LAG-3 antagonist therapy for lung cancer

Abstract

The present disclosure provides methods for treating a human subject with lung cancer with a lymphocyte-activation gene-3 (LAG-3) antagonist. In some embodiments, the methods include combining a LAG-3 antagonist with an additional therapeutic agent (e.g., a programmed death-1 pathway inhibitor) and / or an anti-cancer therapy (e.g., chemotherapy, such as platinum-doublet chemotherapy).

Description

[Technical Field]

[0001] Cross-reference of related applications This PCT application claims the benefit of priority to U.S. Provisional Application No. 63 / 104,744, filed on 23 October 2020, and U.S. Provisional Application No. 63 / 110,210, filed on 5 November 2020, which are incorporated in their entirety by this reference.

[0002] References to sequence listings submitted electronically via EFS-Web The contents of the electronically submitted sequence listing (name: 3338_240PC02_Seqlisting_ST25.txt; size: 94,766 bytes; and creation date: October 21, 2021) are incorporated herein by reference in their entirety.

[0003] Field of Invention The disclosure of this invention provides a method for treating human subjects with lung cancer, comprising a lymphocyte-activating gene-3 (LAG-3) antagonist. [Background technology]

[0004] Lung cancer, and non-small cell lung cancer in particular (NSCLC), continues to be a leading cause of cancer-related deaths worldwide, accounting for approximately 18% of all cancer deaths (Jenal A, et al., CA Cancer J. Clin. 2011;61:69-90).

[0005] Until recently, treatment for advanced NSCLC patients without targetable genetic mutations in the tumor was limited to cytotoxic chemotherapy. Despite treatment, the median survival time for metastatic NSCLC patients treated with dual platinum-based chemotherapy was approximately 10 months, and the 5-year survival rate was less than 5%. The introduction of immune checkpoint inhibitors targeting the PD-1 signaling pathway in the treatment of NSCLC patients had a significant impact on patient survival. Pembrolizumab, an anti-PD-1 antibody, combined with chemotherapy in a frontline setting has demonstrated improved overall survival in NSCLC patients compared to chemotherapy alone (Gandhi L, et al., N.Engl.J.Med.2018;378:2078-2092; Paz-Ares L, et al., N.Engl.J.Med.2018;379:2040-2051). More recently, the anti-PD-1 antibody nivolumab plus the anti-CTLA-4 antibody ipilimumab, and nivolumab plus ipilimumab in combination with chemotherapy, have also shown superior benefits to chemotherapy alone in this setting (Peters S, et al., Annals of Oncology 2019;30(suppl_5):v851-v934; Reck M, J. Clin. Oncol. 2020;(suppl):abstr.9501). However, despite these advances, the median survival time for patients with metastatic NSCLC treated as first-line therapy is approximately 22 months in the non-squamous cell population and 15.9 months in the squamous cell population (Paz-Ares L, et al.; Gadgeel S, et al., J. Clin. Oncol. 2020;38(14):1505-1517).

[0006] There is a need for improved methods for treating people with lung cancer. [Overview of the project] [Means for solving the problem]

[0007] The disclosure of the present invention relates to a method for treating a human subject with lung cancer, comprising administering a lymphocyte-activating gene-3 (LAG-3) antagonist and a dual platinum-based chemotherapy regimen (PDCT) to the subject.

[0008] In some embodiments, this method is a first-line therapy.

[0009] In some embodiments, this method is a second-line therapy.

[0010] In some embodiments, this method is a third-line treatment.

[0011] In some embodiments, the subjects are progressing with prior therapy.

[0012] In some cases, lung cancer recurs after multimodal therapy for locally advanced lung cancer.

[0013] In some embodiments, the subjects have not received systemic therapy for a prior cancer, or for a prior lung cancer, or for a prior advanced or metastatic lung cancer.

[0014] In some embodiments, the subjects have not received prior immuno-oncology therapy, or the subjects have not received prior immuno-oncology therapy for lung cancer, or the lung cancer has not received prior immuno-oncology therapy.

[0015] In some embodiments, lung cancer is unresectable, advanced, recurrent, and / or metastatic.

[0016] In some embodiments, the subjects have stage IV lung cancer.

[0017] For some purposes, lung cancer is small cell lung cancer.

[0018] In some embodiments, lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, NSCLC has a squamous or non-squamous histology.

[0019] In some embodiments, one or more immune cells in tumor tissue from a subject express LAG-3. In some embodiments, at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of immune cells express LAG-3. In some embodiments, at least about 1% of immune cells express LAG-3. In some embodiments, the immune cells are tumor-infiltrating lymphocytes. In some embodiments, the tumor-infiltrating lymphocytes are CD8 + It is a cell.

[0020] In some embodiments, one or more tumor cells in the tumor tissue from the subject express PD-L1. In some embodiments, at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the tumor cells express PD-L1. In some embodiments, at least about 1% of the tumor cells express PD-L1.

[0021] In some embodiments, the LAG-3 antagonist is an anti-LAG-3 antibody.

[0022] In some embodiments, the anti-LAG-3 antibody is a full-length antibody.

[0023] In some embodiments, the anti-LAG-3 antibody is monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is a dual-affinity re-targeting antibody (DART), DVD-Ig, or bispecific antibody.

[0024] In some embodiments, the anti-LAG-3 antibody is an F(ab')2 fragment, Fab' fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment, or single-chain linked polypeptide.

[0025] In some embodiments, the anti-LAG-3 antibody is BMS-986016 (relatrimab), IMP731 (H5L7BW), MK4280 (28G-10, fabezerimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, ieramilimab), aLAG3(0414), aLAG3(0416), Sy m022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tevoterimab), BI754111, FS118, P13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or containing their antigen-binding moieties.

[0026] In some embodiments, the anti-LAG-3 antibody comprises CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4.

[0027] In some embodiments, the anti-LAG-3 antibody comprises (a) a heavy chain variable region CDR1 containing the sequence described in SEQ ID NO: 5; (b) a heavy chain variable region CDR2 containing the sequence described in SEQ ID NO: 6; (c) a heavy chain variable region CDR3 containing the sequence described in SEQ ID NO: 7; (d) a light chain variable region CDR1 containing the sequence described in SEQ ID NO: 8; (e) a light chain variable region CDR2 containing the sequence described in SEQ ID NO: 9; and (f) a light chain variable region CDR3 containing the sequence described in SEQ ID NO: 10.

[0028] In some embodiments, the anti-LAG-3 antibody includes heavy chain and light chain variable regions containing the sequences described in SEQ ID NOs: 3 and 4, respectively.

[0029] In some embodiments, the anti-LAG-3 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs: 1 and 2, respectively.

[0030] In some embodiments, the anti-LAG-3 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 21 and 2, respectively.

[0031] In some embodiments, the LAG-3 antagonist is a soluble LAG-3 polypeptide. In some embodiments, the soluble LAG-3 polypeptide is a fusion polypeptide. In some embodiments, the soluble LAG-3 polypeptide comprises a ligand-binding fragment of the LAG-3 extracellular domain. In some embodiments, the ligand-binding fragment of the LAG-3 extracellular domain comprises SEQ ID NO: 22 and an amino acid sequence having at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity. In some embodiments, the soluble LAG-3 polypeptide further comprises a half-life-extending moiety. In some embodiments, the half-life-extending moiety comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin-binding polypeptide, immunoglobulin G (IgG), an albumin-binding polypeptide (ABP), a PAS-modified moiety, a HES-modified moiety, an XTEN, a pegylated moiety, an Fc region, or any combination thereof. In some embodiments, the soluble LAG-3 polypeptide is IMP321 (eftilagimod alpha).

[0032] In some embodiments, LAG-3 antagonists are formulated for intravenous administration.

[0033] In some embodiments, the LAG-3 antagonist is administered in a uniform dose.

[0034] In some protocols, LAG-3 antagonists are administered in doses of at least approximately 0.25 mg to 2000 mg, approximately 0.25 mg to 1600 mg, approximately 0.25 mg to 1200 mg, approximately 0.25 mg to 800 mg, approximately 0.25 mg to 400 mg, approximately 0.25 mg to 100 mg, approximately 0.25 mg to 50 mg, approximately 0.25 mg to 40 mg, approximately 0.25 mg to 30 mg, approximately 0.25 mg to 20 mg, approximately 20 mg to 2000 mg, approximately 20 mg to 1600 mg, approximately 20 mg to 1200 mg, approximately 20 mg to 800 mg, approximately 20 mg to 400 mg, and approximately It is administered in doses of approximately 20 mg to 100 mg, approximately 100 mg to 2000 mg, approximately 100 mg to 1800 mg, approximately 100 mg to 1600 mg, approximately 100 mg to 1400 mg, approximately 100 mg to 1200 mg, approximately 100 mg to 1000 mg, approximately 100 mg to 800 mg, approximately 100 mg to 600 mg, approximately 100 mg to 400 mg, approximately 400 mg to 2000 mg, approximately 400 mg to 1800 mg, approximately 400 mg to 1600 mg, approximately 400 mg to 1400 mg, approximately 400 mg to 1200 mg, or approximately 400 mg to 1000 mg.

[0035] According to some sources, LAG-3 antagonists are available in doses of approximately 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7 mg, 7.25 mg, 7.5 mg, 7.75 mg, 8 mg, 8.25 mg, 8.5 mg, 8.75 mg, 9 mg, 9.25 mg, 9.5 mg, and 9 mg.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 35 0mg, approx. 360mg, approx. 370mg, approx. 380mg, approx. 390mg, approx. 400mg, approx. 410mg, approx. 420mg, approx. 430mg, approx. 440mg, approx. 450mg, approx. 20mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 6 90mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 1080m It is administered in doses of approximately 1100mg, 1140mg, 1180mg, 1200mg, 1240mg, 1280mg, 1300mg, 1340mg, 1380mg, 1400mg, 1440mg, 1480mg, 1500mg, 1540mg, 1580mg, 1600mg, 1640mg, 1680mg, 1700mg, 1740mg, 1780mg, 1800mg, 1840mg, 1880mg, 1900mg, 1940mg, 1980mg, or 2000mg.

[0036] In some embodiments, LAG-3 antagonists are administered in a dose based on body weight.

[0037] In some aspects, LAG-3 antagonists are present in doses ranging from approximately 0.003 mg / kg to approximately 25 mg / kg, approximately 0.003 mg / kg to approximately 20 mg / kg, approximately 0.003 mg / kg to approximately 15 mg / kg, approximately 0.003 mg / kg to approximately 10 mg / kg, approximately 0.003 mg / kg to approximately 5 mg / kg, approximately 0.003 mg / kg to approximately 1 mg / kg, approximately 0.003 mg / kg to approximately 0.9 mg / kg, and approximately 0.003 mg / kg to approximately 0.8 mg / kg, approximately 0.003 mg / kg to approximately 0.7 mg / kg, approximately 0.003 mg / kg to approximately 0.6 mg / kg, approximately 0.003 mg / kg to approximately 0.5 mg / kg, approximately 0.003 mg / kg to approximately 0.4 mg / kg, approximately 0.003 mg / kg to approximately 0.3 mg / kg, approximately 0.003 mg / kg to approximately 0.2 mg / kg, approximately 0.003 mg / kg to approximately 0.1 mg / kg, approximately 0.1 mg / kg to approximately 25 mg / kg, approximately 0 0.1 mg / kg to approximately 20 mg / kg, approximately 0.1 mg / kg to approximately 15 mg / kg, approximately 0.1 mg / kg to approximately 10 mg / kg, approximately 0.1 mg / kg to approximately 5 mg / kg, approximately 0.1 mg / kg to approximately 1 mg / kg, approximately 1 mg / kg to approximately 25 mg / kg, approximately 1 mg / kg to approximately 20 mg / kg, approximately 1 mg / kg to approximately 15 mg / kg, approximately 1 mg / kg to approximately 10 mg / kg, approximately 1 mg / kg to approximately 5 mg / kg, approximately 5 mg / kg It is administered in doses of approximately 25 mg / kg from g, approximately 20 mg / kg from approximately 5 mg / kg, approximately 15 mg / kg from approximately 5 mg / kg, approximately 10 mg / kg from approximately 10 mg / kg, approximately 25 mg / kg from approximately 10 mg / kg, approximately 20 mg / kg from approximately 10 mg / kg, approximately 15 mg / kg from approximately 15 mg / kg, approximately 25 mg / kg from approximately 15 mg / kg, or approximately 20 mg / kg from approximately 25 mg / kg.

[0038] In some aspects, LAG-3 antagonists are present in doses of approximately 0.003 mg / kg, 0.004 mg / kg, 0.005 mg / kg, 0.006 mg / kg, 0.007 mg / kg, 0.008 mg / kg, 0.009 mg / kg, 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, and 0.8 mg / kg. It is administered in doses of approximately 0.9 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg, 10.0 mg / kg, 11.0 mg / kg, 12.0 mg / kg, 13.0 mg / kg, 14.0 mg / kg, 15.0 mg / kg, 16.0 mg / kg, 17.0 mg / kg, 18.0 mg / kg, 19.0 mg / kg, 20.0 mg / kg, 21.0 mg / kg, 22.0 mg / kg, 23.0 mg / kg, 24.0 mg / kg, or 25.0 mg / kg.

[0039] In some cases, the dosage is administered approximately once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks.

[0040] In some embodiments, PDCT comprises a platinum agent in combination with a nucleoside analog, an antimetabolite, a taxane, a vinca alkaloid, or a topoisomerase inhibitor. In some embodiments, the platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lipoplatin, or phenantriplatin. In some embodiments, the platinum agent is cisplatin. In some embodiments, the platinum agent is carboplatin. In some embodiments, the nucleoside analog is cytarabine, gemcitabine, lamivudine, entecavir, or terbivudine. In some embodiments, the nucleoside analog is gemcitabine. In some embodiments, the antimetabolite is capecitabine, cladribine, clofarabine, cytarabine, phloxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, or thioguanine. In some embodiments, the antimetabolite is carboplatin. In some embodiments, the taxane is paclitaxel, albumin-conjugated paclitaxel, docetaxel, or cabazitaxel. In some embodiments, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vineridine, or vimburnin. In some embodiments, the vinca alkaloid is vinorelbine or vinblastine. In some embodiments, the topoisomerase inhibitor is etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin. In some embodiments, the topoisomerase inhibitor is etoposide. In some embodiments, the topoisomerase inhibitor is irinotecan.

[0041] In some embodiments, PDCT includes cisplatin or carboplatin in combination with gemcitabine, pemetrexed, paclitaxel, albumin-conjugated paclitaxel, docetaxel, vinorelbine, vinblastine, etoposide, or irinotecan.

[0042] In some embodiments, PDCT includes cisplatin or carboplatin in combination with paclitaxel or albumin-conjugated paclitaxel.

[0043] In some embodiments, PDCT, in combination with pemetrexed, includes cisplatin or carboplatin.

[0044] In some embodiments, the method further comprises administering an additional therapeutic agent to a target. In some embodiments, the additional therapeutic agent includes an anticancer agent. In some embodiments, the anticancer agent includes tyrosine kinase inhibitors, anti-angiogenic agents, checkpoint inhibitors, checkpoint stimulants, chemotherapeutic agents, immunotherapeutic agents, platinum agents, alkylating agents, taxanes, nucleoside analogs, antimetabolites, topoisomerase inhibitors, anthracyclines, vinca alkaloids, or any combination thereof.

[0045] In some embodiments, the tyrosine kinase inhibitors include afatinib, erlotinib, dacomitinib, gefitinib, osimertinib, alectinib, brigatinib, ceritinib, crizotinib, lorlatinib, entrectinib, dabrafenib, trametinib, vemurafenib, lalotrectinib, or any combination thereof.

[0046] In some embodiments, anti-angiogenic agents include inhibitors of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase receptors having Ig-like and EGF-like domains (Tie), hepatocyte growth factor (HGF), tyrosine-protein kinase Met (c-MET), C-type lectin family 14 member A (CLEC14A), multimelin 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), EGF receptor (EGFR), or any combination thereof.

[0047] In some embodiments, the anti-angiogenic agents include bevacizumab, ramucirumab, aflibercept, tanibirumab, olaratumab, nesbakumab, AMG780, MEDI3617, vanucizumab, rilotumumab, ficratuzumab, TAK-701, onartuzumab, emibetuzumab, or any combination thereof.

[0048] In some embodiments, checkpoint inhibitors include programmed death-1 (PD-1) pathway inhibitors, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, T cell immunoglobulin and ITIM domain (TIGIT) inhibitors, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B and T cell lymphocyte attenuator (BTLA) inhibitors, V domain Ig suppressor (VISTA) inhibitors for T cell activation, indoleamine 2,3-dioxygenase (IDO) inhibitors, nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitors, and killer cells. This includes follicular immunoglobulin-like receptor (KIR) inhibitors, adenosine A2a receptor (A2aR) inhibitors, transforming growth factor beta (TGF-β) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, CD47 inhibitors, CD48 inhibitors, CD73 inhibitors, CD113 inhibitors, sialic acid-binding immunoglobulin-like lectin-7 (Sigrec-7) inhibitors, Sigrec-9 inhibitors, Sigrec-15 inhibitors, glucocorticoid-induced TNFR-related protein (GITR) inhibitors, galectin-1 inhibitors, galectin-9 inhibitors, carcinoembryonic antigen-associated cell adhesion molecule-1 (CEACAM-1) inhibitors, G protein-coupled receptor 56 (GPR56) inhibitors, glycoprotein A repetitions predominantly (GARP) inhibitors, 2B4 inhibitors, programmed death-1 homolog (PD1H) inhibitors, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitors, or any combination thereof.

[0049] In some embodiments, checkpoint inhibitors include PD-1 pathway inhibitors.

[0050] In some embodiments, PD-1 pathway inhibitors are anti-PD-1 antibodies and / or anti-PD-L1 antibodies.

[0051] In some embodiments, PD-1 pathway inhibitors are anti-PD-1 antibodies.

[0052] In some embodiments, the anti-PD-1 antibody is a full-length antibody.

[0053] In some embodiments, the anti-PD-1 antibody is monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is DART, DVD-Ig, or bispecific antibody.

[0054] In some embodiments, the anti-PD-1 antibody is an F(ab')2 fragment, Fab' fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment, or single-chain linked polypeptide.

[0055] In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, semiprimab, JS001, PF-06801591, BGB-A317, BI754091, INCSHR1210, GLS-010, AM-001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, SSI-361, or contains the antigen-binding moiety thereof.

[0056] In some embodiments, the anti-PD-1 antibody comprises CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14.

[0057] In some embodiments, the anti-PD-1 antibody comprises (a) a heavy chain variable region CDR1 containing the sequence described in SEQ ID NO: 15; (b) a heavy chain variable region CDR2 containing the sequence described in SEQ ID NO: 16; (c) a heavy chain variable region CDR3 containing the sequence described in SEQ ID NO: 17; (d) a light chain variable region CDR1 containing the sequence described in SEQ ID NO: 18; (e) a light chain variable region CDR2 containing the sequence described in SEQ ID NO: 19; and (f) a light chain variable region CDR3 containing the sequence described in SEQ ID NO: 20.

[0058] In some embodiments, the anti-PD-1 antibody includes heavy chain and light chain variable regions containing the sequences described in SEQ ID NOs: 13 and 14, respectively.

[0059] In some embodiments, the anti-PD-1 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs: 11 and 12, respectively.

[0060] In some embodiments, the PD-1 pathway inhibitor is a soluble PD-L2 polypeptide. In some embodiments, the soluble PD-L2 polypeptide is a fusion polypeptide. In some embodiments, the soluble PD-L2 polypeptide comprises a ligand-binding fragment of the PD-L2 extracellular domain. In some embodiments, the soluble PD-L2 polypeptide further comprises a half-life-extending moiety. In some embodiments, the half-life-extending moiety comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin-binding polypeptide, immunoglobulin G (IgG), an albumin-binding polypeptide (ABP), a PAS-modified moiety, a HES-modified moiety, an XTEN, a pegylated moiety, an Fc region, or any combination thereof. In some embodiments, the soluble PD-L2 polypeptide is AMP-224.

[0061] In some embodiments, PD-1 pathway inhibitors are anti-PD-L1 antibodies.

[0062] In some embodiments, anti-PD-L1 antibodies are full-length antibodies.

[0063] In some embodiments, the anti-PD-L1 antibody is monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is DART, DVD-Ig, or bispecific antibody.

[0064] In some embodiments, the anti-PD-L1 antibody is an F(ab')2 fragment, Fab' fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment, or single-chain linked polypeptide.

[0065] In some embodiments, the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO36, FAZ053, CK-301, or contains the antigen-binding moiety thereof.

[0066] In some embodiments, the PD-1 pathway inhibitor is BMS-986189.

[0067] In some embodiments, checkpoint inhibitors include CTLA-4 inhibitors.

[0068] In some embodiments, CTLA-4 inhibitors are anti-CTLA-4 antibodies.

[0069] In some embodiments, the anti-CTLA-4 antibody is a full-length antibody.

[0070] In some embodiments, the anti-CTLA-4 antibody is monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is DART, DVD-Ig, or bispecific antibody.

[0071] In some embodiments, the anti-CTLA-4 antibody is an F(ab')2 fragment, Fab' fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment, or single-chain linked polypeptide.

[0072] In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, MK-1308, AGEN-1884, or comprises an antigen-binding moiety thereof.

[0073] In some embodiments, checkpoint inhibitors are formulated for intravenous administration.

[0074] In some embodiments, the LAG-3 antagonist and the checkpoint inhibitor are formulated separately. In some embodiments, if the checkpoint inhibitor contains more than one checkpoint inhibitor, each checkpoint inhibitor is formulated separately. In some embodiments, the checkpoint inhibitor is administered before the LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is administered before the checkpoint inhibitor.

[0075] In some embodiments, LAG-3 antagonists and checkpoint inhibitors are formulated together. In some embodiments, if the checkpoint inhibitors include more than one checkpoint inhibitor, two or more checkpoint inhibitors are formulated together.

[0076] In some embodiments, LAG-3 antagonists and checkpoint inhibitors are administered simultaneously.

[0077] In some embodiments, checkpoint inhibitors are administered in uniform doses.

[0078] In some embodiments, checkpoint inhibitors are administered in doses of at least approximately 0.25 mg to approximately 2000 mg, approximately 0.25 mg to approximately 1600 mg, approximately 0.25 mg to approximately 1200 mg, approximately 0.25 mg to approximately 800 mg, approximately 0.25 mg to approximately 400 mg, approximately 0.25 mg to approximately 100 mg, approximately 0.25 mg to approximately 50 mg, approximately 0.25 mg to approximately 40 mg, approximately 0.25 mg to approximately 30 mg, approximately 0.25 mg to approximately 20 mg, approximately 20 mg to approximately 2000 mg, approximately 20 mg to approximately 1600 mg, approximately 20 mg to approximately 1200 mg, approximately 20 mg to approximately 800 mg, approximately 20 mg to approximately 400 mg, and approximately It is administered in doses of approximately 20 mg to 100 mg, approximately 100 mg to 2000 mg, approximately 100 mg to 1800 mg, approximately 100 mg to 1600 mg, approximately 100 mg to 1400 mg, approximately 100 mg to 1200 mg, approximately 100 mg to 1000 mg, approximately 100 mg to 800 mg, approximately 100 mg to 600 mg, approximately 100 mg to 400 mg, approximately 400 mg to 2000 mg, approximately 400 mg to 1800 mg, approximately 400 mg to 1600 mg, approximately 400 mg to 1400 mg, approximately 400 mg to 1200 mg, or approximately 400 mg to 1000 mg.

[0079] According to some sources, checkpoint inhibitors are available in doses of approximately 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7 mg, 7.25 mg, 7.5 mg, 7.75 mg, 8 mg, 8.25 mg, 8.5 mg, 8.75 mg, 9 mg, 9.25 mg, 9.5 mg, and 9 mg.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 35 0mg, approx. 360mg, approx. 370mg, approx. 380mg, approx. 390mg, approx. 400mg, approx. 410mg, approx. 420mg, approx. 430mg, approx. 440mg, approx. 450mg, approx. 20mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 6 90mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 1080m It is administered in doses of approximately 1100mg, 1140mg, 1180mg, 1200mg, 1240mg, 1280mg, 1300mg, 1340mg, 1380mg, 1400mg, 1440mg, 1480mg, 1500mg, 1540mg, 1580mg, 1600mg, 1640mg, 1680mg, 1700mg, 1740mg, 1780mg, 1800mg, 1840mg, 1880mg, 1900mg, 1940mg, 1980mg, or 2000mg.

[0080] In some embodiments, checkpoint inhibitors are administered in a body weight-based dose.

[0081] In some aspects, checkpoint inhibitors are administered in doses ranging from approximately 0.003 mg / kg to approximately 25 mg / kg, approximately 0.003 mg / kg to approximately 20 mg / kg, approximately 0.003 mg / kg to approximately 15 mg / kg, approximately 0.003 mg / kg to approximately 10 mg / kg, approximately 0.003 mg / kg to approximately 5 mg / kg, approximately 0.003 mg / kg to approximately 1 mg / kg, approximately 0.003 mg / kg to approximately 0.9 mg / kg, and approximately 0.003 mg / kg to approximately 0 0.8 mg / kg, approximately 0.003 mg / kg to approximately 0.7 mg / kg, approximately 0.003 mg / kg to approximately 0.6 mg / kg, approximately 0.003 mg / kg to approximately 0.5 mg / kg, approximately 0.003 mg / kg to approximately 0.4 mg / kg, approximately 0.003 mg / kg to approximately 0.3 mg / kg, approximately 0.003 mg / kg to approximately 0.2 mg / kg, approximately 0.003 mg / kg to approximately 0.1 mg / kg, approximately 0.1 mg / kg to approximately 25 mg / kg, approximately 0 0.1 mg / kg to approximately 20 mg / kg, approximately 0.1 mg / kg to approximately 15 mg / kg, approximately 0.1 mg / kg to approximately 10 mg / kg, approximately 0.1 mg / kg to approximately 5 mg / kg, approximately 0.1 mg / kg to approximately 1 mg / kg, approximately 1 mg / kg to approximately 25 mg / kg, approximately 1 mg / kg to approximately 20 mg / kg, approximately 1 mg / kg to approximately 15 mg / kg, approximately 1 mg / kg to approximately 10 mg / kg, approximately 1 mg / kg to approximately 5 mg / kg, approximately 5 mg / kg It is administered in doses of approximately 25 mg / kg from g, approximately 20 mg / kg from approximately 5 mg / kg, approximately 15 mg / kg from approximately 5 mg / kg, approximately 10 mg / kg from approximately 10 mg / kg, approximately 25 mg / kg from approximately 10 mg / kg, approximately 20 mg / kg from approximately 10 mg / kg, approximately 15 mg / kg from approximately 15 mg / kg, approximately 25 mg / kg from approximately 15 mg / kg, or approximately 20 mg / kg from approximately 25 mg / kg.

[0082] In some aspects, checkpoint inhibitors are present in doses of approximately 0.003 mg / kg, approximately 0.004 mg / kg, approximately 0.005 mg / kg, approximately 0.006 mg / kg, approximately 0.007 mg / kg, approximately 0.008 mg / kg, approximately 0.009 mg / kg, approximately 0.01 mg / kg, approximately 0.02 mg / kg, approximately 0.03 mg / kg, approximately 0.04 mg / kg, approximately 0.05 mg / kg, approximately 0.06 mg / kg, approximately 0.07 mg / kg, approximately 0.08 mg / kg, approximately 0.09 mg / kg, approximately 0.1 mg / kg, approximately 0.2 mg / kg, approximately 0.3 mg / kg, approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 0.6 mg / kg, approximately 0.7 mg / kg, approximately 0.8 mg / kg, approximately It is administered in doses of 0.9 mg / kg, approximately 1.0 mg / kg, approximately 2.0 mg / kg, approximately 3.0 mg / kg, approximately 4.0 mg / kg, approximately 5.0 mg / kg, approximately 6.0 mg / kg, approximately 7.0 mg / kg, approximately 8.0 mg / kg, approximately 9.0 mg / kg, approximately 10.0 mg / kg, approximately 11.0 mg / kg, approximately 12.0 mg / kg, approximately 13.0 mg / kg, approximately 14.0 mg / kg, approximately 15.0 mg / kg, approximately 16.0 mg / kg, approximately 17.0 mg / kg, approximately 18.0 mg / kg, approximately 19.0 mg / kg, approximately 20.0 mg / kg, approximately 21.0 mg / kg, approximately 22.0 mg / kg, approximately 23.0 mg / kg, approximately 24.0 mg / kg, or approximately 25.0 mg / kg.

[0083] In some cases, the dosage is administered approximately once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks.

[0084] The disclosure of the present invention relates to a method for treating a human subject with lung cancer, comprising administering to the subject an anti-LAG-3 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4, and (b) an anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14.

[0085] The disclosure of the present invention relates to a method for treating a human subject with lung cancer, comprising administering to the subject an anti-LAG-3 antibody at a dose of approximately 720 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4, and (b) an anti-PD-1 antibody at a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14.

[0086] In some embodiments, this method is a first-line therapy.

[0087] In some embodiments, this method is a second-line therapy.

[0088] In some embodiments, this method is a third-line treatment.

[0089] In some embodiments, the subjects are progressing with prior therapy.

[0090] In some embodiments, lung cancer is unresectable, advanced, recurrent, and / or metastatic.

[0091] In some embodiments, the subjects have stage IV lung cancer.

[0092] For some purposes, lung cancer is small cell lung cancer.

[0093] In some embodiments, lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, NSCLC has a squamous epithelial tissue structure. In some embodiments, NSCLC has a non-squamous epithelial tissue structure.

[0094] In some embodiments, the method further comprises administering PDCT. In some embodiments, PDCT comprises a platinum agent in combination with a nucleoside analog, an antimetabolite, a taxane, a vinca alkaloid, or a topoisomerase inhibitor. In some embodiments, the platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lipoplatin, or phenantriplatin. In some embodiments, the platinum agent is cisplatin. In some embodiments, the platinum agent is carboplatin. In some embodiments, the nucleoside analog is cytarabine, gemcitabine, lamivudine, entecavir, or terbivudine. In some embodiments, the nucleoside analog is gemcitabine. In some embodiments, the antimetabolite is capecitabine, cladribine, clofarabine, cytarabine, phloxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, or thioguanine. In some embodiments, the antimetabolite is carboplatin. In some embodiments, the taxane is paclitaxel, albumin-conjugated paclitaxel, docetaxel, or cabazitaxel. In some embodiments, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vineridine, or vimburnin. In some embodiments, the vinca alkaloid is vinorelbine or vinblastine. In some embodiments, the topoisomerase inhibitor is etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin. In some embodiments, the topoisomerase inhibitor is etoposide. In some embodiments, the topoisomerase inhibitor is irinotecan. In some embodiments, PDCT includes cisplatin or carboplatin in combination with gemcitabine, pemetrexed, paclitaxel, albumin-conjugated paclitaxel, docetaxel, vinorelbine, vinblastine, etoposide, or irinotecan.In some embodiments, PDCT comprises cisplatin or carboplatin in combination with paclitaxel or albumin-conjugated paclitaxel. In some embodiments, PDCT comprises cisplatin or carboplatin in combination with pemetrexed.

[0095] The present invention discloses a method for treating a human subject suffering from stage IV or recurrent NSCLC having a squamous epithelial tissue structure, comprising: (a) an anti-LAG-3 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c) (i) a dose of carboplatin with a target area under the concentration-time curve of approximately 6 mg / mL·min and (ii) approximately 200 mg / m² 2 The method is directed towards a first-line therapy that includes administering a dose of paclitaxel to patients with PDCT.

[0096] The present invention discloses a method for treating a human subject suffering from stage IV or recurrent NSCLC having a squamous epithelial tissue structure, comprising: (a) an anti-LAG-3 antibody in a dose of approximately 720 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c) (i) carboplatin in a dose with an area under the target concentration-time curve of approximately 6 mg / mL·min and (ii) approximately 200 mg / m² 2 The method is directed towards a first-line therapy that includes administering a dose of paclitaxel to patients with PDCT.

[0097] The present invention discloses a method for treating a human subject suffering from stage IV or recurrent NSCLC having a squamous epithelial tissue structure, comprising: (a) an anti-LAG-3 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c) (i) carboplatin in a dose with an area under the target concentration-time curve of approximately 6 mg / mL·min and (ii) approximately 100 mg / m² 2 The method is directed towards a first-line therapy that includes administering a dose of paclitaxel to patients with PDCT.

[0098] The disclosure of the present invention relates to a method for treating a human subject suffering from stage IV or recurrent NSCLC having a squamous epithelial tissue structure, comprising: (a) an anti-LAG-3 antibody in a dose of approximately 720 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c) (i) carboplatin in a dose with an area under the target concentration-time curve of approximately 6 mg / mL·min and (ii) approximately 100 mg / m² 2 The method is directed towards a first-line therapy that includes administering albumin-bound paclitaxel to patients with PDCT.

[0099] The disclosure of the present invention relates to a method for treating a human subject suffering from stage IV or recurrent NSCLC having a non-squamous tissue structure, comprising: (a) an anti-LAG-3 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c) (i) carboplatin in a dose with an area under the target concentration-time curve of approximately 5 mg / mL·min or approximately 6 mg / mL·min and (ii) approximately 500 mg / m² 2 The method is directed towards a first-line therapy that includes administering pemetrexed at a dose to patients with PDCT.

[0100] The present disclosure is directed to a method of treating a human subject having stage IV or recurrent non-squamous NSCLC comprising administering to the subject, as a first-line therapy, (a) an anti-LAG-3 antibody at a dose of about 720 mg, wherein the anti-LAG-3 antibody comprises CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 3, and CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 4, (b) an anti-PD-1 antibody at a dose of about 360 mg, wherein the anti-PD-1 antibody comprises CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 13, and CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 14, and (c) a PDCT comprising (i) carboplatin at a dose of area under the concentration-time curve of about 5 mg / mL·min or about 6 mg / mL·min, and (ii) pemetrexed at a dose of about 500 mg / m 2 .

[0101] The present disclosure is directed to a method of treating a human subject having stage IV or recurrent non-squamous NSCLC comprising administering to the subject, as a first-line therapy, (a) an anti-LAG-3 antibody at a dose of about 360 mg, wherein the anti-LAG-3 antibody comprises CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 3, and CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 4, (b) an anti-PD-1 antibody at a dose of about 360 mg, wherein the anti-PD-1 antibody comprises CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 13, and CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 14, and (c) a PDCT comprising (i) cisplatin at a dose of about 75 mg / m 2 and (ii) pemetrexed at a dose of about 500 mg / m 2 .

[0102] The disclosure of the present invention relates to a method for treating a human subject suffering from stage IV or recurrent NSCLC having a non-squamous tissue structure, comprising: (a) an anti-LAG-3 antibody in a dose of approximately 720 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c)(i) approximately 75 mg / m² 2 (ii) a dose of cisplatin and (ii) approximately 500 mg / m² 2 The method is directed towards a first-line therapy that includes administering pemetrexed-containing doses to patients with PDCT.

[0103] In some aspects, lung cancer recurs after multidisciplinary therapy for locally advanced lung cancer.

[0104] In some embodiments, the subjects have not received systemic therapy for a prior cancer, or for a prior lung cancer, or for a prior advanced or metastatic lung cancer.

[0105] In some embodiments, the subjects have not received prior immuno-oncology therapy, or the subjects have not received prior immuno-oncology therapy for lung cancer, or the lung cancer has not received prior immuno-oncology therapy.

[0106] In some embodiments, one or more immune cells in tumor tissue from a subject express LAG-3. In some embodiments, at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of immune cells express LAG-3. In some embodiments, at least about 1% of immune cells express LAG-3. In some embodiments, the immune cells are tumor-infiltrating lymphocytes. In some embodiments, the tumor-infiltrating lymphocytes are CD8 + It is a cell.

[0107] In some embodiments, one or more tumor cells in the tumor tissue from the subject express PD-L1. In some embodiments, at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the tumor cells express PD-L1. In some embodiments, at least about 1% of the tumor cells express PD-L1.

[0108] In some embodiments, (a) an anti-LAG-3 antibody comprises heavy chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively, and light chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively; and (b) an anti-PD-1 antibody comprises heavy chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, respectively, and light chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, respectively.

[0109] In some embodiments, the anti-LAG-3 antibody comprises heavy chain and light chain variable regions containing the sequences described in SEQ ID NOs: 3 and 4, respectively, and the anti-PD-1 antibody comprises heavy chain and light chain variable regions containing the sequences described in SEQ ID NOs: 13 and 14, respectively.

[0110] In some embodiments, the anti-LAG-3 antibody and / or anti-PD-1 antibody are full-length antibodies.

[0111] In some embodiments, the anti-LAG-3 antibody and / or anti-PD-1 antibody is monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is DART, DVD-Ig, or bispecific antibody.

[0112] In some embodiments, the anti-LAG-3 antibody and / or anti-PD-1 antibody is an F(ab')2 fragment, Fab' fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment, or single-chain linked polypeptide.

[0113] In some embodiments, the anti-LAG-3 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs: 1 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs: 11 and 12, respectively.

[0114] In some embodiments, the anti-LAG-3 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 21 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 11 and 12, respectively.

[0115] In some embodiments, the method further comprises administering an additional therapeutic agent to a target. In some embodiments, the additional therapeutic agent includes an anticancer agent. In some embodiments, the anticancer agent includes tyrosine kinase inhibitors, anti-angiogenic agents, checkpoint inhibitors, checkpoint stimulants, chemotherapeutic agents, immunotherapeutic agents, platinum agents, alkylating agents, taxanes, nucleoside analogs, antimetabolites, topoisomerase inhibitors, anthracyclines, vinca alkaloids, or any combination thereof.

[0116] In some embodiments, the tyrosine kinase inhibitor is afatinib, erlotinib, dacomitinib, gefitinib, osimertinib, alectinib, brigatinib, ceritinib, crizotinib, lorlatinib, entrectinib, dabrafenib, trametinib, vemurafenib, lalotrectinib, or any combination thereof.

[0117] In some embodiments, anti-angiogenic agents include inhibitors of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase receptors having Ig-like and EGF-like domains (Tie), hepatocyte growth factor (HGF), tyrosine-protein kinase Met (c-MET), C-type lectin family 14 member A (CLEC14A), multimelin 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), EGF receptor (EGFR), or any combination thereof.

[0118] In some embodiments, the anti-angiogenic agents include bevacizumab, ramucirumab, aflibercept, tanibirumab, olaratumab, nesbacumab, AMG780, MEDI3617, vanucizumab, rilotumumab, ficratuzumab, TAK-701, onartuzumab, emibetuzumab, or any combination thereof.

[0119] In some embodiments, checkpoint inhibitors include programmed death-1 (PD-1) pathway inhibitors, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, T cell immunoglobulin and ITIM domain (TIGIT) inhibitors, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B and T cell lymphocyte attenuator (BTLA) inhibitors, V domain Ig suppressor (VISTA) inhibitors for T cell activation, indoleamine 2,3-dioxygenase (IDO) inhibitors, nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitors, killer cell immunoglobulin-like receptor (KIR) inhibitors, and adenosine A2a receptor (A2a This includes inhibitors of r(R), transforming growth factor beta (TGF-β), phosphoinositide 3-kinase (PI3K), CD47, CD48, CD73, CD113, sialic acid-binding immunoglobulin-like lectin-7 (Sigrec-7), Sigrec-9, Sigrec-15, glucocorticoid-induced TNFR-related protein (GITR), galectin-1, galectin-9, carcinoembryonic antigen-associated cell adhesion molecule-1 (CEACAM-1), G protein-coupled receptor 56 (GPR56), glycoprotein A repeat dominant (GARP) inhibitors, 2B4 inhibitors, programmed death-1 homolog (PD1H), leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), or any combination thereof.

[0120] In some embodiments, PD-1 pathway inhibitors are anti-PD-L1 antibodies.

[0121] In some embodiments, anti-PD-L1 antibodies are full-length antibodies.

[0122] In some embodiments, the anti-PD-L1 antibody is monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is DART, DVD-Ig, or bispecific antibody.

[0123] In some embodiments, the anti-PD-L1 antibody is an F(ab')2 fragment, Fab' fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment, or single-chain linked polypeptide.

[0124] In some embodiments, the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO36, FAZ053, CK-301, or contains the antigen-binding moiety thereof.

[0125] In some embodiments, the PD-1 pathway inhibitor is BMS-986189.

[0126] In some embodiments, checkpoint inhibitors include CTLA-4 inhibitors.

[0127] In some embodiments, CTLA-4 inhibitors are anti-CTLA-4 antibodies.

[0128] In some embodiments, the anti-CTLA-4 antibody is a full-length antibody.

[0129] In some embodiments, the anti-CTLA-4 antibody is monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is DART, DVD-Ig, or bispecific antibody.

[0130] In some embodiments, the anti-CTLA-4 antibody is an F(ab')2 fragment, Fab' fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment, or single-chain linked polypeptide.

[0131] In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, MK-1308, AGEN-1884, or comprises an antigen-binding moiety thereof.

[0132] In some embodiments, anti-LAG-3 antibodies and anti-PD-1 antibodies are formulated for intravenous administration.

[0133] In some embodiments, checkpoint inhibitors are formulated for intravenous administration.

[0134] In some embodiments, the anti-LAG-3 antibody and the anti-PD-1 antibody are formulated separately.

[0135] In some embodiments, anti-LAG-3 antibodies and anti-PD-1 antibodies are formulated together.

[0136] In some embodiments, the anti-PD-1 antibody is administered before the anti-LAG-3 antibody.

[0137] In some embodiments, the anti-LAG-3 antibody is administered before the anti-PD-1 antibody.

[0138] In some embodiments, LAG-3 antibodies and anti-PD-1 antibodies are administered simultaneously.

[0139] In some embodiments, anti-LAG-3 antibodies and anti-PD-1 antibodies are administered once approximately every three weeks. In some embodiments, anti-LAG-3 antibodies and anti-PD-1 antibodies are administered on day 1 of each three-week cycle. In some embodiments, anti-LAG-3 antibodies and anti-PD-1 antibodies are administered intravenously from a single infusion bag over approximately 30 minutes.

[0140] In some embodiments, PDCT is administered every three weeks. In some embodiments, PDCT is administered for up to approximately four three-week cycles.

[0141] The disclosure of the present invention is directed toward a pharmaceutical composition comprising (a) 360 mg of anti-LAG-3 antibody and (b) 360 mg of anti-PD-1 antibody.

[0142] The disclosure of the present invention is directed toward a pharmaceutical composition comprising (a) 720 mg of anti-LAG-3 antibody and (b) 360 mg of anti-PD-1 antibody.

[0143] In some embodiments, (a) the anti-LAG-3 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4, and (b) the anti-PD-1 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14.

[0144] In some embodiments, (a) an anti-LAG-3 antibody comprises CDR1, CDR2, and CDR3 domains of the heavy chain variable region containing the sequences described in SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and CDR1, CDR2, and CDR3 domains of the light chain variable region containing the sequences described in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively; and (b) an anti-PD-1 antibody comprises CDR1, CDR2, and CDR3 domains of the heavy chain variable region containing the sequences described in SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, and CDR1, CDR2, and CDR3 domains of the light chain variable region containing the sequences described in SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, respectively.

[0145] In some embodiments, the anti-LAG-3 antibody comprises heavy chain and light chain variable regions containing the sequences described in SEQ ID NOs: 3 and 4, respectively, and the anti-PD-1 antibody comprises heavy chain and light chain variable regions containing the sequences described in SEQ ID NOs: 13 and 14, respectively.

[0146] In some embodiments, the anti-LAG-3 antibody and / or anti-PD-1 antibody are full-length antibodies.

[0147] In some embodiments, the anti-LAG-3 antibody and / or anti-PD-1 antibody is monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is DART, DVD-Ig, or bispecific antibody.

[0148] In some embodiments, the anti-LAG-3 antibody and / or anti-PD-1 antibody is an F(ab')2 fragment, Fab' fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment, or single-chain linked polypeptide.

[0149] In some embodiments, the anti-LAG-3 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs: 1 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs: 11 and 12, respectively.

[0150] In some embodiments, the anti-LAG-3 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 21 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 11 and 12, respectively.

[0151] The disclosure of the present invention relates to a kit for treating human subjects with lung cancer, comprising (a) 360 mg of anti-LAG-3 antibody; (b) 360 mg of anti-PD-1 antibody; and (c) instructions for use of the anti-LAG-3 antibody and anti-PD-1 antibody in a method for treating human subjects with lung cancer.

[0152] The disclosure of the present invention is directed toward a kit for treating human subjects with lung cancer, comprising (a) 720 mg of anti-LAG-3 antibody, (b) 360 mg of anti-PD-1 antibody, and (c) instructions for using the anti-LAG-3 antibody and the anti-PD-1 antibody in a method for treating human subjects with lung cancer. [Modes for carrying out the invention]

[0153] The disclosure of the present invention provides a method for treating a human subject with lung cancer (e.g., non-small cell lung cancer (NSCLC)), comprising administering a LAG-3 antagonist (e.g., an anti-LAG-3 antibody) to the subject. Some aspects of the disclosure of the present invention are directed toward a method for treating a human subject with lung cancer, which is a first-line, second-line, or third-line therapy. Some aspects of the disclosure of the present invention are directed toward a method for treating a human subject with stage IV or recurrent lung cancer. The disclosure of the present invention is also directed toward a method for treating a human subject with lung cancer, which comprises anticancer therapies and / or therapeutic agents such as chemotherapy (e.g., dual platinum-based chemotherapy) and / or PD-1 pathway inhibitors (e.g., anti-PD-1 antibodies) in combination with a LAG-3 antagonist. This disclosure may provide the following: [Section 1] A method for treating a human subject with lung cancer, comprising administering a lymphocyte-activating gene-3 (LAG-3) antagonist and a dual platinum-based chemotherapy regimen (PDCT). [Section 2] The first-line treatment, as described in item 1. [Section 3] The method described in item 1, which is a second-line treatment. [Section 4] The third-line therapy, as described in item 1. [Section 5] The method described in item 3 or 4 applies to patients whose condition has progressed with prior therapy. [Section 6] The method according to any one of items 1 to 5, wherein the lung cancer has recurred after multidisciplinary therapy for locally advanced lung cancer. [Section 7] The method according to any one of items 1 to 6, wherein the subject has not received systemic therapy for a prior cancer, the subject has not received systemic therapy for a prior lung cancer, or the subject has not received systemic therapy for a prior advanced or metastatic lung cancer. [Section 8] The method according to any one of paragraphs 1 to 7, wherein the subject has not received prior immuno-oncology therapy, the subject has not received prior immuno-oncology therapy for lung cancer, or the lung cancer has not received prior immuno-oncology therapy. [Section 9] The method according to any one of paragraphs 1 to 8, wherein the lung cancer is unresectable, advanced, recurrent, and / or metastatic. [Section 10] The method described in any one of items 1 to 9, wherein the subject has stage IV lung cancer. [Section 11] The method according to any one of items 1 to 10, wherein the lung cancer is small cell lung cancer. [Section 12] The method according to any one of items 1 to 10, wherein the lung cancer is non-small cell lung cancer (NSCLC). [Section 13] The method according to item 12, wherein the NSCLC has a squamous or non-squamous epithelial tissue structure. [Section 14] The method according to any one of claims 1 to 13, wherein one or more immune cells in tumor tissue from a subject express LAG-3. [Section 15] The method according to item 14, wherein at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of immune cells express LAG-3. [Section 16] The method according to section 14 or 15, wherein at least about 1% of immune cells express LAG-3. [Section 17] The method according to any one of claims 1 to 16, wherein one or more tumor cells in the tumor tissue from the subject express PD-L1. [Section 18] The method according to item 17, wherein at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the tumor cells express PD-L1. [Section 19] The method according to section 17 or 18, wherein at least about 1% of the tumor cells express PD-L1. [Section 20] The method according to any one of items 14 to 16, wherein the immune cells are tumor-infiltrating lymphocytes. [Section 21] Tumor-infiltrating lymphocytes, CD8 + The method described in item 20, which is a cell. [Section 22] The method according to any one of items 1 to 21, wherein the LAG-3 antagonist is an anti-LAG-3 antibody. [Section 23] The method according to item 22, wherein the anti-LAG-3 antibody is a full-length antibody. [Section 24] The method according to item 22 or 23, wherein the anti-LAG-3 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. [Section 25] The method according to item 24, wherein the multispecific antibody is a biaffinity retargeting antibody (DART), DVD-Ig, or a bispecific antibody. [Section 26] Anti-LAG-3 antibody, F(ab') 2 The method according to claim 22, wherein the fragment is a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain linked polypeptide. [Section 27] Anti-LAG-3 antibodies include BMS-986016 (relatrimab), IMP731 (H5L7BW), MK4280 (28G-10, fabezerimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, ieramirimab), aLAG3 (0414), aLAG3 (0416), Sym022, TSR-033, TSR-075, X The method according to any one of claims 22 to 26, wherein mAb841 (XmAb22841), MGD013 (tevoterimab), BI754111, FS118, P13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or comprising the antigen-binding moiety thereof. [Section 28] The method according to any one of claims 22 to 27, wherein the anti-LAG-3 antibody comprises CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4. [Section 29] Anti-LAG-3 antibody, (a) Heavy chain variable region CDR1 containing the sequence described in Sequence ID No. 5; (b) Heavy chain variable region CDR2 containing the sequence described in Sequence ID No. 6; (c) Heavy chain variable region CDR3 containing the sequence described in Sequence ID No. 7; (d) Light chain variable region CDR1 containing the sequence described in Sequence ID No. 8; (e) Light chain variable region CDR2 containing the sequence described in Sequence ID No. 9; and (f) Light chain variable region CDR3 containing the sequence described in Sequence ID No. 10 The method described in any one of paragraphs 22 to 28, including the method described in paragraph 22 to 28. [Section 30] The method according to any one of claims 22 to 29, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain variable region containing the sequences described in SEQ ID NOs: 3 and 4, respectively. [Section 31] The method according to any one of claims 22 to 25 and 27 to 30, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain having sequences described in SEQ ID NOs: 1 and 2, respectively. [Section 32] The method according to any one of claims 22 to 25 and 27 to 30, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain having sequences described in SEQ ID NOs. 21 and 2, respectively. [Section 33] The method according to any one of claims 1 to 21, wherein the LAG-3 antagonist is a soluble LAG-3 polypeptide. [Section 34] The method according to item 33, wherein the soluble LAG-3 polypeptide is a fusion polypeptide. [Section 35] The method according to item 33 or 34, wherein the soluble LAG-3 polypeptide comprises a ligand-binding fragment of the LAG-3 extracellular domain. [Section 36] The method according to item 35, wherein the ligand-binding fragment of the LAG-3 extracellular domain comprises an amino acid sequence having at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity with SEQ ID NO: 22. [Section 37] The method according to any one of claims 33 to 36, wherein the soluble LAG-3 polypeptide further comprises a portion that extends the half-life. [Section 38] The method according to claim 37, wherein the half-life-extending portion includes an immunoglobulin constant region or a portion thereof, an immunoglobulin-binding polypeptide, immunoglobulin G (IgG), an albumin-binding polypeptide (ABP), a PAS-modified portion, a HES-modified portion, an XTEN, a pegylated portion, an Fc region, or any combination thereof. [Section 39] The method according to any one of claims 33 to 38, wherein the soluble LAG-3 polypeptide is IMP321 (eftylagimod alpha). [Section 40] The method according to any one of claims 1 to 39, wherein a LAG-3 antagonist is formulated for intravenous administration. [Section 41] The method according to any one of claims 1 to 40, wherein a LAG-3 antagonist is administered in a uniform dose. [Section 42] LAG-3 antagonists are present in doses of at least approximately 0.25 mg to 2000 mg, approximately 0.25 mg to 1600 mg, approximately 0.25 mg to 1200 mg, approximately 0.25 mg to 800 mg, approximately 0.25 mg to 400 mg, approximately 0.25 mg to 100 mg, approximately 0.25 mg to 50 mg, approximately 0.25 mg to 40 mg, approximately 0.25 mg to 30 mg, approximately 0.25 mg to 20 mg, approximately 20 mg to 2000 mg, approximately 20 mg to 1600 mg, approximately 20 mg to 1200 mg, approximately 20 mg to 800 mg, approximately 20 mg to 400 mg, approximately 20 mg to 100 mg, and approximately 1 The method according to any one of items 1 to 41, administered in doses of approximately 00 mg to approximately 2000 mg, approximately 100 mg to approximately 1800 mg, approximately 100 mg to approximately 1600 mg, approximately 100 mg to approximately 1400 mg, approximately 100 mg to approximately 1200 mg, approximately 100 mg to approximately 1000 mg, approximately 100 mg to approximately 800 mg, approximately 100 mg to approximately 600 mg, approximately 100 mg to approximately 400 mg, approximately 400 mg to approximately 2000 mg, approximately 400 mg to approximately 1800 mg, approximately 400 mg to approximately 1600 mg, approximately 400 mg to approximately 1400 mg, approximately 400 mg to approximately 1200 mg, or approximately 400 mg to approximately 1000 mg. [Section 43] LAG-3 anthogonal tonic, approximately 0.25mg, approximately 0.5mg, approximately 0.75mg, approximately 1mg, approximately 1.25mg, approximately 1.5mg, approximately 1.75mg, approximately 2mg, approximately 2.25mg, approximately 2.5mg, approximately 2.75mg, approximately 3mg, approximately 3.25mg, approximately 3.5mg, approximately 3.75mg, approximately 4mg, approximately 4.25mg, approximately 4.5mg, approximately 4.75mg, approximately 5mg, approximately 5.25mg, approximately 5.5mg, approximately 5.75mg, approximately 6mg, approximately 6.25mg, approximately 6.5mg, approximately 6.75mg, approximately 7mg, approximately 7.25mg, approximately 7.5mg, approximately 7.75mg, approximately 8mg, approximately 8.25mg, approximately 8.5mg, approximately 8.75mg, approximately 9mg, approximately 9.25mg, approximately 9.5mg, approximately 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg , approx. 190 mg, approx. 200 mg, approx. 210 mg, approx. 220 mg, approx. 230 mg, approx. 240 mg, approx. 250 mg, approx. 260 mg, approx. 270 mg, approx. 280 mg, approx. 290 mg, approx. 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 53 0mg, approx. 540mg, approx. 550mg, approx. 560mg, approx. 570mg, approx. g, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, About 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 1080mg, about 1100mg, about 1140 The method according to any one of items 1 to 42, administered in doses of mg, approximately 1180 mg, approximately 1200 mg, approximately 1240 mg, approximately 1280 mg, approximately 1300 mg, approximately 1340 mg, approximately 1380 mg, approximately 1400 mg, approximately 1440 mg, approximately 1480 mg, approximately 1500 mg, approximately 1540 mg, approximately 1580 mg, approximately 1600 mg, approximately 1640 mg, approximately 1680 mg, approximately 1700 mg, approximately 1740 mg, approximately 1780 mg, approximately 1800 mg, approximately 1840 mg, approximately 1880 mg, approximately 1900 mg, approximately 1940 mg, approximately 1980 mg, or approximately 2000 mg. [Section 44] The method according to any one of claims 1 to 40, wherein a LAG-3 antagonist is administered in a body weight-based dose. [Section 45] LAG-3 antagonists range from approximately 0.003 mg / kg to approximately 25 mg / kg, approximately 0.003 mg / kg to approximately 20 mg / kg, approximately 0.003 mg / kg to approximately 15 mg / kg, approximately 0.003 mg / kg to approximately 10 mg / kg, approximately 0.003 mg / kg to approximately 5 mg / kg, approximately 0.003 mg / kg to approximately 1 mg / kg, approximately 0.003 mg / kg to approximately 0.9 mg / kg, approximately 0.003 mg / kg to approximately 0.8 mg / kg, and approximately 0.00 From 3 mg / kg to approximately 0.7 mg / kg, from approximately 0.003 mg / kg to approximately 0.6 mg / kg, from approximately 0.003 mg / kg to approximately 0.5 mg / kg, from approximately 0.003 mg / kg to approximately 0.4 mg / kg, from approximately 0.003 mg / kg to approximately 0.3 mg / kg, from approximately 0.003 mg / kg to approximately 0.2 mg / kg, from approximately 0.003 mg / kg to approximately 0.1 mg / kg, from approximately 0.1 mg / kg to approximately 25 mg / kg, and from approximately 0.1 mg / kg to approximately 20 mg / kg Approximately 0.1 mg / kg to approximately 15 mg / kg, approximately 0.1 mg / kg to approximately 10 mg / kg, approximately 0.1 mg / kg to approximately 5 mg / kg, approximately 0.1 mg / kg to approximately 1 mg / kg, approximately 1 mg / kg to approximately 25 mg / kg, approximately 1 mg / kg to approximately 20 mg / kg, approximately 1 mg / kg to approximately 15 mg / kg, approximately 1 mg / kg to approximately 10 mg / kg, approximately 1 mg / kg to approximately 5 mg / kg, approximately 5 mg / kg to approximately 25 mg / kg, approximately 5 mg / kg to The method according to any one of claims 1 to 40 or 44, administered in doses of approximately 20 mg / kg, approximately 5 mg / kg to approximately 15 mg / kg, approximately 5 mg / kg to approximately 10 mg / kg, approximately 10 mg / kg to approximately 25 mg / kg, approximately 10 mg / kg to approximately 20 mg / kg, approximately 10 mg / kg to approximately 15 mg / kg, approximately 15 mg / kg to approximately 25 mg / kg, approximately 15 mg / kg to approximately 20 mg / kg, or approximately 20 mg / kg to approximately 25 mg / kg. [Section 46] LAG-3 antagonists are present in doses of approximately 0.003 mg / kg, 0.004 mg / kg, 0.005 mg / kg, 0.006 mg / kg, 0.007 mg / kg, 0.008 mg / kg, 0.009 mg / kg, 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, and 1.0 mg / kg. The method according to any one of claims 1 to 40 or 44 to 45, administered in doses of approximately 2.0 mg / kg, approximately 3.0 mg / kg, approximately 4.0 mg / kg, approximately 5.0 mg / kg, approximately 6.0 mg / kg, approximately 7.0 mg / kg, approximately 8.0 mg / kg, approximately 9.0 mg / kg, approximately 10.0 mg / kg, approximately 11.0 mg / kg, approximately 12.0 mg / kg, approximately 13.0 mg / kg, approximately 14.0 mg / kg, approximately 15.0 mg / kg, approximately 16.0 mg / kg, approximately 17.0 mg / kg, approximately 18.0 mg / kg, approximately 19.0 mg / kg, approximately 20.0 mg / kg, approximately 21.0 mg / kg, approximately 22.0 mg / kg, approximately 23.0 mg / kg, approximately 24.0 mg / kg, or approximately 25.0 mg / kg. [Section 47] The method according to any one of claims 41 to 46, wherein the dose is administered approximately once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks. [Section 48] The method according to any one of claims 1 to 47, wherein PDCT comprises a platinum agent in combination with a nucleoside analog, an antimetabolite, a taxane, a vinca alkaloid, or a topoisomerase inhibitor. [Section 49] The method according to paragraph 48, wherein the platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lipoplatin, or phenantriplatin. [Section 50] The method according to section 48 or 49, wherein the platinum agent is cisplatin. [Section 51] The method according to section 48 or 49, wherein the platinum agent is carboplatin. [Section 52] The method according to any one of items 48 to 51, wherein the nucleoside analog is cytarabine, gemcitabine, lamivudine, entecavir, or terbivudine. [Section 53] The method according to item 52, wherein the nucleoside analog is gemcitabine. [Section 54] The method according to any one of claims 48 to 51, wherein the antimetabolite is capecitabine, cladribine, clopharabine, cytarabine, phloxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, or thioguanine. [Section 55] The method according to item 54, wherein the antimetabolite is pemetrexed. [Section 56] The method according to any one of claims 48 to 51, wherein the taxane is paclitaxel, albumin-conjugated paclitaxel, docetaxel, or cabazitaxel. [Section 57] The method according to any one of claims 48 to 51, wherein the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vineridine, or vinburnin. [Section 58] The method according to item 57, wherein the vinca alkaloid is vinorelbine or vinblastine. [Section 59] The method according to any one of claims 48 to 51, wherein the topoisomerase inhibitor is etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin. [Section 60] The method according to item 59, wherein the topoisomerase inhibitor is etoposide. [Section 61] The method according to item 59, wherein the topoisomerase inhibitor is irinotecan. [Section 62] The method according to any one of claims 1 to 49, wherein PDCT is in combination with gemcitabine, pemetrexed, paclitaxel, albumin-bound paclitaxel, docetaxel, vinorelbine, vinblastine, etoposide, or irinotecan, and comprises cisplatin or carboplatin. [Section 63] The method according to any one of claims 1 to 49, wherein PDCT comprises cisplatin or carboplatin in combination with paclitaxel or albumin-conjugated paclitaxel. [Section 64] The method according to any one of items 1 to 49, wherein PDCT is in combination with pemetrexed and comprises cisplatin or carboplatin. [Section 65] The method according to any one of claims 1 to 64, further comprising administering an additional therapeutic agent to the subject. [Section 66] The method according to item 65, wherein the additional therapeutic agent includes an anticancer agent. [Section 67] The method according to item 66, wherein the anticancer agent includes tyrosine kinase inhibitors, anti-angiogenic agents, checkpoint inhibitors, checkpoint stimulants, chemotherapeutic agents, immunotherapeutic agents, platinum agents, alkylating agents, taxanes, nucleoside analogs, antimetabolites, topoisomerase inhibitors, anthracyclines, vinca alkaloids, or any combination thereof. [Section 68] The method according to item 67, wherein the tyrosine kinase inhibitor includes afatinib, erlotinib, dacomitinib, gefitinib, osimertinib, alectinib, brigatinib, ceritinib, crizotinib, lorlatinib, entrectinib, dabrafenib, trametinib, vemurafenib, lalotrectinib, or any combination thereof. [Section 69] The method according to item 67, wherein the anti-angiogenic agent comprises an inhibitor of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase receptor having Ig-like and EGF-like domains (Tie), hepatocyte growth factor (HGF), tyrosine-protein kinase Met (c-MET), type C lectin family 14 member A (CLEC14A), multimelin 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), EGF receptor (EGFR), or any combination thereof. [Section 70] The method according to item 67 or 69, wherein the anti-angiogenic agent includes bevacizumab, ramucirumab, aflibercept, tanibirumab, olaratumab, nesbakumab, AMG780, MEDI3617, vanucizumab, rilotumumab, ficratuzumab, TAK-701, onartuzumab, emibetuzumab, or any combination thereof. [Section 71] Checkpoint inhibitors include programmed death-1 (PD-1) pathway inhibitors, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, T cell immunoglobulin and ITIM domain (TIGIT) inhibitors, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B and T cell lymphocyte attenuator (BTLA) inhibitors, V domain Ig suppressor (VISTA) inhibitors for T cell activation, indoleamine 2,3-dioxygenase (IDO) inhibitors, nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitors, killer cell immunoglobulin-like receptor (KIR) inhibitors, adenosine A2a receptor (A2aR) inhibitors, and trans The method according to item 67, comprising forming growth factor beta (TGF-β) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, CD47 inhibitors, CD48 inhibitors, CD73 inhibitors, CD113 inhibitors, sialic acid-binding immunoglobulin-like lectin-7 (Sigrec-7) inhibitors, Sigrec-9 inhibitors, Sigrec-15 inhibitors, glucocorticoid-induced TNFR-related protein (GITR) inhibitors, galectin-1 inhibitors, galectin-9 inhibitors, carcinoembryonic antigen-associated cell adhesion molecule-1 (CEACAM-1) inhibitors, G protein-coupled receptor 56 (GPR56) inhibitors, glycoprotein A repeat dominant (GARP) inhibitors, 2B4 inhibitors, programmed death-1 homolog (PD1H) inhibitors, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitors, or any combination thereof. [Section 72] The method according to either claim 67 or 71, wherein the checkpoint inhibitor comprises a PD-1 pathway inhibitor. [Section 73] The method according to item 71 or 72, wherein the PD-1 pathway inhibitor is an anti-PD-1 antibody and / or an anti-PD-L1 antibody. [Section 74] The method according to any one of items 71 to 73, wherein the PD-1 pathway inhibitor is an anti-PD-1 antibody. [Section 75] The method according to section 73 or 74, wherein the anti-PD-1 antibody is a full-length antibody. [Section 76] The method according to any one of claims 73 to 75, wherein the anti-PD-1 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. [Section 77] The method according to item 76, wherein the multispecific antibody is DART, DVD-Ig, or a bispecific antibody. [Section 78] Anti-PD-1 antibody, F(ab') 2 The method according to claim 73 or 74, wherein the fragment is a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain linked polypeptide. [Section 79] The method according to any one of claims 73 to 78, wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, semiprimab, JS001, PF-06801591, BGB-A317, BI754091, INCSHR1210, GLS-010, AM-001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, SSI-361, or comprises an antigen-binding moiety thereof. [Section 80] The method according to any one of claims 73 to 79, wherein the anti-PD-1 antibody comprises CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14. [Section 81] Anti-PD-1 antibodies, (a) Heavy chain variable region CDR1 containing the sequence described in Sequence ID No. 15; (b) Heavy chain variable region CDR2 containing the sequence described in Sequence ID No. 16; (c) Heavy chain variable region CDR3 containing the sequence described in Sequence ID No. 17; (d) Light chain variable region CDR1 containing the sequence described in Sequence ID No. 18; (e) Light chain variable region CDR2 containing the sequence described in Sequence ID No. 19; and (f) Light chain variable region CDR3 containing the sequence described in Sequence ID No. 20; The method described in any one of paragraphs 73 to 80, including the method described in paragraph 73 to 80. [Section 82] The method according to any one of claims 73 to 81, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain variable region containing the sequences described in SEQ ID NOs. 13 and 14, respectively. [Section 83] The method according to any one of claims 73-77 or 79-82, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 11 and 12, respectively. [Section 84] The method according to item 71 or 72, wherein the PD-1 pathway inhibitor is a soluble PD-L2 polypeptide. [Section 85] The method according to item 84, wherein the soluble PD-L2 polypeptide is a fusion polypeptide. [Section 86] The method according to item 84 or 85, wherein the soluble PD-L2 polypeptide comprises a ligand-binding fragment of the PD-L2 extracellular domain. [Section 87] The method according to any one of claims 84 to 86, wherein the soluble PD-L2 polypeptide further comprises a portion that extends the half-life. [Section 88] The method according to claim 87, wherein the half-life-extending portion includes an immunoglobulin constant region or a portion thereof, an immunoglobulin-binding polypeptide, immunoglobulin G (IgG), an albumin-binding polypeptide (ABP), a PAS-modified portion, a HES-modified portion, an XTEN, a pegylated portion, an Fc region, or any combination thereof. [Section 89] The method according to any one of claims 84 to 88, wherein the soluble PD-L2 polypeptide is AMP-224. [Section 90] The method according to any one of items 71 to 73, wherein the PD-1 pathway inhibitor is an anti-PD-L1 antibody. [Section 91] The method according to section 73 or 90, wherein the anti-PD-L1 antibody is a full-length antibody. [Section 92] The method according to any one of items 73 or 90-91, wherein the anti-PD-L1 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. [Section 93] The method according to item 92, wherein the multispecific antibody is DART, DVD-Ig, or a bispecific antibody. [Section 94] Anti-PD-L1 antibody, F(ab') 2 The method according to claim 73 or 90, wherein the fragment is a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain linked polypeptide. [Section 95] The method according to any one of claims 73 or 91 to 94, wherein the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO36, FAZ053, CK-301, or comprises an antigen-binding moiety thereof. [Section 96] The method according to item 71 or 72, wherein the PD-1 pathway inhibitor is BMS-986189. [Section 97] The method according to any one of claims 67 or 71 to 96, wherein the checkpoint inhibitor comprises a CTLA-4 inhibitor. [Section 98] The method according to item 97, wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody. [Section 99] The method according to item 98, wherein the anti-CTLA-4 antibody is a full-length antibody. [Section 100] The method according to any one of claims 97 to 99, wherein the anti-CTLA-4 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. [Section 101] The method according to item 100, wherein the multispecific antibody is DART, DVD-Ig, or a bispecific antibody. [Section 102] Anti-CTLA-4 antibody, F(ab') 2 The method according to claim 98, wherein the fragment is a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain linked polypeptide. [Section 103] The method according to any one of claims 98 to 102, wherein the anti-CTLA-4 antibody is ipilimumab, tremelimumab, MK-1308, AGEN-1884, or comprises an antigen-binding moiety thereof. [Section 104] The method according to any one of items 67 or 71 to 103, wherein a checkpoint inhibitor is formulated for intravenous administration. [Section 105] The method according to any one of claims 67 or 71 to 104, wherein a LAG-3 antagonist and a checkpoint inhibitor are formulated separately. [Section 106] The method according to item 105, wherein if the checkpoint inhibitor contains more than one checkpoint inhibitor, each checkpoint inhibitor is formulated separately. [Section 107] The method according to any one of items 67 or 71 to 104, wherein a LAG-3 antagonist and a checkpoint inhibitor are formulated together. [Section 108] If the checkpoint inhibitor contains more than one checkpoint inhibitor, two or more checkpoint inhibitors are formulated together, as described in paragraph 107. [Section 109] The method according to section 105 or 106, wherein a checkpoint inhibitor is administered before a LAG-3 antagonist. [Section 110] The method according to section 105 or 106, wherein a LAG-3 antagonist is administered before a checkpoint inhibitor. [Section 111] The method according to any one of claims 105 to 108, wherein a LAG-3 antagonist and a checkpoint inhibitor are administered simultaneously. [Section 112] The method according to any one of paragraphs 67 or 71 to 111, wherein a checkpoint inhibitor is administered in a uniform dose. [Section 113] Checkpoint inhibitors are administered in doses of at least approximately 0.25 mg to 2000 mg, approximately 0.25 mg to 1600 mg, approximately 0.25 mg to 1200 mg, approximately 0.25 mg to 800 mg, approximately 0.25 mg to 400 mg, approximately 0.25 mg to 100 mg, approximately 0.25 mg to 50 mg, approximately 0.25 mg to 40 mg, approximately 0.25 mg to 30 mg, approximately 0.25 mg to 20 mg, approximately 20 mg to 2000 mg, approximately 20 mg to 1600 mg, approximately 20 mg to 1200 mg, approximately 20 mg to 800 mg, approximately 20 mg to 400 mg, approximately 20 mg to 100 mg, and approximately 100 mg. The method according to any one of paragraphs 67 or 71 to 112, administered in doses of approximately 2000 mg, approximately 100 mg to approximately 1800 mg, approximately 100 mg to approximately 1600 mg, approximately 100 mg to approximately 1400 mg, approximately 100 mg to approximately 1200 mg, approximately 100 mg to approximately 1000 mg, approximately 100 mg to approximately 800 mg, approximately 100 mg to approximately 600 mg, approximately 100 mg to approximately 400 mg, approximately 400 mg to approximately 2000 mg, approximately 400 mg to approximately 1800 mg, approximately 400 mg to approximately 1600 mg, approximately 400 mg to approximately 1400 mg, approximately 400 mg to approximately 1200 mg, or approximately 400 mg to approximately 1000 mg. [Section 114] Checkpoint inhibitors are available in approximately 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7 mg, 7.25 mg, 7.5 mg, 7.75 mg, 8 mg, 8.25 mg, 8.5 mg, 8.75 mg, 9 mg, 9.25 mg, 9.5 mg, and 9 mg.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, About 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 36 0mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg , about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 7 10mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880m g, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 1080mg, about 1100mg, about 1140mg, about 11 The method according to any one of items 67 or 71 to 113, administered in doses of 80 mg, approximately 1200 mg, approximately 1240 mg, approximately 1280 mg, approximately 1300 mg, approximately 1340 mg, approximately 1380 mg, approximately 1400 mg, approximately 1440 mg, approximately 1480 mg, approximately 1500 mg, approximately 1540 mg, approximately 1580 mg, approximately 1600 mg, approximately 1640 mg, approximately 1680 mg, approximately 1700 mg, approximately 1740 mg, approximately 1780 mg, approximately 1800 mg, approximately 1840 mg, approximately 1880 mg, approximately 1900 mg, approximately 1940 mg, approximately 1980 mg, or approximately 2000 mg. [Section 115] The method according to any one of paragraphs 67 or 71 to 111, wherein a checkpoint inhibitor is administered as a body weight-based dose. [Section 116] Checkpoint inhibitors range from approximately 0.003 mg / kg to approximately 25 mg / kg, approximately 0.003 mg / kg to approximately 20 mg / kg, approximately 0.003 mg / kg to approximately 15 mg / kg, approximately 0.003 mg / kg to approximately 10 mg / kg, approximately 0.003 mg / kg to approximately 5 mg / kg, approximately 0.003 mg / kg to approximately 1 mg / kg, approximately 0.003 mg / kg to approximately 0.9 mg / kg, approximately 0.003 mg / kg to approximately 0.8 mg / kg, and approximately 0.003 mg / kg. From g / kg to approximately 0.7 mg / kg, from approximately 0.003 mg / kg to approximately 0.6 mg / kg, from approximately 0.003 mg / kg to approximately 0.5 mg / kg, from approximately 0.003 mg / kg to approximately 0.4 mg / kg, from approximately 0.003 mg / kg to approximately 0.3 mg / kg, from approximately 0.003 mg / kg to approximately 0.2 mg / kg, from approximately 0.003 mg / kg to approximately 0.1 mg / kg, from approximately 0.1 mg / kg to approximately 25 mg / kg, from approximately 0.1 mg / kg to approximately 20 mg / kg, and approximately 0. 1 mg / kg to approximately 15 mg / kg, approximately 0.1 mg / kg to approximately 10 mg / kg, approximately 0.1 mg / kg to approximately 5 mg / kg, approximately 0.1 mg / kg to approximately 1 mg / kg, approximately 1 mg / kg to approximately 25 mg / kg, approximately 1 mg / kg to approximately 20 mg / kg, approximately 1 mg / kg to approximately 15 mg / kg, approximately 1 mg / kg to approximately 10 mg / kg, approximately 1 mg / kg to approximately 5 mg / kg, approximately 5 mg / kg to approximately 25 mg / kg, approximately 5 mg / kg to approximately 20 mg The method according to any one of paragraphs 67, 71 to 111 or 115, administered in doses of approximately 5 mg / kg to approximately 15 mg / kg, approximately 5 mg / kg to approximately 10 mg / kg, approximately 10 mg / kg to approximately 25 mg / kg, approximately 10 mg / kg to approximately 20 mg / kg, approximately 10 mg / kg to approximately 15 mg / kg, approximately 15 mg / kg to approximately 25 mg / kg, approximately 15 mg / kg to approximately 20 mg / kg, or approximately 20 mg / kg to approximately 25 mg / kg. [Section 117] Checkpoint inhibitors are available in doses of approximately 0.003 mg / kg, 0.004 mg / kg, 0.005 mg / kg, 0.006 mg / kg, 0.007 mg / kg, 0.008 mg / kg, 0.009 mg / kg, 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, and 2.0 mg / kg. The method according to any one of paragraphs 67, 71 to 111 or 115 to 116, administered in doses of mg / kg, approximately 3.0 mg / kg, approximately 4.0 mg / kg, approximately 5.0 mg / kg, approximately 6.0 mg / kg, approximately 7.0 mg / kg, approximately 8.0 mg / kg, approximately 9.0 mg / kg, approximately 10.0 mg / kg, approximately 11.0 mg / kg, approximately 12.0 mg / kg, approximately 13.0 mg / kg, approximately 14.0 mg / kg, approximately 15.0 mg / kg, approximately 16.0 mg / kg, approximately 17.0 mg / kg, approximately 18.0 mg / kg, approximately 19.0 mg / kg, approximately 20.0 mg / kg, approximately 21.0 mg / kg, approximately 22.0 mg / kg, approximately 23.0 mg / kg, approximately 24.0 mg / kg, or approximately 25.0 mg / kg. [Section 118] The method according to any one of items 112 to 117, wherein the dose is administered approximately once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks. [Section 119] A method for treating human subjects who have lung cancer, (a) An anti-LAG-3 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4, and (b) An anti-PD-1 antibody in a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14. A method including administering to a target. [Section 120] A method for treating human subjects who have lung cancer, (a) An anti-LAG-3 antibody in a dose of approximately 720 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4. (b) An anti-PD-1 antibody in a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14. A method including administering to a target. [Section 121] The method described in paragraph 119 or 120, which is the first-line treatment. [Section 122] The method described in paragraph 119 or 120, which is a second-line treatment. [Section 123] The method described in paragraph 119 or 120, which is a third-line treatment. [Section 124] The method described in paragraph 122 or 123, for patients whose condition is progressing with prior therapy. [Section 125] The method according to any one of paragraphs 119 to 124, wherein the lung cancer is unresectable, advanced, recurrent, and / or metastatic. [Section 126] The method described in any one of items 119-125, wherein the subject has stage IV lung cancer. [Section 127] The method according to any one of paragraphs 119 to 126, wherein the lung cancer is small cell lung cancer. [Section 128] The method according to any one of paragraphs 119 to 126, wherein the lung cancer is non-small cell lung cancer (NSCLC). [Section 129] The method according to item 128, wherein the NSCLC has a squamous or non-squamous epithelial tissue structure. [Section 130] The method according to any one of claims 119 to 129, further comprising administering PDCT. [Section 131] The method according to item 130, wherein PDCT comprises a platinum agent in combination with a nucleoside analog, an antimetabolite, a taxane, a vinca alkaloid, or a topoisomerase inhibitor. [Section 132] The method according to paragraph 131, wherein the platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lipoplatin, or phenantriplatin. [Section 133] The method according to section 131 or 132, wherein the platinum agent is cisplatin. [Section 134] The method according to section 131 or 132, wherein the platinum agent is carboplatin. [Section 135] The method according to any one of items 131 to 134, wherein the nucleoside analog is cytarabine, gemcitabine, lamivudine, entecavir, or terbivudine. [Section 136] The method according to item 135, wherein the nucleoside analog is gemcitabine. [Section 137] The method according to any one of claims 131 to 134, wherein the antimetabolite is capecitabine, cladribine, clopharabine, cytarabine, phloxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, or thioguanine. [Section 138] The method according to item 137, wherein the antimetabolite is pemetrexed. [Section 139] The method according to any one of claims 131 to 134, wherein the taxane is paclitaxel, albumin-conjugated paclitaxel, docetaxel, or cabazitaxel. [Section 140] The method according to any one of claims 131 to 134, wherein the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vineridine, or vinburnin. [Section 141] The method according to item 140, wherein the vinca alkaloid is vinorelbine or vinblastine. [Section 142] The method according to any one of claims 131 to 134, wherein the topoisomerase inhibitor is etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin. [Section 143] The method according to item 142, wherein the topoisomerase inhibitor is etoposide. [Section 144] The method according to item 142, wherein the topoisomerase inhibitor is irinotecan. [Section 145] The method according to any one of items 130 to 132, wherein PDCT is in combination with gemcitabine, pemetrexed, paclitaxel, albumin-conjugated paclitaxel, docetaxel, vinorelbine, vinblastine, etoposide, or irinotecan, and comprises cisplatin or carboplatin. [Section 146] The method according to any one of items 130 to 132, wherein PDCT comprises cisplatin or carboplatin in combination with paclitaxel or albumin-conjugated paclitaxel. [Section 147] The method according to any one of items 130 to 132, wherein PDCT is in combination with pemetrexed and comprises cisplatin or carboplatin. [Section 148] A method for treating human subjects suffering from stage IV or recurrent NSCLC with a squamous epithelial tissue structure, (a) An anti-LAG-3 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4. (b) An anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14. (c) PDCT including the following: (i) Carboplatin at a dose with an area under the target concentration-time curve of approximately 6 mg / mL·min, and (ii) Approximately 200mg / m 2 The dosage of paclitaxel A method that includes administering the drug to the target patient and is the first-line therapy. [Section 149] A method for treating human subjects suffering from stage IV or recurrent NSCLC with a squamous epithelial tissue structure, (a) An anti-LAG-3 antibody in a dose of approximately 720 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4. (b) An anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14. (c) PDCT including the following: (i) Carboplatin at a dose with an area under the target concentration-time curve of approximately 6 mg / mL·min, and (ii) Approximately 200mg / m 2 The dosage of paclitaxel A method that includes administering the drug to the target patient and is the first-line therapy. [Section 150] A method for treating human subjects suffering from stage IV or recurrent NSCLC with a squamous epithelial tissue structure, (a) An anti-LAG-3 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4. (b) An anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14. (c) PDCT including the following: (i) Carboplatin at a dose with an area under the target concentration-time curve of approximately 6 mg / mL·min, and (ii) Approximately 100mg / m 2 The dosage of albumin-bound paclitaxel A method that includes administering the drug to the target patient and is the first-line therapy. [Section 151] A method for treating human subjects suffering from stage IV or recurrent NSCLC with a squamous epithelial tissue structure, (a) An anti-LAG-3 antibody in a dose of approximately 720 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4. (b) An anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14. (c) PDCT including the following: (i) Carboplatin at a dose with an area under the target concentration-time curve of approximately 6 mg / mL·min, and (ii) Approximately 100mg / m 2 The dosage of albumin-bound paclitaxel A method that includes administering the drug to the target patient and is the first-line therapy. [Section 152] A method for treating human subjects with stage IV or recurrent NSCLC having a non-squamous tissue structure, (a) An anti-LAG-3 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4. (b) An anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14. (c) PDCT including the following: (i) Carboplatin at a dose with an area under the target concentration-time curve of approximately 5 mg / mL·min or approximately 6 mg / mL·min, and (ii) Approximately 500mg / m 2 The dosage of pemetrexed A method that includes administering the drug to the target patient and is the first-line therapy. [Section 153] A method for treating human subjects with stage IV or recurrent NSCLC having a non-squamous tissue structure, (a) An anti-LAG-3 antibody in a dose of approximately 720 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4. (b) An anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14. (c) PDCT including the following: (i) Carboplatin at a dose with an area under the target concentration-time curve of approximately 5 mg / mL·min or approximately 6 mg / mL·min, and (ii) Approximately 500mg / m 2 The dosage of pemetrexed A method that includes administering the drug to the target patient and is the first-line therapy. [Section 154] A method for treating human subjects with stage IV or recurrent NSCLC having a non-squamous tissue structure, (a) An anti-LAG-3 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4. (b) An anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14. (c) PDCT including the following: (i) Approximately 75mg / m 2 The dose of cisplatin, and (ii) Approximately 500mg / m 2 The dosage of pemetrexed A method that includes administering the drug to the target patient and is the first-line therapy. [Section 155] A method for treating human subjects with stage IV or recurrent NSCLC having a non-squamous tissue structure, (a) An anti-LAG-3 antibody in a dose of approximately 720 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4. (b) An anti-PD-1 antibody in a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14. (c) PDCT including the following: (i) Approximately 75mg / m 2 The dose of cisplatin, and (ii) Approximately 500mg / m 2 The dosage of pemetrexed A method that includes administering the drug to the target patient and is the first-line therapy. [Section 156] The method described in any one of paragraphs 119 to 155, wherein the lung cancer has recurred after multidisciplinary therapy for locally advanced lung cancer. [Section 157] The method described in any one of paragraphs 119 to 156, wherein the subject has not received systemic therapy for a prior cancer, the subject has not received systemic therapy for a prior lung cancer, or the subject has not received systemic therapy for a prior advanced or metastatic lung cancer. [Section 158] The method according to any one of paragraphs 119 to 157, wherein the subject has not received prior immuno-oncology therapy, the subject has not received prior immuno-oncology therapy for lung cancer, or the lung cancer has not received prior immuno-oncology therapy. [Section 159] The method according to any one of items 119 to 158, wherein one or more immune cells in the tumor tissue from the subject express LAG-3. [Section 160] The method according to paragraph 159, wherein at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of immune cells express LAG-3. [Section 161] The method according to section 159 or 160, wherein at least about 1% of immune cells express LAG-3. [Section 162] The method according to any one of items 119 to 161, wherein one or more tumor cells in the tumor tissue from the subject express PD-L1. [Section 163] The method according to item 162, wherein at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of tumor cells express PD-L1. [Section 164] The method according to section 162 or 163, wherein at least about 1% of the tumor cells express PD-L1. [Section 165] The method according to any one of items 159 to 161, wherein the immune cells are tumor-infiltrating lymphocytes. [Section 166] Tumor-infiltrating lymphocytes, CD8 + The method described in section 165, which is a cell. [Section 167] A method according to any one of paragraphs 119 to 166, (a) The anti-LAG-3 antibody comprises heavy chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively, and light chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively, and (b) The anti-PD-1 antibody comprises heavy chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, respectively, and light chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, respectively. method. [Section 168] The method according to any one of claims 119 to 167, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain variable region containing the sequences described in SEQ ID NOs. 3 and 4, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain variable region containing the sequences described in SEQ ID NOs. 13 and 14, respectively. [Section 169] The method according to any one of claims 119 to 168, wherein the anti-LAG-3 antibody and / or anti-PD-1 antibody are full-length antibodies. [Section 170] The method according to any one of claims 119 to 169, wherein the anti-LAG-3 antibody and / or anti-PD-1 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. [Section 171] The method according to item 170, wherein the multispecific antibody is DART, DVD-Ig, or a bispecific antibody. [Section 172] Anti-LAG-3 antibody and / or anti-PD-1 antibody, F(ab') 2 The method according to any one of claims 119 to 168, wherein the fragment is a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain linked polypeptide. [Section 173] The method according to any one of claims 119 to 171, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs: 1 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs: 11 and 12, respectively. [Section 174] The method according to any one of claims 119 to 171, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 21 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 11 and 12, respectively. [Section 175] The method according to any one of paragraphs 119 to 174, further comprising administering an additional therapeutic agent to the subject. [Section 176] The method according to item 175, wherein the additional therapeutic agent includes an anticancer agent. [Section 177] The method according to item 176, wherein the anticancer agent includes tyrosine kinase inhibitors, anti-angiogenic agents, checkpoint inhibitors, checkpoint stimulants, chemotherapeutic agents, immunotherapeutic agents, platinum agents, alkylating agents, taxanes, nucleoside analogs, antimetabolites, topoisomerase inhibitors, anthracyclines, vinca alkaloids, or any combination thereof. [Section 178] The method according to item 177, wherein the tyrosine kinase inhibitor is afatinib, erlotinib, dacomitinib, gefitinib, osimertinib, alectinib, brigatinib, ceritinib, crizotinib, lorlatinib, entrectinib, dabrafenib, trametinib, vemurafenib, lalotrectinib, or any combination thereof. [Section 179] The method according to item 177, wherein the anti-angiogenic agent comprises inhibitors of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase (Tie) receptors having Ig-like and EGF-like domains, hepatocyte growth factor (HGF), tyrosine-protein kinase Met (c-MET), type C lectin family 14 member A (CLEC14A), multimelin 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), EGF receptor (EGFR), or any combination thereof. [Section 180] The method according to paragraph 177 or 179, wherein the anti-angiogenic agent includes bevacizumab, ramucirumab, aflibercept, tanibirumab, olaratumab, nesbakumab, AMG780, MEDI3617, vanucizumab, rilotumab, ficratuzumab, TAK-701, onaruzumab, emibetuzumab, or any combination thereof. [Section 181] Checkpoint inhibitors include programmed death-1 (PD-1) pathway inhibitors, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, T cell immunoglobulin and ITIM domain (TIGIT) inhibitors, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B and T cell lymphocyte attenuator (BTLA) inhibitors, V domain Ig suppressor (VISTA) inhibitors for T cell activation, indoleamine 2,3-dioxygenase (IDO) inhibitors, nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitors, killer cell immunoglobulin-like receptor (KIR) inhibitors, adenosine A2a receptor (A2aR) inhibitors, and transfer inhibitors. The method according to item 177, comprising a forming growth factor beta (TGF-β) inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, a CD47 inhibitor, a CD48 inhibitor, a CD73 inhibitor, a CD113 inhibitor, a sialic acid-binding immunoglobulin-like lectin-7 (Sigrec-7) inhibitor, a Sigrec-9 inhibitor, a Sigrec-15 inhibitor, a glucocorticoid-induced TNFR-related protein (GITR) inhibitor, a galectin-1 inhibitor, a galectin-9 inhibitor, a carcinoembryonic antigen-associated cell adhesion molecule-1 (CEACAM-1) inhibitor, a G protein-coupled receptor 56 (GPR56) inhibitor, a glycoprotein A repeat dominant (GARP) inhibitor, a 2B4 inhibitor, a programmed death-1 homolog (PD1H) inhibitor, a leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitor, or any combination thereof. [Section 182] The method according to item 181, wherein the PD-1 pathway inhibitor is an anti-PD-L1 antibody. [Section 183] The method according to item 182, wherein the anti-PD-L1 antibody is a full-length antibody. [Section 184] The method according to section 181 or 182, wherein the anti-PD-L1 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. [Section 185] The method according to item 184, wherein the multispecific antibody is DART, DVD-Ig, or a bispecific antibody. [Section 186] Anti-PD-L1 antibody, F(ab') 2 The method according to item 182, wherein the fragment is a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain linked polypeptide. [Section 187] The method according to any one of claims 182 to 186, wherein the anti-PD-L1 antibody is BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO36, CK-301, or comprises an antigen-binding moiety thereof. [Section 188] The method according to item 182, wherein the PD-1 pathway inhibitor is BMS-986189. [Section 189] The method according to either claim 177 or 181, wherein the checkpoint inhibitor comprises a CTLA-4 inhibitor. [Section 190] The method according to item 189, wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody. [Section 191] The method according to item 190, wherein the anti-CTLA-4 antibody is a full-length antibody. [Section 192] The method according to section 190 or 191, wherein the anti-CTLA-4 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. [Section 193] The method according to item 192, wherein the multispecific antibody is DART, DVD-Ig, or a bispecific antibody. [Section 194] Anti-CTLA-4 antibody, F(ab') 2 The method according to claim 190, wherein the fragment is a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain linked polypeptide. [Section 195] The method according to any one of claims 190 to 194, wherein the anti-CTLA-4 antibody is ipilimumab, tremelimumab, MK-1308, AGEN-1884, or comprises an antigen-binding moiety thereof. [Section 196] The method according to any one of claims 119 to 195, wherein an anti-LAG-3 antibody and an anti-PD-1 antibody are formulated for intravenous administration. [Section 197] The method according to any one of claims 181 to 196, wherein a checkpoint inhibitor is formulated for intravenous administration. [Section 198] The method according to any one of claims 119 to 197, wherein an anti-LAG-3 antibody and an anti-PD-1 antibody are formulated separately. [Section 199] The method according to any one of claims 119 to 197, wherein an anti-LAG-3 antibody and an anti-PD-1 antibody are formulated together. [Section 200] The method according to any one of claims 119 to 198, wherein an anti-PD-1 antibody is administered before an anti-LAG-3 antibody. [Section 201] The method according to any one of claims 119 to 198, wherein an anti-LAG-3 antibody is administered before an anti-PD-1 antibody. [Section 202] The method according to any one of claims 119 to 199, wherein a LAG-3 antibody and an anti-PD-1 antibody are administered simultaneously. [Section 203] The method according to any one of items 119 to 202, wherein an anti-LAG-3 antibody and an anti-PD-1 antibody are administered once every three weeks. [Section 204] The method according to item 203, wherein an anti-LAG-3 antibody and an anti-PD-1 antibody are administered on day 1 of each 3-week cycle. [Section 205] The method according to section 203 or 204, wherein an anti-LAG-3 antibody and an anti-PD-1 antibody are administered intravenously from a single infusion bag for approximately 30 minutes. [Section 206] The method described in any one of paragraphs 130 to 205, wherein PDCT is administered every three weeks. [Section 207] The method according to paragraph 206, wherein PDCT is administered for up to approximately four 3-week cycles. [Section 208] A pharmaceutical composition comprising (a) 360 mg of anti-LAG-3 antibody and (b) 360 mg of anti-PD-1 antibody. [Section 209] A pharmaceutical composition comprising (a) 360 mg of anti-LAG-3 antibody and (b) 720 mg of anti-PD-1 antibody. [Section 210] (a) The anti-LAG-3 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4, and (b) The anti-PD-1 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14, A pharmaceutical composition as described in item 208 or 209. [Section 211] (a) The anti-LAG-3 antibody comprises heavy chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively, and light chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively. (b) The pharmaceutical composition according to any one of claims 208 to 210, wherein the anti-PD-1 antibody comprises heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, respectively. [Section 212] A pharmaceutical composition according to any one of claims 208 to 211, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain variable region containing the sequences described in SEQ ID NOs. 3 and 4, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain variable region containing the sequences described in SEQ ID NOs. 13 and 14, respectively. [Section 213] A pharmaceutical composition according to any one of claims 208 to 212, wherein the anti-LAG-3 antibody and / or anti-PD-1 antibody are full-length antibodies. [Section 214] A pharmaceutical composition according to any one of claims 208 to 213, wherein the anti-LAG-3 antibody and / or anti-PD-1 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. [Section 215] The pharmaceutical composition according to item 214, wherein the multispecific antibody is DART, DVD-Ig, or a bispecific antibody. [Section 216] Anti-LAG-3 antibody and / or anti-PD-1 antibody, F(ab') 2 A pharmaceutical composition according to any one of claims 208 to 212, wherein the composition is a fragment, Fab' fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment, or a single-chain linked polypeptide. [Section 217] A pharmaceutical composition according to any one of claims 208 to 215, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 1 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 11 and 12, respectively. [Section 218] A pharmaceutical composition according to any one of claims 208 to 215, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 21 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 11 and 12, respectively. [Section 219] This is a kit for treating humans who have lung cancer. (a) 360 mg of anti-LAG-3 antibody; (b) 360 mg of anti-PD-1 antibody; and (c) Instructions for using anti-LAG-3 antibodies and anti-PD-1 antibodies in a method for treating human subjects with lung cancer. A kit that includes this. [Section 220] This is a kit for treating humans who have lung cancer. (a) 720 mg of anti-LAG-3 antibody; (b) 360 mg of anti-PD-1 antibody; and (c) Instructions for using anti-LAG-3 antibodies and anti-PD-1 antibodies in a method for treating human subjects with lung cancer. A kit that includes this.

[0154] I. Terminology To facilitate a clearer understanding of the disclosures of this invention, certain terms are first defined. Each of the following terms, when used in this application, shall have the meanings set forth below unless otherwise expressly provided herein. Additional definitions are expressly provided throughout this application. Note that the term “a (a)” or “an (an)” entity refers to one or more such entities; for example, “a nucleotide sequence” is understood to represent one or more nucleotide sequences. Thus, the terms “a (a)” (or “an (an)”), “one or more,” and “at least one” may be used synonymously herein.

[0155] Where used herein, the term "and / or" shall be construed as a specific disclosure of each of two identified structures or components, including or excluding the other. Thus, where the term "and / or" is used herein in phrases such as "A and / or B," it is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, where the term "and / or" is used in phrases such as "A, B, and / or C," it is intended to include each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0156] Whenever an aspect is described herein using the language “including,” it is understood that other similar aspects are also provided, described using the terms “consisting of” and / or “essentially consisting of.”

[0157] The terms “approximately” or “essentially constitute” refer to a value or composition that is within an acceptable margin of error with respect to a particular value or composition as determined by those skilled in the art, and such a particular value or composition is expected to depend in part on how the value or composition is measured or determined, i.e., the limits of the measuring system. For example, “approximately” or “essentially constitute” may also mean within 1 or a standard deviation greater than 1 for practices in the art. Alternatively, “approximately” or “essentially constitute” may mean a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, approximately 3 mg may include any value between 2.7 mg and 3.3 mg (in the case of 10%), or any value between 2.4 mg and 3.6 mg (in the case of 20%). Furthermore, in particular with respect to biological systems or processes, this term may also mean a value of up to one order of magnitude or up to five times. Where specific values ​​or compositions are provided in this application and claims, unless otherwise specified, the meaning of “about” or “essentially constitutes” should be assumed to be within an acceptable margin of error with respect to those specific values ​​or compositions.

[0158] Where used herein, any range of concentration, percentage, ratio, or integer includes all integer values ​​within the listed range, and, where appropriate, unless otherwise specified, includes fractions thereof (e.g., one-tenth and one-hundredth of an integer).

[0159] All technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in the relevant field, unless otherwise specified. For example, *Concise Dictionary of Biomedicine and Molecular Biology*, Juo, Pei-Show, 2nd ed., 2002, CRC Press; *The Dictionary of Cell and Molecular Biology*, 5th ed., 2013, Academic Press; and *The Oxford Dictionary of Biochemistry and Molecular Biology*, 2006, Oxford University Press provide those skilled in the art with many common dictionaries of the terms used in this disclosure.

[0160] Units, prefixes, and symbols are presented in the forms accepted by their respective International System of Units (SI). Numerical ranges include the numerical values ​​that define the range.

[0161] The headings provided herein are not limitations on any particular aspect of this disclosure, and such limitations can be obtained by referring to the entire specification. Therefore, the terms defined immediately thereunder are defined in more detail by referring to the entire specification.

[0162] The term "antagonist" includes, but is not limited to, any molecule capable of blocking, reducing, or otherwise restricting the interaction or activity of a target molecule (e.g., LAG-3). In some embodiments, the antagonist is an antibody. In other embodiments, the antagonist includes a small molecule. The terms "antagonist" and "inhibitor" are used synonymously herein.

[0163] "Antibodies" (Ab) are glycoprotein immunoglobulins that specifically bind to an antigen, and include at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each H chain has a heavy chain variable region (V in this specification). H (abbreviated as C) and heavy chain constant region (C in this specification) H It includes (abbreviated as ). The heavy chain constant region consists of three constant domains, C H1 , C H2 and C H3 Each light chain includes a light chain variable region (V in this specification). L (abbreviated as C) and light chain constant region (C in this specification) L It includes (abbreviated as ). The light chain constant region consists of one constant domain, C L Includes. V H and V L The region can be further subdivided into highly variable regions called complementary determination regions (CDRs), which are interspersed with more highly conserved regions called framework regions (FRs). H and V L It contains three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant region of the antibody can mediate the binding of the immunoglobulin to various cells of the immune system (e.g., effector cells) and to host tissues or factors such as the first component of the classical complement system (C1q). The heavy chain may or may not have a C-terminal lysine. In this specification, unless otherwise specified, amino acids in the variable region are numbered using the Kabat numbering system, and amino acids in the constant region are numbered using the EU system.

[0164] Immunoglobulins may be derived from any of the commonly known isotypes, including, but are not limited to, IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those skilled in the art, and examples include, but are not limited to, human IgG1, IgG2, IgG3, and IgG4. “Isotype” refers to an antibody class or subclass (e.g., IgM or IgG1) encoded by a heavy chain constant region gene. The term “antibody” includes, by example, both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human or non-human antibodies; entirely synthetic antibodies; single-chain antibodies; monospecific antibodies; bispecific antibodies; and multispecific antibodies. Non-human antibodies can be humanized by recombinant methods to reduce their immunogenicity in humans. Unless otherwise explicitly stated or specified in the context, the term “antibody” also includes any antigen-binding fragment or antigen-binding site of any of the aforementioned immunoglobulins, including monovalent and bivalent fragments or portions that retain the ability of the entire immunoglobulin to specifically bind to the antigen to which it binds. Examples of “antigen-binding sites” or “antigen-binding fragments” include (1) Fab fragments (fragments cleaved by papain) or V L , V H , L C and C H1 (2) Similar monovalent fragments consisting of domains; (3) F(ab')2 fragments (fragments formed by pepsin cleavage), or similar bivalent fragments containing two Fab fragments linked by disulfide bridges in a hinge region; (4) Fd fragments consisting of VH and CH1 domains; (5) Single-armed V L and V H Fv fragment consisting of domains; (5)V H A single-domain antibody (dAb) fragment consisting of domains (Ward et al., (1989) Nature 341:544-46); (6) Two Vs linked by a hinge HExamples include bi-single domain antibodies (biaffinity retargeting antibodies (DART)) consisting of two domains, or (7) bivariable domain immunoglobulins. Furthermore, the two domains of the Fv fragment, V L and V H Although they are encoded by separate genes, they can be recombined using the V method. L and V H They can be joined by synthetic linkers, which allow the regions to pair up and form a single protein chain that creates a monovalent molecule (known as single-chain Fv (scFv); see, for example, Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).

[0165] "Isolated antibodies" refer to antibodies that substantially contain no other antibodies with different antigen specificities (for example, an isolated antibody that specifically binds to LAG-3 substantially contains no antibodies that do not specifically bind to LAG-3). However, an isolated antibody that specifically binds to LAG-3 may have cross-reactivity to other antigens, such as LAG-3 molecules from different species. Furthermore, isolated antibodies may substantially contain no other cellular material and / or chemical substances.

[0166] The term “monoclonal antibody” (“mAb”) refers to an antibody molecule that does not exist in nature but has a single molecular composition; that is, an antibody molecule whose primary sequence is essentially identical and which exhibits a single binding specificity and affinity for a particular epitope. mAbs are an example of isolated antibodies. mAbs can be produced by hybridoma, recombinant, transgenic, or other techniques known to those skilled in the art.

[0167] A “human” antibody (HuMAb) refers to an antibody having a variable region in which both the framework and CDR region are derived from a human germline immunoglobulin sequence. Furthermore, if the antibody contains a constant region, the constant region may also be derived from a human germline immunoglobulin sequence. The human antibodies of the present invention may contain amino acid residues not encoded by a human germline immunoglobulin sequence (e.g., mutations introduced in vitro by random or site-directed mutagenesis, or in vivo by somatic mutagenesis). However, as used herein, the term “human antibody” is not intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species, such as mouse, is grafted onto a human framework sequence. The terms “human” antibody and “fully human” antibody are used synonymously.

[0168] A "humanized antibody" refers to an antibody in which some, almost all, or all of the amino acids outside the CDR domain of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. In one form of humanized antibody, some, almost all, or all of the amino acids outside the CDR domain are replaced with amino acids from human immunoglobulins, while some, almost all, or all of the amino acids within one or more CDR regions remain unchanged. Small additions, deletions, insertions, substitutions, or modifications of amino acids are acceptable as long as they do not interfere with the antibody's ability to bind to a particular antigen. A "humanized" antibody retains antigen specificity similar to that of the original antibody.

[0169] A "chimeric antibody" refers to an antibody in which the variable region is derived from one species and the constant region is derived from another species. For example, it refers to an antibody in which the variable region is derived from a mouse antibody and the constant region is derived from a human antibody.

[0170] An "anti-antigen" antibody refers to an antibody that specifically binds to an antigen. For example, an anti-LAG-3 antibody specifically binds to LAG-3.

[0171] "LAG-3" refers to the lymphocyte activation gene-3. The term "LAG-3" includes variants, isoforms, homologs, orthologs, and paralogs. For example, an antibody specific to the human LAG-3 protein may, in certain cases, cross-react with LAG-3 proteins from non-human species. In other embodiments, an antibody specific to the human LAG-3 protein may be completely specific to the human LAG-3 protein and not exhibit cross-reactivity with species or other types, or it may cross-react with LAG-3 from specific other species rather than LAG-3 from all other species (e.g., cross-reacting with monkey LAG-3 but not with mouse LAG-3). The term "human LAG-3" refers to the human sequence of LAG-3, for example, the complete amino acid sequence of human LAG-3 with GenBank accession number NP_002277. The term “mouse LAG-3” refers to the complete amino acid sequence of mouse LAG-3, for example, mouse LAG-3 having GenBank accession number NP_032505. LAG-3 is also known in the art, for example, as CD223. Human LAG-3 sequences may differ from human LAG-3 of GenBank accession number NP_002277, for example, by having conserved mutations or mutations in unconserved regions, and LAG-3 may have substantially the same biological function as human LAG-3 of GenBank accession number NP_002277. For example, the biological function of human LAG-3 may be to have an epitope in the extracellular domain of LAG-3 to which the antibody of the disclosure of this invention specifically binds, or the biological function of human LAG-3 may be to bind to MHC class II molecules.

[0172] A particular human LAG-3 sequence is generally expected to be at least approximately 90% identical in amino acid sequence to the human LAG-3 sequence of GenBank accession number NP_002277, and to contain amino acid residues that identify the sequence as human when compared to the amino acid sequence of LAG-3 from other species (e.g., mouse). In particular cases, the human LAG-3 may be at least approximately 95% identical in amino acid sequence to the LAG-3 sequence of GenBank accession number NP_002277, or even at least approximately 96%, at least approximately 97%, at least approximately 98%, at least approximately 99%, or at least approximately 100% identical. In particular embodiments, the human LAG-3 sequence is expected to represent a difference of 10 or fewer amino acids from the LAG-3 sequence of GenBank accession number NP_002277. In certain embodiments, human LAG-3 may represent a difference of five or fewer amino acids, or even a difference of four or fewer, three or fewer, two or fewer, or one or fewer amino acids from the LAG-3 sequence of GenBank accession number NP_002277.

[0173] "Programmed death-1 (PD-1)" refers to an immunosuppressive receptor belonging to the CD28 family. PD-1 is predominantly expressed in vivo on previously activated T cells and binds to two ligands, PD-L1 and PD-L2. The term "PD-1," as used herein, includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, as well as analogs having at least one common epitope with hPD-1. The complete hPD-1 sequence can be found under GenBank accession number U64863. "PD-1" and "PD-1 receptor" are used synonymously herein.

[0174] Cytotoxic T lymphocyte antigen-4 (CTLA-4) refers to an immunosuppressive receptor belonging to the CD28 family. CTLA-4 is exclusively expressed in T cells in vivo and binds to two ligands, CD80 and CD86 (also known as B7-1 and B7-2, respectively). As used herein, the term "CTLA-4" includes human CTLA-4 (hCTLA-4), variants, isoforms, and species homologs of hCTLA-4, as well as analogs having at least one common epitope with hCTLA-4. The complete hCTLA-4 sequence can be found under GenBank accession number AAB59385.

[0175] "Programmed death ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands of PD-1 that, upon binding to PD-1, downregulate T cell activation and cytokine secretion (the other being PD-L2). The term "PD-L1," as used herein, includes human PD-L1 (hPD-L1), variants, isoforms, and species homologs of hPD-L1, as well as analogs having at least one common epitope with hPD-L1. The complete hPD-L1 sequence can be found under GenBank accession number Q9NZQ7.

[0176] "Programmed death ligand-2 (PD-L2)" as used herein includes human PD-L2 (hPD-L2), variants, isoforms, and species homologs of hPD-L2, as well as analogs having at least one common epitope with hPD-L2. The complete hPD-L2 sequence can be found under GenBank accession number Q9BQ51.

[0177] As used herein, “Patient” includes any patient with lung cancer (e.g., NSCLC). The terms “Subject” and “Patient” are used synonymously herein.

[0178] "Administer" means physically introducing a therapeutic agent (e.g., a composition or formulation containing the therapeutic agent) into a subject using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes, such as by injection or infusion. The term "parenteral administration," as used herein, means a mode of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, injection and infusion into intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intrafocal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal regions, in addition to in vivo electroporation. In some embodiments, the formulation is administered via a non-parenteral route, and in some embodiments, it is administered orally. Other non-parenteral routes of administration include topical, cutaneous, or mucosal routes, such as intranasal, transvaginal, rectal, sublingual, or topical. Administration may also be performed, for example, in a single dose, multiple doses, and / or over one or more periods.

[0179] The term "treatment" or "therapy" refers to any type of intervention or process performed on a subject with the aim of restoring, reducing, mitigating, inhibiting, or delaying the progression, development, severity, or recurrence of disease-related symptoms, complications, conditions, or biochemical signs, or the administration of an active agent to such a subject. The Criteria for Evaluation of Solid Tumor Treatment Response (RECIST) are measures of efficacy of treatment and established rules that define when a tumor responds, stabilizes, or progresses during treatment. RECIST 1.1 is the current guideline for the measurement and definition of solid tumors for objective assessment of changes in tumor size for use in clinical trials of adult and pediatric cancers.

[0180] As used herein, “effective treatment” refers to a treatment that produces a beneficial effect, for example, relief of at least one symptom of a disease or disorder. A beneficial effect may take the form of improvement beyond baseline, i.e., improvement beyond the measurement or observation made before the initiation of therapy according to this method. A beneficial effect may also take the form of stopping, slowing, delaying, or stabilizing the adverse progression of a solid tumor marker. An effective treatment may also refer to the alleviation of at least one symptom of a solid tumor. Such an effective treatment may, for example, reduce patient pain, reduce the size and / or number of lesions, reduce or prevent tumor metastasis, and / or delay tumor growth.

[0181] The term “effective dose” refers to the amount of an agent that produces a desired biological, therapeutic, and / or prophylactic outcome. The outcome may be the reduction, mitigation, temporary relief, decrease, delay, and / or reduction of one or more signs, symptoms, or causes of a disease, or any other desired modification of the biological system. In reference to solid tumors, an effective dose includes an amount sufficient to shrink the tumor and / or reduce the rate of tumor growth (e.g., inhibit tumor growth), or delay other unwanted cell growth. In some embodiments, an effective dose is an amount sufficient to prevent or delay tumor recurrence. An effective dose may be administered in one or more doses. An effective dose of a drug or composition can (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, to some extent hinder, slow, or stop the invasion of cancer cells into peripheral organs; (iv) inhibit (i.e., slow to some extent) or stop tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay the appearance and / or recurrence of tumors; and / or (vii) alleviate to some extent one or more of the symptoms associated with cancer. In one example, “effective dose” is the amount of anti-LAG-3 antibody alone, or a combination of anti-LAG-3 antibody and an additional therapeutic agent (e.g., anti-PD-1 antibody), that has been clinically proven to have an effect on a significant reduction in cancer or to slow the progression of cancer, for example, an advanced solid tumor.

[0182] The terms “fixed dose,” “uniform dose,” and “uniform fixed dose,” as used herein, are used synonymously and refer to a dose administered to a patient regardless of the patient’s body weight or body surface area (BSA). Therefore, fixed or uniform doses are provided as an absolute amount of the drug (e.g., in μg or mg), rather than as a mg / kg dose.

[0183] The use of the term “fixed-dose combination” in relation to the compositions of the present invention means that two or more different inhibitors described herein (e.g., anti-LAG-3 antibody and anti-PD-1 antibody) are present in a single composition in a specific (fixed) ratio to one another. In some embodiments, the fixed dose is based on the weight of the inhibitor (e.g., mg). In certain embodiments, the fixed dose is based on the concentration of the inhibitor (e.g., mg / ml). In some aspects, the ratio is at least approximately 1:1, approximately 1:2, approximately 1:3, approximately 1:4, approximately 1:5, approximately 1:6, approximately 1:7, approximately 1:8, approximately 1:9, approximately 1:10, approximately 1:15, approximately 1:20, approximately 1:30, approximately 1:40, approximately 1:50, approximately 1:60, approximately 1:70, approximately 1:80, approximately 1:90, approximately 1:100, approximately 1:120, approximately 1:140, approximately 1:160, approximately 1:180, approximately 1:200, approximately The ratio is mg of the first inhibitor to mg of the second inhibitor, in a ratio of 200:1, approximately 180:1, approximately 160:1, approximately 140:1, approximately 120:1, approximately 100:1, approximately 90:1, approximately 80:1, approximately 70:1, approximately 60:1, approximately 50:1, approximately 40:1, approximately 30:1, approximately 20:1, approximately 15:1, approximately 10:1, approximately 9:1, approximately 8:1, approximately 7:1, approximately 6:1, approximately 5:1, approximately 4:1, approximately 3:1, or approximately 2:1. For example, a 2:1 ratio of the first and second inhibitors may mean that the vial contains approximately 720 mg of the first inhibitor and 360 mg of the second inhibitor, or approximately 12 mg / ml of the first inhibitor and 6 mg / ml of the second inhibitor.

[0184] Where referred to herein, the term “weight-based dosage” means that the dose administered to a patient is calculated based on the patient’s weight.

[0185] When used herein, “dosing interval” means the time elapsed between administrations of multiple doses of the formulation disclosed herein to a subject. Therefore, the dosing interval may be expressed as a range.

[0186] The term “dosage frequency,” as used herein, refers to the frequency with which a dose of the formulation disclosed herein is administered over a given time period. Dosage frequency may be expressed as the number of doses per given time period, for example, once a week or once every two weeks.

[0187] The terms “about once a week,” “about once a week,” “about once every two weeks,” or any other similar terms for dosing intervals, when used herein, mean approximate numbers, and “about once a week” or “about once a week” may include every 7 ± 2 days, i.e., every 5 to 9 days. Thus, “once a week” may be every 5 days, every 6 days, every 7 days, every 8 days, or every 9 days. “About once every three weeks” may include every 21 ± 3 days, i.e., every 25 to 31 days. Similar approximations apply, for example, to every 2 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, and every 12 weeks. In some embodiments, an interval of approximately every six weeks or approximately every twelve weeks means that the first dose may be administered on any day of the first week, and the next dose may be administered on any day of the sixth or twelfth week, respectively. In other embodiments, an interval of approximately every six weeks or approximately every twelve weeks means that the first dose is administered on a specific day of the first week (e.g., Monday), and the next dose is administered on the same day of the sixth or twelfth week (i.e., Monday), respectively.

[0188] When used herein, “adverse event” (AE) is any unfavorable, generally unexpected, or undesirable sign (including unusual experimental findings), symptom, or illness associated with the use of a drug therapy. For example, an adverse event may be related to the activation of the immune system or the expansion and proliferation of immune system cells (e.g., T cells) in response to a treatment. A drug therapy may have one or more associated AEs, each AE may have the same or different levels of severity.

[0189] As used herein, the term “tumor” refers to any mass of tissue resulting from excessive cell growth or proliferation, whether benign (non-cancerous) or malignant (cancerous), including precancerous lesions.

[0190] The term “biological sample,” as used herein, refers to biological material isolated from a subject. A biological sample may contain any biological material suitable for analysis, for example, by sequencing nucleic acids in a tumor (or circulating tumor cells) and identifying genomic alterations in the sequenced nucleic acids. A biological sample may also be any suitable biological tissue or fluid, such as tumor tissue, blood, plasma, and serum. A biological sample may also be a test tissue sample (e.g., a tissue sample containing tumor cells and tumor-infiltrating inflammatory cells). In one embodiment, the sample is a tumor tissue biopsy, such as formalin-fixed paraffin-embedded (FFPE) tumor tissue or fresh-frozen tumor tissue. In another embodiment, the biological sample is a liquid biopsy, which in some embodiments contains one or more of blood, serum, plasma, circulating tumor cells, exoRNA, ctDNA, and cfDNA.

[0191] For example, “anticancer drug” promotes the regression of cancer in a subject. In a preferred embodiment, a therapeutically effective dose of the drug promotes the regression of cancer to the point where the cancer disappears. “Promotes cancer regression” means that administering an effective dose of anticancer drug, alone or in combination with another drug, results in a reduction of tumor growth or size, tumor necrosis, a decrease in the severity of at least one disease symptom, an increase in the frequency and duration of disease-free periods, or prevention of functional impairment or disability due to the suffering of the disease. In addition, the terms “effective” and “efficacy” in relation to a treatment include both pharmacological efficacy and physiological safety. Pharmacological efficacy refers to the ability of a drug to promote cancer regression in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (side effects) at the cellular, organ, and / or biological level resulting from the administration of the drug.

[0192] As an example of tumor treatment, a therapeutically effective dose of an anticancer drug can inhibit cell proliferation or tumor growth by at least about 20%, at least about 40%, at least about 60%, or at least about 80% compared to an untreated subject. In other embodiments of this disclosure, tumor regression can be observed and continued for a period of at least about 20 days, more preferably at least about 40 days, or at least about 60 days. Despite these measures of therapeutic efficacy, the evaluation of immunotherapeutic agents must also take into account immune-related response patterns.

[0193] "Immuno-oncology" therapy or "IO" or "IO" therapy, as used herein, refers to therapy that utilizes an immune response to target and treat a tumor in a subject. As such, IO therapy, as used herein, is a type of anti-cancer therapy. In some embodiments, IO therapy includes administering an antibody to a subject. In some embodiments, IO therapy includes administering immune cells, e.g., T cells, e.g., modified T cells, e.g., T cells modified to express a chimeric antigen receptor or a specific T cell receptor. In some embodiments, IO therapy includes administering a therapeutic vaccine to a subject. In some embodiments, IO therapy includes administering a cytokine or chemokine to a subject. In some embodiments, IO therapy includes administering an interleukin to a subject. In some embodiments, IO therapy includes administering an interferon to a subject. In some embodiments, IO therapy includes administering a colony-stimulating factor to a subject.

[0194] "Immune response" refers to the action of immune system cells (e.g., T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells, and neutrophils) and soluble macromolecules (e.g., antibodies, cytokines, and complements) produced by either these cells or the liver, resulting in the selective targeting, binding to, damage to, destruction of, and / or elimination from the body of a vertebrate of an invading pathogen, a pathogen-infected cell or tissue, a cancerous or other abnormal cell, or normal human cells or tissue in the case of autoimmune or pathological inflammation.

[0195] "Tumor-infiltrating inflammatory cells" or "tumor-associated inflammatory cells" are typically any type of cell that participates in the inflammatory response in a subject and infiltrates tumor tissue. Such cells include tumor-infiltrating lymphocytes (TILs), macrophages, monocytes, eosinophils, histiocytes, and dendritic cells.

[0196] The term "LAG-3 positive" or "LAG-3 expression positive" in relation to LAG-3 expression refers to tumor tissue (e.g., test tissue sample) that has been scored as expressing LAG-3 based on the proportion (i.e., percentage) of immune cells expressing LAG-3 (e.g., tumor-infiltrating lymphocytes, e.g., CD8+ T cells) (e.g., expression greater than or equal to 1%).

[0197] "LAG-3 negative" or "LAG-3 expression negative" refers to tumor tissue (e.g., test tissue sample) that does not express LAG-3 and is therefore not scored (e.g., LAG-3 expression of less than 1%).

[0198] The terms "PD-1 positive" or "PD-1 expression positive" are related to PD-1 expression and refer to immune cells (e.g., CD8). + This refers to tumor tissue (e.g., test tissue sample) that is scored as expressing PD-1 based on the proportion (i.e., percentage) of tumor-infiltrating lymphocytes (such as T cells) (e.g., expression of 1% or more).

[0199] "PD-1 negative" or "PD-1 expression negative" refers to tumor tissue (e.g., test tissue sample) that is not scored as expressing PD-1 (e.g., less than 1% PD-1 expression).

[0200] The term "PD-L1 positive" or "PD-L1 expression positive" in relation to cell surface PD-L1 expression refers to tumor tissue (e.g., test tissue sample) that is scored as expressing PD-L1 based on the proportion (i.e., percentage) of tumor cells expressing PD-L1 (e.g., expression greater than or equal to 1%).

[0201] The term "PD-L1 negative" or "PD-L1 expression negative" refers to tumor tissue (e.g., test tissue sample) that does not express PD-L1 and is therefore not scored (e.g., less than 1% expression).

[0202] The following subsections describe various aspects of the present invention in further detail.

[0203] II. Method of Disclosure A method for treating a human subject with lung cancer is provided herein, comprising administering to the subject a LAG-3 antagonist (e.g., an anti-LAG-3 antibody) alone or in combination with one or more additional therapeutic agents (e.g., PD-1 pathway inhibitors such as anti-PD-1 antibodies) and / or therapies (e.g., chemotherapy such as a dual platinum-based chemotherapy regimen).

[0204] In some embodiments, this method is a first-line (1L) therapy.

[0205] In some embodiments, this method is a second-line (2L) therapy.

[0206] In some embodiments, this method is a third-line (3L) therapy.

[0207] In some embodiments, the subject is progressing with prior therapy (e.g., standard therapy). Standard therapy for different types of cancer is well known to those skilled in the art. For example, the National Comprehensive Cancer Network (NCCN), a coalition of 21 leading cancer centers in the United States, publishes the NCCN Clinical Practice Guidelines in Oncology (NCCN GUIDELINES®), which provides detailed and up-to-date information on standard therapy for a wide variety of cancers. See NCCN GUIDELINES®, 2020, https: / / www.nccn.org / professionals / physician_gls / default.aspx (last accessed October 23, 2020).

[0208] In some aspects, lung cancer recurs after multidisciplinary therapy for locally advanced lung cancer.

[0209] In some embodiments, the subjects have not received systemic therapy for a prior cancer, or for a prior lung cancer, or for a prior advanced or metastatic lung cancer.

[0210] In some embodiments, the subjects have not received prior immuno-oncological (IO) therapy. In some embodiments, the subjects have never received IO therapy before, but have received IO therapy for a cancer other than lung cancer, or have received IO therapy for a previous lung cancer but not the current lung cancer. In some embodiments, the subjects have never received prior IO therapy, and the subjects have never received prior IO therapy for lung cancer, or lung cancer has never received prior IO therapy. In some embodiments, the prior IO therapy is an antibody. In some embodiments, the antibody binds to a checkpoint inhibitor. In some embodiments, the prior IO therapy is an anti-PD-1 antibody and / or a combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody.

[0211] In some embodiments, the methods disclosed herein increase the duration of progression-free survival (PFS), objective response rate (ORR), overall survival (OS), or any combination thereof, compared to standard treatments and / or prior therapies, such as those disclosed herein.

[0212] In some embodiments, the methods of the present disclosure involve reducing tumor size, inhibiting tumor growth, eliminating tumor from a subject, preventing recurrence of lung cancer, inducing remission of lung cancer, providing complete or partial response, or any combination thereof.

[0213] In certain embodiments, the methods of the present disclosure include administering a LAG-3 antagonist to a subject based on the subject's performance status and / or cancer stage. The performance status and / or cancer stage may be indicated by one or more systems in the industry.

[0214] In some embodiments, lung cancer is unresectable, advanced, recurrent, and / or metastatic.

[0215] In some embodiments, performance status is indicated by the Eastern Cooperative Oncology Group Performance Status (ECOG PS), which utilizes standardized criteria for measuring how disease affects a patient's ability to perform daily activities. Exemplary definitions of ECOG PS include: "0" is a patient who is fully active and can continue all pre-disease performance without limitation; "1" is a patient who is able to walk and perform light or sedentary tasks, but is physically limited to strenuous activities; "2" is a patient who is able to walk and can perform all self-care for more than 50% of their waking hours but is unable to perform any work-related activities; "3" is a patient who can only perform limited self-care and is required to remain in bed or chair for more than 50% of their waking hours; and "4" is a patient who is completely disabled, unable to continue any self-care and is required to remain in bed or chair for most of their waking hours.

[0216] In some embodiments, the subject has an ECOG PS of 0, 1, 2, 3, or 4. In some embodiments, the subject has an ECOG PS of ≤ 3. In some embodiments, the subject has an ECOG PS of ≤ 2. In some embodiments, the subject has an ECOG PS of ≤ 1.

[0217] In some embodiments, lung cancer is staged based on tumor / nodule / metastasis (TNM) staging systems such as the Joint Committee on Cancer (AJCC) classification.

[0218] Lung cancer is classified into at least seven stages: occult (latent) stage, stage 0 (in situ carcinoma), stage I, stage II, stage IIIA, stage IIIB, and stage IV. In the occult stage, the cancer cannot be seen by imaging or bronchoscopy. In stage 0, cancer cells are found in the mucous membrane of the airways.

[0219] In some embodiments, the subjects have stage 0 lung cancer.

[0220] In some embodiments, the subjects have stage I lung cancer. Stage I lung cancer is further divided into stages IA and IB. In stage IA, the tumor is confined to the lung and is 3 cm or less in size. In stage IB, the cancer has not spread to the lymph nodes and meets one or more of the following criteria: 1) the tumor is larger than 3 cm but not larger than 5 cm; 2) the cancer has spread to the main bronchus and is at least 2 cm below where the trachea merges with the bronchi; 3) the cancer has spread to the innermost layer of the membrane covering the lung; or 4) part of the lung is collapsed or has pneumonitis (inflammation of the lung) in the area where the trachea connects to the bronchi.

[0221] In some embodiments, the subjects have stage II lung cancer. Stage II is further divided into stages IIA and IIB. In stage IIA, the cancer may or may not have spread to the lymph nodes. If the cancer has spread to the lymph nodes, it has spread only to the lymph nodes on the same side of the chest as the tumor, and the lymph nodes containing the cancer are located in the lung or near the bronchi and meet one or more of the following criteria: 1) the tumor is not larger than 5 cm; 2) the cancer has spread to the main bronchus, at least 2 cm below where the trachea merges with the bronchi; 3) the cancer has spread to the innermost layer of the membrane covering the lung; or 4) part of the lung is collapsed or has pneumonitis (inflammation of the lung) in the area where the trachea connects to the bronchi. Additionally, if the cancer has not spread to the lymph nodes and one or more of the following conditions are met, the tumor is considered to be in stage IIA: 1) the tumor is larger than 3 cm but not larger than 7 cm; 2) the cancer has spread to the main bronchus and is at least 2 cm below where the trachea merges with the bronchus; 5) the cancer has spread to the innermost layer of the membrane covering the lung; or 4) part of the lung is collapsed or has pneumonitis (inflammation of the lung) in the area where the trachea connects to the bronchus. In stage IIB, the cancer may or may not have spread to the lymph nodes. If the cancer has spread to the lymph nodes, it has spread only to the lymph nodes on the same side of the chest as the tumor, and the lymph nodes containing the cancer are located in the lung or near the bronchi and meet one or more of the following criteria: 1) the tumor is larger than 5 cm but not larger than 7 cm; 2) the cancer has spread to the main bronchus, at least 2 cm below where the trachea joins the bronchi; 3) the cancer has spread to the innermost layer of the membrane covering the lung; or 4) part of the lung is collapsed or has pneumonia (inflammation of the lung) in the area where the trachea connects to the bronchi.Additionally, if the cancer has not spread to the lymph nodes and one or more of the following conditions are met, the tumor is considered to be stage IIB: 1) the tumor is larger than 7 cm; 2) the cancer has spread to the main bronchus (at least 2 cm below where the trachea merges with the bronchi), chest wall, diaphragm, or nerves supplying the diaphragm; 3) the cancer has spread to the membranes surrounding the heart or the lining of the chest wall; 4) the entire lung is collapsed or has pneumonia (inflammation of the lung); 5) one or more separate tumors are present in the same lung lobe.

[0222] In some embodiments, the subject has stage III lung cancer. Stage IIIA is divided into three sections. These three sections are based on 1) the size of the tumor; 2) where the tumor is found; and 3) which lymph nodes (if present) the cancer is located in. In the first type of stage IIIA, the cancer has spread to lymph nodes on the same side as the tumor in the chest, with the cancerous lymph nodes located near the sternum or where the bronchi enter the lungs. Furthermore: 1) the tumor may be of any size; 2) part of the lung (where the trachea connects to the bronchi) or the entire lung may be collapsed or have pneumonia (inflammation of the lung); 3) there may be one or more distinct tumors in the same lung lobe; 4) the cancer may have spread to any of the following: a) the major bronchi other than where the trachea connects to the bronchi, b) the chest well, c) the diaphragm and the nerves that control it, d) the membranes surrounding the lungs or the lining of the chest wall, e) the membranes surrounding the heart. In the second type of Stage IIIA, the cancer has spread to lymph nodes on the same side as the tumor in the chest, and the lymph nodes containing the cancer are located within the lung or near the bronchi. Furthermore, 1) the tumor may be of any size; 2) the entire lung may be collapsed or inflamed (inflammation of the lung); 3) one or more separate tumors may be present in any of the lung lobes with cancer; 4) the cancer may have spread to any of the following: a) the major bronchi other than where the trachea connects to the bronchi, b) the chest wall, c) the diaphragm and the nerves that control it, d) the membranes surrounding the lungs or the lining of the chest wall, e) the membranes surrounding the heart or the heart, f) the major blood vessels that enter and leave the heart, g) the trachea, h) the esophagus, i) the nerves that control the larynx (vocal organs), j) the sternum (chest bone) or spine, or k) the tracheal bifurcation (where the trachea connects to the bronchi). In stage IIIA, type 3, the cancer has not spread to the lymph nodes, the tumor may be of any size, and the cancer has spread to one of the following: a) the heart, b) major blood vessels leading to or leaving the heart, c) the trachea, d) the esophagus, e) nerves controlling the larynx (vocal organs), f) the sternum (chest bone) or spine, or g) the tracheal bifurcation (where the trachea connects to the bronchi).Stage IIIB is divided into two types based on 1) the size of the tumor, 2) the location of the tumor, and 3) which lymph nodes are affected by the cancer. In the first type of Stage IIIB, the cancer has spread to the lymph nodes on the opposite side of the chest. Furthermore, 1) the tumor may be of any size; 2) part of the lung (where the trachea joins the bronchi) or the entire lung may be collapsed or have pneumonia (inflammation of the lung); 3) one or more separate tumors may be present in any of the lung lobes with cancer; 4) the cancer may have spread to any of the following: a) the major bronchi, b) the chest wall, c) the diaphragm and the nerves that control it, d) the membranes surrounding the lungs or the lining of the chest wall, e) the heart or the membranes surrounding it, f) the major blood vessels that enter and leave the heart, g) the trachea, h) the esophagus, i) the nerves that control the larynx (vocal organs), j) the sternum (chest bone) or spine, or k) the tracheal bifurcation (where the trachea joins the bronchi). In the second type of stage IIIB, the cancer has spread to lymph nodes on the same side as the tumor in the chest. The lymph nodes containing the cancer are located near the sternum (chest bone) or where the bronchi enter the lungs. Furthermore, 1) the tumor may be of any size; 2) separate tumors may be present in different lobes of the same lung; and 3) the cancer has spread to any of the following: a) the heart, b) major blood vessels leading to or leaving the heart, c) the trachea, d) the esophagus, e) the nerves controlling the larynx (vocal organs), f) the sternum or spine, or g) the tracheal bifurcation (where the trachea connects to the bronchi).

[0223] In some embodiments, the subjects have stage IV lung cancer. In stage IV, the tumor may be of any size, and the cancer may have spread to the lymph nodes. In stage IV, one or more of the following are true: 1) there is one or more tumors in both lungs; 2) the cancer is found in the fluid surrounding the lungs or heart; 3) the cancer has spread to other parts of the body, such as the brain, liver, adrenal glands, kidneys, or bones.

[0224] In some embodiments, lung cancer is small cell lung cancer (SCLC). In some embodiments, SCLC is staging according to the TNM staging system. In some embodiments, SCLC is staging either localized or advanced, rather than according to the TNM staging system. Localized SCLC is confined to one lung and / or a local lymph node. Advanced SCLC is found in the lung and / or distant sites within the body.

[0225] In some embodiments, lung cancer is non-small cell lung cancer (NSCLC). NSCLC includes NSCLC having a "not specifically designated" (NOS) histological structure, NSCLC having a squamous type (SQ) histological structure, and NSCLC having a non-squamous type (including NSQ, adenocarcinoma, large cell, and undifferentiated carcinoma) histological structure. In some embodiments, NSCLC has a squamous epithelial tissue structure. In some embodiments, NSCLC has a non-squamous epithelial tissue structure.

[0226] Surgery (i.e., surgical resection), radiotherapy (RT), and chemotherapy are the three most common treatments for NSCLC patients. As a class, NSCLC is relatively less sensitive to chemotherapy and RT compared to small cell carcinoma. Generally, in patients with stage I or II disease, surgical resection offers the highest chance of cure, and chemotherapy is often used both preoperatively and postoperatively. RT can also be used as adjuvant therapy, primary local treatment, or palliative care for patients with resectable NSCLC. Patients with advanced or metastatic disease who have a good performance status (PS) (e.g., stage IV NSCLC) may benefit from chemotherapy.

[0227] Furthermore, specific targeted therapies are being developed for the treatment of advanced or metastatic NSCLC in patients with sensitizing mutations in the following genes: epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS-1, neurotrophin receptor tyrosine kinase (NTRK), and BRAF (B-rapidly accelerated fibrosarcoma proto-oncogene, e.g., BRAF V600E mutation).

[0228] In some embodiments, subjects have EGFR, ALK, NTRK, ROS-1, or BRAF mutations that make them susceptible to targeted inhibitor therapy.

[0229] In some embodiments, subjects do not have EGFR, ALK, NTRK, ROS-1, or BRAF mutations that make them sensitive to targeted inhibitor therapy.

[0230] In some embodiments, one or more immune cells in tumor tissue from a subject express LAG-3 (i.e., tumor tissue from a patient is LAG-3 positive), and / or one or more tumor cells in tumor tissue from a subject express PD-L1 (i.e., tumor tissue from a patient is PD-L1 positive). In some embodiments, one or more immune cells in tumor tissue from a subject express LAG-3. In some embodiments, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the immune cells express LAG-3. In some embodiments, at least about 1% of immune cells express LAG-3. In some embodiments, more than about 1% of immune cells express LAG-3. In some embodiments, at least about 5% of immune cells express LAG-3. In some embodiments, the immune cells are tumor-infiltrating lymphocytes. In some embodiments, the tumor-infiltrating lymphocytes are CD8 +It is a cell. In some embodiments, one or more tumor cells in tumor tissue from a subject express PD-L1. In some embodiments, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of tumor cells express PD-L1. In some embodiments, at least about 1% of tumor cells express PD-L1. In some embodiments, at least about 1% of tumor cells express PD-L1. In some embodiments, more than about 1% of tumor cells express PD-L1. In some embodiments, at least about 5% of tumor cells express PD-L1. In some embodiments, the value of "at least about X%" is always "≥X%".

[0231] In some embodiments, one or more immune cells in the tumor tissue from the patient do not express LAG-3 (i.e., the tumor tissue from the patient is LAG-3 negative). In some embodiments, if less than about 1% of the immune cells express LAG-3, the tumor tissue is LAG-3 negative.

[0232] In some embodiments, one or more immune cells in patient-derived tumor tissue do not express PD-1 (i.e., patient-derived tumor tissue is PD-1 negative). In some embodiments, tumor tissue is PD-1 negative if less than approximately 1% of immune cells express PD-1.

[0233] In some embodiments, one or more tumor cells in the tumor tissue from the patient do not express PD-L1 (i.e., the tumor tissue from the patient is PD-L1 negative). In some embodiments, if less than approximately 1% of the tumor cells express PD-L1, the tumor tissue is PD-L1 negative.

[0234] In some embodiments, LAG-3, PD-1, and / or PD-L1 expression in the tumor tissue of interest is determined from a test tissue sample. In some embodiments, the test tissue sample may be any clinically relevant tissue sample, e.g., tumor biopsy, core biopsy, incision biopsy, excision biopsy, surgical specimen, fine-needle aspiration, or a sample of bodily fluids, e.g., blood, plasma, serum, lymph, ascites, cystic fluid, or urine. In some embodiments, the test tissue sample is a sample from the primary tumor. In some embodiments, the test tissue sample is a sample from a metastatic site. In some embodiments, the test tissue sample is a sample from multiple time points, e.g., pre-treatment, treatment, and / or post-treatment samples. In some embodiments, the test tissue sample is a sample from different locations of interest, e.g., samples from the primary tumor and metastatic sites.

[0235] In some embodiments, the test tissue sample is a paraffin-embedded tissue sample. In some embodiments, the test tissue sample is a formalin-fixed paraffin-embedded (FFPE) tissue sample. In some embodiments, the test tissue sample is a fresh tissue (e.g., tumor) sample. In some embodiments, the test tissue sample is a frozen tissue sample. In some embodiments, the test tissue sample is a fresh-frozen (FF) tissue (e.g., tumor) sample. In some embodiments, the test tissue sample is cells isolated from fluid. In some embodiments, the test tissue sample contains circulating tumor cells (CTCs). In some embodiments, the test tissue sample contains tumor-infiltrating lymphocytes (TILs). In some embodiments, the test tissue sample contains tumor cells and tumor-infiltrating lymphocytes (TILs). In some embodiments, the test tissue sample contains circulating lymphocytes. In some embodiments, the test tissue sample is an archived tissue sample. In some embodiments, the test tissue sample is an archived tissue sample with a known history of diagnosis, treatment, and / or outcome. In some embodiments, the sample is a block of tissue. In some embodiments, the test tissue sample is dispersed cells. In some embodiments, the sample size is approximately 1 × 10⁶ cells from about one cell. 6 This can range from a single cell to a number of cells or more. In some embodiments, the sample size can range from about 1 cell to about 1 × 10⁶ cells. 5 The sample size is a single cell. In some embodiments, the sample size ranges from approximately 1 cell to approximately 10,000 cells. In some embodiments, the sample size ranges from approximately 1 cell to approximately 1,000 cells. In some embodiments, the sample size ranges from approximately 1 cell to approximately 100 cells. In some embodiments, the sample size ranges from approximately 1 cell to approximately 10 cells. In some embodiments, the sample size is a single cell.

[0236] In some embodiments, LAG-3, PD-1, and / or PD-L1 expression is assessed by performing assays to detect the presence of LAG-3, PD-1, and / or PD-L1 RNA, respectively. In some embodiments, the presence of LAG-3, PD-1, and / or PD-L1 RNA is detected by RT-PCR, in situ hybridization, or RNase protection.

[0237] In some embodiments, LAG-3, PD-1, and / or PD-L1 expression is assessed by performing assays to detect the presence of LAG-3, PD-1, and / or PD-L1 polypeptides, respectively. In some embodiments, the presence of LAG-3, PD-1, and / or PD-L1 polypeptides is detected by immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), in vivo imaging, or flow cytometry.

[0238] II.A.LAG-3 Antagonist LAG-3 antagonists for use in the methods of this disclosure include, but are not limited to, LAG-3 conjugates and soluble LAG-3 polypeptides. LAG-3 conjugates include antibodies that specifically bind to LAG-3 (i.e., “anti-LAG-3 antibodies”). The term “LAG-3 antagonist” is replaceable with the term “LAG-3 inhibitor” as used herein.

[0239] In some embodiments, the LAG-3 antagonist is an anti-LAG-3 antibody.

[0240] Antibodies that bind to LAG-3 are disclosed, for example, in International Publication WO / 2015 / 042246 and U.S. Patent Publications 2014 / 0093511 and 2011 / 0150892, which are incorporated herein by reference in their entirety.

[0241] An exemplary LAG-3 antibody useful in the disclosure of the present invention is 25F7 (described in U.S. Patent Publication No. 2011 / 0150892). An additional exemplary LAG-3 antibody useful in the disclosure of the present invention is BMS-986016 (relatrimab). In some embodiments, the anti-LAG-3 antibody useful in the disclosure of the present invention cross-competes with 25F7 or BMS-986016. In some embodiments, the anti-LAG-3 antibody useful in the disclosure of the present invention binds to the same epitope as 25F7 or BMS-986016. In some embodiments, the anti-LAG-3 antibody contains six CDRs of 25F7 or BMS-986016.

[0242] Other anti-LAG-3 antibodies that can be used in the methods described herein include IMP731 (H5L7BW) described in US2011 / 007023, MK-4280 (28G-10, fabezerimab) described in WO2016028672 and U.S. Public Notice No. 2020 / 0055938, and Burova E, et al., J. Immunother. Cancer. REGN3767 (fianlimab) described in (2016);4(Supp.1):P195 and U.S. Patent No. 10,358,495, humanized BAP050 described in WO2017 / 019894, GSK2831781 described in U.S. Patent No. 10,711,060 and U.S. Patent Publication No. 2020 / 0172617, IMP-701 (LAG525; iera mirimab), aLAG3 (041 4) Examples include aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (formerly XmAb22841), MGD013 (tevoterimab), BI754111, FS118, P13B02-30, AVA-017, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, and ABL501.These and other anti-LAG-3 antibodies useful in the claimed invention include, for example, US10,188,730, WO2016 / 028672, WO2017 / 106129, WO2017 / 062888, WO2009 / 044273, WO2018 / 069500, and WO2016 / 12685. 8, WO2014 / 179664, WO2016 / 200782, WO2015 / 200119, WO2017 / 019846, WO2017 / 19 8741, WO2017 / 220555, WO2017 / 220569, WO2018 / 071500, WO2017 / 015560, WO2017 / 025498, WO2017 / 087589, WO2017 / 087901, WO2018 / 083087, WO2017 / 149143, WO20 17 / 219995, US2017 / 0260271, WO2017 / 086367, WO2017 / 086419, WO2018 / 034227, W These can be found in O2018 / 185046, WO2018 / 185043, WO2018 / 217940, WO19 / 011306, WO2018 / 208868, WO2014 / 140180, WO2018 / 201096, WO2018 / 204374, and WO2019 / 018730. The contents of each of these references are incorporated herein by reference in their entirety.

[0243] Other anti-LAG-3 antibodies that can be used in the methods of this disclosure include isolated antibodies that specifically bind to human LAG-3 and cross-compete with any of the anti-LAG-3 antibodies disclosed herein, such as relatrimab, for binding to human LAG-3. In some embodiments, the anti-LAG-3 antibody binds to the same epitope as any of the anti-LAG-3 antibodies described herein, such as relatrimab.

[0244] In some embodiments, any anti-LAG-3 antibody disclosed herein, such as relatrimab, that cross-competes with or binds to the same epitope region as human LAG-3 is a monoclonal antibody. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0245] The ability of antibodies to cross-compete with an antigen indicates that the antibody binds to the same epitope region of the antigen, spatially interfering with the binding of other cross-competing antibodies to that particular epitope region. These cross-competing antibodies are expected to have functional properties very similar to a reference antibody, e.g., relatrimab, due to their binding to the same epitope region. Cross-competing antibodies can be identified based on their ability to cross-compete in standard binding assays such as Biacore analysis, ELISA assays, or flow cytometry (see, e.g., WO2013 / 173223).

[0246] Other anti-LAG-3 antibodies that can be used in the method of this disclosure include the antigen-binding sites of any of the full-length antibodies described above. It has been well demonstrated that the antigen-binding function of an antibody can be exerted by a fragment of a full-length antibody.

[0247] In some embodiments, the anti-LAG-3 antibody is a full-length antibody.

[0248] In some embodiments, the anti-LAG-3 antibody is monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is a biaffinity retargeting antibody (DART), DVD-Ig, or bispecific antibody.

[0249] In some embodiments, the anti-LAG-3 antibody is an F(ab')2 fragment, Fab' fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment, or single-chain linked polypeptide.

[0250] In some embodiments, the anti-LAG-3 antibodies include BMS-986016 (relatrimab), IMP731 (H5L7BW), MK4280 (28G-10, fabezerimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, ieramirimab), aLAG3(0414), aLAG3(0416), Sym022, TS R-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tevoterimab), BI754111, FS118, P13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or containing their antigen-binding moieties.

[0251] In some embodiments, the anti-LAG-3 antibody is relatrimab.

[0252] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 3, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 4.

[0253] In some embodiments, the method of the present disclosure comprises an anti-LAG-3 antibody comprising (a) a heavy chain variable region CDR1 comprising the sequence described in SEQ ID NO: 5; (b) a heavy chain variable region CDR2 comprising the sequence described in SEQ ID NO: 6; (c) a heavy chain variable region CDR3 comprising the sequence described in SEQ ID NO: 7; (d) a light chain variable region CDR1 comprising the sequence described in SEQ ID NO: 8; (e) a light chain variable region CDR2 comprising the sequence described in SEQ ID NO: 9; and (f) a light chain variable region CDR3 comprising the sequence described in SEQ ID NO: 10.

[0254] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising a heavy chain and a light chain variable region comprising the sequences described in SEQ ID NOs: 3 and 4, respectively.

[0255] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising a heavy chain and a light chain, respectively, containing the sequences described in SEQ ID NOs: 1 and 2.

[0256] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 21 and 2, respectively.

[0257] In some embodiments, the anti-LAG-3 antibody is MGD013 (tevoterimab), a bispecific PD-1×LAG-3DART. In some embodiments, tevoterimab is administered intravenously at a dose of approximately 300 mg or 600 mg once every two or three weeks. In some embodiments, tevoterimab is administered intravenously at a dose of approximately 300 mg once every two weeks. In some embodiments, tevoterimab is administered intravenously at a dose of approximately 600 mg once every three weeks.

[0258] In some embodiments, the anti-LAG-3 antibody is REGN3767 (fianlimab). In some embodiments, fianlimab is administered intravenously once every three weeks at doses of approximately 1 mg / kg, approximately 3 mg / kg, approximately 10 mg / kg, or approximately 20 mg / kg. In some embodiments, fianlimab is administered intravenously once every three weeks at a dose of approximately 1600 mg. In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 25, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 26.

[0259] In some embodiments, the method of the present disclosure comprises an anti-LAG-3 antibody comprising (a) a heavy chain variable region CDR1 comprising the sequence described in SEQ ID NO: 27; (b) a heavy chain variable region CDR2 comprising the sequence described in SEQ ID NO: 28; (c) a heavy chain variable region CDR3 comprising the sequence described in SEQ ID NO: 29; (d) a light chain variable region CDR1 comprising the sequence described in SEQ ID NO: 30; (e) a light chain variable region CDR2 comprising the sequence described in SEQ ID NO: 31; and (f) a light chain variable region CDR3 comprising the sequence described in SEQ ID NO: 32.

[0260] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising a heavy chain and a light chain variable region comprising the sequences described in SEQ ID NOs. 25 and 26, respectively.

[0261] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 23 and 24, respectively.

[0262] In some embodiments, the anti-LAG-3 antibody is LAG525 (ieramimab). In some embodiments, ieramimab is administered intravenously once every two, three, or four weeks in doses of approximately 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, or 1300 mg.

[0263] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 47, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 49.

[0264] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 48, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 50.

[0265] In some embodiments, the method of the present disclosure comprises an anti-LAG-3 antibody comprising (a) a heavy chain variable region CDR1 comprising the sequence described in SEQ ID NO: 51; (b) a heavy chain variable region CDR2 comprising the sequence described in SEQ ID NO: 52; (c) a heavy chain variable region CDR3 comprising the sequence described in SEQ ID NO: 53; (d) a light chain variable region CDR1 comprising the sequence described in SEQ ID NO: 54; (e) a light chain variable region CDR2 comprising the sequence described in SEQ ID NO: 55; and (f) a light chain variable region CDR3 comprising the sequence described in SEQ ID NO: 56.

[0266] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising a heavy chain and a light chain variable region comprising the sequences described in SEQ ID NOs. 47 and 49, respectively.

[0267] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising a heavy chain and a light chain variable region comprising the sequences described in SEQ ID NOs. 48 and 50, respectively.

[0268] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 43 and 45, respectively.

[0269] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 44 and 46, respectively.

[0270] In some embodiments, the anti-LAG-3 antibody is MK4280 (fabezerimab). In some embodiments, fabezerimab is administered intravenously at doses of approximately 7 mg, 21 mg, 70 mg, 210 mg, 700 mg, or 800 mg, once every three weeks or once every six weeks. In some embodiments, fabezerimab is administered intravenously at a dose of approximately 200 mg, once every three weeks. In some embodiments, fabezerimab is administered intravenously at a dose of approximately 800 mg, once every six weeks. In some embodiments, fabezerimab is administered intravenously at a dose of approximately 800 mg on day 1, and then once every three weeks thereafter. In some embodiments, fabezerimab is administered for up to 35 cycles. In some embodiments, fabezerimab is administered intravenously at a dose of approximately 800 mg over approximately 30 minutes on day 1 of a 3-week cycle, for up to 35 cycles.

[0271] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 69, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 70.

[0272] In some embodiments, the method of the present disclosure comprises an anti-LAG-3 antibody comprising (a) a heavy chain variable region CDR1 comprising the sequence described in SEQ ID NO: 71; (b) a heavy chain variable region CDR2 comprising the sequence described in SEQ ID NO: 72; (c) a heavy chain variable region CDR3 comprising the sequence described in SEQ ID NO: 73; (d) a light chain variable region CDR1 comprising the sequence described in SEQ ID NO: 74; (e) a light chain variable region CDR2 comprising the sequence described in SEQ ID NO: 75; and (f) a light chain variable region CDR3 comprising the sequence described in SEQ ID NO: 76.

[0273] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising a heavy chain and a light chain variable region comprising the sequences described in SEQ ID NOs. 69 and 70, respectively.

[0274] In some embodiments, the method of the present disclosure includes an anti-LAG-3 antibody comprising a heavy chain and a light chain, respectively, containing the sequences described in SEQ ID NOs. 67 and 68.

[0275] In some embodiments, the LAG-3 antagonist is a soluble LAG-3 polypeptide. In some embodiments, the soluble LAG-3 polypeptide is a fusion polypeptide, for example, a fusion protein containing the extracellular portion of LAG-3. In some embodiments, the soluble LAG-3 polypeptide is a LAG-3-Fc fusion polypeptide capable of binding to MHC class II. In some embodiments, the soluble LAG-3 polypeptide contains a ligand-binding fragment of the extracellular domain of LAG-3. In some embodiments, the ligand-binding fragment of the extracellular domain of LAG-3 contains an amino acid sequence having sequence identity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% with SEQ ID NO: 22. In some embodiments, the soluble LAG-3 polypeptide further contains a half-life-extending portion. In some embodiments, the half-life-extending portion includes the immunoglobulin constant region or a portion thereof, an immunoglobulin-binding polypeptide, immunoglobulin G (IgG), albumin-binding polypeptide (ABP), a PAS-modified portion, a HES-modified portion, XTEN, a pegylated portion, an Fc region, or any combination thereof. In some embodiments, the soluble LAG-3 polypeptide is IMP321 (effilagimod alfa). See, for example, Brignone C, et al., J.Immunol. (2007); 179:4202-4211 and WO2009 / 044273. In some embodiments, effilagimod alfa is administered in a dose of approximately 30 mg. In some embodiments, effilagimod alfa is administered subcutaneously in a dose of approximately 30 mg once every two weeks.

[0276] In some embodiments, anti-LAG-3 antibodies are used to determine LAG-3 expression. In some embodiments, anti-LAG-3 antibodies are selected based on their ability to bind to LAG-3 in formalin-fixed paraffin-embedded (FFPE) tissue samples. In some embodiments, anti-LAG-3 antibodies are capable of binding to LAG-3 in frozen tissue. In some embodiments, anti-LAG-3 antibodies are capable of distinguishing between membrane-bound, cytoplasmic, and / or soluble forms of LAG-3.

[0277] In some embodiments, an anti-LAG-3 antibody useful for assaying, detecting, and / or quantifying LAG-3 expression according to the methods disclosed herein is a 17B4 mouse IgG1 anti-human LAG-3 monoclonal antibody. See, for example, Matsuzaki, J et al., PNAS (2010); 107:7875.

[0278] In some embodiments, LAG-3 antagonists are formulated for intravenous administration.

[0279] In some embodiments, the anti-LAG-3 antibody is administered intravenously over a period of approximately 30 minutes.

[0280] In some embodiments, the LAG-3 antagonist is administered in a uniform dose.

[0281] In some protocols, LAG-3 antagonists are administered in doses of at least approximately 0.25 mg to 2000 mg, approximately 0.25 mg to 1600 mg, approximately 0.25 mg to 1200 mg, approximately 0.25 mg to 800 mg, approximately 0.25 mg to 400 mg, approximately 0.25 mg to 100 mg, approximately 0.25 mg to 50 mg, approximately 0.25 mg to 40 mg, approximately 0.25 mg to 30 mg, approximately 0.25 mg to 20 mg, approximately 20 mg to 2000 mg, approximately 20 mg to 1600 mg, approximately 20 mg to 1200 mg, approximately 20 mg to 800 mg, approximately 20 mg to 400 mg, and approximately It is administered in doses of approximately 20 mg to 100 mg, approximately 100 mg to 2000 mg, approximately 100 mg to 1800 mg, approximately 100 mg to 1600 mg, approximately 100 mg to 1400 mg, approximately 100 mg to 1200 mg, approximately 100 mg to 1000 mg, approximately 100 mg to 800 mg, approximately 100 mg to 600 mg, approximately 100 mg to 400 mg, approximately 400 mg to 2000 mg, approximately 400 mg to 1800 mg, approximately 400 mg to 1600 mg, approximately 400 mg to 1400 mg, approximately 400 mg to 1200 mg, or approximately 400 mg to 1000 mg.

[0282] According to some sources, LAG-3 antagonists are available in doses of approximately 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7 mg, 7.25 mg, 7.5 mg, 7.75 mg, 8 mg, 8.25 mg, 8.5 mg, 8.75 mg, 9 mg, 9.25 mg, 9.5 mg, and 9 mg.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 35 0mg, approx. 360mg, approx. 370mg, approx. 380mg, approx. 390mg, approx. 400mg, approx. 410mg, approx. 420mg, approx. 430mg, approx. 440mg, approx. 450mg, approx. 20mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 6 90mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 1080m It is administered in doses of approximately 1100mg, 1140mg, 1180mg, 1200mg, 1240mg, 1280mg, 1300mg, 1340mg, 1380mg, 1400mg, 1440mg, 1480mg, 1500mg, 1540mg, 1580mg, 1600mg, 1640mg, 1680mg, 1700mg, 1740mg, 1780mg, 1800mg, 1840mg, 1880mg, 1900mg, 1940mg, 1980mg, or 2000mg.

[0283] In some embodiments, LAG-3 antagonists are administered in a dose based on body weight.

[0284] In some aspects, LAG-3 antagonists are present in doses ranging from approximately 0.003 mg / kg to approximately 25 mg / kg, approximately 0.003 mg / kg to approximately 20 mg / kg, approximately 0.003 mg / kg to approximately 15 mg / kg, approximately 0.003 mg / kg to approximately 10 mg / kg, approximately 0.003 mg / kg to approximately 5 mg / kg, approximately 0.003 mg / kg to approximately 1 mg / kg, approximately 0.003 mg / kg to approximately 0.9 mg / kg, and approximately 0.003 mg / kg to approximately 0.8 mg / kg, approximately 0.003 mg / kg to approximately 0.7 mg / kg, approximately 0.003 mg / kg to approximately 0.6 mg / kg, approximately 0.003 mg / kg to approximately 0.5 mg / kg, approximately 0.003 mg / kg to approximately 0.4 mg / kg, approximately 0.003 mg / kg to approximately 0.3 mg / kg, approximately 0.003 mg / kg to approximately 0.2 mg / kg, approximately 0.003 mg / kg to approximately 0.1 mg / kg, approximately 0.1 mg / kg to approximately 25 mg / kg, approximately 0 0.1 mg / kg to approximately 20 mg / kg, approximately 0.1 mg / kg to approximately 15 mg / kg, approximately 0.1 mg / kg to approximately 10 mg / kg, approximately 0.1 mg / kg to approximately 5 mg / kg, approximately 0.1 mg / kg to approximately 1 mg / kg, approximately 1 mg / kg to approximately 25 mg / kg, approximately 1 mg / kg to approximately 20 mg / kg, approximately 1 mg / kg to approximately 15 mg / kg, approximately 1 mg / kg to approximately 10 mg / kg, approximately 1 mg / kg to approximately 5 mg / kg, approximately 5 mg / kg It is administered in doses of approximately 25 mg / kg from g, approximately 20 mg / kg from approximately 5 mg / kg, approximately 15 mg / kg from approximately 5 mg / kg, approximately 10 mg / kg from approximately 10 mg / kg, approximately 25 mg / kg from approximately 10 mg / kg, approximately 20 mg / kg from approximately 10 mg / kg, approximately 15 mg / kg from approximately 15 mg / kg, approximately 25 mg / kg from approximately 15 mg / kg, or approximately 20 mg / kg from approximately 25 mg / kg.

[0285] In some aspects, LAG-3 antagonists are present in doses of approximately 0.003 mg / kg, 0.004 mg / kg, 0.005 mg / kg, 0.006 mg / kg, 0.007 mg / kg, 0.008 mg / kg, 0.009 mg / kg, 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, and 0.8 mg / kg. It is administered in doses of approximately 0.9 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0 mg / kg, 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg, 10.0 mg / kg, 11.0 mg / kg, 12.0 mg / kg, 13.0 mg / kg, 14.0 mg / kg, 15.0 mg / kg, 16.0 mg / kg, 17.0 mg / kg, 18.0 mg / kg, 19.0 mg / kg, 20.0 mg / kg, 21.0 mg / kg, 22.0 mg / kg, 23.0 mg / kg, 24.0 mg / kg, or 25.0 mg / kg.

[0286] In some cases, the dosage is administered approximately once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks.

[0287] In some embodiments, the LAG-3 antagonists described herein are administered as monotherapy, i.e., the LAG-3 antagonist is not administered in combination with one or more additional therapeutic agents.

[0288] In some embodiments, the LAG-3 antagonists described herein are administered as combination therapy, i.e., the LAG-3 antagonist is administered in combination with one or more additional therapeutic agents and / or anticancer therapies.

[0289] II.B. Combination Therapy Additional therapeutic agents and / or anticancer therapies may include any known therapeutic agents or anticancer therapies, including standard treatments in the art for the treatment of subjects with lung cancer. In some embodiments, LAG-3 antagonists are combined with therapeutic agents and / or therapies listed in the NCCN Guidelines® for the Treatment of NSCLC. For example, see the therapeutic agents and therapies listed below: https: / / www.cancertherapyadvisor.com / home / cancer-topics / lung-cancer / lung-cancer-treatment-regimens-landing-page / non-small-cell-lung-cancer-treatment-regimens / , last accessed October 23, 2020.

[0290] II.B.1. Anti-cancer therapy In some embodiments, additional anticancer therapies include surgery, radiotherapy, chemotherapy, immunotherapy, or any combination thereof. In some embodiments, additional anticancer therapies include chemotherapy, such as any chemotherapeutic agent disclosed herein. In some embodiments, chemotherapy includes platinum-doublet chemotherapy.

[0291] In some embodiments, PDCT comprises a platinum agent in combination with a nucleoside analog, an antimetabolite, a taxane, a vinca alkaloid, or a topoisomerase inhibitor.

[0292] In some embodiments, the platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lipoplatin, or phenantriplatin.

[0293] In some embodiments, the nucleoside analog is cytarabine, gemcitabine, lamivudine, entecavir, or terbivudine. In some embodiments, the nucleoside analog is gemcitabine.

[0294] In some embodiments, the antimetabolite is capecitabine, cladribine, clofarabine, cytarabine, phloxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, or thioguanine. In some embodiments, the antimetabolite is carboplatin.

[0295] In some embodiments, the taxane is paclitaxel, albumin-conjugated paclitaxel (also known as nab-paclitaxel), docetaxel, or cabazitaxel.

[0296] In some embodiments, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vineridine, or vinburnin. In some embodiments, the vinca alkaloid is vinorelbine or vinblastine.

[0297] In some embodiments, the topoisomerase inhibitor is etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin. In some embodiments, the topoisomerase inhibitor is etoposide. In some embodiments, the topoisomerase inhibitor is irinotecan.

[0298] In some cases, PDCT is administered over a period of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks.

[0299] In some embodiments, PDCT is administered approximately every three weeks for approximately 1, 2, 3, 4, 5, 6, 7, or 8 cycles. In some embodiments, PDCT is administered approximately every three weeks for approximately 1, 2, 3, 4, 5, or 6 cycles. In some embodiments, PDCT is administered approximately every three weeks for approximately 1, 2, 3, or 4 cycles.

[0300] In some embodiments, PDCT is administered for up to approximately 4, 5, or 6 three-week cycles. In some embodiments, PDCT is administered for up to approximately 4 three-week cycles.

[0301] In some embodiments, the platinum agent is cisplatin. In some embodiments, the cisplatin is approximately 25 mg / m². 2 From approximately 150 mg / m² 2 , about 50mg / m 2 From approximately 100 mg / m² 2 , about 75mg / m 2 From approximately 100 mg / m² 2 , or approximately 75 mg / m² 2 From approximately 80 mg / m² 2 It is administered in the following dose. In some embodiments, cisplatin is approximately 50 mg / m². 2 , about 55mg / m 2 , about 60mg / m 2 , about 65mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 76mg / m 2 , about 77mg / m 2 , about 78mg / m 2 , about 79mg / m 2 , about 80mg / m2 , about 85mg / m 2 , about 90mg / m 2 , about 95mg / m 2 , or approximately 100 mg / m² 2 It is administered in the following doses. In some embodiments, cisplatin is administered intravenously over approximately 60 minutes. In some embodiments, cisplatin is administered on day 1 of a 3-week cycle for up to approximately 4, 5, or 6 cycles.

[0302] In some embodiments, the platinum agent is carboplatin. In some embodiments, carboplatin is administered in doses with a target concentration-time area under the curve (AUC) ranging from approximately 1 mg / mL·min to approximately 10 mg / mL·min. In some embodiments, carboplatin is administered in doses with a target AUC of approximately 1 mg / mL·min, approximately 2 mg / mL·min, approximately 3 mg / mL·min, approximately 4 mg / mL·min, approximately 5 mg / mL·min, approximately 6 mg / mL·min, approximately 7 mg / mL·min, approximately 8 mg / mL·min, approximately 9 mg / mL·min, or approximately 10 mg / mL·min. In some embodiments, carboplatin is administered in a dose with a target AUC of approximately 2 mg / mL·min. In some embodiments, carboplatin is administered in a dose with a target AUC of approximately 5 mg / mL·min. In some embodiments, carboplatin is administered in a dose with a target AUC of approximately 6 mg / mL·min. In some embodiments, carboplatin is administered intravenously over approximately 30 minutes. In some embodiments, carboplatin is administered on day 1 of a 3-week cycle for up to approximately 4, 5, or 6 cycles.

[0303] The dose of carboplatin can be calculated according to methods known in the art. In some embodiments, the dose of carboplatin is calculated using the Calvert formula as follows: Carboplatin dose (mg) = Target AUC × (CrCl [mL / min] + 25). The calculation of creatine clearance (CrCl) in the Calvert formula can be determined using the Cockcroft-Gault formula: Cockcroft-Gault's CrCl = [(140 - age) × (weight in kg) × (0.85 for women)] / (72 × Cr). The Cockcroft-Gault formula includes the subject's most recent body weight (kg) and most recent serum creatinine (Cr) concentration (mg / dL). In some embodiments, if the calculation of CrCl using the Cockcroft-Gault formula results in a value exceeding 125 mL / min, CrCl is calculated using an alternative formula according to the institution's standards or limited to 125 mL / min.

[0304] In some embodiments, PDCT includes cisplatin or carboplatin in combination with gemcitabine, paclitaxel, albumin-conjugated paclitaxel, docetaxel, pemetrexed, vinorelbine, vinblastine, etoposide, or irinotecan.

[0305] In some embodiments, PDCT, in combination with gemcitabine, contains cisplatin or carboplatin. In some embodiments, gemcitabine is approximately 1,000 mg / m² 2 From approximately 1,250 mg / m² 2 It is administered in the following dose. In some embodiments, gemcitabine is administered at approximately 1,000 mg / m². 2 , about 1,050mg / m 2 , about 1,100mg / m 2 , about 1,150mg / m 2 , about 1,200mg / m 2 , or approximately 1,250 mg / m² 2 It is administered in the following doses. In some embodiments, gemcitabine is administered intravenously over approximately 30 minutes. In some embodiments, gemcitabine is administered on days 1, 8, and 15 of a 3-week cycle for up to approximately 4, 5, or 6 cycles. In some embodiments, gemcitabine is administered on days 1 and 8 of a 3-week cycle for up to approximately 4, 5, or 6 cycles. In some embodiments, PDCT is administered intravenously for approximately 30 minutes on days 1 and 8 of a 3-week cycle for approximately 4 to 6 cycles, at a dose of approximately 1,000 mg / m². 2 From approximately 1,250 mg / m²2 of gemcitabine at a dose of about 75 mg / m administered intravenously over about 60 minutes on day 1 of each cycle 2 to about 80 mg / m 2 of cisplatin. In some embodiments, PDCT comprises about 1,000 mg / m gemcitabine administered intravenously over about 30 minutes on day 1, day 8, and day 15 of a 3-week cycle 2 of gemcitabine, and carboplatin at a dose targeting an AUC of about 5 mg / mL·min administered intravenously over about 30 minutes on day 1 of each cycle.

[0306] In some embodiments, PDCT comprises cisplatin or carboplatin in combination with paclitaxel or albumin-bound paclitaxel.

[0307] In some embodiments, PDCT comprises cisplatin or carboplatin in combination with paclitaxel. In some embodiments, paclitaxel is administered at about 45 mg / m 2 to about 200 mg / m 2 . In some embodiments, paclitaxel is dosed at about 45 mg / m 2 , about 50 mg / m 2 , about 55 mg / m 2 , about 60 mg / m 2 , about 65 mg / m 2 , about 70 mg / m 2 , about 75 mg / m 2 , about 80 mg / m 2 , about 85 mg / m 2 , about 90 mg / m 2 , about 95 mg / m 2 , about 100 mg / m 2 , about 105 mg / m 2 , about 110 mg / m 2 , about 115 mg / m 2 , about 120 mg / m 2 , about 125 mg / m 2 , about 130 mg / m 2 , about 135 mg / m 2 , about 140 mg / m 2 , about 145 mg / m 2 , about 150 mg / m2 , about 155mg / m 2 , about 160mg / m 2 , about 165mg / m 2 , about 170mg / m 2 , about 175mg / m 2 , about 180mg / m 2 , about 185mg / m 2 , about 190mg / m 2 , about 195mg / m 2 , or approximately 200 mg / m² 2 It is administered in the following doses. In some embodiments, paclitaxel is administered intravenously for about 60 to 180 minutes. In some embodiments, PDCT is administered intravenously for about 180 minutes on day 1 of a 3-week cycle for about 4 to 6 cycles at a dose of about 200 mg / m². 2 The dose of paclitaxel is administered intravenously for approximately 60 minutes on day 1 of each cycle, with a dose of approximately 75 mg / m². 2 From approximately 80 mg / m² 2 The PDCT contains a dose of cisplatin. In some embodiments, PDCT is administered intravenously for approximately 180 minutes on day 1 of a 3-week cycle, for approximately 4 to approximately 6 cycles, at a dose of approximately 135 mg / m². 2 The dose of paclitaxel is administered intravenously for approximately 60 minutes on day 1 of each cycle, with a dose of approximately 75 mg / m². 2 The PDCT contains a dose of cisplatin. In some embodiments, PDCT is administered intravenously for about 180 minutes on day 1 of a 3-week cycle, for about 4 to about 6 cycles, at a dose of about 200 mg / m². 2 The PDCT comprises a dose of paclitaxel and a dose of carboplatin with a target AUC of approximately 6 mg / mL·min, administered intravenously for approximately 30 minutes on day 1 of each cycle. In some embodiments, the PDCT is administered intravenously for approximately 7 cycles, with a dose of approximately 45 mg / m² administered intravenously for approximately 60 minutes on day 1 of each weekly cycle. 2 From approximately 50 mg / m² 2 The treatment includes a dose of paclitaxel and a dose of carboplatin with a target AUC of approximately 2 mg / mL·min, administered intravenously for approximately 30 minutes on day 1 of each cycle.

[0308] In some embodiments, PDCT contains cisplatin or carboplatin in combination with albumin-conjugated paclitaxel. In some embodiments, albumin-conjugated paclitaxel is approximately 100 mg / m². 2 It is administered in the following doses. In some embodiments, albumin-bound paclitaxel is administered intravenously for about 30 minutes. In some embodiments, PDCT is administered intravenously for about 30 minutes on days 1, 8, and 15 of a 3-week cycle for about 4 cycles, at a dose of about 100 mg / m². 2 The dose of albumin-bound paclitaxel is administered intravenously for approximately 60 minutes on day 1 of each cycle, with a dose of approximately 75 mg / m². 2 From approximately 80 mg / m² 2 It contains a dose of cisplatin. In some embodiments, PDCT is administered intravenously for about 30 minutes on days 1, 8, and 15 of a 3-week cycle at a dose of approximately 100 mg / m². 2 The treatment includes a dose of albumin-bound paclitaxel and a dose of carboplatin with a target AUC of approximately 6 mg / mL·min, administered intravenously for approximately 30 minutes on day 1 of each cycle.

[0309] In some embodiments, PDCT contains cisplatin or carboplatin in combination with docetaxel. In some embodiments, docetaxel is approximately 75 mg / m². 2 It is administered in the following doses. In some embodiments, docetaxel is administered intravenously over approximately 60 minutes. In some embodiments, PDCT is administered intravenously over approximately 60 minutes on day 1 of a 3-week cycle for approximately 4 to 6 cycles, at a dose of approximately 75 mg / m². 2 The dose of docetaxel is administered intravenously for approximately 60 minutes on day 1 of each cycle, with an additional dose of approximately 75 mg / m². 2 The PDCT contains a dose of cisplatin. In some embodiments, PDCT is administered intravenously for about 60 minutes on day 1 of a 3-week cycle, for about 4 to about 6 cycles, at a dose of about 75 mg / m². 2 The treatment includes a dose of docetaxel and a dose of carboplatin with a target AUC of approximately 6 mg / mL·min, administered intravenously for approximately 30 minutes on day 1 of each cycle.

[0310] In some embodiments, PDCT, in combination with pemetrexed, contains cisplatin or carboplatin. In some embodiments, pemetrexed is approximately 500 mg / m². 2 It is administered in the following doses. In some embodiments, pemetrexed is administered intravenously over approximately 10 minutes. In some embodiments, PDCT is administered intravenously over approximately 10 minutes on day 1 of a 3-week cycle for approximately 4 to 6 cycles, at a dose of approximately 500 mg / m². 2 The dose of pemetrexed is administered intravenously for approximately 60 minutes on day 1 of each cycle, with a dose of approximately 75 mg / m². 2 It contains a dose of cisplatin. In some embodiments, PDCT is administered intravenously for about 10 minutes on day 1 of a 3-week cycle for about 6 cycles, at a dose of about 500 mg / m². 2 The dose of pemetrexed is administered intravenously for approximately 60 minutes on day 1 of each cycle, with a dose of approximately 75 mg / m². 2 It contains a dose of cisplatin. In some embodiments, PDCT is administered intravenously for about 60 minutes on day 1 of a 3-week cycle for about 4 to about 6 cycles, at a dose of about 500 mg / m². 2 The PDCT includes a dose of pemetrexed and a dose of carboplatin with a target AUC of approximately 6 mg / mL·min, administered intravenously for approximately 30 minutes on day 1 of each cycle. In some embodiments, the PDCT is administered intravenously for approximately 60 minutes on day 1 of a 3-week cycle, for approximately 4 to approximately 6 cycles, at a dose of approximately 500 mg / m². 2 The treatment includes a dose of pemetrexed and a dose of carboplatin with a target AUC of approximately 5 mg / mL·min, administered intravenously for approximately 30 minutes on day 1 of each cycle.

[0311] In some embodiments, PDCT contains cisplatin or carboplatin in combination with etoposide. In some embodiments, etoposide is approximately 50 mg / m². 2 From approximately 100 mg / m² 2 It is administered in the following doses. In some embodiments, etoposide is administered intravenously over approximately 30 to 60 minutes. In some embodiments, PDCT is administered intravenously over approximately 60 minutes on days 1 to 3 of a 3-week cycle for approximately 4 to 6 cycles, at a dose of approximately 100 mg / m². 2The dose of etoposide is administered intravenously for approximately 60 minutes on day 1 of each cycle, with a dose of approximately 100 mg / m². 2 It contains a dose of cisplatin. In some embodiments, PDCT is administered intravenously for about 60 minutes on days 1-3 of a 4-week cycle for about 4 cycles, at a dose of about 100 mg / m². 2 The dose of etoposide is administered intravenously for approximately 60 minutes on day 1 of each cycle, with a dose of approximately 100 mg / m². 2 The PDCT contains a dose of cisplatin. In some embodiments, PDCT is administered intravenously for approximately 60 minutes on days 1-5 of a 4-week cycle, for approximately two cycles, at a dose of approximately 50 mg / m². 2 The dose of etoposide is administered intravenously for approximately 60 minutes on days 1 and 8 of each cycle, with approximately 50 mg / m² administered intravenously. 2 It contains a dose of cisplatin. In some embodiments, PDCT is administered intravenously for about 30 minutes on days 1-3 of a 3-week cycle for about 4 to about 6 cycles, at a dose of about 100 mg / m². 2 The treatment includes a dose of etoposide and a dose of carboplatin with a target AUC of approximately 5 mg / mL·min, administered intravenously for approximately 30 minutes on day 1 of each cycle.

[0312] In some embodiments, PDCT contains cisplatin and vinorelbine. In some embodiments, vinorelbine is approximately 25 mg / m². 2 From approximately 30 mg / m² 2 It is administered in the following doses. In some embodiments, vinorelbine is administered intravenously over approximately 5 to 10 minutes. In some embodiments, PDCT is administered intravenously over approximately 5 to 10 minutes on days 1 and 8 of a 3-week cycle for approximately 4 cycles, at a dose of approximately 25 mg / m². 2 From approximately 30 mg / m² 2 The dose of vinorelbine is administered intravenously for approximately 60 minutes on day 1 of each cycle, with a dose of approximately 75 mg / m². 2 From approximately 80 mg / m² 2 It contains a dose of cisplatin. In some embodiments, PDCT is administered intravenously for about 5 to 10 minutes on days 1, 8, 15, and 22 of a 4-week cycle, for about 4 cycles, at a dose of about 25 mg / m². 2The dose of vinorelbine is administered intravenously for approximately 60 minutes on days 1 and 8 of each cycle, with a dose of approximately 50 mg / m². 2 It contains a dose of cisplatin. In some embodiments, PDCT is administered intravenously for about 5 to 10 minutes on days 1, 8, 15, and 22 of a 4-week cycle, for about 4 cycles, at a dose of about 30 mg / m². 2 The dose of vinorelbine is administered intravenously for approximately 60 minutes on day 1 of each cycle, and approximately 100 mg / m² is administered intravenously. 2 Contains a dose of cisplatin.

[0313] In some embodiments, PDCT contains cisplatin and vinblastine. In some embodiments, vinblastine is approximately 5 mg / m². 2 It is administered in the following doses. In some embodiments, vinblastine is administered intravenously for about 5 to 10 minutes. In some embodiments, PDCT is administered intravenously for about 5 to 10 minutes for about 4 cycles, on days 1, 8, 15, 22, and 29 of a 4-week cycle, at a dose of about 5 mg / m². 2 Vinblastine is administered in doses of approximately 100 mg / m² intravenously over approximately 60 minutes on days 1 and 29 of the cycle. 2 Contains a dose of cisplatin.

[0314] In some embodiments, PDCT is administered in combination with bevacizumab (also known as AVASTIN®). In some embodiments, bevacizumab is administered intravenously at a dose of approximately 15 mg / kg on day 1 of each 3-week cycle for approximately 6 cycles, and paclitaxel is administered at a dose of approximately 200 mg / m² for approximately 180 minutes on day 1 of each cycle. 2 Carboplatin is administered intravenously at a dose of approximately 6 mg / mL·min with a target AUC for approximately 30 minutes on day 1 of each cycle. In some embodiments, bevacizumab is administered intravenously at a dose of approximately 15 mg / kg on day 1 of a 3-week cycle for approximately 4 to 6 cycles, and pemetrexed is administered at a dose of approximately 500 mg / m² for approximately 10 minutes on day 1 of each cycle. 2Carboplatin is administered intravenously at a dose of approximately 6 mg / mL·min with a target AUC over approximately 30 minutes on day 1 of each cycle. In some embodiments, bevacizumab is administered intravenously at a dose of approximately 7.5 mg / kg on day 1 of a 3-week cycle for approximately 4 to approximately 6 cycles, and pemetrexed is administered at a dose of approximately 500 mg / m² over approximately 10 minutes on day 1 of each cycle. 2 It is administered intravenously at a dose of approximately 75 mg / m² on day 1 of each cycle, and cisplatin is also administered intravenously at a dose of approximately 75 mg / m². 2 It is administered intravenously over approximately 60 minutes at this dose.

[0315] II.B.2. Therapeutic Agents In some embodiments, the additional therapeutic agent includes an anticancer agent. In some embodiments, the anticancer agent includes tyrosine kinase inhibitors, anti-angiogenic agents, checkpoint inhibitors, checkpoint stimulants, chemotherapeutic agents, immunotherapeutic agents, platinum agents, alkylating agents, taxanes, nucleoside analogs, antimetabolites, topoisomerase inhibitors, anthracyclines, vinca alkaloids, or any combination thereof.

[0316] In some embodiments, tyrosine kinase inhibitors include sorafenib (e.g., sorafenib tosylate, also known as NEXAVAR®), lenvatinib (e.g., lenvatinib mesylate, also known as LENVIMA®), regorafenib (e.g., STIVARGA®), cabozantinib (e.g., cabozantinib S-malate, also known as CABOMETYX®), sunitinib (e.g., sunitinib malate, also known as SUTENT®), brivanib, lini Fanib, pemigatinib (also known as PEMAZYRE®), everolimus (also known as AFINITOR® or ZORTRESS®), gefitinib (IRESSA®, a small molecule TKI of EGFR), imatinib (e.g., imatinib mesylate), lapatinib (e.g., lapatinib ditosylate, also known as TYKERB®), nilotinib (e.g., nilotinib hydrochloride, also known as TASIGNA®), pazopanib (e.g., pazopanib hydrochloride, also known as VOTRIE) (also known as NT(registered trademark)), temsirolimus (also known as TORISEL(registered trademark)), erlotinib (e.g., erlotinib hydrochloride, also known as Tarceva(registered trademark), a low-molecular-weight EGFR TKI), afatinib (GILOTRIF(registered trademark), a low-molecular-weight EGFR TKI), dacomitinib (VIZIMPRO(registered trademark), a low-molecular-weight EGFR TKI), osimeritib (TAGRISSO(registered trademark), a low-molecular-weight EGFR TKI), alectinib (ALECENSA(registered trademark), a low-molecular-weight EGFR TKI) Small molecule TKIs), ceritinib (ZYKADIA®, a small molecule TKI for ALK and ROS-1), brigatinib (ALUNBRIG®, a small molecule TKI for ALK), crizotinib (XALKORI®, a small molecule TKI for ALK and ROS-1), lorlatinib (LORBRENA®, a small molecule TKI for ALK and ROS-1), entrectinib (ROZLYTREK®, a small molecule TKI for ROS-1 and NTRK), dabrafenib (TAFINLAR®, a small molecule TKI for BRAF),This includes trametinib (MEKINIST®, a small-molecule TKI for BRAF), vemurafenib (ZELBORAF®, a small-molecule TKI for BRAF), larotrectinib (ROZLYTREK®, a small-molecule TKI for NTRK), or any combination thereof.

[0317] In some embodiments, anti-angiogenic agents include inhibitors of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase receptors having Ig-like and EGF-like domains (Tie), hepatocyte growth factor (HGF), tyrosine-protein kinase Met (c-MET), C-type lectin family 14 member A (CLEC14A), multimelin 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), EGFR, or any combination thereof. In some embodiments, the anti-angiogenic agents include bevacizumab (also known as AVASTIN®), ramucirumab (also known as CYRAMZA®), aflibercept (also known as EYLEA® or ZALTRAP®), tanibirumab, olaratumab (also known as LARTRUVO®), nesbacumab, AMG780, MEDI3617, vanucizumab, rilotumumab, ficratuzumab, TAK-701, onartuzumab, emibetuzumab, or any combination thereof.

[0318] In some embodiments, the anti-angiogenic agent is bevacizumab. In some embodiments, bevacizumab is administered at a dose of approximately 15 mg / kg. In some embodiments, bevacizumab is administered at a dose of approximately 15 mg / kg on day 1 of a 3-week cycle.

[0319] In some embodiments, the checkpoint stimulant includes agonists of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, GITR, inducible T cell costimulator (ICOS), ICOS-L, OX40, OX40L, CD70, CD27, CD40, death receptor 3 (DR3), CD28H, or any combination thereof.

[0320] In some embodiments, the chemotherapeutic agent includes alkylating agents, antimetabolites, antitumor antibiotics, mitotic inhibitors, hormones or hormone modulators, protein tyrosine kinase inhibitors, epidermal growth factor inhibitors, proteasome inhibitors, other oncological agents, or any combination thereof.

[0321] In some embodiments, the immunotherapy agent includes antibodies that specifically bind to EGFR (e.g., cetuximab (ERBITUX®)), ALK, ROS-1, NTRK, BRAF, ICOS, CD137 (4-1BB), CD134 (OX40), NKG2A, CD27, CD96, GITR, herpesvirus entry mediator (HVEM), PD-1, PD-L1, CTLA-4, BTLA, TIM-3, A2aR, killer cell lectin-like receptor G1 (KLRG-1), natural killer cell receptor 2B4 (CD244), CD160, TIGIT, VISTA, KIR, TGFβ, IL-10, IL-8, B7-H4, Fas ligand, CSF1R, CXCR4, mesothelin, CEACAM-1, CD52, HER2, MICA, MICB, or any combination thereof.

[0322] In some embodiments, the platinum agent includes cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin (e.g., triplatin tetranitrate), lipoplatin, phenanthriplatin, or any combination thereof.

[0323] In some embodiments, the alkylating agent includes altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechloretamine, melphalan, oxaliplatin, procarbazine, streptozocin, temozolomide, thiotepa, or any combination thereof.

[0324] In some embodiments, the taxane includes paclitaxel, albumin-conjugated paclitaxel (i.e., nab-paclitaxel), docetaxel, cabazitaxel, or any combination thereof.

[0325] In some embodiments, the taxane contains paclitaxel. In some embodiments, paclitaxel is administered at approximately 200 mg / m² for approximately 180 minutes on day 1 of a 3-week cycle for approximately 4 to approximately 6 cycles. 2 From approximately 225 mg / m² 2 It is administered intravenously at the dose. In some embodiments, paclitaxel is administered at approximately 80 mg / m² for approximately 60 minutes on days 1, 8, and 15 of a 4-week cycle for approximately 4 to 6 cycles. 2 It is administered intravenously in the specified dose.

[0326] In some embodiments, the taxane comprises albumin-conjugated paclitaxel. In some embodiments, albumin-conjugated paclitaxel is administered at approximately 260 mg / m² for approximately 30 minutes on day 1 of a 3-week cycle for approximately 4 to approximately 6 cycles. 2 It is administered intravenously at the dose indicated. In some embodiments, albumin-bound paclitaxel is administered at approximately 125 mg / m² for approximately 30 minutes on days 1, 8, and 15 of a 4-week cycle for approximately 4 to 6 cycles. 2 It is administered intravenously in the specified dose.

[0327] In some embodiments, the taxane contains docetaxel. In some embodiments, docetaxel is administered at approximately 75 mg / m² for approximately 60 minutes on day 1 of a 3-week cycle. 2It is administered intravenously at the dose indicated. In some embodiments, docetaxel is administered at approximately 75 mg / m² for approximately 60 minutes on day 1 of a 3-week cycle for approximately 4 to 6 cycles. 2 It is administered intravenously in the specified dose.

[0328] In some embodiments, the nucleoside analog includes cytarabine, gemcitabine, lamivudine, entecavir, terbivudine, or any combination thereof.

[0329] In some embodiments, the nucleoside analog is gemcitabine. In some embodiments, gemcitabine is administered at approximately 1,000 mg / m² for approximately 30 minutes on days 1, 8, and 15 of a 4-week cycle. 2 From approximately 1,250 mg / m² 2 It is administered intravenously at the dose. In some embodiments, gemcitabine is administered at approximately 1,000 mg / m² for approximately 30 minutes on days 1, 8, and 15 of a 4-week cycle for approximately 4 to 6 cycles. 2 From approximately 1,250 mg / m² 2 It is administered intravenously at the specified dose. In some embodiments, gemcitabine is administered at approximately 1,250 mg / m² for approximately 30 minutes on days 1 and 8 of a 3-week cycle. 2 It is administered intravenously at the specified dose. In some embodiments, gemcitabine is administered at approximately 1,250 mg / m² for approximately 30 minutes on days 1 and 8 of a 3-week cycle, for approximately 4 to 6 cycles. 2 It is administered intravenously in the specified dose.

[0330] In some embodiments, the antimetabolites include capecitabine, cladribine, clopharabine, cytarabine, furoxiuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, thioguanine, or any combination thereof.

[0331] In some embodiments, the antimetabolite is pemetrexed. In some embodiments, pemetrexed is administered at approximately 500 mg / m² for approximately 10 minutes on day 1 of a 3-week cycle. 2It is administered intravenously at the specified dose. In some embodiments, pemetrexed is administered at approximately 500 mg / m² for about 10 minutes on day 1 of a 3-week cycle for about 4 to 6 cycles. 2 It is administered intravenously in the specified dose.

[0332] In some embodiments, the topoisomerase inhibitor includes etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, camptothecin, or any combination thereof.

[0333] In some embodiments, the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, or any combination thereof.

[0334] In some embodiments, vinca alkaloids are vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vineridine, vinbrunin, or any combination thereof.

[0335] In some embodiments, the anticancer agent comprises gemcitabine and docetaxel. In some embodiments, gemcitabine is administered at approximately 1,000 mg / m² for approximately 30 minutes on days 1 and 8 of a 3-week cycle for approximately 4 to approximately 6 cycles. 2 From approximately 1,250 mg / m² 2 The dose is administered intravenously at approximately 85 mg / m² for about 30 to 60 minutes on day 1 of each cycle. 2 It is administered intravenously in the specified dose.

[0336] In some embodiments, the anticancer agent comprises gemcitabine and vinorelbine. In some embodiments, gemcitabine is administered at a dose of approximately 1,000 mg / m² for approximately 30 minutes on days 1 and 8 of a 3-week cycle for approximately 4 to approximately 6 cycles. 2 Vinorelbine is administered intravenously at a dose of approximately 25 mg / m² over approximately 5 to 10 minutes on days 1 and 8 of each cycle. 2 It is administered intravenously in the specified dose.

[0337] In some embodiments, the anticancer agents include ramucirumab and docetaxel. In some embodiments, ramucirumab is administered intravenously at a dose of approximately 10 mg / kg over approximately 60 minutes on day 1 of a 3-week cycle, and docetaxel is administered at a dose of approximately 75 mg / m² over 60 minutes on day 1 of each cycle. 2 It is administered intravenously in the specified dose.

[0338] In some embodiments, the anticancer agents include bevacizumab and pemetrexed. In some embodiments, bevacizumab is administered intravenously at a dose of approximately 7.5 mg / kg to approximately 15 mg / kg over approximately 10 minutes on day 1 of a 3-week cycle, and pemetrexed is administered at a dose of approximately 500 mg / m² over approximately 10 minutes on day 1 of each cycle. 2 It is administered intravenously in the specified dose.

[0339] II.B.3. Checkpoint Inhibitors In some embodiments, the anticancer agent administered as an additional therapeutic agent in the method of this disclosure is a checkpoint inhibitor.

[0340] In some embodiments, checkpoint inhibitors include programmed death-1 (PD-1) pathway inhibitors, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, T cell immunoglobulin and ITIM domain (TIGIT) inhibitors, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B and T cell lymphocyte attenuator (BTLA) inhibitors, and T cell Activation V-domain Ig suppressor (VISTA) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors (e.g., indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, epacadostat (INCB24360), napoximod (GDC-0919), or lindrodostat (BMS-986205) including lindrodostat salts such as lindrodostat mesylate), nicotinamide adenine dinucleotide phosphate Acid oxidase isoform 2 (NOX2) inhibitors, killer cell immunoglobulin-like receptor (KIR) inhibitors, adenosine A2a receptor (A2aR) inhibitors, transforming growth factor beta (TGF-β) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, CD47 inhibitors, CD48 inhibitors, CD73 inhibitors, CD113 inhibitors, sialic acid-binding immunoglobulin-like lectin-7 (Sigrec-7) inhibitors, Sigrec-9 inhibitors, Sigrec-15 This includes inhibitors, glucocorticoid-induced TNFR-related protein (GITR) inhibitors, galectin-1 inhibitors, galectin-9 inhibitors, carcinoembryonic antigen-associated cell adhesion molecule-1 (CEACAM-1) inhibitors, G protein-coupled receptor 56 (GPR56) inhibitors, glycoprotein A repeat dominant (GARP) inhibitors, 2B4 inhibitors, programmed death-1 homolog (PD1H) inhibitors, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitors, or any combination thereof.

[0341] In some embodiments, checkpoint inhibitors are formulated for intravenous administration.

[0342] In some embodiments, the LAG-3 antagonist and the checkpoint inhibitor are formulated separately. In some embodiments, if the checkpoint inhibitor contains more than one checkpoint inhibitor, each checkpoint inhibitor is formulated separately. In some embodiments, the checkpoint inhibitor is administered before the LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is administered before the checkpoint inhibitor.

[0343] In some embodiments, LAG-3 antagonists and checkpoint inhibitors are formulated together. In some embodiments, if the checkpoint inhibitors include more than one checkpoint inhibitor, two or more checkpoint inhibitors are formulated together.

[0344] In some embodiments, LAG-3 antagonists and checkpoint inhibitors are administered simultaneously.

[0345] In some embodiments, checkpoint inhibitors are administered in uniform doses.

[0346] In some embodiments, checkpoint inhibitors are administered in doses of at least approximately 0.25 mg to approximately 2000 mg, approximately 0.25 mg to approximately 1600 mg, approximately 0.25 mg to approximately 1200 mg, approximately 0.25 mg to approximately 800 mg, approximately 0.25 mg to approximately 400 mg, approximately 0.25 mg to approximately 100 mg, approximately 0.25 mg to approximately 50 mg, approximately 0.25 mg to approximately 40 mg, approximately 0.25 mg to approximately 30 mg, approximately 0.25 mg to approximately 20 mg, approximately 20 mg to approximately 2000 mg, approximately 20 mg to approximately 1600 mg, approximately 20 mg to approximately 1200 mg, approximately 20 mg to approximately 800 mg, approximately 20 mg to approximately 400 mg, and approximately It is administered in doses of approximately 20 mg to 100 mg, approximately 100 mg to 2000 mg, approximately 100 mg to 1800 mg, approximately 100 mg to 1600 mg, approximately 100 mg to 1400 mg, approximately 100 mg to 1200 mg, approximately 100 mg to 1000 mg, approximately 100 mg to 800 mg, approximately 100 mg to 600 mg, approximately 100 mg to 400 mg, approximately 400 mg to 2000 mg, approximately 400 mg to 1800 mg, approximately 400 mg to 1600 mg, approximately 400 mg to 1400 mg, approximately 400 mg to 1200 mg, or approximately 400 mg to 1000 mg.

[0347] According to some sources, checkpoint inhibitors are available in doses of approximately 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7 mg, 7.25 mg, 7.5 mg, 7.75 mg, 8 mg, 8.25 mg, 8.5 mg, 8.75 mg, 9 mg, 9.25 mg, 9.5 mg, and 9 mg.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 35 0mg, approx. 360mg, approx. 370mg, approx. 380mg, approx. 390mg, approx. 400mg, approx. 410mg, approx. 420mg, approx. 430mg, approx. 440mg, approx. 450mg, approx. 20mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 6 90mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 1080m It is administered in doses of approximately 1100mg, 1140mg, 1180mg, 1200mg, 1240mg, 1280mg, 1300mg, 1340mg, 1380mg, 1400mg, 1440mg, 1480mg, 1500mg, 1540mg, 1580mg, 1600mg, 1640mg, 1680mg, 1700mg, 1740mg, 1780mg, 1800mg, 1840mg, 1880mg, 1900mg, 1940mg, 1980mg, or 2000mg.

[0348] In some embodiments, checkpoint inhibitors are administered in a body weight-based dose.

[0349] In some aspects, checkpoint inhibitors are administered in doses ranging from approximately 0.003 mg / kg to approximately 25 mg / kg, approximately 0.003 mg / kg to approximately 20 mg / kg, approximately 0.003 mg / kg to approximately 15 mg / kg, approximately 0.003 mg / kg to approximately 10 mg / kg, approximately 0.003 mg / kg to approximately 5 mg / kg, approximately 0.003 mg / kg to approximately 1 mg / kg, approximately 0.003 mg / kg to approximately 0.9 mg / kg, and approximately 0.003 mg / kg to approximately 0 0.8 mg / kg, approximately 0.003 mg / kg to approximately 0.7 mg / kg, approximately 0.003 mg / kg to approximately 0.6 mg / kg, approximately 0.003 mg / kg to approximately 0.5 mg / kg, approximately 0.003 mg / kg to approximately 0.4 mg / kg, approximately 0.003 mg / kg to approximately 0.3 mg / kg, approximately 0.003 mg / kg to approximately 0.2 mg / kg, approximately 0.003 mg / kg to approximately 0.1 mg / kg, approximately 0.1 mg / kg to approximately 25 mg / kg, approximately 0 0.1 mg / kg to approximately 20 mg / kg, approximately 0.1 mg / kg to approximately 15 mg / kg, approximately 0.1 mg / kg to approximately 10 mg / kg, approximately 0.1 mg / kg to approximately 5 mg / kg, approximately 0.1 mg / kg to approximately 1 mg / kg, approximately 1 mg / kg to approximately 25 mg / kg, approximately 1 mg / kg to approximately 20 mg / kg, approximately 1 mg / kg to approximately 15 mg / kg, approximately 1 mg / kg to approximately 10 mg / kg, approximately 1 mg / kg to approximately 5 mg / kg, approximately 5 mg / kg It is administered in doses of approximately 25 mg / kg from g, approximately 20 mg / kg from approximately 5 mg / kg, approximately 15 mg / kg from approximately 5 mg / kg, approximately 10 mg / kg from approximately 10 mg / kg, approximately 25 mg / kg from approximately 10 mg / kg, approximately 20 mg / kg from approximately 10 mg / kg, approximately 15 mg / kg from approximately 15 mg / kg, approximately 25 mg / kg from approximately 15 mg / kg, or approximately 20 mg / kg from approximately 25 mg / kg.

[0350] In some aspects, checkpoint inhibitors are present in doses of approximately 0.003 mg / kg, approximately 0.004 mg / kg, approximately 0.005 mg / kg, approximately 0.006 mg / kg, approximately 0.007 mg / kg, approximately 0.008 mg / kg, approximately 0.009 mg / kg, approximately 0.01 mg / kg, approximately 0.02 mg / kg, approximately 0.03 mg / kg, approximately 0.04 mg / kg, approximately 0.05 mg / kg, approximately 0.06 mg / kg, approximately 0.07 mg / kg, approximately 0.08 mg / kg, approximately 0.09 mg / kg, approximately 0.1 mg / kg, approximately 0.2 mg / kg, approximately 0.3 mg / kg, approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 0.6 mg / kg, approximately 0.7 mg / kg, approximately 0.8 mg / kg, approximately It is administered in doses of 0.9 mg / kg, approximately 1.0 mg / kg, approximately 2.0 mg / kg, approximately 3.0 mg / kg, approximately 4.0 mg / kg, approximately 5.0 mg / kg, approximately 6.0 mg / kg, approximately 7.0 mg / kg, approximately 8.0 mg / kg, approximately 9.0 mg / kg, approximately 10.0 mg / kg, approximately 11.0 mg / kg, approximately 12.0 mg / kg, approximately 13.0 mg / kg, approximately 14.0 mg / kg, approximately 15.0 mg / kg, approximately 16.0 mg / kg, approximately 17.0 mg / kg, approximately 18.0 mg / kg, approximately 19.0 mg / kg, approximately 20.0 mg / kg, approximately 21.0 mg / kg, approximately 22.0 mg / kg, approximately 23.0 mg / kg, approximately 24.0 mg / kg, or approximately 25.0 mg / kg.

[0351] In some aspects, the checkpoint inhibitor dose is administered every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every nine weeks, every ten weeks, every eleven weeks, or every twelve weeks.

[0352] In some embodiments, each dose of the LAG-3 antagonist and / or checkpoint inhibitor is administered in a fixed amount.

[0353] In some embodiments, each dose of the LAG-3 antagonist and / or checkpoint inhibitor is administered in varying amounts. For example, in some embodiments, the maintenance (or continuing) dose of the LAG-3 antagonist and / or checkpoint inhibitor may be higher than or equal to the initial loading dose. In some embodiments, the maintenance dose of the LAG-3 antagonist and / or checkpoint inhibitor may be lower than or equal to the loading dose.

[0354] II.B.3.a. PD-1 pathway inhibitors In some embodiments, the checkpoint inhibitors for use in the methods of this disclosure include PD-1 pathway inhibitors.

[0355] In some embodiments, PD-1 pathway inhibitors are PD-1 inhibitors and / or PD-L1 inhibitors.

[0356] In some embodiments, PD-1 inhibitors and / or PD-L1 inhibitors are small molecules.

[0357] In some embodiments, PD-1 inhibitors and / or PD-L1 inhibitors are miramolecules.

[0358] In some embodiments, PD-1 inhibitors and / or PD-L1 inhibitors are macrocyclic peptides.

[0359] In a particular embodiment, the PD-1 inhibitor and / or PD-L1 inhibitor is BMS-986189.

[0360] In some embodiments, the PD-1 inhibitor is an inhibitor disclosed in International Publication WO2014 / 151634, which is incorporated herein by reference in its entirety.

[0361] In some embodiments, the PD-1 inhibitor is INCMGA00012 (Insight Pharmaceuticals).

[0362] In some embodiments, the PD-1 inhibitor includes a combination of an anti-PD-1 antibody and a PD-1 small molecule inhibitor as disclosed herein.

[0363] In some embodiments, PD-L1 inhibitors are expressed by formula (I): [ka] It includes a miramolecule having the formula described above, in which R 1 ~R 13 R is an amino acid side chain. a ~R n is hydrogen, methyl, or forms a ring with a vicinal R group, R 14 is -C(O)NHR 15 And R 15 is either hydrogen or a glycine residue that may optionally be substituted with an additional glycine residue and / or a tail that can improve pharmacokinetic properties. In some embodiments, the PD-L1 inhibitor includes compounds disclosed in International Publication WO2014 / 151634, which is incorporated herein by reference in its entirety. In some embodiments, the PD-L1 inhibitors include compounds disclosed in International Publications WO2016 / 039749, WO2016 / 149351, WO2016 / 077518, WO2016 / 100285, WO2016 / 100608, WO2016 / 126646, WO2016 / 057624, WO2017 / 151830, WO2017 / 176608, WO2018 / 085750, WO2018 / 237153, or WO2019 / 070643, which are incorporated herein by reference in their entirety.

[0364] In some embodiments, the PD-L1 inhibitors include small molecule PD-L1 inhibitors disclosed in International Publications WO2015 / 034820, WO2015 / 160641, WO2018 / 044963, WO2017 / 066227, WO2018 / 009505, WO2018 / 183171, WO2018 / 118848, WO2019 / 147662, or WO2019 / 169123, each of which is incorporated herein by reference in whole.

[0365] In some embodiments, the PD-1 pathway inhibitor is a soluble PD-L2 polypeptide. In some embodiments, the soluble PD-L2 polypeptide is a fusion polypeptide. In some embodiments, the soluble PD-L2 polypeptide comprises a ligand-binding fragment of the PD-L2 extracellular domain. In some embodiments, the soluble PD-L2 polypeptide further comprises a half-life-extending moiety. In some embodiments, the half-life-extending moiety comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin-binding polypeptide, immunoglobulin G (IgG), an albumin-binding polypeptide (ABP), a PAS-modified moiety, a HES-modified moiety, an XTEN, a pegylated moiety, an Fc region, or any combination thereof. In some embodiments, the soluble PD-L2 polypeptide is AMP-224 (see, for example, US2013 / 0017199).

[0366] In some embodiments, PD-1 pathway inhibitors are anti-PD-1 antibodies and / or anti-PD-L1 antibodies.

[0367] II.B.3.ai anti-PD-1 antibody Anti-PD-1 antibodies known in the industry can be used in the methods of this disclosure. Various human monoclonal antibodies that bind specifically to PD-1 with high affinity are disclosed in U.S. Patent No. 8,008,449. The anti-PD-1 human antibodies disclosed in U.S. Patent No. 8,008,449 have the following characteristics: (a) When determined by surface plasmon resonance using the Biacore biosensor system, they bind to 1 × 10⁻¹⁶ -7 M or less K D(b) binding to human PD-1; (c) substantially not binding to human CD28, CTLA-4, or ICOS; (d) increasing T cell proliferation in a mixed lymphocyte reaction (MLR) assay; (e) increasing interferon-γ production in an MLR assay; (f) increasing IL-2 secretion in an MLR assay; (g) binding to human PD-1 and cynomolgus monkey PD-1; (h) inhibiting the binding of PD-L1 and / or PD-L2 to PD-1; (i) stimulating an antigen-specific memory response; (j) stimulating an antibody response; and (j) inhibiting tumor cell proliferation in vivo. Suitable anti-PD-1 antibodies for use in the disclosure of the present invention include monoclonal antibodies that specifically bind to human PD-1 and represent at least one, and in some embodiments at least five, of the aforementioned features.

[0368] Other anti-PD-1 monoclonal antibodies that can be used in the methods of this disclosure include, for example, U.S. Patents 6,808,710, 7,488,802, 8,168,757 and 8,354,509, U.S. Patent Publication 2016 / 0272708, and PCT Publications WO2012 / 145493, WO2008 / 156712, WO2015 / 112900, WO2012 / 145493, WO2015 / 112800, WO2014 / 206107, WO2015 / 35606, WO2015 / 085847, WO2014 / 179664, WO2017 / 020291, WO2017 / 020858, WO2 016 / 197367, WO2017 / 024515, WO2017 / 025051, WO2017 / 123557, WO2016 / 106159, W O2014 / 194302, WO2017 / 040790, WO2017 / 133540, WO2017 / 132827, WO2017 / 024465 These are described in WO2017 / 025016, WO2017 / 106061, WO2017 / 19846, WO2017 / 024465, WO2017 / 025016, WO2017 / 132825, and WO2017 / 133540, each of which is incorporated in whole by reference.

[0369] Anti-PD-1 antibodies that can be used in the methods of this disclosure include nivolumab (also known as OPDIVO®, 5C4, BMS-936558, MDX-1106, and ONO-4538), pembrolizumab (Merck; also known as Keytruda®, lambrolizumab, and MK3475; see WO2008 / 156712), PDR001 (Novartis; also known as spartalizumab; see WO2015 / 112900 and U.S. Patent No. 9,683,048), MEDI-0680 (AstraZeneca; also known as AMP-514; see WO2012 / 145493), and TSR-042 (Tesaro Biopharmaceutical; also known as ANB011 or dostallimab; see WO2014 / 179664), semiprimab (Regeneron; also known as LIBTAYO® or REGN2810; see WO2015 / 112800 and U.S. Patent No. 9,987,500), JS001 (TAIZHOU JUNSHI PHARMA; also known as tripalimab; Si-Yang Liu et al.) See al., J. Hematol. Oncol. 10:136 (2017), PF-06801591 (Pfizer; also known as sasanlimab; US2016 / 0159905), BGB-A317 (Beigene; also known as tisrelizumab; see WO2015 / 35606 and US2015 / 0079109), BI754091 (Boehringer Ingelheim; Zettl M et al., Cancer. Res. (2018); 78(13Suppl): Abstract 4558), INCSHR1210 (Jiangsu Hengrui Medicine; also known as SHR-1210 or camrelizumab; WO2015 / 085847; Si-Yang Liu et See al., J. Hematol. Oncol. 10:136 (2017), GLS-010 (Wuxi / Harbin Gloria Pharmaceuticals; also known as WBP3055; Si-Yang Liu et al., J. Hematol. Oncol.)See 10:136 (2017), AM-0001 (Armo), STI-1110 (Sorrento Therapeutics; see WO2014 / 194302), AGEN2034 (Agenus; see WO2017 / 040790), MGA012 (Macrogenics, see WO2017 / 19846), BCD-100 (Biocad; Kaplon et al., mAbs 10(2):183-203 (2018), IBI308 (Innovent; also known as cintirimab; see WO2017 / 024465, WO2017 / 025016, WO2017 / 132825, and WO2017 / 133540), and SSI-361 (Lyvgen Biopharma Holdings Limited (US2018 / 0346569) is one example.

[0370] Other anti-PD-1 antibodies that can be used in the methods of this disclosure include isolated antibodies that specifically bind to human PD-1 and cross-compete with any of the anti-PD-1 antibodies disclosed herein for binding to human PD-1, such as nivolumab (see, e.g., U.S. Patents 8,008,449 and 8,779,105; WO2013 / 173223). In some embodiments, the anti-PD-1 antibody binds to the same epitope as any of the anti-PD-1 antibodies described herein, such as nivolumab.

[0371] In some embodiments, antibodies that cross-compete with any of the anti-PD-1 antibodies disclosed herein for binding to human PD-1, or antibodies that bind to the same epitope region as any of the anti-PD-1 antibodies disclosed herein, such as nivolumab, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0372] Other examples of anti-PD-1 antibodies that can be used in the method of this disclosure include the antigen-binding sites of any of the full-length antibodies described above.

[0373] The anti-PD-1 antibodies that can be used in the methods disclosed herein are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and / or PD-L2, and inhibit the immunosuppressive effect of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, the anti-PD-1 "antibody" includes an antigen-binding site or fragment that exhibits functional properties similar to those of the whole antibody in that it binds to the PD-1 receptor, inhibits ligand binding, and upmodulates the immune system. In certain embodiments, the anti-PD-1 antibody or its antigen-binding site cross-competes with nivolumab for binding to human PD-1.

[0374] In some embodiments, the anti-PD-1 antibody is a full-length antibody. In some embodiments, the anti-PD-1 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is DART, DVD-Ig, or a bispecific antibody.

[0375] In some embodiments, the anti-PD-1 antibody is an F(ab')2 fragment, Fab' fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment, or single-chain linked polypeptide.

[0376] In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, semiprimab, JS001, PF-06801591, BGB-A317, BI754091, INCSHR1210, GLS-010, AM-001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, SSI-361, or contains the antigen-binding moiety thereof.

[0377] In some embodiments, anti-PD-1 antibodies are formulated for intravenous administration.

[0378] In some embodiments, the anti-PD-1 antibody is administered intravenously over a period of approximately 30 minutes.

[0379] In some embodiments, the anti-PD-1 antibody is nivolumab. Nivolumab is a fully human IgG4(S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the downregulation of antitumor T cell function (U.S. Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9):846-56).

[0380] In some embodiments, nivolumab is administered in a uniform dose of approximately 240 mg once every two weeks. In some embodiments, nivolumab is administered in a uniform dose of approximately 240 mg once every three weeks. In some embodiments, nivolumab is administered in a uniform dose of approximately 360 mg once every three weeks. In some embodiments, nivolumab is administered in a uniform dose of approximately 480 mg once every four weeks.

[0381] In some embodiments, nivolumab is administered intravenously at a dose of approximately 240 mg over approximately 30 minutes on day 1 of a two-week cycle.

[0382] In some embodiments, nivolumab is administered intravenously at a dose of approximately 480 mg over approximately 30 minutes on day 1 of a 4-week cycle.

[0383] In some embodiments, the method of the present disclosure includes an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 13, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 14.

[0384] In some embodiments, the method of the present disclosure comprises an anti-PD-1 antibody comprising (a) a heavy chain variable region CDR1 comprising the sequence described in SEQ ID NO: 15; (b) a heavy chain variable region CDR2 comprising the sequence described in SEQ ID NO: 16; (c) a heavy chain variable region CDR3 comprising the sequence described in SEQ ID NO: 17; (d) a light chain variable region CDR1 comprising the sequence described in SEQ ID NO: 18; (e) a light chain variable region CDR2 comprising the sequence described in SEQ ID NO: 19; and (f) a light chain variable region CDR3 comprising the sequence described in SEQ ID NO: 20.

[0385] In some embodiments, the method of the present disclosure includes an anti-PD-1 antibody comprising a heavy chain and a light chain variable region comprising the sequences described in SEQ ID NOs: 13 and 14, respectively.

[0386] In some embodiments, the method of the present disclosure includes an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs: 11 and 12, respectively.

[0387] In some embodiments, the method of the present disclosure includes a combination of relatrimab and nivolumab.

[0388] In some embodiments, the method of the present disclosure includes (a) an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 3, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 4; and (b) an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 13, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 14.

[0389] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively, and (b) an anti-PD-1 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, respectively.

[0390] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising heavy chain and light chain variable regions comprising the sequences described in SEQ ID NOs: 3 and 4, respectively, and (b) an anti-PD-1 antibody comprising heavy chain and light chain variable regions comprising the sequences described in SEQ ID NOs: 13 and 14, respectively.

[0391] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs: 1 and 2, respectively, and (b) an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs: 11 and 12, respectively.

[0392] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 21 and 2, respectively, and (b) an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 11 and 12, respectively.

[0393] In some embodiments, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 (S228P) antibody directed at the human cell surface receptor PD-1. Pembrolizumab is described, for example, in U.S. Patent Nos. 8,354,509 and 8,900,587.

[0394] In some embodiments, pembrolizumab is administered in a uniform dose of approximately 200 mg once every two weeks. In some embodiments, pembrolizumab is administered in a uniform dose of approximately 200 mg once every three weeks. In some embodiments, pembrolizumab is administered in a uniform dose of approximately 400 mg once every six weeks. In some embodiments, pembrolizumab is administered in a uniform dose of approximately 300 mg once every four to five weeks.

[0395] In some embodiments, pembrolizumab is administered intravenously at a dose of approximately 200 mg on day 1, and then once every approximately 3 weeks thereafter. In some embodiments, pembrolizumab is administered for up to 35 cycles. In some embodiments, pembrolizumab is administered intravenously at a dose of approximately 200 mg over approximately 30 minutes on day 1 of each 3-week cycle, for up to 35 cycles.

[0396] In some embodiments, pembrolizumab is administered intravenously at a dose of approximately 200 mg over approximately 30 minutes on day 1 of each 3-week cycle, for up to 35 cycles, while pemetrexed is administered at a dose of approximately 500 mg / m² over approximately 10 minutes on day 1 of each cycle. 2 It is administered intravenously at the above dose, followed by approximately 500 mg / m² intravenously on day 1 of the 3-week cycle. 2 Maintenance therapy with a dose of pemetrexed is administered. In some embodiments, maintenance therapy is continued until disease progression or unacceptable toxicity occurs.

[0397] In some embodiments, pembrolizumab is administered intravenously at a dose of approximately 200 mg over approximately 30 minutes on day 1 of a 3-week cycle for approximately 4 to 6 cycles, while pemetrexed is administered at a dose of approximately 500 mg / m² over approximately 10 minutes on day 1 of each cycle. 2 Carboplatin is administered intravenously at a dose of approximately 5 mg / mL·min with a target AUC for approximately 30 minutes on day 1 of each cycle.

[0398] In some embodiments, pembrolizumab is administered intravenously at a dose of approximately 200 mg over approximately 30 minutes on day 1 of a 3-week cycle for approximately 4 to 6 cycles, while pemetrexed is administered at a dose of approximately 500 mg / m² over approximately 10 minutes on day 1 of each cycle. 2 It is administered intravenously at a dose of approximately 75 mg / m² on day 1 of each cycle, and cisplatin is also administered intravenously at a dose of approximately 75 mg / m². 2 It is administered intravenously over approximately 60 minutes at this dose.

[0399] In some embodiments, pembrolizumab is administered intravenously at a dose of approximately 200 mg for approximately 30 minutes on day 1 of each 3-week cycle for approximately 4 cycles, while albumin-bound paclitaxel is administered at approximately 100 mg / m² for approximately 30 minutes on days 1, 8, and 15 of each cycle. 2 Carboplatin is administered intravenously at a dose of approximately 6 mg / mL·min with a target AUC for approximately 30 minutes on day 1 of each cycle.

[0400] In some embodiments, pembrolizumab is administered intravenously at a dose of approximately 200 mg for approximately 30 minutes on day 1 of each 3-week cycle for approximately 4 cycles, while paclitaxel is administered at a dose of approximately 200 mg / m² for approximately 180 minutes on day 1 of each cycle. 2 Carboplatin is administered intravenously at a dose of approximately 6 mg / mL·min with a target AUC for approximately 30 minutes on day 1 of each cycle.

[0401] In some embodiments, pembrolizumab is administered intravenously at a dose of approximately 200 mg for approximately 30 minutes on day 1 of each 3-week cycle for approximately 4 cycles, while albumin-bound paclitaxel is administered at approximately 100 mg / m² for approximately 30 minutes on days 1, 8, and 15 of each cycle. 2 It is administered intravenously at a dose of approximately 75 mg / m² on day 1 of each cycle, and cisplatin is also administered intravenously at a dose of approximately 75 mg / m². 2 From approximately 80 mg / m² 2 It is administered intravenously over approximately 60 minutes at this dose.

[0402] In some embodiments, pembrolizumab is administered intravenously at a dose of approximately 200 mg for approximately 30 minutes on day 1 of each 3-week cycle for approximately 4 cycles, while paclitaxel is administered at a dose of approximately 200 mg / m² for approximately 180 minutes on day 1 of each cycle. 2 It is administered intravenously at a dose of approximately 75 mg / m² on day 1 of each cycle, and cisplatin is also administered intravenously at a dose of approximately 75 mg / m². 2 From approximately 80 mg / m² 2 It is administered intravenously over approximately 60 minutes at this dose.

[0403] In some embodiments, the method of the present disclosure includes an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 79, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 80.

[0404] In some embodiments, the method of the present disclosure comprises an anti-PD-1 antibody comprising (a) a heavy chain variable region CDR1 comprising the sequence described in SEQ ID NO: 81; (b) a heavy chain variable region CDR2 comprising the sequence described in SEQ ID NO: 82; (c) a heavy chain variable region CDR3 comprising the sequence described in SEQ ID NO: 83; (d) a light chain variable region CDR1 comprising the sequence described in SEQ ID NO: 84; (e) a light chain variable region CDR2 comprising the sequence described in SEQ ID NO: 85; and (f) a light chain variable region CDR3 comprising the sequence described in SEQ ID NO: 86.

[0405] In some embodiments, the method of the present disclosure includes an anti-PD-1 antibody comprising a heavy chain and a light chain variable region comprising the sequences described in SEQ ID NOs. 79 and 80, respectively.

[0406] In some embodiments, the method of the present disclosure includes an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 77 and 78, respectively.

[0407] In some embodiments, the method of this disclosure includes a combination of fabezerimab and pembrolizumab. In some embodiments, 800 mg of fabezerimab and 200 mg of pembrolizumab are administered intravenously on day 1, and thereafter once every approximately 3 weeks. In some embodiments, the combination of fabezerimab and pembrolizumab is administered for up to 35 cycles. In some embodiments, 800 mg of fabezerimab and 200 mg of pembrolizumab are administered intravenously for approximately 30 minutes on day 1 of a 3-week cycle, for up to 35 cycles.

[0408] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 69, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 70; and (b) an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 79, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 80.

[0409] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 71, SEQ ID NO: 72, and SEQ ID NO: 73, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 74, SEQ ID NO: 75, and SEQ ID NO: 76, respectively, and (b) an anti-PD-1 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 81, SEQ ID NO: 82, and SEQ ID NO: 83, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 84, SEQ ID NO: 85, and SEQ ID NO: 86, respectively.

[0410] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising heavy chain and light chain variable regions comprising the sequences described in SEQ ID NOs. 69 and 70, respectively, and (b) an anti-PD-1 antibody comprising heavy chain and light chain variable regions comprising the sequences described in SEQ ID NOs. 79 and 80, respectively.

[0411] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 67 and 68, respectively, and (b) an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 77 and 78, respectively.

[0412] In some embodiments, the anti-PD-1 antibody is cemiprimab (REGN2810). Cemiprimab is described, for example, in WO2015 / 112800 and U.S. Patent No. 9,987,500.

[0413] In some embodiments, semiprimab is administered intravenously once every three weeks at a dose of approximately 3 mg / kg or approximately 350 mg.

[0414] In some embodiments, the method of the present disclosure includes an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 35, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 36.

[0415] In some embodiments, the method of the present disclosure comprises an anti-PD-1 antibody comprising (a) a heavy chain variable region CDR1 comprising the sequence described in SEQ ID NO: 37; (b) a heavy chain variable region CDR2 comprising the sequence described in SEQ ID NO: 38; (c) a heavy chain variable region CDR3 comprising the sequence described in SEQ ID NO: 39; (d) a light chain variable region CDR1 comprising the sequence described in SEQ ID NO: 40; (e) a light chain variable region CDR2 comprising the sequence described in SEQ ID NO: 41; and (f) a light chain variable region CDR3 comprising the sequence described in SEQ ID NO: 42.

[0416] In some embodiments, the method of the present disclosure includes an anti-PD-1 antibody comprising a heavy chain and a light chain variable region comprising the sequences described in SEQ ID NOs. 35 and 36, respectively.

[0417] In some embodiments, the method of the present disclosure includes an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 33 and 34, respectively.

[0418] In some embodiments, the method of the present disclosure includes a combination of fianlimab and semiprimab.

[0419] In some embodiments, the method of the present disclosure includes (a) an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 25, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 26; and (b) an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 35, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 36.

[0420] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 27, SEQ ID NO: 28, and SEQ ID NO: 29, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 30, SEQ ID NO: 31, and SEQ ID NO: 32, respectively, and (b) an anti-PD-1 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively.

[0421] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising heavy chain and light chain variable regions comprising the sequences described in SEQ ID NOs. 25 and 26, respectively, and (b) an anti-PD-1 antibody comprising heavy chain and light chain variable regions comprising the sequences described in SEQ ID NOs. 35 and 36, respectively.

[0422] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 23 and 24, respectively, and (b) an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 33 and 34, respectively.

[0423] In some embodiments, the anti-PD-1 antibody is spartalizumab (PDR001). Spartalizumab is described, for example, in WO2015 / 112900 and U.S. Patent No. 9,683,048.

[0424] In some embodiments, spartalizumab is administered intravenously at a dose of approximately 300 mg once every three weeks, or at a dose of 400 mg once every four weeks.

[0425] In some embodiments, the method of the present disclosure includes an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 59, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 60.

[0426] In some embodiments, the method of the present disclosure comprises an anti-PD-1 antibody comprising (a) a heavy chain variable region CDR1 comprising the sequence described in SEQ ID NO: 61; (b) a heavy chain variable region CDR2 comprising the sequence described in SEQ ID NO: 62; (c) a heavy chain variable region CDR3 comprising the sequence described in SEQ ID NO: 63; (d) a light chain variable region CDR1 comprising the sequence described in SEQ ID NO: 64; (e) a light chain variable region CDR2 comprising the sequence described in SEQ ID NO: 65; and (f) a light chain variable region CDR3 comprising the sequence described in SEQ ID NO: 66.

[0427] In some embodiments, the method of the present disclosure includes an anti-PD-1 antibody comprising a heavy chain and a light chain variable region comprising the sequences described in SEQ ID NOs. 59 and 60, respectively.

[0428] In some embodiments, the method of the present disclosure includes an anti-PD-1 antibody comprising a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 57 and 58, respectively.

[0429] In some embodiments, the method of this disclosure includes a combination of ieramirimab and spartalizumab. In some embodiments, ieramirimab is administered intravenously at a dose of approximately 400 mg once every three weeks, and spartalizumab is administered intravenously at a dose of approximately 300 mg once every three weeks. In some embodiments, ieramirimab is administered intravenously at a dose of approximately 600 mg once every four weeks, and spartalizumab is administered intravenously at a dose of approximately 400 mg once every four weeks.

[0430] In some embodiments, the method of the present disclosure includes (a) an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 47, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 49; and (b) an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 59, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 60.

[0431] In some embodiments, the method of the present disclosure includes (a) an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 48, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 50; and (b) an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence described in SEQ ID NO: 59, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence described in SEQ ID NO: 60.

[0432] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 51, SEQ ID NO: 52, and SEQ ID NO: 53, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 54, SEQ ID NO: 55, and SEQ ID NO: 56, respectively, and (b) an anti-PD-1 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 61, SEQ ID NO: 62, and SEQ ID NO: 63, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences described in SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 66, respectively.

[0433] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising heavy chain and light chain variable regions comprising the sequences described in SEQ ID NOs. 47 and 49, respectively, and (b) an anti-PD-1 antibody comprising heavy chain and light chain variable regions comprising the sequences described in SEQ ID NOs. 59 and 60, respectively.

[0434] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising heavy chain and light chain variable regions comprising the sequences described in SEQ ID NOs. 48 and 50, respectively, and (b) an anti-PD-1 antibody comprising heavy chain and light chain variable regions comprising the sequences described in SEQ ID NOs. 59 and 60, respectively.

[0435] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 43 and 45, respectively, and (b) an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 57 and 58, respectively.

[0436] In some embodiments, the method of the present disclosure comprises (a) an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 44 and 46, respectively, and (b) an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences described in SEQ ID NOs. 57 and 58, respectively.

[0437] A method for treating a human subject with lung cancer is provided herein, comprising administering (a) an anti-LAG-3 antibody and (b) an anti-PD-1 antibody to the subject.

[0438] In some embodiments, this method further includes administering the method to patients with PDCT.

[0439] A method for treating a human subject with stage IV or recurrent NSCLC having a squamous epithelial tissue structure is provided herein, comprising administering (a) an anti-LAG-3 antibody, (b) an anti-PD-1 antibody, and (c) PDCT to the subject.

[0440] A method for treating a human subject with stage IV or recurrent NSCLC having a non-squamous tissue structure is provided herein, comprising administering (a) an anti-LAG-3 antibody, (b) an anti-PD-1 antibody, and (c) PDCT to the subject.

[0441] Anti-LAG-3 antibodies and anti-PD-1 antibodies may be administered in any dose or combination of doses as described herein.

[0442] In some embodiments, the dose of the anti-LAG-3 antibody is 80 mg.

[0443] In some embodiments, the dose of the anti-LAG-3 antibody is 160 mg.

[0444] In some embodiments, the dose of the anti-LAG-3 antibody is 360 mg.

[0445] In some embodiments, the dose of the anti-LAG-3 antibody is 480 mg.

[0446] In some embodiments, the dose of the anti-LAG-3 antibody is 720 mg.

[0447] In some embodiments, the dose of the anti-LAG-3 antibody is 800 mg.

[0448] In some embodiments, the dose of the anti-LAG-3 antibody is 960 mg.

[0449] In some embodiments, the dose of the anti-PD-1 antibody is 200 mg.

[0450] In some embodiments, the dose of the anti-PD-1 antibody is 240 mg.

[0451] In some embodiments, the dose of the anti-PD-1 antibody is 360 mg.

[0452] In some embodiments, the dose of the anti-PD-1 antibody is 480 mg.

[0453] In some embodiments, the dose of the anti-LAG-3 antibody is 80 mg, and the dose of the anti-PD-1 antibody is 240 mg.

[0454] In some embodiments, the dose of the anti-LAG-3 antibody is 160 mg, and the dose of the anti-PD-1 antibody is 480 mg.

[0455] In some embodiments, the dose of the anti-LAG-3 antibody is 360 mg, and the dose of the anti-PD-1 antibody is 360 mg.

[0456] In some embodiments, the dose of the anti-LAG-3 antibody is 480 mg, and the dose of the anti-PD-1 antibody is 480 mg.

[0457] In some embodiments, the dose of the anti-LAG-3 antibody is 720 mg, and the dose of the anti-PD-1 antibody is 360 mg.

[0458] In some embodiments, the dose of the anti-LAG-3 antibody is 800 mg, and the dose of the anti-PD-1 antibody is 200 mg.

[0459] In some embodiments, the dose of the anti-LAG-3 antibody is 960 mg, and the dose of the anti-PD-1 antibody is 480 mg.

[0460] A method for treating a human subject with lung cancer is provided herein, comprising administering to the subject an anti-LAG-3 antibody at a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4, and (b) an anti-PD-1 antibody at a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14.

[0461] A method for treating a human subject with lung cancer is provided herein, comprising administering to the subject an anti-LAG-3 antibody at a dose of approximately 720 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4, and (b) an anti-PD-1 antibody at a dose of approximately 360 mg, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14.

[0462] A method for treating human subjects with stage IV or recurrent NSCLC having a squamous epithelial tissue structure, comprising: (a) an anti-LAG-3 antibody in a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody in a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c) (i) carboplatin in a dose with an area under the target concentration-time curve of approximately 6 mg / mL·min and (ii) approximately 200 mg / m² 2A method is provided herein that is a first-line therapy comprising administering a dose of paclitaxel to patients with PDCT.

[0463] A method for treating human subjects with stage IV or recurrent NSCLC having a squamous epithelial tissue structure, comprising: (a) an anti-LAG-3 antibody in a dose of approximately 720 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody in a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c) (i) carboplatin in a dose with an area under the target concentration-time curve of approximately 6 mg / mL·min and (ii) approximately 200 mg / m² 2 A method is provided herein that is a first-line therapy comprising administering a dose of paclitaxel to patients with PDCT.

[0464] A method for treating human subjects with stage IV or recurrent NSCLC having a squamous epithelial tissue structure, comprising: (a) an anti-LAG-3 antibody at a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody at a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c) (i) carboplatin at a dose with an area under the target concentration-time curve of approximately 6 mg / mL·min and (ii) approximately 100 mg / m² 2 A method is provided herein that is a first-line therapy comprising administering a PDCT containing a dose of paclitaxel.

[0465] A method for treating human subjects with stage IV or recurrent NSCLC having a squamous epithelial tissue structure, comprising: (a) an anti-LAG-3 antibody in a dose of approximately 720 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody in a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c) (i) carboplatin in a dose with an area under the target concentration-time curve of approximately 6 mg / mL·min and (ii) approximately 100 mg / m² 2 A method is provided herein that is a first-line therapy comprising administering a dose of albumin-bound paclitaxel to patients with PDCT.

[0466] A method for treating human subjects with stage IV or recurrent NSCLC having a non-squamous tissue structure, comprising: (a) an anti-LAG-3 antibody in a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody in a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c) (i) carboplatin in a dose with an area under the target concentration-time curve of approximately 5 mg / mL·min or approximately 6 mg / mL·min and (ii) approximately 500 mg / m² 2 A method is provided herein that is a first-line therapy comprising administering a dose of pemetrexed to patients with PDCT.

[0467] A method for treating human subjects with stage IV or recurrent NSCLC having a non-squamous tissue structure, comprising: (a) an anti-LAG-3 antibody in a dose of approximately 720 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody in a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c) (i) carboplatin in a dose with an area under the target concentration-time curve of approximately 5 mg / mL·min or approximately 6 mg / mL·min and (ii) approximately 500 mg / m² 2 A method is provided herein that is a first-line therapy comprising administering a dose of pemetrexed to patients with PDCT.

[0468] A method for treating human subjects with stage IV or recurrent NSCLC having a non-squamous tissue structure, comprising: (a) an anti-LAG-3 antibody in a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody in a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c)(i) approximately 75 mg / m² 2 (ii) a dose of cisplatin and (ii) approximately 500 mg / m² 2 A method is provided herein that is a first-line therapy comprising administering a dose of pemetrexed to patients with PDCT.

[0469] A method for treating human subjects with stage IV or recurrent NSCLC having a non-squamous tissue structure, comprising: (a) an anti-LAG-3 antibody in a dose of approximately 720 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 4; (b) an anti-PD-1 antibody in a dose of approximately 360 mg, containing the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence described in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence described in SEQ ID NO: 14; and (c)(i) approximately 75 mg / m² 2 (ii) a dose of cisplatin and (ii) approximately 500 mg / m² 2 A method is provided herein that is a first-line therapy comprising administering a dose of pemetrexed to patients with PDCT.

[0470] In some embodiments, anti-LAG-3 antibodies and anti-PD-1 antibodies are administered once every three weeks. In some embodiments, anti-LAG-3 antibodies and anti-PD-1 antibodies are administered on day 1 of each three-week cycle.

[0471] In some embodiments, the anti-LAG-3 antibody is administered intravenously over a period of approximately 30 minutes.

[0472] In some embodiments, the anti-PD-1 antibody is administered intravenously over a period of approximately 30 minutes.

[0473] In some embodiments, the composition comprising an anti-LAG-3 antibody and an anti-PD-1 antibody is administered intravenously for about 30 minutes.

[0474] In some embodiments, the anti-LAG-3 antibody and the anti-PD-1 antibody are administered intravenously from a single infusion bag over a period of approximately 30 minutes.

[0475] In some embodiments, PDCT is administered every three weeks. In some embodiments, PDCT is administered in three-week cycles for up to approximately four cycles.

[0476] In some embodiments, anti-LAG-3 antibodies and anti-PD-1 antibodies are administered prior to PDCT.

[0477] In some embodiments, PDCT comprises carboplatin and paclitaxel. In some embodiments, paclitaxel is administered for approximately 180 minutes on day 1 of each cycle, followed by intravenous administration of carboplatin for approximately 30 minutes on day 1 of each cycle. In some embodiments, NSCLC has a squamous epithelial tissue structure.

[0478] In some embodiments, PDCT comprises carboplatin and albumin-conjugated paclitaxel. In some embodiments, albumin-conjugated paclitaxel is administered for approximately 30 minutes on days 1, 8, and 15 of each cycle, followed by intravenous administration of carboplatin for approximately 30 minutes on day 1 of each cycle. In some embodiments, NSCLC has a squamous epithelial tissue structure.

[0479] In some embodiments, PDCT comprises carboplatin and pemetrexed. In some embodiments, pemetrexed is administered intravenously for approximately 10 minutes on day 1 of each cycle, followed by carboplatin administered intravenously for approximately 30 minutes on day 1 of each cycle. In some embodiments, pemetrexed is administered at a maintenance dose alone or in combination with anti-LAG-3 and anti-PD-1 antibodies in subjects with stable disease or response after approximately four 3-week cycles of PDCT. In some embodiments, the maintenance dose of pemetrexed is 500 mg / m². 2 In some embodiments, the maintenance dose is administered on day 1 of a 3-week cycle. In some embodiments, the maintenance dose is continued until disease progression or unacceptable toxicity occurs. In some embodiments, NSCLC has a non-squamous epithelial tissue structure.

[0480] In some embodiments, PDCT comprises cisplatin and pemetrexed. In some embodiments, pemetrexed is administered intravenously for approximately 10 minutes on day 1 of each cycle, followed by cisplatin administered intravenously for approximately 30 minutes on day 1 of each cycle. In some embodiments, pemetrexed is administered at a maintenance dose alone or in combination with anti-LAG-3 and anti-PD-1 antibodies...

Claims

1. A pharmaceutical composition comprising an anti-LAG-3 antibody for use in combination with an anti-PD-1 antibody in the treatment of non-small cell lung cancer (NSCLC) in human subjects, (a) The anti-LAG-3 antibody comprises heavy chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively, and light chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively, and is administered to the subject at a dose of approximately 360 mg. (b) The anti-PD-1 antibody comprises heavy chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, respectively, and light chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, respectively, and is administered to the subject at a dose of approximately 360 mg, and (c) A pharmaceutical composition in which the treatment is the first-line therapy.

2. The pharmaceutical composition according to claim 1, further combined with PDCT.

3. The pharmaceutical composition according to claim 1 or 2, wherein an anti-LAG-3 antibody and an anti-PD-1 antibody are formulated together.

4. The pharmaceutical composition according to claim 1 or 2, wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are formulated separately.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are to be administered intravenously to a subject from a single infusion bag for approximately 30 minutes.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein an anti-LAG-3 antibody and an anti-PD-1 antibody are administered in a cycle once every three weeks.

7. (a) NSCLC is unresectable, progressive, recurrent, and / or metastatic, and / or (b) The pharmaceutical composition according to any one of claims 1 to 6, wherein the subject has stage IV NSCLC.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the NSCLC has a squamous epithelial tissue structure.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein the NSCLC has a non-squamous epithelial tissue structure.

10. The pharmaceutical composition according to any one of claims 2 to 9, wherein PDCT contains a platinum agent in combination with a nucleoside analog, an antimetabolite, a taxane, a vinca alkaloid, or a topoisomerase inhibitor.

11. PDCT (i) cisplatin, carboplatin, or nedaplatin, and (ii) A pharmaceutical composition according to any one of claims 2 to 10, comprising gemcitabine, pemetrexed, paclitaxel, albumin-bound paclitaxel, docetaxel, vinorelbine, etoposide, or irinotecan.

12. The pharmaceutical composition according to any one of claims 2 to 11, wherein PDCT is administered in a cycle once every three weeks.

13. The pharmaceutical composition according to claim 12, wherein PDCT is administered for four cycles.

14. The patient has stage IV or recurrent NSCLC with a squamous epithelial tissue structure, and the PDCT results are as follows: (i) Carboplatin at a dose with an area under the target concentration-time curve of approximately 6 mg / mL·min, and (ii) Approximately 200mg / m ２ Paclitaxel at doses of approximately 100 mg / m². ２ A pharmaceutical composition according to any one of claims 2 to 8 or 10 to 13, comprising albumin-bound paclitaxel in a dose of [amount].

15. The patient has stage IV or recurrent NSCLC with a non-squamous tissue structure, and the PDCT results are as follows: (i) Carboplatin at a dose with an area under the target concentration-time curve of approximately 5 mg / mL·min or approximately 6 mg / mL·min, or approximately 75 mg / min ２ The dose of cisplatin, and (ii) Approximately 500mg / m ２ A pharmaceutical composition according to any one of claims 2 to 7 or 9 to 13, comprising pemetrexed in a dose of [specified value].

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein one or more immune cells in the tumor tissue from the subject express LAG-3, and / or one or more tumor cells in the tumor tissue from the subject express PD-L1.

17. (a) At least about 1% of immune cells express LAG-3, and / or (b) The pharmaceutical composition according to claim 16, wherein at least about 1% of the tumor cells express PD-L1.

18. The pharmaceutical composition according to claim 16 or 17, wherein approximately 1% to approximately 50% of the tumor cells express PD-L1.

19. A pharmaceutical composition for use in the treatment of non-small cell lung cancer (NSCLC) in human subjects, comprising approximately 360 mg of anti-LAG-3 antibody and approximately 360 mg of anti-PD-1 antibody, (a) The anti-LAG-3 antibody comprises heavy chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively, and light chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively, and (b) A pharmaceutical composition comprising an anti-PD-1 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, respectively, and light chain variable regions CDR1, CDR2, and CDR3 containing the sequences described in SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, respectively.

20. (a) The anti-LAG-3 antibody comprises a heavy chain variable region and a light chain variable region containing the sequences described in SEQ ID NOs: 3 and 4, respectively, and the anti-PD-1 antibody comprises a heavy chain variable region and a light chain variable region containing the sequences described in SEQ ID NOs: 13 and 14, respectively. (b) The anti-LAG-3 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs: 1 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs: 11 and 12, respectively. (c) The anti-LAG-3 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 21 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain containing the sequences described in SEQ ID NOs. 11 and 12, respectively, or (d) The pharmaceutical composition according to any one of claims 1 to 19, wherein the anti-LAG-3 antibody comprises relatrimab and the anti-PD-1 antibody comprises nivolumab.

21. A kit for use in the treatment of NSCLC in human subjects, comprising a pharmaceutical composition according to any one of claims 1 to 20, and instructions for use.

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