked by a full or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies of the present disclosure may be linked to each other and / or to one or more monomeric V H Or V L It may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed above in non-covalent association with the domains (eg, via disulfide bonds).

[0054] As used herein, the term "antibody" also includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies typically contain at least two different variable domains, each capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in conjunction with the antibodies or antigen-binding fragments of antibodies of the present disclosure using routine techniques available in the art. For example, the present disclosure includes methods involving the use of bispecific antibodies, where one arm of the immunoglobulin is specific for PD-1 or LAG-3, or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Exemplary bispecific formats that can be used in connection with the present disclosure include, but are not limited to, for example, scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadromas, knobs-into-holes, common light chains (e.g., common light chains with knobs-into-holes), CrossMab, CrossFab, (SEED) bodies, leucine zippers, duobodies, IgG1 / IgG2, dual acting Fab (DAF)-IgG, and Mab 2 Bispecific formats (see, for example, Klein et al. 2012, mAbs 4:6, 1-11, and references cited therein, for a discussion of the aforementioned formats) are included. Bispecific antibodies may be constructed using peptide / nucleic acid conjugation. For example, unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates that are then self-assembled into multimeric complexes with defined composition, valency and structure. (See, for example, Kazane et al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012]).

[0055] The antibody used in the method of the present disclosure may be a human antibody. The term "human antibody" as used herein is intended to include antibodies with variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibody of the present disclosure may include amino acid residues that are not encoded by human germline immunoglobulin sequences, for example in CDRs, particularly in CDR3 (e.g., mutations are introduced by in vitro random or site-specific mutagenesis, or by in vivo somatic mutation). However, the term "human antibody" as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as mouse, are grafted onto human framework sequences.

[0056] The antibody used in the method of the present disclosure may be a recombinant human antibody. The term "recombinant human antibody" as used herein is intended to include all human antibodies prepared, expressed, created, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transduced into a host cell (described in more detail below), antibodies isolated from recombinants, combinatorial human antibody libraries (described in more detail below), antibodies isolated from animals (e.g., mice) transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, created, or isolated by any other means, including splicing antibodies from human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis, when animals transgenic for human Ig sequences are used), thereby improving the V H Area and V L The amino acid sequence of the region isH Array and V L While the sequences are derived from and related to the sequences, they may not naturally occur in the human antibody germline repertoire in vivo.

[0057] Although any methods and materials similar or equivalent to those described herein can be used in the practice of this disclosure, exemplary methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

[0058] General method The standard method in molecular biology is described by Sambrook, Fritsch and Maniatis (1982 & 1989 2 nd Edition, 2001 3 rd (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, Calif.). Standard methods are also found in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc. New York, NY, which describes cloning and DNA mutagenesis in bacterial cells (vol. 1), cloning in mammalian cells and yeast (vol. 2), glycoconjugates and protein expression (vol. 3), and bioinformatics (vol. 4).

[0059] Methods for protein purification, including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization have been described (Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York). Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, and glycosylation of proteins have been described (e.g., Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York, Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, NY, pp. 16.0.5-16.22.17, Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, Mo.; pp. 45-89, Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, NJ, pp. 384-391). The production, purification, and fragmentation of polyclonal and monoclonal antibodies have been described (Coligan, et al. (2001) Current Protocols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Harlow and Lane, supra). Standard techniques for characterizing ligand / receptor interactions are available (e.g., Coligan, et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York).

[0060] Monoclonal, polyclonal, and humanized antibodies can be prepared (see, e.g., Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New York, NY; Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer-Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 139-243; Carpenter, et al. (2000) J. Immunol. 165:6205; He, et al. (1998) J. Immunol. 160:1029; Tang et al. (1999) J. Biol. Chem. 274:27371-27378; Baca et al. (1999) J. Immunol. 274:27371-27378). (see, e.g., Chothia et al. (1997) J. Biol. Chem. 272:10678-10684; Chothia et al. (1989) Nature 342:877-883; Foote and Winter (1992) J. Mol. Biol. 224:487-499; U.S. Pat. No. 6,329,511).

[0061] An alternative method of humanization is to use human antibody libraries displayed on phage or in transgenic mice (Vaughan et al. (1996) Nature Biotechnol. 14:309-314; Barbas (1995) Nature Medicine 1:837-839; Mendez et al. (1997) Nature Genetics 15:146-156; Hoogenboom and Chames (2000) Immunol. Today 21:371-377; Barbas et al. (2001) Phage Display:A Laboratory Manual,Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Kay et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, Calif.; de Bruin et al. (1999) Nature Biotechnol. 17:397-399. Single chain antibodies and diabodies have been described (e.g., Malecki, et al., 1999). (see Conrath et al. (2002) Proc. Natl. Acad. Sci. USA 99:213-218, Conrath et al. (2001) J. Biol. Chem. 276:7346-7350, Desmyter et al. (2001) J. Biol. Chem. 276:26285-26290, Hudson and Kortt (1999) J. Immunol. Methods 231:177-189, and U.S. Patent No. 4,946,778). Bifunctional antibodies have been provided (e.g., Mack, et al. (1995) Proc. Natl. Acad. Sci. USA 92:7021-7025; Carter (2001) J. Immunol. Methods 248:7-15; Volkel, et al. (2001) Protein Engineering 14:815-823; Segal, et al. (2001) J. Immunol. Methods 248:1-6; Brennan, et al. (1985) Science 229:81-83; Raso, et al. (1997) J. Biol. Chem. 272:27623; Morrison (1985) Science 229:1202-1207; Traunecker, et al. (1991) EMBO (See, e.g., J. 10:3655-3659, and U.S. Patent Nos. 5,932,448, 5,532,210, and 6,129,914.) Fully human antibodies can also be developed in genetically engineered mice, such as the VelociMouse.See, e.g., DeChiara et al., Producing fully ES cell-derived mice from eight-cell stage embryo injections, Methods Enzymol, 476:285-94 (2010); Dechiara et al., VelociMouse: fully ES cell-derived F0-generation mice obtained from the injection of ES cells into eight-cell-stage embryos. Methods Mol Biol, 530:311-24 (2009); U.S. Patent Nos. 7,576,259, 7,659,442, or 7,294,754, and US2008 / 0078000A1.

[0062] Purification of antigens is typically not required for the production of antibodies. Animals can be immunized with cells bearing the antigen of interest. Spleen cells can then be isolated from the immunized animals, and the spleen cells can be fused with myeloma cell lines to produce hybridomas (see, for example, Meyaard et al. (1997) Immunity 7:283-290; Wright et al. (2000) Immunity 13:233-242; Preston et al., supra; Kaithana et al. (1999) J. Immunol. 163:5157-5164).

[0063] Antibodies can be conjugated to, for example, small drug molecules, enzymes, liposomes, polyethylene glycol (PEG).Antibodies are useful for treatment, diagnosis, kits, or other purposes, including, for example, antibodies conjugated to dyes, radioisotopes, enzymes, or metals, such as gold colloids (see, for example, Le Doussal et al. (1991) J.Immunol.146:169-175, Gibellini et al. (1998) J.Immunol.160:3891-3898, Hsing and Bishop (1999) J.Immunol.162:2804-2811, Everts et al. (2002) J.Immunol.168:883-889).

[0064] Methods for flow cytometry, including fluorescence-activated cell sorting (FACS), are available (see, e.g., Owens, et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, NJ; Givan (2001) Flow Cytometry, 2nd ed.; Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). For example, fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies for use as diagnostic reagents are available (Molecular Probes (2003) Catalogue, Molecular Probes, Inc., Eugene, Oreg.; Sigma-Aldrich (2003) Catalogue, St. Louis, Mo.).

[0065] Standard methods for immune system histology have been described (see, e.g., Muller-Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology, Springer Verlag, New York, NY; Hiatt, et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Phila, Pa.; Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, NY).

[0066] For example, software packages and databases for determining antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments are available (e.g., GenBank, Vector NTI® Suite (Informax, Inc., Bethesda, Md.), GCG Wisconsin Package (Accelrys, Inc., San Diego, Calif.), DeCypher® (TimeLogic Corp., Crystal Bay, Nev.), Menne, et al. (2000) Bioinformatics 16:741-742, Menne, et al. (2000) Bioinformatics Applications Note 16:741-742, Wren, et al. (2002) Comput.Methods Programs Biomed.68:177-181, von Heijne (1983) Eur.J.Biochem.133:17-21, von Heijne (1986) Nucleic Acids Res.14:4683-4690).

[0067] PD-1 inhibitors According to certain exemplary embodiments of the present disclosure, the method comprises administering a therapeutically effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof. The term "PD-1" refers to the programmed death-1 protein, also known as CD279, a T-cell co-inhibitor. The amino acid sequence of full-length PD-1 is provided in GenBank under accession number NP_005009.2. PD-1 is a member of the T-cell co-inhibitor CD28 / CTLA-4 / ICOS family. PD-1 is a 288 amino acid protein with an extracellular N-terminal domain that is IgV-like, a transmembrane domain, and an intracellular domain that contains immunoreceptor tyrosine-based inhibition (ITIM) motifs and immunoreceptor tyrosine-based switch (ITSM) motifs (Chattopadhyay et al 2009, Immunol. Rev.). The PD-1 receptor has two ligands, PD-ligand-1 (PD-L1) and PD-L2.

[0068] PD-L1 is a 290 amino acid protein with an extracellular IgV-like domain, a transmembrane domain, and a highly conserved intracellular domain of about 30 amino acids. PD-L1 is constitutively expressed on many cells, such as antigen-presenting cells (e.g., dendritic cells, macrophages, and B cells), as well as hematopoietic and non-hematopoietic cells (e.g., vascular endothelial cells, pancreatic islets, and immune privileged sites). PD-L1 is also expressed on a wide variety of tumors, virus-infected cells, and autoimmune tissues, and is a component of the immunosuppressive environment (Ribas et al., 2003). 2012, NEJM 366:2517-2519).

[0069] PD-1 inhibitors include antibodies and antigen-binding fragments thereof, as well as other substances (e.g., peptides and small molecules) that specifically bind to PD-1 and antagonize one or more biological activities of PD-1. Molecules that specifically bind to PD-1 may be referred to as "anti-PD-1." In an embodiment of the present disclosure, the PD-1 inhibitor is an antibody or antigen-binding fragment thereof that binds to PD-L1 or PD-L2.

[0070] In an embodiment of the disclosure, the PD-1 inhibitor is an antibody or antigen-binding fragment thereof described in U.S. Pat. No. 9,987,500.

[0071] According to certain embodiments, the antibody used in the method of the present disclosure specifically binds to PD-1. The term "specifically binds" and the like means that the antibody or antigen-binding fragment thereof forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, as used in the context of the present disclosure, an antibody that "specifically binds" to PD-1 has a K of less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM as measured by a surface plasmon resonance assay. D However, an isolated antibody that specifically binds human PD-1 may have cross-reactivity to other antigens, such as PD-1 molecules from other (non-human) species.

[0072] According to certain exemplary embodiments of the present disclosure, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity determining region (CDR) comprising any of the amino acid sequences of the anti-PD-1 antibodies described in U.S. Pat. No. 9,987,500.

[0073] In certain exemplary embodiments, an anti-PD-1 antibody or antigen-binding fragment thereof that may be used in the context of the disclosed methods comprises a heavy chain complementarity determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain complementarity determining region (LCDR) of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. According to certain embodiments, an anti-PD-1 antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In yet other embodiments, an anti-PD-1 antibody or antigen-binding fragment thereof comprises a HCVR comprising SEQ ID NO: 1 and a LCVR comprising SEQ ID NO: 2. In certain embodiments, the methods of the disclosure include the use of an anti-PD-1 antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-PD-1 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. An exemplary antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2 is the fully human anti-PD-1 antibody, also known as REGN2810 (cemiplimab; LIBTAYO®).

[0074] According to certain exemplary embodiments, the methods of the present disclosure include the use of REGN2810, or a biological equivalent thereof. As used herein, the term "biological equivalent" refers to an anti-PD-1 antibody or PD-1 binding protein or fragment thereof that is a pharmaceutical equivalent or pharmaceutical substitute that exhibits no significant difference in rate and / or extent of absorption from REGN2810 when administered in either single or multiple doses at the same molar dose under similar experimental conditions. In the context of the present disclosure, the term refers to an antigen binding protein that binds to PD-1 that has no clinically meaningful difference in safety, purity and / or potency from REREGN2810.

[0075] Other anti-PD-1 antibodies that may be used in the context of the methods of the present disclosure include antibodies referred to or known in the art as, for example, nivolumab (U.S. Pat. No. 8,008,449), pembrolizumab (U.S. Pat. No. 8,354,509), MEDI0608 (U.S. Pat. No. 8,609,089), pidilizumab (U.S. Pat. No. 8,686,119), or any of the anti-PD-1 antibodies described in U.S. Pat. Nos. 6,808,710, 7,488,802, 8,168,757, 8,354,509, 8,779,105, or 8900587. In embodiments of the present disclosure, the PD-1 inhibitor is described in any of U.S. Publication No. 20110008369, U.S. Publication No. 20130017199, U.S. Publication No. 20130022595, WO Publication No. 2006121168, WO Publication No. 20091154335, WO Publication No. 2012145493, WO Publication No. 2013014668, WO Publication No. 2009101611, European Publication No. 2262837, and European Publication No. 2504028.

[0076] Anti-PD-1 antibodies used in the context of the methods of the present disclosure may have pH-dependent binding characteristics. For example, anti-PD-1 antibodies for use in the methods of the present disclosure may exhibit reduced binding to PD-1 at acidic pH compared to neutral pH. Alternatively, anti-PD-1 antibodies of the present disclosure may exhibit enhanced binding to their antigen at acidic pH compared to neutral pH. The term "acidic pH" includes pH values ​​less than about 6.2, e.g., about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0 or less. As used herein, the term "neutral pH" refers to a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0077] In certain instances, "reduced binding to PD-1 at acidic pH compared to neutral pH" refers to the K D K values ​​for antibody binding to PD-1 at acidic pH D For example, an antibody or antigen-binding fragment thereof may have an acidic / neutral K of about 3.0 or greater. D When a ratio is presented, it may be considered to indicate "reduced binding to PD-1 at acidic pH compared to neutral pH for purposes of this disclosure. In certain exemplary embodiments, the acidic / neutral K ratio for an antibody or antigen-binding fragment of the disclosure is D The ratio can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or more.

[0078] Antibodies with pH-dependent binding properties can be obtained, for example, by screening a collection of antibodies for decreased (or increased) binding to a particular antigen at acidic pH compared to neutral pH. In addition, modification of the antigen-binding region in amino acid concentration can produce antibodies with pH-dependent characteristics. For example, by replacing one or more amino acids in the antigen-binding region (e.g., in the CDRs) with histidine residues, an antibody can be obtained that has decreased antigen binding at acidic pH compared to neutral pH. As used herein, the term "acidic pH" refers to a pH of 6.0 or less.

[0079] LAG-3 inhibitors The term "LAG-3" refers to lymphocyte-activation gene-3 protein, also known as CD223, an immune checkpoint receptor or T cell co-inhibitor. The amino acid sequence of full-length LAG-3 is provided in GenBank under accession number NP_002277.4. LAG-3 is a member of the immunoglobulin (Ig) superfamily. LAG-3 is a 503 amino acid type 1 transmembrane protein with four extracellular Ig-like domains D1-D4, and is expressed on activated T cells, natural killer cells, B cells, plasmacytoid dendritic cells, and regulatory T cells. The LAG-3 receptor binds to MHC class II molecules present on antigen-presenting cells (APCs).

[0080] As used herein, the term "T cell co-inhibitor" refers to ligands and / or receptors that regulate immune responses through T cell activation or suppression. The term "T cell co-inhibitor" is also known as T cell co-signaling molecules, which include, but are not limited to, programmed cell death-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), B and T lymphocyte attenuator (BTLA), CD-28, 2B4, LY108, T cell immunoglobulin and mucin 3 (TIM3), T cell immunoglobulin and T cell immunoreceptor with ITIM (TIGIT, also known as VSIG9), leukocyte-associated immunoglobulin-like receptor 1 (LAIR1, also known as CD305), inducible T cell co-stimulatory molecule (ICOS, also known as CD278), V domain Ig inhibitor of T cell activation (VISTA) and CD160.

[0081] LAG-3 inhibitors include antibodies and antigen-binding fragments thereof, as well as other substances (e.g., peptides and small molecules) that specifically bind to LAG-3 and antagonize one or more biological activities of LAG-3. Molecules that specifically bind to LAG-3 may be referred to as "anti-LAG-3."

[0082] In an embodiment of the disclosure, the LAG-3 inhibitor is an antibody or antigen-binding fragment thereof described in US20170101472.

[0083] According to certain embodiments, the antibody used in the method of the present disclosure specifically binds to LAG-3. The term "specifically binds" and the like means that the antibody or its antigen-binding fragment forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art, and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, as used in the context of the present disclosure, an antibody that "specifically binds" to LAG-3 has a K of less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM as measured by a surface plasmon resonance assay. D However, an isolated antibody that specifically binds human LAG-3 may have cross-reactivity to other antigens, such as LAG-3 molecules from other (non-human) species.

[0084] According to certain exemplary embodiments of the present disclosure, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity determining region (CDR) comprising any of the amino acid sequences of the anti-LAG-3 antibodies described in U.S. Patent No. 20170101472.

[0085] In certain exemplary embodiments, an anti-LAG-3 antibody or antigen-binding fragment thereof that may be used in the context of the disclosed methods comprises a heavy chain complementarity determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 11 and a light chain complementarity determining region (LCDR) of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 12. According to certain embodiments, an anti-LAG-3 antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO: 13, HCDR2 comprises the amino acid sequence of SEQ ID NO: 14, HCDR3 comprises the amino acid sequence of SEQ ID NO: 15, LCDR1 comprises the amino acid sequence of SEQ ID NO: 16, LCDR2 comprises the amino acid sequence of SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 18. In yet other embodiments, an anti-LAG-3 antibody or antigen-binding fragment thereof comprises a HCVR comprising SEQ ID NO: 11 and a LCVR comprising SEQ ID NO: 12. In certain embodiments, the methods of the disclosure include the use of an anti-LAG-3 antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-LAG-3 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 20. An exemplary antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12 is the fully human anti-LAG-3 antibody, also known as REGN3767.

[0086] According to certain exemplary embodiments, the method of the present disclosure includes the use of REGN3767, or its biological equivalent. As used herein, the term "biological equivalent" refers to an anti-LAG-3 antibody or LAG-3 binding protein or fragment thereof that is a pharmaceutical equivalent or pharmaceutical substitute that exhibits no significant difference in rate and / or extent of absorption from REGN3767 when administered in either single or multiple doses at the same molar dose under similar experimental conditions. In the context of the present disclosure, the term refers to an antigen binding protein that binds to LAG-3 that does not have clinically meaningful differences from REGN3767 in safety, purity and / or potency.

[0087] Other anti-LAG-3 antibodies that may be used in the context of the methods of the present disclosure include, for example, antibodies referred to and known in the art as rialtimab (U.S. Publication No. 20110150892), LAG525 (WO Publication No. 2017 / 037203), GSK2831781 (U.S. Publication No. 2016 / 0017037), Sym022 (WO Publication No. 2018 / 069500), INCAGN02385 (U.S. Publication No. 20180127499), or antibodies described in U.S. Patent / Publication Nos. 5,976,877, 6,143,273, 6,197,524, 8,551,481, 20110070238, 20110150892, 20130095114, 20140 093511, 20140127226, 20140286935, as well as WO 95 / 30750, WO 97 / 03695, WO 98 / 58059, WO 2004 / 078928, WO 2008 / 132601, WO 2010 / 019570, WO 201 4 / 008218, European Publication No. 0510079B1, European Publication No. 0758383B1, European Publication No. 0843557B1, European Publication No. 0977856B1, European Publication No. 1897548B2, European Publication No. 2142210A1, and European Publication No. 2320940B1.

[0088] Methods for Treating Cancer or Inhibiting Tumor Growth The present disclosure includes a method of treating, ameliorating, or reducing the severity of at least one symptom or sign, or inhibiting the growth of cancer in a subject. The method according to this embodiment includes administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds PD-1 in combination with a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds LAG-3. As used herein, the terms "treat," "treating," and the like, refer to alleviating a symptom, eliminating the cause of a symptom, either temporarily or permanently, slowing or inhibiting tumor growth, reducing tumor cell mass or burden, promoting tumor regression, causing tumor shrinkage, necrosis, and / or disappearance, and / or increasing the survival of a subject.

[0089] As used herein, the phrase "subject in need thereof" refers to a human or non-human mammal exhibiting one or more symptoms or signs of cancer, and / or a human or non-human mammal diagnosed with cancer and in need of treatment for cancer. In many embodiments, the term "subject" may be used interchangeably with the term "patient." For example, a human subject may be diagnosed with a primary or metastatic tumor and / or with one or more symptoms or signs, including, but not limited to, enlarged lymph nodes, abdominal distension, chest pain / tightness, unexplained weight loss, fever, night sweats, persistent fatigue, loss of appetite, enlarged spleen, and itching. In certain embodiments, the expressions include a human subject having and in need of treatment for astrocytoma, bladder cancer, blood cancer, blood cancer, bone cancer, brain cancer, breast cancer, cervical cancer, renal clear cell carcinoma, colorectal cancer, microsatellite intermediate colorectal cancer, cutaneous squamous cell carcinoma, diffuse large B-cell lymphoma, endometrial cancer, esophageal cancer, fibrosarcoma, gastric cancer, glioblastoma, glioblastoma multiforme, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, leukemia, liver cancer, leiomyosarcoma, lung cancer, lymphoma, melanoma, mesothelioma, myeloma, nasopharyngeal carcinoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, primary and / or recurrent carcinoma, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, squamous cell carcinoma, synovial sarcoma, thyroid cancer, triple negative breast cancer, uterine cancer, or Wilms' tumor. In certain embodiments, the phrase "subject in need thereof" includes patients with cancer that is resistant or refractory to previous therapy (e.g., treatment with conventional anti-cancer agents or therapies such as radiation, chemotherapy, or surgery, or treatment with anti-cancer biologics), or that is not adequately controlled by previous therapy. For example, the phrase includes subjects who have been treated with PD-1 or PD-L1 inhibitors (e.g., anti-PD-1 antibodies). The phrase also includes subjects with cancer for which conventional anti-cancer therapy is not advisable, e.g., due to toxic side effects. For example, the phrase includes patients who have undergone one or more cycles of chemotherapy with toxic side effects. In certain embodiments, the phrase "subject in need thereof" includes patients with cancer that has been treated but has subsequently recurred or metastasized.For example, patients with cancer who may have undergone treatment with one or more anti-cancer agents that results in tumor regression, but who have subsequently relapsed with cancer that is resistant to the one or more anti-cancer agents (e.g., a chemotherapy-resistant cancer), are treated using the methods provided herein.

[0090] The phrase "subject in need thereof" also includes subjects at risk of developing cancer, such as those with a family history of cancer, those with a personal history of cancer, or those with a compromised immune system. In some aspects, the subject is resistant or inadequately responsive to a previous therapy, or has relapsed after a previous therapy.

[0091] In certain embodiments, the methods provided herein may be used to treat patients who exhibit elevated levels of one or more cancer-associated biomarkers (e.g., PD-L1, or LAG-3). For example, the methods of the present invention include administering a therapeutically effective amount of an anti-LAG-3 antibody in combination with an anti-PD-1 antibody to a patient with elevated levels of LAG-3 and / or PD-L1. In one embodiment, the methods are used in patients with cancer selected based on LAG-3 expression in cancer tissue, the cancer tissue comprising tumor cells and tumor-infiltrating immune cells. In certain embodiments, the methods are used in patients with cancer selected based on ≧1% LAG-3 expression in cancer tissue and / or immune cells. In one embodiment, the methods are used in patients with cancer selected based on LAG-3 expression in cancer tissue, the cancer tissue comprising tumor cells and tumor-infiltrating immune cells. In certain embodiments, the methods are used in patients with cancer selected based on ≧1% LAG-3 expression in cancer tissue and / or immune cells. The method of determining LAG-3 or PD-L1 expression in cancer tissue and / or tumor-associated immune cells is well known in the art.In certain embodiments, the expression of LAG-3 in tumor tissue is determined by any assay known in the art, for example, by ELISA assay or by immunohistochemistry (IHC) assay (for example, as described in He et al 2017, J.Thoracic Oncol.12:814-823; WO2016124558 or WO2016191751).In certain embodiments, the expression of LAG-3 or PD-L1 is determined by quantifying RNA expression, for example, by in situ hybridization or by RT-PCR. In certain embodiments, expression of LAG-3 is determined by imaging with a labeled anti-LAG-3 antibody, e.g., by immunopositron emission tomography or iPET [see, e.g., The Oncologist, 12:1379 (2007); Journal of Nuclear Medicine, 52(8):1171 (2011); U.S. Patent Publication No. 2018 / 0228926].In certain embodiments, PD-L1 expression is determined by imaging with a labeled anti-PD-L1 antibody, for example by immunopositron emission tomography, or iPET (U.S. Patent Publication No. 2018 / 0161464).

[0092] In certain embodiments, the methods provided herein are used in subjects with cancer. The terms "tumor," "cancer," and "malignant tumor" are used interchangeably herein. Examples of cancer include, but are not limited to, astrocytoma, bladder cancer, blood cancer, blood cancer, bone cancer, brain cancer, breast cancer, cervical cancer, renal clear cell carcinoma, colorectal cancer, microsatellite intermediate colorectal cancer, cutaneous squamous cell carcinoma, diffuse large B-cell lymphoma, endometrial cancer, esophageal cancer, fibrosarcoma, gastric cancer, glioblastoma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, leukemia, liver cancer, leiomyosarcoma, lung cancer, lymphoma, melanoma, mesothelioma, myeloma, nasopharyngeal carcinoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, primary and / or recurrent cancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, squamous cell carcinoma, synovial sarcoma, thyroid cancer, triple negative breast cancer, uterine cancer, and Wilms' tumor. In some embodiments, the cancer is a primary cancer. In some embodiments, the cancer is a metastatic and / or recurrent cancer.

[0093] In certain embodiments, the cancer or tumor is selected from the group consisting of melanoma, renal clear cell carcinoma, non-small cell lung cancer, triple-negative breast cancer, endometrial cancer, cutaneous squamous cell carcinoma, diffuse large B-cell lymphoma, and head and neck squamous cell carcinoma.

[0094] According to certain embodiments, the disclosure includes a method of treating, slowing, or inhibiting tumor growth. In certain embodiments, this includes a method of promoting tumor regression. In certain embodiments, this includes a method of reducing tumor cell burden or reducing tumor burden. In certain embodiments, the disclosure includes a method of preventing tumor recurrence. The method according to this aspect includes sequentially administering a therapeutically effective amount of an anti-PD-1 antibody in combination with an anti-LAG-3 antibody to a subject in need thereof, each antibody being administered to the subject in multiple doses, for example, as part of a particular therapeutic dosing regimen. For example, the therapeutic dosing regimen may include administering one or more doses of an anti-PD-1 antibody to the subject about once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every six weeks, once every two months, once every three months, or once every four months. In certain embodiments, one or more doses of an anti-PD-1 antibody are administered in combination with one or more therapeutically effective doses of an anti-LAG-3 antibody, and the one or more doses of an anti-LAG-3 antibody are administered to a subject no more frequently than about once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every three weeks, once every four weeks, once a month, once every six weeks, once every two months, once every three months, or once every four months.

[0095] In certain embodiments, the present disclosure includes a method of inhibiting, slowing, or stopping tumor metastasis or tumor invasion into peripheral organs. The method according to this aspect includes administering a therapeutically effective amount of an anti-PD-1 antibody to a subject in need thereof. In certain embodiments, the anti-PD-1 antibody is administered in combination with an anti-LAG-3 antibody.

[0096] In certain embodiments, the present disclosure provides methods for increasing anti-tumor efficacy or increasing tumor inhibition. In certain embodiments, methods are provided for increasing tumor inhibition by, for example, about 20%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, or more than 80%, compared to subjects administered any antibody as monotherapy.

[0097] Methods provided herein, according to certain embodiments, include administering to a subject having cancer a therapeutically effective amount of an anti-PD-1 antibody before, simultaneously with, or after administering a therapeutically effective amount of an anti-LAG-3 antibody. In some aspects, the anti-PD-1 antibody may be administered about 1 day, more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, or more than 8 days before the anti-LAG-3 antibody. In some aspects, the anti-PD-1 antibody and the anti-LAG-3 antibody are administered simultaneously, or within 30 minutes, or within 60 minutes, or within 2 hours, or within 3 hours, or within 1 day of each other.

[0098] In certain embodiments, the methods provided herein include administering a therapeutically effective amount of an anti-PD-1 antibody to a subject with cancer. In certain embodiments, the cancer is indolent or aggressive. In certain embodiments, the subject is unresponsive to a previous therapy or has relapsed after a previous therapy. The previous therapy may include surgery, radiation, and / or chemotherapy, or treatment with a PD-1 inhibitor, a PD-L1 inhibitor, and / or any other anti-cancer biologic.

[0099] In certain embodiments, the methods of the disclosure include administering an anti-PD-1 antibody in combination with an anti-LAG-3 antibody to a subject in need thereof as a "first line" treatment (e.g., initial treatment). In other embodiments, the anti-PD-1 antibody in combination with an anti-LAG-3 antibody is administered as a "second line" treatment (e.g., after prior therapy). For example, the anti-PD-1 antibody in combination with an anti-LAG-3 antibody is administered as a "second line" treatment to a subject who has relapsed after prior therapy, e.g., with chemotherapy or rituximab.

[0100] In certain embodiments, the method of the present disclosure is used to treat patients with MRD-positive disease. Minimal residual disease (MRD) refers to a small number of cancer cells remaining in a patient during or after treatment, and the patient may or may not show symptoms or signs of disease. If such residual cancer cells are not removed, they often lead to disease recurrence. The present disclosure includes methods of inhibiting and / or removing residual cancer cells in patients upon MRD testing. MRD may be assayed according to methods known in the art (e.g., MRD flow cytometry). The method according to this aspect of the present disclosure includes administering an anti-PD-1 antibody in combination with an anti-LAG-3 antibody to a subject in need thereof.

[0101] The methods provided herein, according to certain embodiments, include administering to a subject a therapeutically effective amount of each of an anti-PD-1 antibody and an anti-LAG-3 antibody in combination with a third therapeutic agent, such as, for example, radiation, chemotherapy, surgery, a cancer vaccine, CART, a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody), a CD3 inhibitor, a CD20 inhibitor, a CTLA-4 inhibitor, a CD38 inhibitor, a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, an indoleamine-2,3-dioxygenase (IDO) inhibitor, a vascular endothelial growth factor (VEGF) antagonist, an Ang2 inhibitor, a transforming growth factor beta (TGFβ) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an antitumor agent against a tumor-specific antigen, or an anti-PD-L1 antibody. Antibodies that induce inflammatory bowel disease (e.g., CA9, CA125, melanoma associated antigen 3 (MAGE3), carcinoembryonic antigen (CEA)], sterile Mycobacterium bovis vaccine, granulocyte-macrophage colony-stimulating factor, oncolytic viruses, cytotoxins, CD28 agonists, GITR agonists, 4-1BB agonists, CD20×CD3 bispecific antibodies (e.g., REGN1979), MUC16×CD3 bispecific antibodies, vimentin, tumor-M2-PK, prostate-specific antigen (PSA), mucin-1, MART-1, and CA19-9), vaccines (e.g., Bacillus Calmette-Guerin), granulocyte macrophage colony stimulating factor, cytotoxins, chemotherapeutic agents, IL-6R inhibitors, IL-4R inhibitors, IL-10 inhibitors, cytokines such as IL-2, IL-7, IL-12, IL-21, and IL-15, anti-inflammatory agents such as corticosteroids, and non-steroidal anti-inflammatory agents.

[0102] In certain embodiments, the antibody may be administered in combination with a therapy including a chemotherapy agent, radiation, or surgery. As used herein, the phrase "in combination with" means that the antibody is administered to the subject simultaneously with, immediately before, or immediately after administration of a third therapeutic agent. In certain embodiments, the third therapeutic agent is administered as a co-formulation with the antibody. In related embodiments, the disclosure includes a method comprising administering a therapeutically effective amount of an anti-PD-1 antibody in combination with an anti-LAG-3 antibody to a subject on a background anti-cancer treatment regimen. The background anti-cancer treatment regimen may include, for example, a course of chemotherapy, or radiation. The anti-PD-1 antibody in combination with the anti-LAG-3 antibody may be added at the beginning of the background anti-cancer treatment regimen. In some embodiments, the antibody is added as part of a "background step-down" scheme, where the background anti-cancer therapy is gradually withdrawn from the subject over time (e.g., in a step-wise manner) while the antibody is administered to the subject at a constant dose, or at increasing or decreasing doses over time.

[0103] In certain embodiments, the methods of the disclosure include administering to a subject in need thereof a therapeutically effective amount of an anti-PD-1 antibody in combination with a therapeutically effective amount of an anti-LAG-3 antibody, where administration of the antibodies leads to increased inhibition of tumor growth. In certain embodiments, tumor growth is inhibited by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80% compared to untreated subjects or subjects administered either antibody as monotherapy. In certain embodiments, administration of an anti-PD-1 antibody and / or an anti-LAG-3 antibody to a subject leads to increased tumor regression, tumor shrinkage, and / or elimination. In certain embodiments, administration of an anti-PD-1 antibody and / or an anti-LAG-3 antibody leads to a delay and onset of tumor growth, e.g., tumor growth may be delayed by about 3 days, more than 3 days, about 7 days, more than 7 days, at least 10 days, more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 1 year, more than 2 years, or more than 3 years, compared to untreated subjects or subjects treated with either antibody as monotherapy. In certain embodiments, administration of an anti-PD-1 antibody in combination with an anti-LAG-3 antibody prevents tumor recurrence and / or increases the duration of survival of a subject, e.g., by more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 12 months, more than 18 months, more than 24 months, more than 36 months, or more than 48 months, compared to untreated subjects or subjects administered either antibody as monotherapy. In certain embodiments, administration of the antibodies in combination increases progression-free survival or overall survival. In certain embodiments, administration of an anti-PD-1 antibody in combination with an anti-LAG-3 antibody increases the response and duration of response in a subject by, for example, more than 2%, more than 3%, more than 4%, more than 5%, more than 6%, more than 7%, more than 8%, more than 9%, more than 10%, more than 20%, more than 30%, more than 40%, or more than 50% over untreated subjects or subjects receiving either antibody as monotherapy. In certain embodiments, administration of an anti-PD-1 antibody and / or an anti-LAG-3 antibody to a subject with cancer leads to a complete disappearance of all evidence of tumor cells (a "complete response"). In certain embodiments, administration of an anti-PD-1 antibody and / or an anti-LAG-3 antibody to a subject with cancer leads to at least a 30% or greater increase in tumor cells or tumor size (a "partial response").In certain embodiments, administration of anti-PD-1 and / or anti-LAG-3 antibodies to subjects with cancer leads to complete or partial disappearance of tumor cells / lesions, including new measurable lesions. Tumor reduction can be measured by any method known in the art, such as X-ray, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetic analysis. In some aspects, administration of anti-PD-1 antibodies in combination with anti-LAG-3 antibodies to a patient population results in more patients responding to treatment, results in patients responding to treatment for longer even if more patients do not respond, and / or patients who respond to therapy have a stronger response.

[0104] In certain embodiments, the administered antibody combination is safe or well tolerated by the patient, and there is no increase or a tolerable increase in serious side effects compared to patients receiving either antibody as monotherapy.

[0105] Combination therapy According to certain embodiments, the method of the disclosure includes administering to a subject an anti-LAG-3 antibody in combination with an anti-PD-1 antibody. In certain embodiments, the method of the disclosure includes administering an antibody of additive or synergistic activity to treat cancer. As used herein, the term "in combination with" means that the anti-LAG-3 antibody is administered before, after, or simultaneously with the anti-PD-1 antibody. The term "in combination with" also includes sequential or simultaneous administration of the anti-PD-1 antibody and the anti-LAG-3 antibody. For example, when administered "before" the anti-LAG-3 antibody, the anti-PD-1 antibody may be administered more than 150 hours, about 150 hours, about 100 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before the administration of the anti-LAG-3 antibody. When administered "after" an anti-LAG-3 antibody, the anti-PD-1 antibody may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours after administration of the anti-LAG-3 antibody. Administered "concurrently" with an anti-LAG-3 antibody means that the anti-PD-1 antibody is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or simultaneously) of administration of the anti-LAG-3 antibody, e.g., within 5 minutes of completion of an anti-LAG-3 antibody infusion, or is administered to the subject as a single combined dosage formulation including both the anti-PD-1 antibody and the anti-LAG-3 antibody. In some embodiments, the anti-PD-1 antibody is administered on the same day as the anti-LAG-3 antibody. In some embodiments, the anti-PD-1 antibody and the anti-LAG-3 antibody are administered in separate dosage forms but within 8 hours of each other, e.g., within 6 hours, or within 5 hours, or within 4 hours, or within 3 hours, or within 2 hours, or within 60 minutes of each other.

[0106] In certain embodiments, the method provided herein includes administration of a third therapeutic agent, and the third therapeutic agent is an anti-cancer agent.As used herein, "anti-cancer agent" refers to any agent useful for treating cancer, including, but not limited to, cytotoxins and agents such as antimetabolites, alkylating agents, anthracyclines, antibiotics, antimitotics, procarbazine, hydroxyurea, asparaginase, corticosteroids, mitotane (O,P'-(DDD)), biologics (e.g., antibodies and interferons) and radioactive agents.As used herein, "cytotoxins or cytotoxic agents" also refers to chemotherapeutic agents and refers to any agent that is harmful to cells. Examples include Taxol® (paclitaxel), temozolamide, cytochalasin B, gramicidin D, ethidium bromide, emetine, cisplatin, mitomycin, etoposide, tenoposide, vincristine, vinbiastine, koicin, doxorubicin, daunorubicin, dihydroxyanthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin, as well as analogs or homologs thereof. In certain embodiments, the methods provided herein may involve the use of any combination of chemotherapy, chemotherapy alone or in combination with radiation, surgery, a cancer vaccine, a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody), a CD20 inhibitor, a CD3 inhibitor, a CTLA-4 inhibitor (e.g., ipilimumab), a CD38 inhibitor, a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, another T cell co-inhibitor or ligand antagonist (e.g., an antibody against CD-28, 2B4, LY108, LAIR1, ICOS, CD160, or VISTA), an indoleamine-2,3-dioxygenase (IDO) inhibitor, a vascular endothelial growth factor (VEGF) antagonist [e.g., a "VEGF-Trap" such as aflibercept or a combination of chemotherapy with other anti-cancer drugs, as described in U.S. Pat. No. 7,087,331, or ...VEGF inhibitory fusion proteins described in US Pat. No. 411, or anti-VEGF antibodies or antigen-binding fragments thereof (e.g., bevacizumab, or ranibizumab) or small molecule kinase inhibitors of VEGF receptors (e.g., sunitinib, sorafenib, or pazopanib), Ang2 inhibitors (e.g., nesvacumab), transforming growth factor beta (TGFβ) inhibitors, epidermal growth factor receptor (EGFR) inhibitors (e.g., erlotinib, cetuximab), agonists for costimulatory receptors (e.g., glucocorticoids, erythrocyte serine / erythrocyte sarcoma, leuk ... agonists against cytoplasmic nephropathy-inducible TNFR-associated proteins), antibodies against tumor-specific antigens [e.g., CA9, CA125, melanoma-associated antigen 3 (MAGE3), carcinoembryonic antigen (CEA)], CD28 agonists, GITR agonists, 4-1BB agonists, CD20×CD3 bispecific antibodies (e.g., REGN1979), MUC16×CD3 bispecific antibodies, vimentin, tumor-M2-PK, prostate-specific antigen (PSA), mucin-1, MART-1, and CA19-9), vaccines (e.g., Bacillus Calmette-Guerin, cancer vaccines), adjuvants to increase antigen presentation (e.g., granulocyte-macrophage colony-stimulating factor), oncolytic viruses, cytotoxins, chemotherapeutic agents (e.g., dacarbazine, temozolomide, cyclophosphamide, docetaxel, doxorubicin, daunorubicin, cisplatin, carboplatin, gemcitabine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, and vincristine), radiation therapy, IL-6R inhibitors (e.g., sarilumab), IL-4R inhibitors (e.g., dupilumab), IL-10 inhibitors, cytokines such as IL-2, IL-7, IL-12, IL-21, and IL-15, antibody drug conjugates (ADCs) (e.g., anti-CD19-DM4 ADC, and anti-DS6-DM4 ADC). ADC), chimeric antigen receptor T cells (e.g., CD19-targeted T cells) or other cellular therapies, and administration of a third therapeutic agent selected from the group consisting of anti-inflammatory agents (e.g., corticosteroids, and nonsteroidal anti-inflammatory drugs).

[0107] In certain embodiments, the methods provided herein include administering an anti-PD-1 antibody and an anti-LAG-3 antibody in combination with radiation therapy / chemotherapy to produce a long-lasting anti-tumor response and / or enhance survival of patients with cancer.

[0108] In some embodiments, the method of the present disclosure includes administering radiation therapy before, simultaneously with, or after administering anti-PD-1 and anti-LAG-3 antibodies to a cancer patient. For example, radiation therapy may be administered in one or more doses to a tumor lesion after administration of one or more doses of the antibody. In some embodiments, radiation therapy may be administered locally to a tumor lesion to increase the local immunogenicity of the patient's tumor (adjuvinating radiation) and / or kill tumor cells (ablative radiation) before or after systemic administration of anti-PD-1 and / or anti-LAG-3 antibodies. In certain embodiments, the antibody may be administered in combination with radiation therapy and a chemotherapeutic agent (e.g., temozolomide or cyclophosphamide) or a VEGF antagonist (e.g., aflibercept).

[0109] Pharmaceutical Compositions and Administration Methods are provided herein that include administering an anti-PD-1 antibody in combination with an anti-LAG-3 antibody to a subject, the antibodies being contained in separate or combined (single) pharmaceutical compositions. The pharmaceutical compositions of the present disclosure may be formulated with suitable carriers, excipients, and other agents that provide suitable transport, delivery, tolerability, etc. Numerous suitable formulations can be found in the formulary known to every pharmacist: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipids (cationic or anionic) containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

[0110] A variety of delivery systems are known and can be used to administer the pharmaceutical compositions of the present disclosure, such as, for example, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis, etc. (see, for example, Wu et al., 1987, J.Biol.Chem.262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (such as, for example, oral mucosa, rectal mucosa, and intestinal mucosa), and can be administered together with other biologically active agents.

[0111] The pharmaceutical composition of the present disclosure can be delivered subcutaneously or intravenously with a standard needle and syringe. In one embodiment, the syringe is a pre-filled syringe. In addition, for subcutaneous delivery, a pen delivery device easily finds use in delivering the pharmaceutical composition of the present disclosure. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge containing the pharmaceutical composition. Once all of the pharmaceutical composition inside the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device is sold pre-filled with the pharmaceutical composition held in a reservoir inside the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0112] In certain circumstances, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump can be used. In another embodiment, a polymeric material can be used. See Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Fla. In yet another embodiment, the controlled release system can be placed in the vicinity of the target of the composition. Thus, only a fraction of the systemic dose is required (see, for example, Goodson, 1984, Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0113] The injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injections, drip infusions, and the like. These injectable preparations may be prepared by known methods. For example, the injectable preparations may be prepared by dissolving, suspending, or emulsifying the above-mentioned antibody or its salt in a sterile aqueous or oily medium conventionally used for injections. The aqueous medium for injection may be, for example, physiological saline, an isotonic solution containing glucose, and other auxiliary agents, which may be combined with a suitable solubilizing agent such as alcohol (e.g., ethanol), polyalcohol (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], and the like. The oily medium may be, for example, sesame oil, soybean oil, and the like, which may be combined with a solubilizing agent such as benzyl benzoate, benzyl alcohol, and the like. The injection solution thus prepared is preferably filled into a suitable ampoule.

[0114] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared in dosage forms with unit doses suitable for the dosage of active ingredients.Such dosage forms in unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0115] Dosing regimen The disclosure includes methods comprising administering to a subject an anti-PD-1 antibody at a dosing frequency of about 4 times per week, twice per week, once per week, once per 2 weeks, once per 3 weeks, once per 4 weeks, once per 5 weeks, once per 6 weeks, once per 8 weeks, once per 12 weeks or less, so long as a therapeutic response is achieved. In certain embodiments, the disclosure includes methods comprising administering to a subject an anti-LAG-3 antibody at a dosing frequency of about 4 times per week, twice per week, once per week, once per 2 weeks, once per 3 weeks, once per 4 weeks, once per 5 weeks, once per 6 weeks, once per 8 weeks, once per 12 weeks or less, so long as a therapeutic response is achieved. In certain embodiments, the methods include administration of an anti-PD-1 antibody in combination with an anti-LAG-3 antibody at a dosing frequency of about 4 times per week, twice per week, once per week, once per 2 weeks, once per 3 weeks, once per 4 weeks, once per 5 weeks, once per 6 weeks, once per 8 weeks, once per 9 weeks, once per 12 weeks or less, so long as a therapeutic response is achieved.

[0116] According to certain embodiments of the present disclosure, multiple doses of an anti-PD-1 antibody in combination with an anti-LAG-3 antibody may be administered to a subject over a defined time course. The method according to this aspect of the present disclosure includes sequentially administering to a subject one or more doses of an anti-PD-1 antibody in combination with one or more doses of an anti-LAG-3 antibody. As used herein, "sequentially administering" means that each dose of the antibody is administered to the subject at different times, such as on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present disclosure includes methods that include sequentially administering to a patient a single initial dose of an anti-PD-1 antibody, followed by one or more secondary doses of an anti-PD-1 antibody, optionally followed by one or more tertiary doses of an anti-PD-1 antibody. In certain embodiments, the method further includes sequentially administering to a patient a single initial dose of an anti-LAG-3 antibody, followed by one or more secondary doses of an anti-LAG-3 antibody, optionally followed by one or more tertiary doses of an anti-LAG-3 antibody.

[0117] According to certain embodiments of the present disclosure, multiple doses of anti-PD-1 antibody and anti-LAG-3 antibody may be administered to a subject over a defined time course. The method according to this aspect of the disclosure includes sequentially administering multiple doses of anti-PD-1 antibody and anti-LAG-3 antibody to a subject. As used herein, "sequentially administered" means that each dose of anti-PD-1 antibody in combination with anti-LAG-3 antibody is administered to a subject at different times, such as on different days separated by a predetermined interval (e.g., hours, days, weeks, or months).

[0118] According to certain embodiments of the present disclosure, multiple doses of anti-LAG-3 antibody can be administered to the subject once every 3 or 6 weeks for months or years, and then the subject is administered an anti-PD-1 antibody in combination with the anti-LAG-3 antibody for months or years. In some aspects, the anti-LAG-3 antibody dosing is different for monotherapy and combination therapy. In some aspects, the anti-LAG-3 antibody dosing is the same whether administered as monotherapy or in combination with an anti-PD-1 antibody.

[0119] The terms "initial dose", "secondary dose" and "tertiary dose" refer to the temporal order of administration. Thus, an "initial dose" is a dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose"), a "secondary dose" is a dose administered after the initial dose, and a "tertiary dose" is a dose administered after the secondary dose. The initial dose, secondary dose, and tertiary dose may all contain the same amount of antibody (anti-PD-1 antibody or anti-LAG-3 antibody). However, in certain embodiments, the amount contained in the initial dose, secondary dose, and / or tertiary dose differs from each other (e.g., adjusted up or down) during the course of treatment. In certain embodiments, one or more doses (e.g., 1, 2, 3, 4, or 5) are administered as a "loading dose" at the beginning of a treatment regimen, with subsequent doses administered on a less frequent basis (e.g., "maintenance doses"). For example, an anti-PD-1 antibody may be administered to a patient with cancer at a loading dose of about 1-20 mg / kg, followed by one or more maintenance doses of about 3 mg / kg of the patient's body weight.

[0120] In one exemplary embodiment of the present disclosure, each secondary and / or tertiary dose is administered in a dose that is ½ to 14 (e.g., ½, 1, 1 1 / 2 , 2, 2 1 / 2 , 3, 3 1 / 2 , 4, 4 1 / 2 , 5, 5 1 / 2 , 6, 6 1 / 2 , 7, 7 1 / 2 , 8, 8 1 / 2 , 9, 9 1 / 2 , 10, 10 1 / 2 , 11, 11 1 / 2 , 12, 12 1 / 2 , 13, 13 1 / 2 , 14, 14 1 / 2 As used herein, the phrase "immediately preceding" refers to a dose of an anti-PD-1 antibody (and / or anti-LAG-3 antibody) in a series of multiple doses that is administered to a patient prior to administration of the immediately succeeding dose in the series, with no intervening doses.

[0121] Methods according to some aspects may include administering any number of secondary and / or tertiary doses of an anti-PD-1 antibody (and / or anti-LAG-3 antibody) to a patient. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0122] In embodiments including multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1-2 weeks after the immediately preceding dose. Similarly, in embodiments including multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2-4 weeks after the immediately preceding dose. Alternatively, the frequency with which the secondary and / or tertiary doses are administered to the patient may vary over the course of the treatment regimen. The frequency of administration may be adjusted during the course of treatment by the physician depending on the needs of the individual patient after clinical testing.

[0123] In certain embodiments, one or more doses of anti-PD-1 antibody and / or anti-LAG-3 antibody are administered on a more frequent basis (e.g., twice a week, once a week, or once every two weeks) at the start of a treatment regimen as an "induction dose," followed by subsequent doses ("consolidation doses" or "maintenance doses") administered on a less frequent basis (e.g., once every 4-12 weeks).

[0124] Contemplated herein is co-administration of an anti-PD-1 antibody and an anti-LAG-3 antibody, in some embodiments, administered in separate doses at similar or different frequencies compared to the anti-PD-1 antibody. In some embodiments, the anti-LAG-3 antibody is administered before, after, or simultaneously with the anti-PD-1 antibody. In certain embodiments, the anti-LAG-3 antibody is administered with the anti-PD-1 antibody as a single dose formulation.

[0125] The present disclosure relates to methods comprising sequential administration of an anti-PD-1 antibody in combination with an anti-LAG-3 antibody to a patient for treating cancer. In some embodiments, the method comprises administering one or more doses of an anti-PD-1 antibody, followed by one or more doses of an anti-LAG-3 antibody. In certain embodiments, the method comprises administering one dose of an anti-PD-1 antibody, followed by one dose of an anti-LAG-3 antibody. In some embodiments, one or more doses of about 0.1 mg / kg to about 20 mg / kg of an anti-PD-1 antibody may be administered, followed by one or more doses of about 0.1 mg / kg to about 50 mg / kg of an anti-LAG-3 antibody to inhibit tumor growth and / or prevent tumor recurrence in a subject with cancer. In some embodiments, an anti-PD-1 antibody is administered in one or more doses, followed by one or more doses of an anti-LAG-3 antibody, which results in increased anti-tumor efficacy (e.g., greater inhibition of tumor growth, increased prevention of tumor recurrence, compared to untreated subjects or subjects administered either antibody as monotherapy).

[0126] The present disclosure also relates to methods comprising sequential administration of an anti-LAG-3 antibody in combination with an anti-PD-1 antibody to a patient to treat cancer. In some embodiments, the method comprises administering one or more doses of an anti-LAG-3 antibody, followed by one or more doses of an anti-PD-1 antibody. In certain embodiments, the method comprises administering one dose of an anti-LAG-3 antibody, followed by one dose of an anti-PD-1 antibody. In some embodiments, one or more doses of about 0.1 mg / kg to about 50 mg / kg of an anti-LAG-3 antibody may be administered, followed by one or more doses of about 0.1 mg / kg to about 20 mg / kg of an anti-PD-1 antibody to inhibit tumor growth and / or prevent tumor recurrence in a subject with cancer. In some embodiments, one or more doses of about 50 mg to about 8000 mg of an anti-LAG-3 antibody may be administered, followed by one or more doses of about 50 mg to about 1500 mg of an anti-PD-1 antibody to inhibit tumor growth and / or prevent tumor recurrence in a subject with cancer. In some embodiments, an anti-LAG-3 antibody is administered in one or more doses followed by one or more doses of an anti-PD-1 antibody, resulting in increased anti-tumor efficacy (e.g., greater inhibition of tumor growth, increased prevention of tumor recurrence compared to untreated subjects or subjects receiving either antibody as monotherapy).

[0127] Dosage The amount of anti-PD-1 antibody and / or anti-LAG-3 antibody administered to a subject by the method of the present disclosure is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to an amount of antibody (anti-PD-1 antibody or anti-LAG-3 antibody) that produces or has one or more therapeutic effects, compared to untreated subjects or subjects administered either antibody as monotherapy: (a) reduction in the severity of cancer or duration of symptoms of cancer; (b) inhibition of tumor growth or increase in tumor necrosis, tumor shrinkage and / or tumor disappearance; (c) delay in tumor growth and development; (d) inhibition or delay or halt of tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of subjects with cancer; and / or (g) reduction in the use or need for conventional anti-cancer therapy (e.g., reduction or elimination of the use of chemotherapeutic or cytotoxic agents).

[0128] In the case of an anti-PD-1 antibody, a therapeutically effective amount is about 0.05 mg to about 1500 mg of an anti-PD-1 antibody, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, or the like. g, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1500 mg. In certain embodiments, 350 mg of anti-PD-1 antibody is administered. In certain embodiments, 1050 mg of anti-PD-1 antibody is administered.

[0129] In the case of an anti-LAG-3 antibody, a therapeutically effective amount is about 10 mg to about 8000 mg of an anti-LAG-3 antibody, for example, about 10 mg, about 20 mg, about 50 mg, about 70 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, It can be about 1000 mg, about 1050 mg, about 1100 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2200 mg, about 2500 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3200 mg, about 4000 mg, about 5000 mg, about 6000 mg, about 7000 mg, or about 8000 mg.

[0130] The amount of either the anti-PD-1 antibody or the anti-LAG-3 antibody contained in an individual dose may be expressed in terms of milligrams per kilogram of the subject's body weight (i.e., mg / kg). In certain embodiments, either the anti-PD-1 antibody or the anti-LAG-3 antibody used in the methods of the present disclosure may be administered to a subject at a dose of about 1 to about 50 mg / kg of the subject's body weight. For example, the anti-PD-1 antibody may be administered at a dose of about 0.1 mg / kg of the subject's body weight to about 20 mg / kg of the subject's body weight. The anti-LAG-3 antibody may be administered at a dose of about 0.1 mg / kg of the subject's body weight to about 50 mg / kg of the subject's body weight. EXAMPLES

[0131] The following examples are presented to provide those skilled in the art with a complete disclosure and description of how to make and use the disclosed methods and compositions, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, and temperature is in ° C (Celsius) at or near atmospheric pressure. The compositions and methods described in the examples form part of this disclosure.

[0132] Example 1: Clinical Trial of Anti-PD-1 and Anti-LAG-3 Antibodies in Patients with Advanced Malignancies This is a Phase I first-in-human (FIH), open-label, multicenter, dose-escalation study of the safety, tolerability, activity, and pharmacokinetics of REGN3767 administered as monotherapy and in combination with REGN2810 in patients with advanced malignancies. The study flow diagram (for individual patients) is shown in Figure 1, and the study design showing the dose-escalation scheme and cohorts is shown in Figure 2.

[0133] An exemplary anti-PD-1 antibody used in this example is REGN2810 (also known as cemiplimab, LIBTAYO®). An exemplary anti-LAG2 antibody used in this example is REGN3767.

[0134] the purpose The primary objective of this study is to evaluate the safety and pharmacokinetics to determine the selected dose levels for expansion of REGN3767 administered as monotherapy and in combination with REGN2810 in patients with advanced malignancies, including lymphoma. The primary objective in the dose expansion phase is to evaluate the preliminary antitumor activity of REGN3767 alone and in combination with REGN2810 (separately by cohort), as measured by objective response rate (ORR).

[0135] Secondary objectives are: (i) to evaluate the preliminary antitumor activity of REGN3767 alone or in combination with REGN2810 (separately by cohort) in dose escalation as measured by objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (solid tumors) or Lugano criteria (lymphoma); (ii) to evaluate the ORR based on Immune Response Evaluation Criteria in Solid Tumors (iRECIST), best overall response (BOR), duration of response (DOR), disease control rate, and progression-free survival (PFS) based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1), to evaluate the preliminary anti-tumor activity of REGN3767 alone and in combination with REGN2810 (separately by cohort) in dose escalation and expansion as measured by iRECIST, and Lugano criteria; (iii) to characterize the safety profile in each expansion cohort, as determined in the dose escalation phase; (iv) to characterize the pharmacokinetics of REGN3767 as monotherapy and of REGN3767 and REGN2810 when given in combination; and (v) to evaluate immunogenicity, as measured by anti-drug antibodies (ADA), for REGN3767 and REGN2810.

[0136] Additional objectives include: (i) assessing overall survival; (ii) assessing tumor volume; (iii) evaluating any relationship with drug concentration of immunogenicity for REGN2810 and REGN3767 as measured by ADA; (iv) evaluating pharmacodynamic changes in putative serum biomarkers (which may include, but are not limited to, cytokines, circulating tumor nucleic acids, etc.); (v) performing pharmacokinetic / pharmacodynamic analyses (ER analyses) for relevant exploratory biomarkers; (vi) PBMC subset distribution and expansion of circulating tumor nucleic acids, immune checkpoint molecules of interest, and other biomarkers. This includes assessing the predictability and correlation to clinical response of biomarkers of interest, which may include, but are not limited to, tumor RNA expansion, numbers and distribution of tumor infiltrating lymphocytes (such as CD8+ T cells, CD4+ T cells, T regulatory cells, and other subtypes such as tissue tolerance, B cells, bone marrow derived cells, NK cells, etc.), expression levels (messenger RNA and / or protein) of PD-1, PD-L1, LAG-3, MHC class II and potentially other immune modulators or their ligands, mutations in known oncogenes and potential tumor neoantigens, and tumor mutational burden.

[0137] Study population The target population for the dose escalation phase includes patients with advanced malignancies who have not received prior therapy with an anti-LAG-3 drug and who are not candidates for standard therapy or for whom there is no available therapy expected to provide clinical benefit, and patients with malignancies that are incurable, have failed to respond to standard therapy, or have demonstrated tumor progression despite standard therapy.

[0138] The target population for the expansion cohort includes patients with selected malignancies (see Table 1) who have not received prior therapy with an anti-LAG-3 agent and who: · have not previously received anti-PD-PD1 / PD-L1 therapy but are appropriate candidates to receive anti-PD-1-based therapy (cohorts 1, 3, 5, 6, 9, and 11), or had already tolerated anti-PD-1 / PD-L1-based therapy for at least 6 weeks but then progressed on that therapy or had SD or PR as best response with a subsequent stable response for 6 months (cohorts 2, 4, 7, 10, 12, and 13); or are not candidates for standard therapy or have no available therapy expected to provide clinical benefit and are suitable for REGN3767 monotherapy (Cohort 8); or suitable for REGN3767 monotherapy and do not have access to approved anti-PD-1 therapy for their disease (cohort 14), or have unresectable or metastatic cutaneous melanoma and have not received systemic therapy (Cohort 15), or · had not received prior systemic therapy for unresectable or metastatic cutaneous melanoma, but had received neoadjuvant or adjuvant therapy (which may have included anti-PD-1 / PD-L1 therapy) during a treatment-free and disease-free interval of >6 months (Cohort 16). [Table 1]

[0139] Selection Criteria Patients must meet the following criteria to be eligible for enrollment in the study:

[0140] 1. Men and women aged 18 and over.

[0141] 2. Dose escalation cohort: Patients with a histologically or cytologically confirmed diagnosis of malignancy (including lymphoma) presenting with tumor progression, no available therapy likely to provide clinical benefit, and who have been previously treated with a PD-1 / PD-L1 inhibitor not present Patients. These patients do not need to have measurable disease according to RECIST 1.1 or Lugano criteria.

[0142] 3. Dose expansion cohort: measurable disease according to RECIST 1.1 or Lugano criteria meeting the following criteria: +Patients with a histologically or cytologically confirmed diagnosis of one of the following tumors, including: Anti-PD-1 / PD-L1 naive stage IIIB, IIIC, or IV NSCLC with no prior therapy for metastatic disease or disease progression / recurrence after one platinum-containing regimen. Patients with known targetable genetic mutations or rearrangements (EGFR mutations, ALK rearrangements, ROS1 rearrangements) are excluded (Cohort 1). The decision to test or not and which testing method to use will be subject to local procedure or guideline requirements. Anti-PD-1 / PD-L1-experienced with ≤2 prior therapies for metastatic disease * , stage IIIB, IIIC, or IV NSCLC. Patients with known targetable genetic mutations or rearrangements (EGFR mutations, ALK rearrangements, ROS1 rearrangements) are excluded (Cohort 2). The decision to test and which testing method to use will be subject to local procedure or guideline requirements. · Anti-PD-1 / PD-L1 naive advanced or metastatic ccRCC with clear cell component who received ≤2 prior regimens of antiangiogenic therapy (Cohort 3). Received ≤2 prior regimens of antiangiogenic therapy, with clear cell component, anti-PD-1 / PD-L1 experienced * , ccRCC or metastatic ccRCC (renal clear cell carcinoma) (Cohort 4). Anti-PD-1 / PD-L1 naive metastatic TNBC (estrogen, progesterone, and human epidermal growth factor receptor 2 negative breast cancer) who had received ≤5 prior lines of therapy (Cohort 5). Anti-PD-1 / PD-L1 naive advanced non-uveal melanoma or metastatic non-uveal melanoma who have received ≤2 prior regimens for metastatic disease # (Cohort 6). Received ≤2 prior regimens for metastatic disease; anti-PD-1 / PD-L1 experienced * Advanced or metastatic nonuveal melanoma # (Cohort 7). Anti-PD-1 / PD-L1 naive relapsed / refractory DLBCL (diffuse large B-cell lymphoma) that has progressed after autologous stem cell transplant or is not a candidate for autologous stem cell transplant. The definition includes patients with complex histology that is predominantly DLBCL or high-grade B-cell lymphoma with MYC, BCL2 and / or BCL6 rearrangements ("double-hit or triple-hit") with DLBCL morphology (Cohorts 8 and 9). Anti-PD-1 / PD-L1 experienced, who have progressed after autologous stem cell transplant or are not candidates for autologous stem cell transplant * Relapsed / refractory DLBCL. Definition includes patients with complex histology, primarily DLBCL or high-grade B-cell lymphoma with MYC, BCL2 and / or BCL6 rearrangements ("double-hit or triple-hit") with DLBCL morphology (Cohort 10). Anti-PD-1 / PD-L1 naive recurrent and / or metastatic HNSCC (irrespective of HPV status) without curative options who have declined or are ineligible for platinum-based chemotherapy or have tumor progression or recurrence within 6 months of the last dose of platinum therapy in the adjuvant (i.e., with radiation after surgery), primary (i.e., with radiation), recurrent, or metastatic setting. In addition to radiological progression, clinical progression is defined as progression of a lesion at least 10 mm in size that is tolerated and suitable for caliper measurement (e.g., superficial skin lesions by RECIST 1.1) or a lesion that is visualized, photographically documented by measurement, and shown to be progressing. For further details, see inclusion criteria

[0154] (Cohort 11). Anti-PD-1 / PD-L1 experienced with no curative options * Recurrent and / or metastatic HNSCC (irrespective of HPV status). See inclusion criteria for further details (Cohort 12). Anti-PD-1 / PD-L1 experience *Locally advanced or metastatic CSCC (cutaneous squamous cell carcinoma). Patients with locally advanced CSCC are not suitable for surgery. Acceptable reasons for surgery to be considered inappropriate are 1) predicted recurrence of CSCC after ≥2 surgical procedures and low likelihood of curative resection, and / or 2) substantial expected morbidity or deformity from surgery. See inclusion criteria for further details (Cohort 13). · Anti-PD-1 / PD-L1 naive locally advanced or metastatic CSCC. Patients may not have access to anti-PD-1 therapy approved for the treatment of advanced CSCC. Patients with locally advanced CSCC are not suitable for surgery. Acceptable reasons for surgery to be considered inappropriate are 1) prediction of recurrence of CSCC after ≥2 surgical procedures and low likelihood of curative resection, and / or 2) substantial morbidity or deformity expected from surgery. See inclusion criteria

[0155] for further details (Cohort 14). Systemic treatment naive unresectable or metastatic cutaneous melanoma§. Cohort 6 must be met prior to enrollment in this cohort (Cohort 15). Unresectable or metastatic cutaneous melanoma who have received prior neoadjuvant and / or adjuvant therapy for melanoma but have not received prior systemic therapy for unresectable or metastatic disease § (Cohort 16). To be eligible for this cohort, patients must: - No prior systemic therapy for unresectable or metastatic disease Treatment therapies that have received neoadjuvant and / or adjuvant therapy may include, but are not limited to, anti-PD-1 / anti-PD-L1, anti-CTLA-4, BRAF / MEK inhibitors. Completed neoadjuvant and / or adjuvant treatment regimens (i.e., did not discontinue due to toxicity) · Had a treatment-free and disease-free interval of >6 months. Note:

[0143] † Previously irradiated lesions may be followed as target lesions as long as progression is confirmed after radiation therapy. Previously irradiated lesions may be followed as non-target lesions if there is at least one other measurable target lesion.

[0144] * Anti-PD-1 / PD-L1 experienced patients must have received their most recent anti-PD-1 / PD-L1 dose within 3 months of screening (Blasig, 2017). Anti-PD-1 / PD-L1 experienced is defined as having tolerated or been tolerating (i.e., not discontinued due to toxicity) anti-PD-1 / PD-L1 therapy for at least 6 weeks and (i) disease progression either during therapy with anti-PD-1 / PD-L1 or within 12 weeks of the last dose; or (ii) SD or PR as best response (70% or less decline from baseline), including stable response thereafter, for 6 months between anti-PD-1 / PD-L1 therapies.

[0145] * Anti-PD-1 / PD-L1 experienced patients must have had at least 6 weeks of an anti-PD-1 / PD-L1 containing regimen to be considered experienced. If patients received anti-PD-1 / PD-L1 for less than 6 weeks and did not discontinue due to toxicity and / or on-treatment imaging indicating disease progression, they may be considered anti-PD-1 / PD-L1 naive for enrollment.

[0146] #Combined acral lentiginous melanoma and mucosal melanoma are limited to <15% of each cohort.

[0147] § Acral lentiginous melanoma is limited to <15% of each cohort.

[0148] ¶ Patients in Cohort 9 must have received 89Zr-DFO-REGN3767 (anti-LAG-3 immunoPET [iPET] antibody) prior to study enrollment.

[0149] Eastern Cooperative Oncology Group performance status of 4.0 or 1

[0150] 5. Life expectancy of at least 3 months

[0151] 6. Adequate organ and bone marrow function of: Hemoglobin ≥ 9.0g / dL Absolute neutrophil count ≥ 1.5 × 10 9 / L Platelet count ≥ 75 × 10 9 / L (for lymphoma patients, ≥ 50 × 10 9 / L) Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or estimated glomerular filtration rate > 50 mL / min / 1.73 m 2 (dose escalation cohort) or estimated glomerular filtration rate >30 mL / min / 1.73 m 2 (Dose expansion cohort) Total bilirubin ≤ 1.5 x ULN (Note: for patients with known Gilbert syndrome, ≤ 3 x institutional ULN is acceptable) Aspartate aminotransferase and alanine aminotransferase (ALT) ≤ 3 x ULN (or ≤ 5 x ULN in liver metastases) Alkaline phosphatase ≤ 2.5 x ULN (or ≤ 5.0 x ULN for liver or bone metastases) Calcium ≤ 12.5 mg / dL. Patients with a history of hypercalcemia controlled with bisphosphonate therapy that was reduced to ≤ 12.5 mg / dL at screening were eligible.

[0152] 7. Willing and able to comply with clinic visit and study related procedures.

[0153] 8. Have a signed informed consent

[0154] 9. For patients with HNSCC, patients have a primary tumor site that is the oral cavity, oropharynx, larynx, or hypopharynx. Squamous cell carcinoma of lymph nodes in the cervical chain of the neck, with unknown primary, is a qualifying diagnosis for HPV-associated or not (by p16 IHC or HPV in situ hybridization and / or HPV polymerase chain reaction [PCR]). Patients with nasopharyngeal carcinoma are excluded.

[0155] 10. Histologically confirmed diagnosis of invasive CSCC for patients with CSCC

[0156] Note regarding primary site of tumor: The intent is to study patients whose tumors may be attributable to UV exposure. Patients whose primary site of squamous cell carcinoma was the dry red lips (vermilion) are not eligible. Patients with tumors arising on the dry red lips (vermilion) with cutaneous extension (not hairless) may be eligible after communication with and approval by the medical monitor. Patients whose primary site of squamous cell carcinoma is the anogenital region (penis, scrotum, and perianal area) are not eligible. Patients whose primary site is nasal are eligible only if it can be clearly established that the primary site is skin, not nasal mucosa, with outward extension to the skin.

[0157] Note on tumor histology: Patients with mixed histology (e.g., sarcomatoid, adenosquamous) are generally not eligible. Patients with mixed histology (having only a minimal component of mixed histology) with predominant histology being invasive CSCC may be eligible after communication with and approval by Medical Monitor.

[0158] Exclusion criteria Patients who meet any of the following criteria will be excluded from the study:

[0159] 1. Currently receiving treatment in another trial, either participated in and received treatment with an investigational drug study, or used an investigational device within 4 weeks of the first dose of an investigational therapy (except 89Zr-DFO-REGN3767), or received treatment with an approved systemic therapy within 3 weeks of the first dose of an investigational therapy, or received any prior systemic therapy within 5 half-lives of the first dose of an investigational therapy (whichever is longer). Patients previously treated with bevacizumab, cetuximab, rituximab, or other non-immunomodulatory antibodies with a half-life longer than 7 days are allowed if at least 30 days have elapsed since their last treatment. Patients previously treated with an immunomodulatory antibody with a half-life longer than 7 days, such as ipilimumab, are allowed if at least 3 half-lives have elapsed since their last treatment. Patients previously treated with an immunomodulatory cell therapy, such as CAR-T cells, are allowed if at least 30 days have elapsed since their last treatment.

[0160] NOTE: For anti-PD-1 / PD-L1 experienced patients enrolled in the appropriate cohort, the clearance period noted above for systemic therapy does not apply to prior anti-PD-1 / PD-L1 therapy. Prior anti-PD-1 / PD-L1 therapy must have occurred more than 3 weeks prior to the first dose of study drug, regardless of drug half-life or approval status. Prior anti-PD-1 / PD-L1 therapy must have occurred less than 3 months prior to screening. Patients who received 89Zr-DFO-REGN3767 (anti-LAG-3 immuno-PET [iPET] antibody) will be allowed in expansion cohort 9, regardless of time since administration. Patients previously treated with bevacizumab, cetuximab, rituximab, or other non-immunomodulatory antibodies with a half-life longer than 7 days will be allowed, after discussion with the sponsor, if at least 30 days have elapsed since the last treatment. Patients previously treated with immune modulating antibodies with half-lives longer than 7 days, such as ipilimumab, will be allowed, after discussion with the sponsor, if at least 3 half-lives have elapsed since their last treatment. Patients previously treated with cell therapies, such as CAR-T cells, will be allowed, after discussion with the sponsor, if at least 30 days have elapsed since their last treatment.

[0161] 2. Previous treatment with any LAG-3 targeted biologic or small molecule, except for 89Zr-DFO-REGN3767 (anti-LAG-3 iPET antibody).

[0162] 3.Has not recovered to baseline from radiation-related AEs from radiation therapy within 2 weeks prior to enrollment.

[0163] 4. Expansion cohort only: Another malignancy requiring effective treatment, excluding non-melanoma skin cancer or in situ cervical carcinoma that is progressing or has undergone potentially curative therapy, or any other tumor deemed to have been effectively treated with definitive local control for at least 2 years prior to enrollment.

[0164] 5. Primary brain tumors and untreated or active central nervous system metastases. Patients with previously treated central nervous system metastases may participate as long as they are stable (i.e., no evidence of progression and return of neurological symptoms to baseline by imaging for at least 6 weeks prior to the first dose of study treatment), there is no evidence of new metastases or spread of central nervous system metastases, and the patient does not require systemic corticosteroids for management of central nervous system metastases within 4 weeks prior to the first dose of REGN3767 / REGN2810.

[0165] 6. Encephalitis, meningitis, or uncontrollable seizures in the year prior to informed consent.

[0166] 7. Evidence of ongoing or recent (within 5 years) significant autoimmune disease requiring treatment with systemic immunosuppressive measures that may indicate risk of irAEs. The following are not excluded: vitiligo, remitted childhood asthma, hypothyroidism requiring hormone replacement only, type 1 diabetes, or psoriasis not requiring systemic treatment.

[0167] 8. Corticosteroid therapy (>10 mg prednisone / day or equivalent) within 1 week prior to the first dose of study drug. Patients requiring short-term steroids will not be excluded.

[0168] 9. History or any evidence of interstitial lung disease or active non-infectious pneumonitis (last 5 years). History of radiation pneumonitis in previous radiation fields is acceptable.

[0169] 10. Diagnosis of uncontrolled infection with human immunodeficiency virus, hepatitis B or hepatitis C infection, or immunodeficiency associated with or resulting in chronic infection. Mild cancer-associated immunodeficiency (e.g., immunodeficiency treated with gamma globulin and without chronic or recurrent infection) is acceptable.

[0170] Note: Patients are tested for HIV, HCV, and HBV at screening.

[0171] Patients with controlled HIV infection (either spontaneous or on a stable antiviral regimen, with undetectable viral load and CD4 count >350) will be admitted. Patients with controlled HIV infection will be monitored according to local standards.

[0172] Patients with Hepatitis B who have a controlled infection (HepBsAg+) (serum Hepatitis B virus DNA PCR below the limit of detection and receiving antiviral therapy for Hepatitis B) will be accepted. Patients with controlled infection must undergo regular monitoring for HBV DNA. Patients must continue to receive antiviral therapy for at least 6 months after the last dose of investigational study drug.

[0173] Patients who are hepatitis C virus antibody positive (HCV Ab+) and have controlled infection (undetectable HCV RNA by PCR, either spontaneous or responding adequately to a course of anti-HCV therapy) will be admitted.

[0174] Patients with HIV or hepatitis must be monitored for their disease by a specialist managing the disease (eg, infectious disease or hepatologist) before starting the study and throughout their participation in the study.

[0175] 11. Active infection requiring systemic therapy.

[0176] 12. Receipt of live vaccine within 30 days of planned study drug initiation.

[0177] 13. Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to screening.

[0178] 14. Myocardial infarction within 6 months prior to the first dose of study therapy.

[0179] 15. History of allogeneic stem cell transplant or solid organ transplant.

[0180] 16. Any medical condition where study participation is not in the patient's best interest.

[0181] 17.Patient has grade ≥2 treatment-related immune-mediated AEs that required permanent discontinuation of current anti-PD-1 / PD-L1 or anti-CTLA-4 therapy or that have not resolved to baseline at least 30 days prior to initiation of study therapy.

[0182] Note: Endocrine immune-mediated AEs managed with hormonal therapy or other non-immunosuppressive therapy (without resolution), or Grade 1 irAEs in any organ system with resolution prior to enrollment.

[0183] 18. [Exclusion criteria deleted]

[0184] 19. Known psychiatric or substance abuse disorder that would prevent participation in the study requirements.

[0185] 20.Women who are pregnant, breastfeeding, planning to become pregnant, or men planning to father a child within the project duration of the study (from the screening visit through 180 days after the last dose of study drug).

[0186] 21. Males of childbearing potential who are not willing to use highly effective contraception prior to the start of initial treatment, during the study, and for at least 6 months after the last dose of study drug.* Or female ** Adequate contraceptive measures included stable use of oral contraceptives such as hormonal contraceptives or other prescription contraceptives alone, estrogen-progestogen-progestogen combinations, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal banding, vasectomy, and sexual abstinence for at least two menstrual cycles prior to screening. ***

[0187] * Men with documented vasectomies do not require contraception.

[0188] ** Postmenopausal women must be amenorrhea-free for at least 12 months to be considered fertile. Pregnancy testing and contraception are not required for women with documented proof of hysterectomy or tubal ligation.

[0189] *** Sexual abstinence is considered highly effective only if it is defined as abstinence from heterosexual intercourse for the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the patient's preferred usual lifestyle.

[0190] 22. Members of the clinical trial site study team and / or their immediate families.

[0191] 23. [Exclusion criteria deleted]

[0192] Test Design This is a Phase I, first-in-human, open-label, multicenter, dose-escalation study of the safety, tolerability, activity, and pharmacokinetics of REGN3767 administered as monotherapy and in combination with REGN2810 in patients with advanced malignancies. Eleven dose-escalation cohorts with REGN3767 as monotherapy and in combination with REGN2810 are planned. The study flow diagram (for individual patients) is shown in Figure 1, and the study design showing the dose-escalation scheme and cohorts is shown in Figure 2.

[0193] period After a screening period of up to 28 days, patients will receive up to 17 21-day treatment cycles (for a total of up to 51 weeks of treatment), followed by a 24-week follow-up period. Each patient will receive REGN3767 (+ / -REGN2810) every 21 days. The total duration of the study, excluding the screening period, will be approximately 78 weeks (546 days). However, an additional 51 weeks of treatment will be available for patients who continue to show benefit.

[0194] Treatment will continue until the 51-week treatment period is completed or until disease progression, unacceptable toxicity, withdrawal of consent, or study discontinuation criteria are met. After completion of 51 weeks of therapy, therapy may be continued for an additional 51 weeks.

[0195] Response assessments are performed every 6 weeks for the first 24 weeks, and then every 9 weeks for the next 27 weeks, regardless of delays in dosing of study drug. After at least 24 weeks of treatment (at least 8 treatment cycles), patients who have confirmed a complete response (CR) may choose to discontinue treatment and continue all relevant treatment evaluations. Similarly, patients who have been treated for at least 24 weeks with stable disease (SD) or partial response (PR), maintained for three consecutive tumor evaluations, may choose to continue treatment but continue all relevant study evaluations.

[0196] Patients who progress within 6 months after discontinuation of CR or stable PR or SD (including completion of study therapy) may resume study treatment (after confirmation of relevant study eligibility criteria) at the same dose (at restart cycle 1) or at the dose selected for expansion (whichever is higher). Patients may receive up to 17 cycles of therapy. If patients resume the same dose, pharmacokinetic and biomarker samples will be collected according to the restart of event treatment schedule. If patients begin treatment at a dose or combination different from the dose or combination initially treated, samples and safety assessments are required and patients will begin according to the retreatment schedule of the event.

[0197] For patients who experience a response and then progress, a tumor biopsy at the time of progression is required.

[0198] Patients in dose escalation who tolerate a minimum of two doses of REGN3767 monotherapy, and patients in the expansion cohort who tolerate a minimum of one dose of REGN3767 monotherapy, however, subsequently exhibit progressive disease (PD) and enter a retreatment phase, with the option to add REGN3767 in combination with REGN2810 at 350 mg to the maximum dose level or up to that point (if known) in an attempt to "salvage" the response by combined LAG-3 and PD-1 blockade. The choice of REGN2810 dose is based on the dose level known to be an acceptable combination with REGN3767 at the time of the patient's transition from monotherapy to combination with retreatment to receive "salvage" therapy. In the expansion cohort, patients receiving monotherapy who tolerate a minimum of one dose of REGN3767 have the option to receive the combination therapy dose selected from the expansion (cemiplimab 350 mg + REGN3767 1600 mg). Patients will enter "rescue combination cycle 1" and receive up to 17 cycles of combination therapy. If there is a discrepancy between the patient's current REGN3767 monotherapy dose and the known tolerated dose of REGN3767 in combination with REGN2810, the appropriate time to begin administration of each drug in the combination therapy to allow the REGN3767 drug concentration in the blood to decline to a level that is tolerated in combination will be determined. Patients should continue with scheduled visits. Pharmacokinetic and biomarker samples will be collected according to the event rescue schedule. Incorporation of these patient safety data into the dose evaluation (dose escalation) phase is described below.

[0199] Patients will enter follow-up after completing up to 51 weeks of treatment (or at the end of another 51 weeks of treatment if the patient enters continuation or rescue). Patients who restart or undergo retreatment should also receive follow-up care after each treatment cessation. Patients may enter follow-up multiple times.

[0200] Safety assessments will be conducted at each study drug dosing visit.

[0201] Eleven dose escalation cohorts are planned. Five dose levels of REGN3767 (1, 3, 10, 20 and 40 mg / kg) are investigated as monotherapy. Three dose levels of REGN3767 (1, 3 and 10 mg / kg) are investigated in combination with 3 mg / kg REGN2810. 10 mg / kg REGN3767 in combination with 3 mg / kg REGN2810 is determined to be tolerable, and subsequent dose levels of REGN3767 (10, 20 and 40 mg / kg, or equivalent fixed doses) are investigated in combination with REGN2810. REGN3767 is dosed in dose escalation in combination with cemiplimab at a fixed dose of 350 mg, as both weight-based (in mg / kg) and fixed dosing (in mg) are similar across a wide range of monoclonal antibody therapies tested with respect to reducing pharmacokinetic inter-individual variability. Because the MTD of REGN3767 has not been reached, two additional cohorts using 40 mg / kg REGN3767 (monotherapy and in combination with cemiplimab 350 mg) will be investigated. The first cohort to enroll will receive REGN3767 monotherapy at 1 mg / kg. Subsequent enrollment of each additional cohort may be limited by the number of dose-limiting toxicities (DLTs) observed in the previous cohort.

[0202] Once a range of acceptable dose levels is identified in dose escalation, enrollment into expansion cohorts will be disclosed. More than one dose level may be tested in the expansion cohort.

[0203] Following confirmation of the selected dose, additional expansion cohorts may be enrolled. The solid tumor expansion cohort has a Simon two-stage design, and the DLBCL expansion cohort has a single (pilot) stage. Patients are assigned to specific treatment cohorts based on the patient's tumor type; prior anti-PD-1 / anti-programmed death-ligand 1 (PD-L1) therapy, an assessment of the adequacy of the therapy regimen for the patient, and the availability of patient slots in the assigned treatment cohort. If safety issues arise in individual expansion cohorts during stage 1 of the Simon two-stage design or lymphoma pilot cohort, enrollment may be paused. Enrollment may be resumed with the same or lower dose of REGN3767. Safety issues that cause pause may include early or late safety events. Patients are assigned to specific treatment cohorts based on the patient's tumor type; prior anti-PD-1 / anti-programmed death-ligand 1 (PD-L1) therapy, an assessment of the adequacy of the therapy regimen for the patient, and the availability of patient slots in the assigned treatment cohort. If safety issues arise in individual expansion cohorts during stage 1 of the Simon two-stage design or lymphoma pilot cohort, enrollment may be paused. Enrollment may be resumed with the same or lower dose of REGN3767. Treat with Q3W REGN3767 monotherapy (at dose determined from monotherapy dose escalation findings), or fixed dose equivalent, or combination of REGN3767 and REGN2810 (at dose levels to be determined by combination dose escalation findings) for up to 51 weeks. Enrollment in Stage 2 for each solid tumor expansion cohort will occur only if a minimum number of tumor responses are observed in Stage 1.

[0204] For REGN3767 and REGN2810, both weight-based and fixed doses are tested in this study.Since both fixed and weight-based dosing have been shown to behave similarly with reduced pharmacokinetic variability, weight-based dosing may be converted to a suitable fixed dose.Therefore, the study design provides for the selection of fixed dose REGN3767 and REGN2810 combination.

[0205] For patients in the expansion cohort, a pre-treatment biopsy is required (unless the patient has had a recent biopsy from another study) and an on-treatment tumor biopsy on day 29 ± 7 unless the patient is clinically unstable or cannot tolerate this procedure. If an on-treatment (day 29) biopsy is not medically appropriate, a discussion with the medical monitor must occur prior to day 29 and the rationale explained and documented.

[0206] Study cohort Dose Escalation Cohort Eleven dose escalation cohorts are planned (Figure 2). Five dose levels of REGN3767 (1, 3, 10, 20, and 40 mg / kg) will be investigated as monotherapy. Three dose levels of REGN3767 (1, 3, and 10 mg / kg) will be investigated in combination with 3 mg / kg REGN2810. If 10 mg / kg REGN3767 in combination with 3 mg / kg REGN2810 is determined to be tolerable, subsequent dose levels of REGN3767 (10, 20, and 40 mg / kg) will be investigated in combination with REGN2810. REGN3767 will be dosed in dose escalation in combination with a fixed dose of 350 mg of REGN2810, as both weight-based (in mg / kg) and fixed dosing (in mg) are similar across a wide range of monoclonal antibody therapies tested with respect to reducing pharmacokinetic inter-individual variability. Two additional cohorts using 40 mg / kg REGN3767 (or equivalent fixed dose) (monotherapy and in combination with REGN2810 350 mg) will be investigated.

[0207] Expansion cohort Disease-specific cohorts will be enrolled after the selection of dose levels for expansion. The timing and sequence of enrollment start for the expansion cohorts will be determined based on available data. The cohorts may be open at different times during the study. The solid tumor expansion cohort will have a Simon two-stage design, and the DLBCL expansion cohort will have a single (pilot) stage. Patients will be assigned to specific treatment cohorts based on the patient's tumor type; the presence or absence of prior anti-PD-1 / anti-PD-L1 therapy, an assessment of the adequacy of the therapy regimen for the patient, and the availability of patient slots in the assigned treatment cohort. If a safety issue arises in an individual expansion cohort during stage 1 of the Simon two-stage design or lymphoma pilot cohort, enrollment may be paused. Enrollment may be resumed with the same or lower doses of REGN3767 and / or REGN2810. Safety issues that cause pauses may include early or late safety events. Patients are treated with 20mg / kg REGN3767 monotherapy (at a dose selected from the monotherapy dose escalation experience) or a combination of REGN3767 and REGN2810 (at a dose determined by the combination dose escalation experience) for up to 51 weeks. Since both fixed dosing and weight-based dosing are similar across a wide range of tested monoclonal antibody therapies with reduced pharmacokinetic inter-individual variability, the weight-based dosing for REGN3767 and REGN2810 may be converted to an appropriate fixed dose (Wang, 2009). For the fixed dose cohort, patients are treated with REGN3767 monotherapy 1600mg or a combination of REGN3767 and REGN2810 (REGN3767 1600mg and REGN2810 350mg). Enrollment in stage 2 for each solid tumor expansion cohort occurs when a minimum number of tumor responses are observed in stage 1.

[0208] Because both weight-based and fixed dosing are similar across a wide range of tested monoclonal antibody therapies with respect to reducing pharmacokinetic inter-individual variability, weight-based dosing for REGN3767 (in mg / kg) and REGN2810 may be converted to an appropriate fixed dose (in mg) in most expansion cohorts, except for expansion cohort 8.

[0209] Patients in monotherapy expansion cohorts 8 and 14 will be treated with 20mg / kg REGN3767 and 1600mg fixed dose equivalent (converted from 20mg / kg REGN3767 for an estimated patient weight of 80kg), respectively, for up to 51 weeks. This weight-based dose and fixed dose equivalent were selected based on information collected during dose escalation, as well as from weight-based experience with monotherapy in expansion cohort 8 (for the fixed dose in cohort 14). During the dose escalation phase, the MTD was not reached for REGN3767, and there were no safety concerns for 20mg / kg REGN3767 monotherapy or for the combination of 20mg / kg REGN3767 and REGN2810 350mg. Additionally, in expansion cohort 8, REGN3767 monotherapy activity was observed at 20mg / kg Q3W. Thus, new monotherapy cohorts in dose expansion (e.g., Cohort 14) will open with a fixed dose equivalent of REGN3767 1600 mg. See Table 2.

[0210] If a given cohort in stage 2 meets the success criteria, then additional patients may be enrolled in the cohort, up to a maximum of 40 patients for solid tumor cohorts. For DLBCL, if the cohort is successful, the cohort size may be expanded to 20 patients. For DLBCL expansion cohort 9, 20 patients who meet the enrollment requirements of the anti-LAG-3 iPET study will be enrolled. Furthermore, if the characteristics of a given enrollment cohort vary from the predicted patient population based on baseline clinical data (e.g., tumor subtype) or emerging biomarker data (e.g., tumor PD-L1 and / or LAG-3 expression, etc.), such that the true response rate is higher than the observed response rate, additional cohorts may be open in that tumor type with more defined selection criteria. [Table 2-1] [Table 2-2]

[0211] Dose Titration Rules A variation of the traditional 3+3 design ("4+3") was used to evaluate all dose levels for both the REGN3767 monotherapy and the REGN3767+REGN2810 cohorts. A diagram of the study design is shown in Figure 2.

[0212] The evaluation period for DLT is 28 days. A minimum of 3 patients at each dose level must be evaluable for DLT to maximize the efficiency of Phase I dose escalation while maintaining patient safety, however, if a patient discontinues before being evaluable for DLT, 4 patients will be enrolled at each dose level. Tolerability rules are as follows: A dose level will be considered tolerable if all potential DLT-evaluable patients complete the 28-day DLT period without a DLT (0 of 3 patients or 0 of 4 patients). If three patients complete the DLT period without experiencing a DLT, but there is a fourth patient in the DLT evaluation period, the dose level will be considered tolerable only if the fourth patient discontinues therapy before completing the DLT evaluation period or being evaluable for DLT. If there is 1 DLT in any of 3 or 4 evaluable patients, then enroll 4 or more or 3 or more patients, respectively, for a total of 7 patients. If there is 1 DLT in 6 patients or 1 DLT in 7 patients, the dose is considered tolerable. If there are 2 or more DLTs in 2-7 evaluable patients, the MTD is achieved. At the highest tolerated dose level, 3-4 additional patients may be enrolled for further evaluation of safety, for a total of 6-10 DLT-evaluable patients. A dose will be considered tolerable if there are 0-1 DLT in 6-8 patients or 2 DLTs in 9-10 patients.

[0213] Three to four additional patients may be enrolled at any dose level to further evaluate safety. These additional patients treated in the combination therapy cohort must meet all other eligibility criteria, but must have previously been treated with anti-PD-1 or anti-PD-L1 therapy.

[0214] Dose escalation (Figure 2) will proceed as follows: If 1.0 mg / kg REGN3767 (DL1) is deemed tolerable (3-7 patients), enrollment will begin with 3.0 mg / kg REGN3767 (DL2). After enrollment of 4 patients in DL2, enrollment in the first combination cohort (1.0 mg / kg REGN3767 + 3.0 mg / kg REGN2810; DL3) may begin. Once 3.0 mg / kg REGN3767 (DL2) is deemed to be tolerated, dose escalation to 10 mg / kg REGN3767 (DL4) may be initiated. The 3.0 mg / kg REGN3767 + 3.0 mg / kg REGN2810 combination cohort (DL5) will be enrolled only after both DL2 and DL3 are deemed tolerable. The 10mg / kg REGN3767 + 3.0mg / kg REGN2810 combination cohort (DL6) will be enrolled only after both DL4 and DL5 are deemed tolerable. Once 10 mg / kg REGN3767 (DL4) is deemed to be tolerated, dose escalation to 20 mg / kg REGN3767 (DL7) may be initiated.

[0215] Once the combination MTD or selection dose has been identified in the three combination cohorts with 3 mg / kg REGN2810 (DL3, DL5 and DL6), enrollment may begin at the identified dose of REGN3767 in combination with REGN2810 350 mg (fixed dose) (DL8). Subsequent combination cohorts will also include REGN2810 350 mg, as follows: · The 20mg / kg REGN3767 + REGN2810 350mg combination cohort (DL9) will be enrolled only after both DL8 and DL7 are deemed tolerable. Based on the total data, the dose level selected for progression to expansion after enrolling DL9 may be determined. Once 20 mg / kg REGN3767 (DL7) is deemed tolerable, dose escalation to 40 mg / kg REGN3767 (DL10) may be initiated. · The 40mg / kg REGN3767 + REGN2810 350mg combination cohort (DL11) will be enrolled only after both DL9 and DL10 are deemed tolerable. If multiple cohorts are open at the same time, priority should be given to the cohort with fewer numbers.

[0216] There will be no intrapatient dose escalation permitted in this study (except in the retreatment or rescue setting). All patients initially enrolled in a cohort (screening for the next dose cohort may begin prior to confirmation that the current dose is tolerated) will complete the dose-limiting toxicity observation period and escalate to the next cohort once the data have been reviewed.

[0217] The first monotherapy cohort requires 48 hours from the first dose of study drug for the first four patients enrolled (i.e., in DL1). For example, if patient 1 is treated on Monday, patient 2 cannot be treated before Wednesday. If unexpected toxicity is observed, each subsequent monotherapy cohort can enroll patients without a waiting period. This same approach (a 48 hour waiting period) is utilized for the initial enrollment of the first combination cohort (i.e., in DL3).

[0218] Dose-limiting toxicity The DLT observation period for the safety of dose escalation or the decision to start a new combination therapy is intended to monitor the safety and tolerability of the first two doses of study drug (REGN3767 with or without REGN2810, as appropriate) and is defined as 28 days starting on day 1 of cycle 1. To be evaluable for DLT, patients must receive at least the first two doses of study drug (i.e., days 1 and 22) and be monitored for at least 28 days after the first dose and at least 7 days after the second dose, or experience a DLT (as defined below) before the completion of the DLT period. A delay in administration of the second dose of study drug after day 35 and / or study drug discontinuation is considered a DLT if related to study drug. Thus, the duration of the DLT observation period is longer for patients who have delayed the second dose and for patients experiencing an AE, the duration of which needs to be evaluated to determine whether the event is a DLT.

[0219] In addition to failure to administer Dose 2 within the dosing window (due to study drug toxicity), an overall DLT is generally defined as any of the following study drug-related toxicities: Non-hematological toxicity: o Grade ≥2 uveitis o Any grade ≥ 3 non-hematologic toxicity (excluding clinically insignificant laboratory abnormalities such as asymptomatic amylase or lipase elevations) Hematological toxicity: Grade 4 neutropenia lasting >7 days Grade 4 thrombocytopenia Grade 3 thrombocytopenia with bleeding Febrile neutropenia of grade ≥3 or neutropenia of grade ≥3 with documented infection

[0220] The frequency, time to onset, and severity of toxicity, as well as the success of standard medical management and dose interruptions / delays, will be analyzed to determine whether a given toxicity should be considered a DLT for dose escalation purposes. Both irAEs and non-irAEs that meet the definition of a DLT will be considered DLTs.

[0221] In general, treat AEs as unexpected. When data with anti-LAG-3 antibodies (alone or in combination) become publicly available, continue to monitor such TEAEs to assess the possibility that the frequency or severity of events may differ from that observed with other agents blocking LAG-3, anti-PD-1 / PD-L1, or combinations.

[0222] Treatment-emergent adverse events (TEAEs) that may meet the definition of a DLT will be considered, and the final determination of whether an AE meets the DLT definition will be based on careful consideration of all relevant data and consensus.

[0223] If an event occurs during the DLT observation period, regardless of whether the patient remains in the treatment study and / or continues to participate in the trial procedure, such event will be counted as a DLT for the cohort involved.

[0224] Maximum Tolerated Dose The MTD is defined as the dose level immediately preceding discontinuation due to DLT in 2 or more of 6-7 evaluable patients and is determined separately for monotherapy and combination therapy. However, due to the known occurrence of AEs resulting from monotherapy with REGN2810 and other PD-1 / PD-L1 antibodies, for combination cohorts, the intensity, frequency and novelty of combination toxicity may be considered in determining the MTD and the decision to add additional patients at the dose level. If dose escalation is not stopped for DLT, the MTD is considered not to be determined. An additional 3 patients are enrolled in each of the monotherapy and combination cohorts at what is considered the maximum dose level tolerated (i.e., 6-10 patients in each of these cohorts). If dose escalation for REREGN3767 monotherapy or combination therapy with REGN2810 is stopped at 1.0 mg / kg due to DLT, the cohort is enrolled at the dose of 0.3 mg / kg. If dose escalation for REGN3767 monotherapy or combination therapy is discontinued at the 3.0, 10, or 20 mg / kg dose levels due to a DLT, the dose of REGN3767 will be reduced to the previously tested dose level for newly enrolled patients (in the monotherapy or combination therapy cohort, respectively). No patient will be able to initiate combination therapy with a dose of REGN3767 that is not tolerated as monotherapy.

[0225] Additional Testing Procedures An additional 51 weeks of study treatment may be provided after the initial 51 weeks of treatment for patients who: Patients who developed PD on study after stopping therapy due to CR or prolonged PR / SD after ≥24 weeks of treatment Patients who developed PD during a follow-up period of ≥51 weeks / 17 cycles after completing treatment Patients who developed PD during monotherapy treatment and during the transition to combination therapy Patients without progressive disease who decided to continue treatment after completion of 51 weeks / 17 cycles of treatment.

[0226] Dose levels selected for expansion or recommended Phase 2 dose The dose level selected for expansion is below the MTD or the highest dose tested and may be different for the monotherapy and combination therapy cohorts. The decision on the dose level selected for expansion is based on safety and PK data.

[0227] Adding REGN2810 to REGN3767 for Patients with Progressive Disease Patients in the monotherapy cohort who tolerate a minimum of two doses of REGN3767 during dose escalation, and patients who tolerate a minimum of one dose of REGN3767 in the expansion cohort, however, subsequently demonstrate PD and have the option to add the maximum dose of REGN3767 tolerated in combination with REGN2810 at the REGN2810 3.0 mg / kg or 350 mg~ level or up to that point (if known) in an attempt to "salvage" the response by combined LAG-3 and PD-1 blockade. If the combination REGN3767 dose level with REGN2810 350 mg is found to be tolerable, patients transitioning to combination ("rescue") therapy will receive REGN3767 in combination with REGN2810 350 mg. If there is a discrepancy between the patient's current REGN3767 monotherapy dose and the known acceptable dose of REGN3767 in combination with REGN2810, determine the appropriate time to begin administering each drug in the combination therapy to allow the REGN3767 drug concentration in the blood to decay to a level that is acceptable in combination. The appropriate time to administer the study drug is based on a linear PK model assuming a conservative half-life of REGN3767 of 21 days, or the most recent available half-life. Patients should continue with scheduled visits. Patients may then receive up to 17 additional cycles of therapy. Additional samples and safety evaluations are required as patients begin treatment at the combination dose. Patient treatment and evaluation will follow the event rescue schedule. These patients will not be involved in the first 3-4 in the combination cohort required for DLT evaluation. However, their safety data will be evaluated in the determination of the MTD. Patients previously using idelalisib therapy are not eligible for rescue with REGN2810.

[0228] Treatment and Evaluation Monotherapy Treatment Schedule REGN3767 will be administered via IV infusion in the patient outpatient setting. If interruption is necessary, infusion periods longer than those specified below for each cohort will be tolerated. Planned monotherapy regimens include: DL1: 1.0 mg / kg REGN3767 IV infusion over 30 minutes every 21 days for 51 weeks DL2: 3.0 mg / kg REGN3767 IV infusion over 30 minutes every 21 days for 51 weeks DL4: 10mg / kg REGN3767 IV infusion over 30 minutes every 21 days for 51 weeks DL7: 20mg / kg REGN3767 IV infusion over 30 minutes every 21 days for 51 weeks DL10: 40mg / kg REGN3767 IV infusion over 60 minutes every 21 days for 51 weeks DL-1m: 0.3 mg / kg REGN3767 IV infusion over 30 minutes every 21 days for 51 weeks (as needed) Expansion Cohort 8: 20mg / kg REGN3767 IV infusion over 30 minutes every 21 days for 51 weeks Expansion Cohort 14: REGN3767 1600mg IV infusion over 30 minutes every 21 days for 51 weeks.

[0229] Combination Treatment Schedule For combination therapy, the sequence of study drug administration will be REGN3767 first, followed by REGN2810 on the same day. Study drugs will be administered in patient outpatient settings via IV infusion. In the event of interruption, longer infusion periods than those specified below for each cohort will be permitted. The planned combination regimens to be assigned will include the following: DL3: 1.0 mg / kg REGN3767 and 3.0 mg / kg REGN2810 IV infusion over 30 minutes every 21 days for 51 weeks DL5: 3.0 mg / kg REGN3767 and 3.0 mg / kg REGN2810 IV infusion over 30 minutes every 21 days for 1 week DL6: 10 mg / kg REGN3767 and 3.0 mg / kg REGN2810 IV infusion over 30 minutes every 21 days for 51 weeks DL8: 10mg / kg REGN3767 and REGN2810 350mg (fixed dose) IV infusion over 30 minutes every 21 days for 51 weeks DL9: REGN3767 and REGN2810, 20 mg / kg each, 350 mg IV infusion over 30 minutes every 21 days for 51 weeks DL11: REGN3767 40mg / kg over 60 minutes and REGN2810 350mg IV infusion over 60 minutes every 21 days for 51 weeks DL-1c: 0.3 mg / kg REGN3767 and 3.0 mg / kg REGN2810 IV infusion over 30 minutes (as needed) every 21 days for 51 weeks. Combination Therapy Expansion Cohort: REGN3767 1600mg and REGN2810 350mg IV infusion over 30 minutes every 21 days for 51 weeks.

[0230] Contraindicated drugs While participating in this study, patients may not receive any standard or investigational agents for the treatment of tumors other than REGN3767 as monotherapy or in combination with REGN2810, depending on the specific dosing regimen of the study. Patients may not receive live vaccines during the study. Once patients have completed 8 weeks of study treatment, focal symptomatic treatment (e.g., radiation) may allow for local control of the tumor. Any other medications deemed necessary for the patient's welfare and anticipated not to interfere with the evaluation of the study drug may be administered.

[0231] Patients using immunosuppressive doses other than corticosteroid replacement (>10 mg prednisone per day or equivalent) are not eligible for this study. It is recommended that patients not receive systemic corticosteroids such as hydrocortisone, prednisone, prednisolone (Solu-Medrol®) or dexamethasone (Decadron®) at any time throughout the study, except to treat life-threatening emergencies and / or irAEs.

[0232] Similarly, patients are encouraged not to receive other immunosuppressive medications (e.g., methotrexate) at any time throughout the study except to treat life-threatening emergencies and / or irAEs. Other immunosuppressive medications may be used as necessary to treat irAEs, infusion-related reactions, or life-threatening emergencies. Adverse events requiring immunosuppressants may be treated with medications not specifically mentioned in the protocol.

[0233] Permitted medicines Allow systemic corticosteroids in physiologic replacement doses, even if >10 mg / day prednisone equivalent. Allow short-term corticosteroids for prevention (e.g., contrast allergy) or treatment (e.g., delayed-type hypersensitivity reactions triggered by contact allergens) of non-autoimmune conditions.

[0234] Gonadotropin-releasing hormone agonist therapy (eg, for prostate cancer) may be continued and is not prohibited.

[0235] Treatment of bone metastases (bisphosphonates, denosumab) is not prohibited.

[0236] safety methods An adverse event (AE) is any untoward medical occurrence in a patient administered a study drug, which may or may not have a causal relationship to the study drug. Thus, an AE is any untoward, unintended sign (including abnormal clinical laboratory findings), symptom, or disease that is temporally associated with the use of the study drug, whether or not it is considered to be related to the study drug. AEs also include any worsening of a pre-existing condition (i.e., any clinically meaningful change in frequency and / or intensity) that is temporally associated with the use of the study drug. Progression of the underlying malignancy is not considered an AE if it clearly matches the typical progression pattern of the underlying cancer (including time course, organs affected, etc.). Clinical manifestations of progression may be reported as AEs if the symptoms cannot be determined to be solely due to progression of the underlying malignancy or do not fit the expected progression pattern for the disease under study. A serious AE (SAE) is any adverse medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization, results in persistent or significant disability, and / or is a significant medical event.

[0237] Patients are monitored for vital signs including temperature, resting blood pressure (sitting), pulse, and respiratory rate. Patients are also monitored for anti-drug antibodies, monitored for changes in ECG from baseline, monitored for immune changes (e.g., changes in rheumatoid factor, thyroid stimulating hormone, and antinuclear antibody titers and patterns), monitored for coagulation changes, and monitored for changes in B symptoms.

[0238] REGN2810 (anti-PD-1), along with other checkpoint blockade agents (e.g., anti-CTLA-4), are associated with a unique set of toxicities called immune-related adverse events (irAEs). Immune-related AEs are thought to be caused by uncontrolled cellular immunity directed against normal host tissues. irAEs can occur soon after the first dose or months after the last dose of treatment. Early detection and management reduces the risk of severe drug-induced toxicity. Because LAG-3 is also a checkpoint molecule, anti-LAG-3 antibodies, such as REREGN3767, can also be associated with irAEs.

[0239] The onset of irAE symptoms (e.g., pneumonia) can be subtle, necessitating early intervention in the management of irAEs.

[0240] If scheduled at the same visit as other procedures, vital signs should be measured prior to clinical laboratory evaluation, pharmacokinetics, or exploratory specimen collection.

[0241] Efficacy Analysis For purposes of determining study eligibility or characterizing the baseline population, the following procedures will be performed prior to the first dose of study drug: height, serum pregnancy test, chest x-ray (if CT was performed), brain CT or MRI, archived tumor specimen collection, RF, ANA, and troponin, HPV testing (tumor). Chest x-ray is required to provide a baseline for any subsequent in-study chest x-rays (e.g., in evaluation of potential pneumonia). Specimen collection for HPV status and future HPV testing is for HNSCC patients only. Human immunodeficiency virus, hepatitis C, and hepatitis B will be tested at screening. For patients with controlled HBV infection, patients will be monitored periodically throughout the study. For patients with controlled HIV or HCV infection, monitoring will be performed according to local standards.

[0242] Primary efficacy analyses will include best overall response as determined by RECIST version 1.1 (Eisenhauer, 2009) for the solid tumor cohort and by Lugano criteria (Cheson, 2014) for the DLBCL cohort. Such results will be summarized using descriptive statistics with two-sided 95% confidence intervals by each expansion cohort.

[0243] ORR will be summarized by descriptive statistics with 95% confidence intervals. Patients who are not evaluable for BOR will be considered non-responders.

[0244] For a given expansion cohort, if the number of responders is equal to or greater than the minimum number of responders specified in Simon's two-stage design, the treatment is considered effective and worthy of further investigation.

[0245] Within applicable expansion cohorts, type I error will be controlled by Simon's two-stage design. Adjusting significance levels for purposes of multiple testing is not applicable to expansion cohorts. Efficacy statistical analyses for these expansion cohorts will be performed and reported separately, i.e., efficacy results and clinical conclusions from each cohort will not affect the other cohort and vice versa.

[0246] Secondary efficacy analyses will include ORR as measured by iRECIST, DOR, disease control rate and PFS. These secondary efficacy endpoints will be summarized narratively by dose escalation and expansion cohorts.

[0247] Efficacy Methods CT or MRI for tumor evaluation is performed at a specific time point. If the choice is made to use a CT scan or MRI, subsequent evaluations should be performed using the same treatment modality whenever possible.

[0248] Tumor response assessment will be performed by RECIST version 1.1 criteria (Eisenhauer, 2009), Lugano criteria (lymphoma patients only) and irRC (Wolchok, 2009) (Table 3). [Table 3]

[0249] NOTE: Patients with a global deterioration in health status necessitating treatment discontinuation without objective evidence of disease progression at that time should be reported as "symptomatic worsening." Every effort must be made to document objective progression even after treatment has been discontinued.

[0250] Additional guidance for response assessment in patients with CSCC: In some patients with unresectable locoregionally advanced basal cell carcinoma (BCC) or CSCC, disease may not be measurable on radiographs. For radiologically non-measurable CSCC lesions, an approach from a phase II trial of vismodegib in BCC ( Sekulic, 2012 ). Response is defined as a 30% or greater decrease in the externally visible or radiographic dimensions (if applicable) of the ulcer or complete disappearance (if present at baseline). Residual scarring should be included when measuring the externally visible dimensions. Response must be confirmed at least 4 weeks after the initial determination of response. Progressive disease is defined as a 20% or greater increase in the externally visible or radiographic dimensions (if applicable), new ulcers, new lesions ( Sekulic, 2012 ). These criteria apply to CSCC lesions that are not radiographically measurable in the current study. A central review of photographic images may be performed.

[0251] Response Assessment for Patients with Lymphoma Disease response in patients with lymphoma is assessed using the Lugano criteria (Cheson 2014) (Table 4). [Table 4-1] [Table 4-2]

[0252] CT or MRI scans of the neck, chest, abdomen, pelvis, liver, and spleen, as well as any other known disease sites, are performed at specific time points and any time disease progression is suspected. Scans should include description of nodal location, and the six largest primary nodes or nodal disease masses should be selected as index lesions and measured in the perpendicular dimension. Evaluation of tumor lesions includes the two-dimensional diameters of all lymph nodes, spleen, and liver enlargement. All measurable and evaluable lesions must be evaluated and recorded.

[0253] PET scans will be performed at designated time points. If FDG-PET-CT slice thickness is ≦5 mm, FDG-PET-CT is feasible and reliable measurements of lesions can be measured and recorded.

[0254] Collection of bone marrow samples is optional for patients with lymphoma and is performed at designated time points.

[0255] Methodology and Evaluation The safety and tolerability of REGN3767 alone or in combination with REGN2810 will be monitored by clinical assessment of AEs and repeated measurements of clinical evaluations, including vital signs (temperature, blood pressure, pulse, and respiration), physical examination (complete and limited), 12-lead electrocardiogram (ECG), and clinical laboratory evaluations including standard hematology, chemistry, and urinalysis.

[0256] Collect blood samples for determining functional REGN3767 and functional REGN2810 in serum and ADA (anti-REGN3767 or anti-REGN2810) samples.

[0257] Serum and plasma samples will be collected for analysis of additional biomarkers. Clinically active or underlying disease will be investigated in serum, plasma, peripheral blood mononuclear cells (PBMCs), and tumor tissue.

[0258] Antitumor activity will be assessed by positron emission tomography (PET), computed tomography (CT), CT and magnetic resonance imaging (MRI).

[0259] Genomic DNA samples will be collected from patients who consent to any pharmacogenomic substudy.

[0260] Study Evaluation Items In the dose escalation phase, the primary endpoint is safety, including DLT rate, adverse events (AEs; including immune-related), serious adverse events (SAEs), deaths, and laboratory abnormalities (grade ≥3 by Common Terminology Criteria for Adverse Events [CTCAE]), and pharmacokinetics. In the dose expansion phase, the primary endpoint is overall response rate (ORR) based on RECIST 1.1 (solid tumors) and Lugano criteria (lymphoma). Secondary endpoints include response rate (for the escalation phase) based on RECIST 1.1 (solid tumors) and Lugano criteria (lymphoma); best overall response (BOR), duration of response (DOR), disease control rate, and progression-free survival (PFS) based on RECIST, irRC, and Lugano criteria; AEs, SAEs, deaths, and laboratory abnormalities (grade ≥3 by CTCAE), including immune-related, as well as pharmacokinetics and ADAs.

[0261] result In this study, the initial safety, pharmacokinetics (PK), and efficacy of a dose-escalation study of an exemplary anti-LAG-3 antibody, REGN3767, alone (mono) or in combination with an exemplary anti-PD-1 antibody, REGN2810; (cemiplimab-rwlc), was determined in patients with advanced malignancies.

[0262] Patients who had progressed on prior therapy and / or therapy without appreciable clinical benefit were enrolled, with the majority of patients enrolled in the dose escalation cohorts being anti-PD-1 / PD-L1 treatment naive. Patients received REGN3767 at doses of 1, 3, 10, or 20 mg / kg every 3 weeks (Q3W) and REGN2810 at doses of 3 mg / kg or 350 mg IV Q3W for ≤51 weeks. Crossover from monotherapy REGN3767 to combination with REGN2810 (cemiplimab) was permitted at the time of progression. Pharmacokinetics of REGN3767 was evaluated. Tumor measurements were performed every 6 weeks for the first 24 weeks, then every 9 weeks thereafter.

[0263] Patient Characteristics and Dispositions: The monotherapy cohort included 27 patients with a median age of 68 years (range 22-83 years), with 4 patients having an ECOG performance status (ECOG PS, a measure of a patient's ability to tolerate chemotherapy) of 0 and 23 patients having an ECOG PS of 1. The combination therapy cohort included 42 patients with a median age of 60 years (range 30-83 years), with 15 patients having an ECOG PS of 0 and 27 patients having an ECOG PS of 1 (Tables 5 and 6). [Table 5] [Table 6]

[0264] Table 7 shows patient exposure to REGN3767. [Table 7]

[0265] Safety: Treatment-emergent adverse events (TEAEs) recorded in patients treated with monotherapy, combination therapy, and in patients who transitioned from monotherapy to combination therapy are shown in Tables 8-10. [Table 8] [Table 9] [Table 10]

[0266] There were no DLTs observed in patients treated with REGN3767 monotherapy or in patients who crossed over from monotherapy to the combination therapy.

[0267] Pharmacokinetics: REGN3767 concentrations increased dose-dependently and were unaffected by combination with REGN2810. REGN3767 exposure was similar at 1600 mg Q3W compared to 20 mg / kg Q3W.

[0268] Efficacy: A trend towards higher PD-1+ effector memory T cell expansion was observed with increasing REGN3767 dose in the cemiplimab combination cohort (Figure 3). Table 11 shows a preliminary evaluation of response rates in patients in the monotherapy and combination cohorts. [Table 11]

[0269] Two patients with small cell lung cancer had partial responses, with one patient showing a sustained extended response (>12 months). A patient with cholangiocarcinoma showed tumor shrinkage and stable disease several months after progression on cemiplimab monotherapy. Both a patient with endometrial cancer and another patient with cutaneous squamous cell carcinoma had partial responses. The patient with the partial response showed a durable response (>1 year).

[0270] Conclusions: The safety profile of REGN3767 in combination with REGN2810 was generally tolerable. There were no new safety warnings with REGN3767 monotherapy or REGN3767 + cemiplimab compared to those previously reported for cemiplimab. REGN3767 concentrations increased in a dose-dependent manner and were not affected by coadministration with cemiplimab. There were no pharmacological effects on peripheral T cells observed for REGN3767 monotherapy. Preliminary data suggest a dose-dependent association between REGN3767 + cemiplimab dosing and generation of PD-1-expressing memory T cell subsets. Early efficacy signals were detected despite a highly difficult-to-treat patient population. REGN3767 20mg / kg or 1600mg fixed-dose equivalent Q3W as monotherapy and in combination with cemiplimab were selected for further evaluation.

[0271] Dose expansion cohort results Results so far show promising efficacy in melanoma patients for the combination of R3767 and cemiplimab. Overall response for PD-(L)1 naive melanoma patients was 66.7%, with partial responses observed in 6 of 9 patients. In the patient population with PD-(L)1 experienced melanoma, 2PRs were observed in 15 patients (ORR 13.3%). As shown in Tables 12 and 13 below, numerous partial responses were also observed in both PD-(L)1 naive and PD-(L)1 experienced patients with head and neck squamous cell carcinoma (HNSCC), renal cell carcinoma, NSCLC, and DLBCL. [Table 12] [Table 13]

[0272] Overall, at the time of filing, responses were observed in patients with CSCC and DLBCL (unconfirmed partial responses).

[0273] The present disclosure is not limited in scope by the specific embodiments described herein. Indeed, various modifications of the present disclosure, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to be within the scope of the appended claims. In certain embodiments, for example, the following are provided: (Item 1) A method for treating cancer or inhibiting tumor growth, comprising administering to a subject in need thereof a therapeutically effective amount of each of: (a) an antibody or antigen-binding fragment thereof that specifically binds to programmed death 1 (PD-1); and (b) an antibody or antigen-binding fragment thereof that specifically binds to lymphocyte activation gene-3 (LAG-3). (Item 2) 2. The method according to item 1, wherein the anti-PD-1 antibody is contained in an amount of 50 to 1500 mg. (Item 3) 3. The method of claim 1 or 2, wherein the anti-PD-1 antibody comprises 350 mg. (Item 4) 4. The method according to any one of items 1 to 3, wherein the anti-LAG-3 antibody comprises 0.1 mg / kg to 50 mg / kg of body weight of the subject. (Item 5) 4. The method according to any one of items 1 to 3, wherein the therapeutically effective amount of the anti-LAG-3 antibody comprises 50 to 8000 mg. (Item 6) 6. The method of any one of items 1 to 5, wherein the anti-LAG-3 antibody is administered before, simultaneously with, or after the anti-PD-1 antibody. (Item 7) 7. The method of claim 6, wherein the anti-LAG-3 antibody is administered prior to the anti-PD-1 antibody. (Item 8) 7. The method of item 6, wherein the anti-LAG-3 antibody is administered on the same day as the anti-PD-1 antibody. (Item 9) 9. The method of any one of items 1-8, wherein one or more doses of said anti-LAG-3 antibody are administered in combination with one or more doses of said anti-PD-1 antibody. (Item 10) 10. The method of claim 9, wherein each dose of the anti-PD-1 antibody comprises 0.3, 1, 3, or 10 mg / kg of the subject's body weight. (Item 11) 10. The method of item 9, wherein each dose of the anti-PD-1 antibody contains 350 mg. (Item 12) 12. The method of any one of items 9 to 11, wherein each dose of the anti-LAG-3 antibody comprises 0.1 mg / kg to 50 mg / kg of body weight of the subject. (Item 13) 12. The method according to any one of items 9 to 11, wherein each dose of the anti-LAG-3 antibody contains 50 to 8000 mg. (Item 14) 13. The method of claim 12, wherein each dose of the anti-PD-1 antibody comprises 1, 3, or 10 mg / kg of the subject's body weight and each dose of the anti-LAG-3 antibody comprises 1, 3, 10, 20, 30, or 40 mg / kg of the subject's body weight. (Item 15) 14. The method of claim 13, wherein each dose of the anti-PD-1 antibody comprises 200 mg, 250 mg, or 350 mg, and each dose of the anti-LAG-3 antibody comprises 800 mg, 1000 mg, 1400 mg, or 1600 mg. (Item 16) 16. The method of any one of items 9 to 15, wherein each dose of the anti-PD-1 antibody is administered 0.5 weeks to 12 weeks after the immediately preceding dose. (Item 17) 17. The method of any one of items 9 to 16, wherein each dose of the anti-LAG-3 antibody is administered 0.5 weeks to 12 weeks after the immediately preceding dose. (Item 18) 18. The method of any one of items 9 to 17, wherein each dose of the anti-PD-1 antibody is administered once every 3 weeks or once every 6 weeks. (Item 19) 19. The method of any one of items 9 to 18, wherein each dose of the anti-LAG-3 antibody is administered once every 3 weeks or once every 6 weeks. (Item 20) 20. The method of any one of items 1 to 19, wherein the antibody is administered intravenously, subcutaneously, or intraperitoneally. (Item 21) 21. The method according to any one of items 1 to 20, wherein the cancer is selected from the group consisting of astrocytoma, bladder cancer, blood cancer, blood cancer, bone cancer, brain cancer, breast cancer, cervical cancer, renal clear cell carcinoma, colorectal cancer, microsatellite intermediate colorectal cancer, cutaneous squamous cell carcinoma, diffuse large B-cell lymphoma, endometrial cancer, esophageal cancer, fibrosarcoma, gastric cancer, glioblastoma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, leukemia, liver cancer, leiomyosarcoma, lung cancer, lymphoma, melanoma, mesothelioma, myeloma, nasopharyngeal carcinoma, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, primary and / or recurrent carcinoma, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, squamous cell carcinoma, synovial sarcoma, thyroid cancer, triple negative breast cancer, uterine cancer, and Wilms' tumor. (Item 22) 22. The method of any one of items 1 to 21, wherein the subject has undergone a previous anti-cancer therapy comprising one or more of a PD-1 inhibitor, a PD-L1 inhibitor, surgery, radiation therapy, or chemotherapy. (Item 23) 23. The method of any one of items 1 to 22, wherein the subject is resistant to or has had an inadequate response to or relapsed from a previous therapy. (Item 24) 22. The method of any one of items 1 to 21, wherein the subject has not received any previous anti-cancer therapy. (Item 25) 23. The method of claim 22, wherein the previous anticancer therapy comprises a PD-1 inhibitor or a PD-L1 inhibitor. (Item 26) 26. The method of any one of items 1 to 25, wherein the treatment produces a therapeutic effect selected from the group consisting of delayed tumor growth, reduction in tumor cell count, tumor regression, increased survival, partial response, and complete response. (Item 27) 27. The method of claim 26, wherein tumor growth is delayed by at least 10 days compared to untreated controls. (Item 28) 27. The method of claim 26, wherein the tumor growth is inhibited by at least 50% compared to an untreated control. (Item 29) 27. The method of claim 26, wherein the tumor growth is inhibited by at least 20% compared to subjects administered either antibody as monotherapy. (Item 30) and administering to the subject a third therapeutic agent or therapy, the third therapeutic agent or therapy being selected from the group consisting of radiation, surgery, chemotherapy, cancer vaccines, PD-L1 inhibitors, CTLA-4 inhibitors, TIM3 inhibitors, BTLA inhibitors, TIGIT inhibitors, CD47 inhibitors, CD28 agonists, CD38 inhibitors, indoleamine-2,3-dioxygenase (IDO) inhibitors, vascular endothelial growth factor (VEGF) antagonists, angiopoietin-2 (Ang2) inhibitors, transforming growth factor beta (TGFβ) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, antibodies against tumor-specific antigens, Bacillus Calmette-Guerin vaccines, granulocyte-macrophage colony-stimulating factor, oncolytic viruses, cytotoxins, interleukin-6 receptor (IL-6R) inhibitors, interleukin-4 receptor (IL-4R) inhibitors, 30. The method of any one of items 1 to 29, wherein the therapeutic agent is selected from the group consisting of an IL-10 inhibitor, IL-2, IL-7, IL-21, IL-12, IL-15, an antibody drug conjugate, a GITR agonist, a 4-1BB agonist, a CD20xCD3 bispecific antibody, a MUC16xCD3 bispecific antibody, and an anti-inflammatory drug. (Item 31) 31. The method of any one of Items 1 to 30, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) of a heavy chain variable region (HCVR) and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) of a light chain variable region (LCVR), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. (Item 32) 32. The method of claim 31, wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 1 and the LCVR comprises the amino acid sequence of SEQ ID NO: 2. (Item 33) 33. The method of any one of items 1 to 32, wherein the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. (Item 34) 34. The method according to any one of items 1 to 33, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the heavy chain CDRs (HCDR1, HCDR2 and HCDR3) of HCVR and three light chain CDRs (LCDR1, LCDR2 and LCDR3) of LCVR, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 13, HCDR2 comprises the amino acid sequence of SEQ ID NO: 14, HCDR3 comprises the amino acid sequence of SEQ ID NO: 15, LCDR1 comprises the amino acid sequence of SEQ ID NO: 16, LCDR2 comprises the amino acid sequence of SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 18. (Item 35) 35. The method of claim 34, wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 11 and the LCVR comprises the amino acid sequence of SEQ ID NO: 12. (Item 36) 36. The method according to any one of items 1 to 35, wherein the anti-LAG-3 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20. (Item 37) 37. The method of any one of items 1 to 36, wherein said inhibition is more effective than administration of either antibody as a monotherapy. (Item 38) 1. A method of treating cancer or inhibiting tumor growth, comprising: (1) selecting a patient having a tumor, wherein the selected patient has received a prior treatment comprising a PD-1 inhibitor or a PD-L1 inhibitor; and (2) administering to the patient: (a) 350 mg of an anti-PD-1 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:1 / 2; and (b) 1, 3, 10, 20, or 40 mg / kg or 1600 mg of an anti-LAG-3 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:11 / 12. (Item 39) 39. The method of claim 38, wherein the administration of step (2) occurs once every 3 weeks or once every 6 weeks. (Item 40) The patient meets the following criteria: (i) ineligibility for platinum-based therapy or tumor progression or recurrence within 6 months of the last dose of platinum therapy; (ii) a confirmed diagnosis of malignancy; (iii) presentation of tumor progression with no available therapy likely to provide clinical benefit; (iv) disease progression / recurrence after one platinum-containing regimen; (v) anti-PD-1 / PD-L1-experienced stage IIIB, IIIC, or IV NSCLC with ≤2 prior therapies for metastatic disease; (vi) anti-PD-1 / PD-L1-experienced advanced or metastatic ccRCC with a clear cell component that has received ≤2 prior regimens of antiangiogenic therapy; (vii) anti-PD-1 / PD-L1-experienced advanced nonuveal melanoma or metastatic nonuveal melanoma that has received ≤2 prior regimens for metastatic disease; (xiii) relapsed / refractory DLBCL undergoing anti-PD-1 / PD-L1 that has progressed after autologous stem cell transplant or is not a candidate for autologous stem cell transplant; (ix) anti-PD-1 / PD-L1-experienced recurrent and / or metastatic HNSCC (irrespective of HPV status) without curative options; (x) anti-PD-1 / PD-L1-experienced locally advanced or metastatic CSCC not suitable for surgery; and (xi) The method of claim 38, wherein the patient is selected as having one or more of the following: LAG-3 expression of ≧1% in tumor tissue; and the tumor tissue comprises tumor cells and tumor-infiltrating immune cells. (Item 41) 1. A method of treating cancer or inhibiting tumor growth, comprising: (1) selecting a patient having a tumor, wherein the selected patient has not received prior treatment with a PD-1 inhibitor or a PD-L1 inhibitor; and (2) administering to the patient: (a) 350 mg of an anti-PD-1 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:1 / 2; and (b) 1, 3, 10, 20, or 40 mg / kg or 1600 mg of an anti-LAG-3 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:11 / 12. (Item 42) 42. The method of claim 41, wherein the administration of step (2) occurs once every 3 weeks or once every 6 weeks. (Item 43) The patient meets the following criteria: (i) were ineligible for platinum-based therapy or had tumor progression or recurrence within 6 months of the last dose of platinum therapy; (ii) a confirmed diagnosis of malignancy; (iii) presentation of tumor progression with no available therapy likely to provide clinical benefit; (iv) either anti-PD-1 / PD-L1 naive stage IIIB, IIIC, or IV NSCLC without prior therapy for metastatic disease; (v) disease progression / recurrence after one platinum-containing regimen; (vi) anti-PD-1 / PD-L1 naive advanced or metastatic ccRCC with clear cell components that received ≤2 prior regimens of antiangiogenic therapy; (vii) anti-PD-1 / PD-L1 naive metastatic TNBC (estrogen, progesterone, and human epidermal growth factor receptor 2 negative) who have received ≤5 prior lines of therapy; (viii) anti-PD-1 / PD-L1 naive advanced nonuveal melanoma or metastatic nonuveal melanoma who have received ≤2 prior regimens for metastatic disease; (ix) anti-PD-1 / PD-L1 naive relapsed / refractory DLBCL that has progressed after autologous stem cell transplant or is not a candidate for autologous stem cell transplant; (x) anti-PD-1 / PD-L1 naive recurrent and / or metastatic HNSCC (irrespective of HPV status) with no curative options; (xi) anti-PD-1 / PD-L1 naive locally advanced or metastatic CSCC not suitable for surgery; and (xii) The method of claim 41, wherein the patient is selected as having one or more of the following: LAG-3 expression of ≧1% in tumor tissue; and the tumor tissue comprises tumor cells and tumor-infiltrating immune cells. (Item 44) 1. A method of treating cancer or inhibiting tumor growth, comprising: (1) Selecting patients with tumors; and (2) administering to the patient (a) 1, 3, 10, 20, or 40 mg / kg of an anti-LAG-3 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:11 / 12, as monotherapy, for about 1 month to about 12 months; and then further administering to the patient, in combination with (a), (b) 350 mg of an anti-PD-1 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO:1 / 2. (Item 45) 45. The method of claim 44, wherein the administering step occurs once every three weeks or once every six weeks. (Item 46) A method for treating cancer or inhibiting tumor growth comprising administering to a patient in need thereof (1) an initial loading dose comprising an anti-PD-1 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs:1 / 2; and an anti-LAG-3 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs:11 / 12; and (2) administering one or more secondary doses, the one or more secondary doses occurring 1 to 4 weeks after the immediately preceding dose. (Item 47) For patients who need it, (3) The method of item 46, further comprising administering one or more tertiary doses, wherein the one or more tertiary doses occur 3 to 12 weeks after the immediately preceding dose. (Item 48) 47. The method of claim 46, wherein the one or more secondary doses occur three weeks after the immediately preceding dose. (Item 49) 48. The method of claim 47, wherein the one or more tertiary doses occur 3 weeks or 6 weeks after the immediately preceding dose. (Item 50) 47. The method of item 46, wherein the initial loading dose comprises (a) 500 mg to 1500 mg of an anti-PD-1 antibody and (b) 20 or 40 mg / kg of an anti-LAG-3 antibody. (Item 51) 47. The method of item 46, wherein the one or more secondary doses comprise (a) 350 mg of an anti-PD-1 antibody and (b) 1, 3, 10, 20, or 40 mg / kg of an anti-LAG-3 antibody. (Item 52) 48. The method of item 47, wherein the one or more tertiary doses comprise (a) 350 mg of an anti-PD-1 antibody and (b) 1, 3, 10, 20, or 40 mg / kg of an anti-LAG-3 antibody. (Item 53) 47. The method of item 46, wherein the initial loading dose comprises (a) 500 mg to 1500 mg of an anti-PD-1 antibody and (b) 50 mg to 8000 mg of an anti-LAG-3 antibody. (Item 54) 47. The method of item 46, wherein the one or more secondary doses comprise (a) 350 mg of an anti-PD-1 antibody and (b) 800 mg, 1000 mg, 1400 mg, 1600 mg, or 2000 mg of an anti-LAG-3 antibody. (Item 55) 48. The method of item 47, wherein the one or more tertiary doses comprise (a) 350 mg of an anti-PD-1 antibody and (b) 800 mg, 1000 mg, 1400 mg, 1600 mg, or 2000 mg of an anti-LAG-3 antibody.

Claims

[Claim 1] The invention described in the specification.

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