CN116568307A

CN116568307A - LAG-3 antagonist therapy for lung cancer

Info

Publication number: CN116568307A
Application number: CN202180082561.9A
Authority: CN
Inventors: L·D·汤姆斯; P·A·巴夏诺
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2020-10-23
Filing date: 2021-10-22
Publication date: 2023-08-08

Abstract

The present disclosure provides a method of treating a human subject having lung cancer with a lymphocyte activating gene-3 (LAG-3) antagonist. In some aspects, the methods comprise the LAG-3 antagonist in combination with an additional therapeutic agent (e.g., a apoptosis protein-1 pathway inhibitor) and/or an anti-cancer therapy (e.g., chemotherapy, such as platinum-containing dual drug chemotherapy).

Description

LAG-3 antagonist therapy for lung cancer

Cross Reference to Related Applications

The present PCT application claims priority from U.S. provisional application No. 63/104,744, filed on 10/23 in 2020, and U.S. provisional application No. 63/110,210, filed on 11/5 in 2020, which are incorporated herein by reference in their entireties.

Reference to sequence Listing

Electronic submission via EFS-WEB

The contents of the electronically submitted sequence listing (name 3338_240PC02_seqlipping_ST25. Txt, size 94,766 bytes, and creation date 2021, 10/21) are incorporated herein by reference in their entirety.

Technical Field

The present disclosure provides methods of treating a human subject having lung cancer comprising a lymphocyte activation gene-3 (LAG-3) antagonist.

Background

Lung Cancer and in particular non-small cell lung Cancer (NSCLC) remains the leading cause of Cancer-related death worldwide, accounting for approximately 18% of all Cancer deaths (Jenal a et al, CA Cancer j. Clin.2011; 61:69-90).

Until recently, treatment of patients with advanced NSCLC and whose tumors have no targetable genetic changes was only cytotoxic chemotherapy. Although treated, metastatic NSCLC patients treated with platinum-containing dual-drug chemotherapy had a median survival of about 10 months and a 5-year survival rate of less than 5%. The introduction of immune checkpoint inhibitors targeting the PD-1 signaling pathway in the treatment of NSCLC patients has a significant impact on patient survival. The combination of the anti-PD-1 antibody pembrolizumab with chemotherapy in a first-line setting has shown improvement in 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). Recently, the anti-PD-1 antibody, na Wu Shankang plus anti-CTLA-4 antibody, ipilimumab, and the combination of Na Wu Shankang plus ipilimumab with chemotherapy, also showed benefits over chemotherapy in this setting (Peters S et al Annals of Oncology 2019;30 (journal 5): v851-v934; reck M, J.Clin.Oncol.2020, (journal) abstract 9501. However, despite these advances, the median survival of first line patients with metastatic NSCLC is approximately 22 months in the non-squamous cell carcinoma population and approximately 15.9 months in the squamous cell carcinoma population (Paz-Ares L et al; gadgel S et al J. Clin. Oncol.2020;38 (14): 1505-1517).

There is a need for improved methods for treating human subjects with lung cancer.

Disclosure of Invention

The present disclosure relates to methods of treating a human subject having lung cancer, the methods comprising administering to the subject a lymphocyte activating gene-3 (LAG-3) antagonist and platinum-containing dual drug chemotherapy (PDCT).

In some aspects, the method is first line therapy.

In some aspects, the method is two-wire therapy.

In some aspects, the method is three-wire therapy.

In some aspects, the subject has progressed on prior therapy.

In some aspects, the lung cancer recurs after multi-modal therapy for locally advanced lung cancer.

In some aspects, the subject has not received prior systemic therapy for cancer, the subject has not received prior systemic therapy for lung cancer, or the subject has not received prior systemic therapy for advanced or metastatic lung cancer.

In some aspects, the subject is primary treated for prior immunooncology for lung cancer, or the lung cancer is primary treated for prior immunooncology.

In some aspects, the lung cancer is unresectable, advanced, recurrent, and/or metastatic.

In some aspects, the subject has stage IV lung cancer.

In some aspects, the lung cancer is small cell lung cancer.

In some aspects, the lung cancer is non-small cell lung cancer (NSCLC). In some aspects, the NSCLC has squamous or non-squamous histology.

In some aspects, one or more immune cells in tumor tissue from the subject express LAG-3. In some aspects, at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, toAbout 70%, at least about 80%, at least about 90%, or about 100% less of the immune cells express LAG-3. In some aspects, at least about 1% of the immune cells express LAG-3. In some aspects, the immune cells are tumor-infiltrating lymphocytes. In some aspects, the tumor-infiltrating lymphocyte is CD8 ⁺ And (3) cells.

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

In some aspects, the LAG-3 antagonist is an anti-LAG-3 antibody.

In some aspects, the anti-LAG-3 antibody is a full-length antibody.

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

In some aspects, the anti-LAG-3 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments, scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

In some aspects, the anti-LAG-3 antibody is BMS-986016 (Ruila Li Shan antibody), IMP731 (H5L 7 BW), MK4280 (28G-10, fei Weize Li Shan antibody (favezelimab)), REGN3767 (Fuolimumab), GSK2831781, humanized BAP050, IMP-701 (LAG 525, ELa Li Shan antibody), aLAG3 (0414), aLAG3 (0416), sym022, TSR-033, TSR-075, xmAb841 (XmAb 22841), MGD013 (terpolimumab), BI754111, FS118, P13B 02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or an antigen binding portion comprising the same.

In some aspects, the anti-LAG-3 antibody comprises CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence shown in SEQ ID NO. 3 and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence shown in SEQ ID NO. 4.

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

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

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

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

In some aspects, the LAG-3 antagonist is a soluble LAG-3 polypeptide. In some aspects, the soluble LAG-3 polypeptide is a fusion polypeptide. In some aspects, the soluble LAG-3 polypeptide comprises a ligand binding fragment of a LAG-3 extracellular domain. In some aspects, 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 to SEQ ID No. 22. In some aspects, the soluble LAG-3 polypeptide further comprises a half-life extending moiety. In some aspects, the half-life extending moiety comprises an immunoglobulin constant region or portion thereof, an immunoglobulin binding polypeptide, an immunoglobulin G (IgG), an Albumin Binding Polypeptide (ABP), a PAS moiety, a HES moiety, XTEN, a pegylated moiety, an Fc region, or any combination thereof. In some aspects, the soluble LAG-3 polypeptide is IMP321 (etimod a).

In some aspects, the LAG-3 antagonist is formulated for intravenous administration.

In some aspects, the LAG-3 antagonist is administered in a flat dose.

In some aspects, the LAG-3 antagonist is administered at the following doses: at least about 0.25mg to about 2000mg, about 0.25mg to about 1600mg, about 0.25mg to about 1200mg, about 0.25mg to about 800mg, about 0.25mg to about 400mg, about 0.25mg to about 100mg, about 0.25mg to about 50mg, about 0.25mg to about 40mg, about 0.25mg to about 30mg, about 0.25mg to about 20mg, about 20mg to about 2000mg, about 20mg to about 1600mg, about 20mg to about 1200mg, about 20mg to about 800mg, about 20mg to about 400mg, about 20mg to about 100mg, about 100mg to about 2000mg, about 100mg to about 1800mg, about 100mg to about 1600mg, about 100mg to about 1400mg, about 100mg to about 1200mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 400mg to about 400mg, about 400mg to about 2000mg, about 400mg to about 400mg, about 400mg to about 400mg, or about 400mg to about 400 mg.

In some aspects, the LAG-3 antagonist is administered at the following doses: about 0.25mg, about 0.5mg, about 0.75mg, about 1mg, about 1.25mg, about 1.5mg, about 1.75mg, about 2mg, about 2.25mg, about 2.5mg, about 2.75mg, about 3mg, about 3.25mg, about 3.5mg, about 3.75mg, about 4mg, about 4.25mg, about 4.5mg, about 4.75mg, about 5mg, about 5.25mg, about 5.5mg, about 5.75mg, about 6mg, about 6.25mg, about 6.5mg, about 6.75mg, about 7mg, about 7.25mg, about 7.5mg, about 7.75mg, about 8mg, about 8.25mg, about 8.5mg, about 8.75mg, about 9mg, about 9.5mg, about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, 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 850mg 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 1180mg, about 1200mg, about 1240mg, about 1280mg, about 1300mg, about 1340mg, about 1380mg, about 1400mg, about 1440mg, about 1480mg, about 1500mg, about 1540mg, about 1580mg, about 1600mg, about 1640mg, about 1680mg, about 1700mg, about 1740mg, about 1780mg, about 1800mg, about 1840mg, about 1880mg, about 1900mg, about 1940mg, about 1980mg, or about 2000mg.

In some aspects, the LAG-3 antagonist is administered in a weight-based dose.

In some aspects, the LAG-3 antagonist is administered at the following doses: about 0.003mg/kg to about 25mg/kg, about 0.003mg/kg to about 20mg/kg, about 0.003mg/kg to about 15mg/kg, about 0.003mg/kg to about 5mg/kg, about 0.003mg/kg to about 1mg/kg, about 0.003mg/kg to about 0.9mg/kg, about 0.003mg/kg to about 0.8mg/kg, about 0.003mg/kg to about 0.7mg/kg, about 0.003mg/kg to about 0.6mg/kg, about 0.003mg/kg to about 0.5mg/kg, about 0.003mg/kg to about 0.4mg/kg, about 0.003mg/kg to about 0.3mg/kg, about 0.003mg/kg to about 0.2mg/kg, about 0.003mg/kg to about 0.1mg/kg, about 25mg/kg to about 1mg to about 25mg/kg, about 1mg to about 25mg/kg to about 15mg/kg, about 1mg to about 25mg/kg, about 15mg to about 5mg/kg to about 25mg/kg, about 25mg to about 15 mg/kg.

In some aspects, the LAG-3 antagonist is administered at the following doses: about 0.003mg/kg, about 0.004mg/kg, about 0.005mg/kg, about 0.006mg/kg, about 0.007mg/kg, about 0.008mg/kg, about 0.009mg/kg, about 0.01mg/kg, about 0.02mg/kg, about 0.03mg/kg, about 0.04mg/kg, about 0.05mg/kg, about 0.06mg/kg, about 0.07mg/kg, about 0.08mg/kg, about 0.09mg/kg, about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 0.6mg/kg, about 0.7mg/kg, about 0.8mg/kg, about 0.9mg/kg about 1.0mg/kg, about 2.0mg/kg, about 3.0mg/kg, about 4.0mg/kg, about 5.0mg/kg, about 6.0mg/kg, about 7.0mg/kg, about 8.0mg/kg, about 9.0mg/kg, about 10.0mg/kg, about 11.0mg/kg, about 12.0mg/kg, about 13.0mg/kg, about 14.0mg/kg, about 15.0mg/kg, about 16.0mg/kg, about 17.0mg/kg, about 18.0mg/kg, about 19.0mg/kg, about 20.0mg/kg, about 21.0mg/kg, about 22.0mg/kg, about 23.0mg/kg, about 24.0mg/kg or about 25.0mg/kg.

In some aspects, the dose is administered about once every week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, about once every eight weeks, about once every nine weeks, about once every ten weeks, or about once every twelve weeks.

In some aspects, the PDCT comprises a platinum agent in combination with a nucleoside analog, an antimetabolite, a taxane, a vinca alkaloid, or a topoisomerase inhibitor. In some aspects, the platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, liposomal platinum (lipoplatin), or phenanthreneplatin (phenanthraplatin). In some aspects, the platinum agent is cisplatin. In some aspects, the platinum agent is carboplatin. In some aspects, the nucleoside analog is cytarabine, gemcitabine, lamivudine, entecavir, or telbivudine. In some aspects, the nucleoside analog is gemcitabine. In some aspects, the antimetabolite is capecitabine, cladribine, clofarabine, cytarabine, fluorouridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pennisetum, pralatrexed, or thioguanine. In some aspects, the antimetabolite is pemetrexed. In some aspects, the taxane is paclitaxel, albumin-bound paclitaxel, docetaxel, or carbopaclitaxel. In some aspects, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincamine alcohol (vincaminol), vinri dine, or vinbunting. In some aspects, the vinca alkaloid is vinorelbine or vinblastine. In some aspects, the topoisomerase inhibitor is etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin. In some aspects, the topoisomerase inhibitor is etoposide. In some aspects, the topoisomerase inhibitor is irinotecan.

In some aspects, the PDCT comprises cisplatin or carboplatin in combination with gemcitabine, pemetrexed, paclitaxel, albumin-bound paclitaxel, docetaxel, vinorelbine, vinblastine, etoposide, or irinotecan.

In some aspects, the PDCT comprises cisplatin or carboplatin in combination with paclitaxel or albumin-bound paclitaxel.

In some aspects, the PDCT comprises cisplatin or a combination of carboplatin and pemetrexed.

In some aspects, the method further comprises administering an additional therapeutic agent to the subject. In some aspects, the additional therapeutic agent comprises an anticancer agent. In some aspects, the anti-cancer agent comprises a tyrosine kinase inhibitor, an anti-angiogenesis agent, a checkpoint inhibitor, a checkpoint stimulant, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topoisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof.

In some aspects, the tyrosine kinase inhibitor comprises afatinib, erlotinib, dactinib, gefitinib, octtinib, ai Leti, buntinib, ceritinib, crizotinib, loratidine, emtrictinib, dabrafenib, trimetinib, vitamin Mo Feini, lartinib, or any combination thereof.

In some aspects, the anti-angiogenic agent comprises an inhibitor of Vascular Endothelial Growth Factor (VEGF), VEGF receptor (VEGFR), platelet Derived Growth Factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase (Tie) receptor having Ig-like and EGF-like domains, hepatocyte Growth Factor (HGF), tyrosine protein kinase Met (C-Met), C-lectin family 14 member a (CLEC 14A), polyprotein 2 (MMRN 2), shock protein 70-1A (HSP 70-1A), epidermal Growth Factor (EGF), EGF receptor (EGFR), or any combination thereof.

In some aspects, the anti-angiogenic agent comprises bevacizumab, ramucirumab, aflibercept, taniriumab, olamumab, nevastatin Su Shan antibody, AMG780, MEDI3617, vannoociclizumab, rituximab, non-lattuzumab, TAK-701, onatuzumab, imatuzumab, or any combination thereof.

In some aspects of the present invention, the checkpoint inhibitors include inhibitors of the programmed death protein-1 (PD-1) pathway, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, T cell immunoglobulin and ITIM domain (TIGIT) inhibitors, T cell immunoglobulin and mucin domain protein-3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B and T cell lymphocyte attenuator (BTLA) inhibitors, T cell activated V domain Ig inhibitor (VISTA) inhibitors, indoleamine 2, 3-dioxygenase (IDO) inhibitors, nicotinamide adenine dinucleotide phosphate oxidase subtype 2 (NOX 2) inhibitors killer cell immunoglobulin-like receptor (KIR) inhibitors, adenosine A2a receptor (A2 aR) inhibitors, transforming growth factor beta (TGF-beta) inhibitors, phosphoinositide 3-kinase (PI 3K) inhibitors, CD47 inhibitors, CD48 inhibitors, CD73 inhibitors, CD113 inhibitors, sialic acid binding immunoglobulin-like lectin-7 (SIGLEC-7) inhibitors, SIGLEC-9 inhibitors, SIGLEC-15 inhibitors, glucocorticoid-induced TNFR-associated protein (GITR) inhibitors, galectin-1 inhibitors, galectin-9 inhibitors, carcinoembryonic antigen-associated cell adhesion molecule-1 (CEACAM-1) inhibitors, G protein coupled receptor 56 (GPR 56) inhibitors, glycoprotein a repeat dominant (GARP) inhibitors, 2B4 inhibitors, inhibitors of programmed death protein-1 homolog (PD 1H), inhibitors of leukocyte associated immunoglobulin-like receptor 1 (LAIR 1), or any combination thereof.

In some aspects, the checkpoint inhibitor comprises a PD-1 pathway inhibitor.

In some aspects, the PD-1 pathway inhibitor is an anti-PD-1 antibody and/or an anti-PD-L1 antibody.

In some aspects, the PD-1 pathway inhibitor is an anti-PD-1 antibody.

In some aspects, the anti-PD-1 antibody is a full-length antibody.

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

In some aspects, the anti-PD-1 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments, scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

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

In some aspects, the anti-PD-1 antibodies comprise CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO. 13 and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO. 14.

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

In some aspects, the anti-PD-1 antibodies comprise heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 13 and 14, respectively.

In some aspects, the anti-PD-1 antibodies comprise heavy and light chains comprising the sequences set forth in SEQ ID NOs 11 and 12, respectively.

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

In some aspects, the PD-1 pathway inhibitor is an anti-PD-L1 antibody.

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

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

In some aspects, the anti-PD-L1 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments, scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

In some aspects, the anti-PD-L1 antibody is BMS-936559, ab-lizumab, duvaluzumab, avstuzumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301, or comprises an antigen binding portion thereof.

In some aspects, the PD-1 pathway inhibitor is BMS-986189.

In some aspects, the checkpoint inhibitor comprises a CTLA-4 inhibitor.

In some aspects, the CTLA-4 inhibitor is an anti-CTLA-4 antibody.

In some aspects, the anti-CTLA-4 antibody is a full-length antibody.

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

In some aspects, the anti-CTLA-4 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments, scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

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

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

In some aspects, the LAG-3 antagonist and the checkpoint inhibitor are formulated separately. In some aspects, when the checkpoint inhibitor comprises more than one checkpoint inhibitor, each checkpoint inhibitor is formulated separately. In some aspects, the checkpoint inhibitor is administered prior to the LAG-3 antagonist. In some aspects, the LAG-3 antagonist is administered prior to the checkpoint inhibitor.

In some aspects, the LAG-3 antagonist and the checkpoint inhibitor are formulated together. In some aspects, when the checkpoint inhibitor comprises more than one checkpoint inhibitor, two or more checkpoint inhibitors are formulated together.

In some aspects, the LAG-3 antagonist and the checkpoint inhibitor are administered concurrently.

In some aspects, the checkpoint inhibitor is administered in a flat dose.

In some aspects, the checkpoint inhibitor is administered at the following dose: at least about 0.25mg to about 2000mg, about 0.25mg to about 1600mg, about 0.25mg to about 1200mg, about 0.25mg to about 800mg, about 0.25mg to about 400mg, about 0.25mg to about 100mg, about 0.25mg to about 50mg, about 0.25mg to about 40mg, about 0.25mg to about 30mg, about 0.25mg to about 20mg, about 20mg to about 2000mg, about 20mg to about 1600mg, about 20mg to about 1200mg, about 20mg to about 800mg, about 20mg to about 400mg, about 20mg to about 100mg, about 100mg to about 2000mg, about 100mg to about 1800mg, about 100mg to about 1600mg, about 100mg to about 1400mg, about 100mg to about 1200mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 400mg to about 400mg, about 400mg to about 2000mg, about 400mg to about 400mg, about 400mg to about 400mg, or about 400mg to about 400 mg.

In some aspects, the checkpoint inhibitor is administered at the following dose: about 0.25mg, about 0.5mg, about 0.75mg, about 1mg, about 1.25mg, about 1.5mg, about 1.75mg, about 2mg, about 2.25mg, about 2.5mg, about 2.75mg, about 3mg, about 3.25mg, about 3.5mg, about 3.75mg, about 4mg, about 4.25mg, about 4.5mg, about 4.75mg, about 5mg, about 5.25mg, about 5.5mg, about 5.75mg, about 6mg, about 6.25mg, about 6.5mg, about 6.75mg, about 7mg, about 7.25mg, about 7.5mg, about 7.75mg, about 8mg, about 8.25mg, about 8.5mg, about 8.75mg, about 9mg, about 9.5mg, about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, 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 850mg 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 1180mg, about 1200mg, about 1240mg, about 1280mg, about 1300mg, about 1340mg, about 1380mg, about 1400mg, about 1440mg, about 1480mg, about 1500mg, about 1540mg, about 1580mg, about 1600mg, about 1640mg, about 1680mg, about 1700mg, about 1740mg, about 1780mg, about 1800mg, about 1840mg, about 1880mg, about 1900mg, about 1940mg, about 1980mg, or about 2000mg.

In some aspects, the checkpoint inhibitor is administered in a weight-based dose.

In some aspects, the checkpoint inhibitor is administered at the following dose: about 0.003mg/kg to about 25mg/kg, about 0.003mg/kg to about 20mg/kg, about 0.003mg/kg to about 15mg/kg, about 0.003mg/kg to about 5mg/kg, about 0.003mg/kg to about 1mg/kg, about 0.003mg/kg to about 0.9mg/kg, about 0.003mg/kg to about 0.8mg/kg, about 0.003mg/kg to about 0.7mg/kg, about 0.003mg/kg to about 0.6mg/kg, about 0.003mg/kg to about 0.5mg/kg, about 0.003mg/kg to about 0.4mg/kg, about 0.003mg/kg to about 0.3mg/kg, about 0.003mg/kg to about 0.2mg/kg, about 0.003mg/kg to about 0.1mg/kg, about 25mg/kg to about 1mg to about 25mg/kg, about 1mg to about 25mg/kg to about 15mg/kg, about 1mg to about 25mg/kg, about 15mg to about 5mg/kg to about 25mg/kg, about 25mg to about 15 mg/kg.

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

The present disclosure relates to a method of treating a human subject having lung cancer, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 360 mg; and (b) an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence shown in SEQ ID NO. 13 and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence shown in SEQ ID NO. 14 at a dose of about 360 mg.

The present disclosure relates to a method of treating a human subject having lung cancer, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 720 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14.

In some aspects, the method is first line therapy.

In some aspects, the method is two-wire therapy.

In some aspects, the method is three-wire therapy.

In some aspects, the subject has progressed on prior therapy.

In some aspects, the subject has stage IV lung cancer.

In some aspects, the lung cancer is small cell lung cancer.

In some aspects, the lung cancer is non-small cell lung cancer (NSCLC). In some aspects, the NSCLC has squamous histology. In some aspects, the NSCLC has non-squamous histology.

In some aspects, the method further comprises administering PDCT. In some aspects, the PDCT comprises a platinum agent in combination with a nucleoside analog, an antimetabolite, a taxane, a vinca alkaloid, or a topoisomerase inhibitor. In some aspects, the platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, liposomal platinum, or phenanthriplatin. In some aspects, the platinum agent is cisplatin. In some aspects, the platinum agent is carboplatin. In some aspects, the nucleoside analog is cytarabine, gemcitabine, lamivudine, entecavir, or telbivudine. In some aspects, the nucleoside analog is gemcitabine. In some aspects, the antimetabolite is capecitabine, cladribine, clofarabine, cytarabine, fluorouridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pennisetum, pralatrexed, or thioguanine. In some aspects, the antimetabolite is pemetrexed. In some aspects, the taxane is paclitaxel, albumin-bound paclitaxel, docetaxel, or carbopaclitaxel. In some aspects, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincamine alcohol, vinri dine, or vinbunting. In some aspects, the vinca alkaloid is vinorelbine or vinblastine. In some aspects, the topoisomerase inhibitor is etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin. In some aspects, the topoisomerase inhibitor is etoposide. In some aspects, the topoisomerase inhibitor is irinotecan. In some aspects, the PDCT comprises cisplatin or carboplatin in combination with gemcitabine, pemetrexed, paclitaxel, albumin-bound paclitaxel, docetaxel, vinorelbine, vinblastine, etoposide, or irinotecan. In some aspects, the PDCT comprises cisplatin or carboplatin in combination with paclitaxel or albumin-bound paclitaxel. In some aspects, the PDCT comprises cisplatin or a combination of carboplatin and pemetrexed.

The present disclosure relates to a method of treating a human subject having stage IV or recurrent NSCLC with squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 360 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) Carboplatin at a dose of about 6 mg/mL-min in area under the target concentration-time curve, and (ii) at a dose of about 200mg/m ² Wherein the method is first line therapy.

The present disclosure relates to a method of treating a human subject having stage IV or recurrent NSCLC with squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 720 mg; (b) An anti-PD-1 antibody comprising the CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence shown in SEQ ID NO. 13 and the CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence shown in SEQ ID NO. 14 at a dose of about 360mg The method comprises the steps of carrying out a first treatment on the surface of the (c) PDCT, comprising: (i) Carboplatin at a dose of about 6 mg/mL-min in area under the target concentration-time curve, and (ii) at a dose of about 200mg/m ² Wherein the method is first line therapy.

The present disclosure relates to a method of treating a human subject having stage IV or recurrent NSCLC with squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 360 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) Carboplatin at a dose of about 6 mg/mL-min in area under the target concentration-time curve, and (ii) at a dose of about 100mg/m ² Albumin-bound paclitaxel, wherein the method is first line therapy.

The present disclosure relates to a method of treating a human subject having stage IV or recurrent NSCLC with squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 720 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) Carboplatin at a dose of about 6 mg/mL-min in area under the target concentration-time curve, and (ii) at a dose of about 100mg/m ² Albumin-bound paclitaxel, wherein the method is first line therapy.

The present disclosure relates to a method of treating a human subject having stage IV or recurrent NSCLC with non-squamous histology, the method comprising administering to the subjectTrial application: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 360 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) Carboplatin at a target concentration-time curve area of about 5 mg/mL-min or about 6 mg/mL-min, and (ii) at a dose of about 500mg/m ² Wherein the method is first line therapy.

The present disclosure relates to a method of treating a human subject having stage IV or recurrent NSCLC with non-squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 720 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) Carboplatin at a target concentration-time curve area of about 5 mg/mL-min or about 6 mg/mL-min, and (ii) at a dose of about 500mg/m ² Wherein the method is first line therapy.

The present disclosure relates to a method of treating a human subject having stage IV or recurrent NSCLC with non-squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 360 mg; (b) An anti-PD-1 antibody comprising the CDR1, CDR2 and CDR3 junctions of the heavy chain variable region having the sequence shown in SEQ ID NO. 13 at a dose of about 360mgDomains, CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence shown in SEQ ID NO. 14; (c) PDCT, comprising: (i) The dosage is about 75mg/m ² And (ii) a dose of about 500mg/m ² Wherein the method is first line therapy.

The present disclosure relates to a method of treating a human subject having stage IV or recurrent NSCLC with non-squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 720 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) The dosage is about 75mg/m ² And (ii) a dose of about 500mg/m ² Wherein the method is first line therapy.

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

In some aspects, (a) the anti-LAG-3 antibody comprises heavy chain variable regions CDR1, CDR2 and CDR3 comprising the sequences shown 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 shown 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 comprising the sequences shown 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 shown in SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20, respectively.

In some aspects, the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 3 and 4, respectively, and the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 13 and 14, respectively.

In some aspects, the anti-LAG-3 antibody and/or the anti-PD-1 antibody is a full-length antibody.

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

In some aspects, the anti-LAG-3 antibody and/or anti-PD-1 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments, scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

In some aspects, the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOS: 1 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOS: 11 and 12, respectively.

In some aspects, the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOS: 21 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOS: 11 and 12, respectively.

In some aspects, the tyrosine kinase inhibitor is afatinib, erlotinib, dactinib, gefitinib, octtinib, ai Leti, buntinib, ceritinib, crizotinib, loratidine, emtrictinib, dabrafenib, trimetinib, vitamin Mo Feini, lartinib, or any combination thereof.

In some aspects, the PD-1 pathway inhibitor is an anti-PD-L1 antibody.

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

In some aspects, the PD-1 pathway inhibitor is BMS-986189.

In some aspects, the checkpoint inhibitor comprises a CTLA-4 inhibitor.

In some aspects, the CTLA-4 inhibitor is an anti-CTLA-4 antibody.

In some aspects, the anti-CTLA-4 antibody is a full-length antibody.

In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are formulated for intravenous administration.

In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are formulated separately.

In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are formulated together.

In some aspects, the anti-PD-1 antibody is administered prior to the anti-LAG-3 antibody.

In some aspects, the anti-LAG-3 antibody is administered prior to the anti-PD-1 antibody.

In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are administered concurrently.

In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are administered about once every three weeks. In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are administered on day 1 of a three week cycle. In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are administered intravenously from a single iv bag for about 30 minutes.

In some aspects, the PDCT is administered every three weeks. In some aspects, the PDCT is administered for up to about 4 three week periods.

The present disclosure relates to a pharmaceutical composition comprising (a) 360mg of an anti-LAG-3 antibody and (b) 360mg of an anti-PD-1 antibody.

The present disclosure relates to a pharmaceutical composition comprising (a) 720mg of an anti-LAG-3 antibody and (b) 360mg of an anti-PD-1 antibody

In some aspects, (a) the anti-LAG-3 antibody comprises CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID No. 4; and (b) the anti-PD-1 antibody comprises CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence shown in SEQ ID NO:13 and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence shown in SEQ ID NO: 14.

The present disclosure relates to a kit for treating a human subject having lung cancer, the kit comprising: (a) 360mg of anti-LAG-3 antibody; (b) 360mg of anti-PD-1 antibody; and (c) instructions for using the anti-LAG-3 antibody and the anti-PD-1 antibody in a method of treating a human subject with lung cancer.

The present disclosure relates to a kit for treating a human subject having lung cancer, the kit comprising: (a) 720mg of an anti-LAG-3 antibody; (b) 360mg of anti-PD-1 antibody; and (c) instructions for using the anti-LAG-3 antibody and the anti-PD-1 antibody in a method of treating a human subject with lung cancer.

Detailed Description

The present disclosure provides a method of treating a human subject having lung cancer (e.g., non-small cell lung cancer (NSCLC)), the method comprising administering a LAG-3 antagonist (e.g., an anti-LAG-3 antibody) to the subject. Some aspects of the disclosure relate to a method of treating a human subject having lung cancer, wherein the method is first-line, second-line or third-line therapy. Some aspects of the disclosure relate to a method of treating a human subject having stage IV or recurrent lung cancer. The disclosure also relates to methods of treating a human subject having lung cancer comprising a combination of an anti-cancer therapy and/or therapeutic agent with a LAG-3 antagonist, such as chemotherapy (e.g., platinum-containing dual drug chemotherapy) and/or a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody).

I. Terminology

In order that the present disclosure may be more readily understood, certain terms are first defined. As used herein, each of the following terms shall have the meanings set forth below, unless the context clearly provides otherwise. Additional definitions are set forth throughout this application. It should be noted that the term "a" or "an" entity refers to one/one or more/more of said entities: for example, "a nucleotide sequence" is understood to represent one or more nucleotide sequences. Thus, the terms "a" and "an" are used interchangeably herein.

The term "and/or" as used herein is to be taken as a specific disclosure of each of the two specified features or components with or without the other. Thus, the terms "and/or" as used herein in terms such as "a and/or B" are intended to include "a and B", "a or B", "a" (alone) and "B" (alone). Also, the term "and/or" as used in terms of phrases such as "A, B and/or C" is intended to encompass each of the following aspects: A. b and C; A. b or C; a or C; a or B; b or C; a and C; a and B; b and C; a (alone); b (alone); and C (alone).

It should be appreciated that any aspect described herein, whether described in the language "comprising," is also provided with other similar aspects described as "consisting of … …" and/or "consisting essentially of … ….

The term "about" or "consisting essentially of … …" refers to a value or composition that is within acceptable tolerances of the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, according to the practice in the art, "about" or "consisting essentially of … …" may mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially comprises … …" may represent a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3mg may include any amount between 2.7mg and 3.3mg (10%) or between 2.4mg and 3.6mg (20%). Furthermore, in particular with respect to biological systems or processes, the term may mean up to one order of magnitude of value or up to 5 times the value. When a particular value or composition is provided in the application and claims, unless otherwise indicated, it should be assumed that the meaning of "about" or "consisting essentially of … …" is within an acceptable error range for that particular value or composition.

As described herein, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range should be understood to include the value of any integer within the range and include scores thereof (such as one tenth and one hundredth of an integer) as appropriate.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For example, concise Dictionary of Biomedicine and Molecular Biology, juo, pei-Show, 2 nd edition, 2002, CRC Press; the Dictionary of Cell and Molecular Biology, 5 th edition, 2013,Academic Press; and Oxford Dictionary Of Biochemistry And Molecular Biology,2006,Oxford University Press provide a general dictionary of many terms used in this disclosure to a skilled artisan.

Units, prefixes, and symbols are expressed in terms of their international system of units (SI) acceptance. Numerical ranges include numbers defining the range.

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

An "antagonist" shall include, but is not limited to, any molecule capable of blocking, reducing, or otherwise limiting the interaction or activity of a target molecule (e.g., LAG-3). In some aspects, the antagonist is an antibody. In other aspects, the antagonist comprises a small molecule. The terms "antagonist" and "inhibitor" are used interchangeably herein.

An "antibody" (Ab) shall include, but is not limited to, a glycoprotein immunoglobulin that specifically binds to an antigen and comprises at least two heavy (H) chains and two light (L) chains that are interconnected by disulfide bonds. Each H chain comprises a heavy chain variable region (abbreviated herein as V _H ) And a heavy chain constant region (abbreviated herein as C _H ). The heavy chain constant region comprises three constant domains, C _H1 、C _H2 And C _H3 . Each light chain comprises a light chain variable region (abbreviated herein as V _L ) And a light chain constant region (abbreviated herein as C _L ). The light chain constant region comprises a constant domain C _L 。V _H And V _L The regions can be further subdivided into regions of high variability, termed Complementarity Determining Regions (CDRs), interspersed with regions that are more conserved, termed Framework Regions (FR). Each V _H And V _L Comprising three CDRs and four FRs arranged from amino-terminus to 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 antigens. The constant region of an antibody may mediate the binding of an immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component of the classical complement system (C1 q). The heavy chain may or may not have a C-terminal lysine. Unless otherwise specified herein, amino acids in the variable region are numbered using the Kabat numbering system, an And amino acids in the constant region are numbered using the EU system.

The immunoglobulin may be derived from any known isotype, including but not limited to IgA, secretory IgA, igG, and IgM. Subclasses of IgG are also well known to those of skill in the art, including but not limited to human IgG1, igG2, igG3, and IgG4. "isotype" refers to the class or subclass of antibodies (e.g., igM or IgG 1) encoded by the heavy chain constant region gene. For example, the term "antibody" includes both naturally occurring antibodies and non-naturally occurring antibodies; monoclonal antibodies and polyclonal antibodies; chimeric and humanized antibodies; a human antibody or a non-human antibody; fully synthesizing an antibody; a single chain antibody; a monospecific antibody; a bispecific antibody; a multispecific antibody. The non-human antibodies may be humanized by recombinant methods to reduce their immunogenicity in humans. Where not explicitly stated, and unless the context indicates otherwise, the term "antibody" also includes antigen-binding fragments or antigen-binding portions of any of the above immunoglobulins, and includes monovalent and divalent fragments or portions that retain the ability to specifically bind to antigens bound by whole molecule immunoglobulins. Examples of "antigen binding portions" or "antigen binding fragments" include: (1) Fab fragments (fragments from papain cleavage) or similar monovalent fragments, which are derived from V _L 、V _H 、L _C And C _H1 Domain composition; (2) A F (ab') 2 fragment (fragment from pepsin cleavage) or a similar bivalent fragment comprising two Fab fragments linked by disulfide bonds at the hinge region; (3) Fd fragment consisting of VH and CH1 domains; (4) Fv fragments consisting of a single set of V _L And V _H Domain composition; (5) Single domain antibody (dAb) fragments (Ward et al, (1989) Nature 341:544-46) from V _H Domain composition; (6) A double single domain antibody consisting of two V linked by a hinge _H Domain composition (amphipathic re-targeting antibody (DART)); or (7) a dual variable domain immunoglobulin. Furthermore, although the two domains of the Fv fragment V _L And V _H Encoded by separate genes, but they can be joined by synthetic linkers using recombinant methods, enabling them to be made into individual eggsWhite matter chain in which V _L And V _H The pairing of regions forms monovalent molecules, known as single chain Fv (scFv); see, e.g., bird et al (1988) Science 242:423-426; huston et al (1988) Proc.Natl. Acad. Sci. USA 85:5879-5883).

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

The term "monoclonal antibody" ("mAb") refers to a non-naturally occurring preparation of antibody molecules having a single molecular composition, i.e., antibody molecules whose primary sequences are substantially identical and exhibit a single binding specificity and affinity for a particular epitope. mabs are examples of isolated antibodies. MAbs may be produced by hybridomas, recombination, transgenes, or other techniques known to those skilled in the art.

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

"humanized antibody" refers to an antibody in which some, most, or all of the amino acids outside the CDR domains of a non-human antibody are replaced with the corresponding amino acids derived from a human immunoglobulin. In one aspect of the humanized form of the antibody, some, most or all of the amino acids outside the CDR domains have been replaced with amino acids from a human immunoglobulin, while some, most or all of the amino acids within one or more CDR regions have not been altered. Minor additions, deletions, insertions, substitutions or modifications of amino acids are permissible provided they do not abrogate the ability of the antibody to bind to a particular antigen. "humanized" antibodies retain antigen specificity similar to the original antibody.

"chimeric antibody" refers to an antibody in which the variable region is derived from one species and the constant region is derived from another species, such as an antibody in which the variable region is derived from a mouse antibody and the constant region is derived from a human antibody.

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.

"LAG-3" refers to lymphocyte activating gene-3. The term "LAG-3" includes variants, subtypes, homologs, orthologs, and paralogs. For example, in some cases, antibodies specific for a human LAG-3 protein may cross-react with LAG-3 proteins from species other than humans. In other aspects, antibodies specific for human LAG-3 proteins may be fully specific for human LAG-3 proteins and may not exhibit species or other types of cross-reactivity, or may cross-react with LAG-3 from some other species but not all other species (e.g., cross-react with monkey LAG-3 but not with mouse LAG-3). The term "human LAG-3" refers to the human sequence LAG-3, such as the complete amino acid sequence of human LAG-3 with GenBank accession NP-002277. The term "mouse LAG-3" refers to the complete amino acid sequence of the mouse sequence LAG-3, such as mouse LAG-3 with GenBank accession NP-032505. LAG-3 is also known in the art as, for example, CD223. The human LAG-3 sequence may differ from human LAG-3 of GenBank accession number NP-002277 by having, for example, a mutation in a conserved or non-conserved region, and the LAG-3 has substantially the same biological function as human LAG-3 of GenBank accession number NP-002277. For example, the biological function of human LAG-3 is to have an epitope in the extracellular domain of LAG-3 that is specifically bound by an antibody of the disclosure, or the biological function of human LAG-3 is to bind to an MHC class II molecule.

The particular human LAG-3 sequence will generally have at least about 90% identity in amino acid sequence to human LAG-3 of GenBank accession No. np_002277 and contain amino acid residues that identify the amino acid sequence as human when compared to LAG-3 amino acid sequences of other species (e.g., murine). In certain instances, human LAG-3 may have at least about 95%, or even at least about 96%, at least about 97%, at least about 98%, at least about 99% or about 100% identity in amino acid sequence to LAG-3 of GenBank accession No. np_002277. In certain aspects, the human LAG-3 sequence will exhibit no more than a 10 amino acid difference from the LAG-3 sequence of GenBank accession No. np_002277. In certain aspects, human LAG-3 may exhibit no more than 5, or even no more than 4, 3, 2, or 1 amino acid differences from the LAG-3 sequence of GenBank accession No. np_002277.

"programmed death protein-1 (PD-1)" refers to an immunosuppressive receptor belonging to the CD28 family. PD-1 is expressed primarily on previously activated T cells in vivo and binds to two ligands, namely PD-L1 and PD-L2. As used herein, the term "PD-1" includes variants, subtypes and species homologs of human PD-1 (hPD-1), hPD-1, and analogs having at least one common epitope with hPD-1. Complete hPD-1 sequences can be found under GenBank accession number U64863. "PD-1" and "PD-1 receptor" are used interchangeably herein.

"cytotoxic T lymphocyte antigen-4 (CTLA-4)" refers to an immunosuppressive receptor belonging to the CD28 family. CTLA-4 is expressed only on T cells in vivo and binds to two ligands, namely CD80 and CD86 (also referred to as B7-1 and B7-2, respectively). As used herein, the term "CTLA-4" includes human CTLA-4 (hCTLA-4), variants, subtypes and species homologs of hCTLA-4, and analogs having at least one common epitope with hCTLA-4. The complete hCTLA-4 sequence can be found under GenBank accession number AAB 59385.

"programmed death protein ligand-1 (PD-L1)" is one of the two cell surface glycoprotein ligands for PD-1 (the other is PD-L2), which down-regulates T cell activation and cytokine secretion upon binding to PD-1. As used herein, the term "PD-L1" includes human PD-L1 (hPD-L1), variants, subtypes and species homologs of hPD-L1, and analogs having at least one common epitope with hPD-L1. Complete hPD-L1 sequences can be found under GenBank accession number Q9 NZQ.

As used herein, "programmed death protein ligand-2 (PD-L2)" includes human PD-L2 (hPD-L2), variants, subtypes and species homologs of hPD-L2, and analogs having at least one common epitope with hPD-L2. The complete hPD-L2 sequence can be found under GenBank accession number Q9BQ 51.

As used herein, "patient" includes any patient with cancer (e.g., NSCLC). The terms "subject" and "patient" are used interchangeably herein.

"administering" refers to physically introducing a therapeutic agent (e.g., a composition or formulation comprising a therapeutic agent) into a subject using any of a variety of methods and delivery systems known to those of skill in the art. Exemplary routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, such as by injection or infusion. As used herein, the phrase "parenteral administration" means modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. In some aspects, the formulation is administered via a non-parenteral route, in some aspects, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, such as intranasal, vaginal, rectal, sublingual or topical. Administration may also be performed, for example, one time, multiple times, and/or over one or more extended periods of time.

"treatment" or "therapy" of a subject refers to any type of intervention or treatment performed on the subject, or administration of an active agent to the subject, with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing the progression, development, severity, or recurrence of symptoms, complications or disorders, or biochemical indicators associated with the disease. The solid tumor response assessment criteria (RECIST) is a measure of the efficacy of a treatment and is a established rule defining when a tumor responds, stabilizes or progresses during the treatment. RECIST 1.1 is the current guideline for solid tumor measurement and definition for objective assessment of tumor size change for adult and pediatric cancer clinical trials.

As used herein, "effective treatment" refers to treatment that produces a beneficial effect (e.g., ameliorates at least one symptom of a disease or disorder). The beneficial effect may take the form of an improvement over baseline, i.e., an improvement over measurements or observations made prior to initiation of therapy according to the method. The beneficial effect may also take the form of preventing, slowing, delaying or stabilizing the detrimental progression of a solid tumor marker. An effective treatment may refer to alleviation of at least one symptom of a solid tumor. Such effective treatment may, for example, reduce pain in the patient, reduce the size and/or number of lesions, may reduce or prevent metastasis of a tumor, and/or may slow down tumor growth.

The term "effective amount" refers to the amount of an agent that provides a desired biological, therapeutic, and/or prophylactic result. The result may be a reduction, improvement, alleviation, attenuation, delay, and/or alleviation of one or more signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. With respect to solid tumors, an effective amount includes an amount sufficient to cause tumor shrinkage and/or reduce the tumor growth rate (such as inhibiting tumor growth) or delay other unwanted cell proliferation. In some aspects, an effective amount is an amount sufficient to prevent or delay tumor recurrence. The effective amount may be administered in one or more administrations. An effective amount of the drug or composition may be: (i) reducing the number of cancer cells; (ii) reducing tumor size; (iii) Inhibit, delay, slow down to some extent, and can prevent cancer cells from infiltrating into peripheral organs; (iv) In one example, an "effective amount" is an amount of anti-LAG-3 antibody alone or in combination with an amount of an additional therapeutic agent (e.g., an anti-PD-1 antibody) that has been clinically demonstrated to affect a significant reduction in cancer or a slowing in progression of cancer (e.g., advanced solid tumor).

As used herein, the terms "fixed dose", "flat dose" and "flat fixed dose" are used interchangeably and refer to a dose administered to a patient irrespective of the patient's body weight or Body Surface Area (BSA). Thus, a fixed or flat dose is not provided in mg/kg doses, but in absolute amounts of the agent (e.g., amounts in μg or mg).

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

The term "weight-based dose" as referred to herein means the dose administered to a patient calculated based on the weight of the patient.

As used herein, "dosing interval" means the amount of time that passes between administration of multiple doses of a formulation disclosed herein to a subject. Thus, the dosing interval may be indicated as a range.

As used herein, the term "dosing frequency" refers to the frequency of doses of the formulations disclosed herein administered over a given period of time. The frequency of administration may be indicated as the number of doses per given time, e.g. once a week or once a week, etc.

As used herein, the terms "about once a week", "about once every two weeks" or any other similar dosing interval term means approximate numbers, and "about once a week" or "about once a week" may include every seven days ± two days, i.e., every five to every nine days. Thus, the dosing frequency of "once a week" may be every five days, every six days, every seven days, every eight days, or every nine days. "about once every three weeks" may include every 21 days + -3 days, i.e., every 25 days to every 31 days. Similar approximations apply, for example, about once every two weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, about once every eight weeks, about once every nine weeks, about once every ten weeks, about once every eleven weeks, and about once every twelve weeks. In some aspects, a dosing interval of about once every six weeks or about once every twelve weeks, respectively, means that a first dose may be administered on any date of the first week, and then a next dose may be administered on any date of the sixth or twelfth week. In other aspects, a dosing interval of about once every six weeks or about once every twelve weeks means that a first dose is administered on a particular day of the first week (e.g., monday) and then the next dose is administered on the same day of the sixth or twelfth week (i.e., monday), respectively.

As used herein, an "adverse event" (AE) is any adverse and often unintended or undesired sign (including abnormal laboratory findings), symptom, or disease associated with treatment with a drug. For example, an adverse event may be associated with activation of the immune system or expansion of immune system cells (e.g., T cells) in response to treatment. Medical treatment may have one or more associated AEs, and each AE may have the same or different levels of severity.

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 pre-cancerous lesions.

As used herein, the term "biological sample" refers to biological material isolated from a subject. The 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. The biological sample may be any suitable biological tissue or fluid, such as tumor tissue, blood, plasma and serum. The biological sample may be a test tissue sample (e.g., a tissue sample comprising tumor cells and tumor-infiltrating inflammatory cells). In one aspect, the sample is a tumor tissue biopsy, such as formalin-fixed paraffin embedded (FFPE) tumor tissue or freshly frozen tumor tissue, or the like. In another aspect, the biological sample is a liquid biopsy, which in some aspects includes one or more of blood, serum, plasma, circulating tumor cells, exornas, ctDNA, and cfDNA.

For example, an "anticancer agent" promotes cancer regression in a subject. In a preferred aspect, a therapeutically effective amount of the agent promotes regression of the cancer to the point of eliminating the cancer. By "promoting cancer regression" is meant that administration of an effective amount of an anti-cancer agent alone or in combination with another agent results in a reduction in tumor growth or size, tumor necrosis, a reduction in the severity of at least one disease symptom, an increase in the frequency and duration of disease-free periods of symptoms, or prevention of injury or disability due to disease affliction. In addition, the terms "effective" and "effectiveness" with respect to treatment include both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of an agent to promote regression of cancer in a patient. Physiological safety refers to toxic levels caused by administration of an agent or other adverse physiological effects (adverse effects) at the cellular, organ and/or organism level.

For treatment of a tumor, for example, a therapeutically effective amount of an anti-cancer agent can inhibit cell growth or tumor growth by at least about 20%, at least about 40%, at least about 60%, or at least about 80% relative to an untreated subject. In other aspects of the disclosure, tumor regression may be observed 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 effectiveness, the evaluation of immunotherapeutic drugs must also take into account immune-related response patterns.

As used herein, "immunooncology" therapy or "I-O" or "IO" therapy refers to a therapy that includes utilizing an immune response to target and treat a tumor in a subject. Thus, as used herein, I-O therapy is a class of anti-cancer therapies. In some aspects, the I-O therapy comprises administering an antibody to a subject. In some aspects, I-O therapy comprises administering immune cells, such as T cells, e.g., modified T cells, e.g., T cells modified to express a chimeric antigen receptor or a specific T cell receptor, to a subject. In some aspects, the I-O therapy comprises administering a therapeutic vaccine to a subject. In some aspects, the I-O therapy comprises administering a cytokine or chemokine to a subject. In some aspects, the I-O therapy comprises administering an interleukin to a subject. In some aspects, the I-O therapy comprises administering an interferon to a subject. In some aspects, the I-O therapy comprises administering a colony stimulating factor to a subject.

By "immune response" is meant the action of cells of the immune system (e.g., T lymphocytes, B lymphocytes, natural Killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells, or neutrophils) and soluble macromolecules (including antibodies, cytokines, and complement) produced by either of these cells or the liver, which results in selective targeting, binding, damaging, destroying, and/or eliminating pathogens invading, pathogen-infected cells or tissues, cancerous or other abnormal cells in vertebrates, or in the case of autoimmune or pathological inflammation, in normal human cells or tissues.

A "tumor-infiltrating inflammatory cell" or "tumor-associated inflammatory cell" is any type of cell that typically participates in an inflammatory response in a subject and infiltrates tumor tissue. Such cells include tumor-infiltrating lymphocytes (TIL), macrophages, monocytes, eosinophils, tissue cells, and dendritic cells.

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 is scored as expressing LAG-3 (e.g., greater than or equal to 1% expression) based on the proportion (i.e., percent) of immune cells (e.g., tumor-infiltrating lymphocytes, such as cd8+ T cells) that express LAG-3.

"LAG-3 negative" or "LAG-3 expression negative" refers to tumor tissue (e.g., test tissue sample) that has not been scored as expressing LAG-3 (e.g., less than 1% LAG-3 expression).

The term "PD-1 positive" or "PD-1 expression positive" in relation to PD-1 expression refers to tumor tissue (e.g., test tissue sample) that is scored as expressing PD-1 (e.g., greater than or equal to 1% expression) based on the proportion (i.e., percentage) of immune cells (e.g., tumor-infiltrating lymphocytes, such as cd8+ T cells) that express PD-1.

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

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 (e.g., greater than or equal to 1% expression) based on the proportion (i.e., percentage) of tumor cells that express PD-L1.

The term "PD-L1 negative" or "PD-L1 expression negative" refers to tumor tissue (e.g., test tissue sample) that is not scored as expressing PD-L1 (e.g., less than 1% expression).

Various aspects of the invention are described in further detail in the subsections that follow.

Methods of the present disclosure

Provided herein are methods of treating a human subject having lung cancer, the methods comprising administering a LAG-3 antagonist (e.g., an anti-LAG-3 antibody) to the subject alone or in combination with one or more additional therapeutic agents (e.g., a PD-1 pathway inhibitor, such as an anti-PD-1 antibody) and/or therapy (e.g., chemotherapy, such as platinum-containing dual-drug chemotherapy).

In some aspects, the method is a first line (1L) therapy.

In some aspects, the method is two-line (2L) therapy.

In some aspects, the method is three-wire (3L) therapy.

In some aspects, the subject has progressed on prior therapy (e.g., standard care therapy). Standard care therapies for different types of cancer are well known to those skilled in the art. For example, national Comprehensive Cancer Network (NCCN), which is the 21 major cancer center consortium in the united states, issued oncology NCCN clinical practice guidelines (NCCN) It provides detailed up-to-date information about standard caretaking treatments for a variety of cancers. See NCCN->2020, https:// www.nccn.org/pro-fessionals/physiogn_gls/default. Aspx, last day of visit 2020, 10, 23.

In some aspects, the subject is primary to a prior immunooncology (I-O) therapy. In some aspects, the subject has never received I-O therapy, has received I-O therapy for a cancer other than lung cancer, or has received I-O therapy for a previous lung cancer but not a current lung cancer. In some aspects, the subject is primary treated for a prior I-O therapy for lung cancer, or the lung cancer is primary treated for a prior I-O therapy. In some aspects, the prior I-O therapy is an antibody. In some aspects, the antibody binds to a checkpoint inhibitor. In some aspects, the prior I-O therapy is an anti-PD-1 antibody and/or a combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody.

In some aspects, the methods of the present disclosure increase the duration of Progression Free Survival (PFS), objective Response Rate (ORR), total survival (OS), or any combination thereof, as compared to standard caretaking and/or prior therapies as disclosed herein.

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

In some aspects, the methods of the disclosure include administering a LAG-3 antagonist to a subject based on the physical state and/or cancer stage of the subject. Physical performance status and/or cancer stage may be indicated by any one or more systems in the art.

In some aspects, the physical status is indicated by an eastern tumor cooperative group physical status (ECOG PS) that utilizes standardized criteria to measure how the disease affects the patient's ability to survive daily. Exemplary definitions of ECOG PS include: "0" means that the patient is fully active and is able to perform all pre-illness activities without restriction; "1" means that the patient is limited in strenuous physical activity, but can walk and be able to do work of a mild or sedentary nature; "2" means that the patient is ambulatory and is able to self-care in its entirety, with about more than 50% awake time, but is unable to perform any work activities; "3" means that the patient is only given limited self-care and more than 50% of the awake time is confined to bed or chair; and "4" means that the patient is completely disabled, unable to do any self-care, and is completely confined to a bed or chair.

In some aspects, the subject has an ECOG PS of 0, 1, 2, 3, or 4. In some aspects, the subject has an ECOG PS of ∈3. In some aspects, the subject has an ECOG PS of ∈2. In some aspects, the subject has an ECOG PS of ∈1.

In some aspects, lung cancer is staged based on a tumor/lymph node/metastasis (TNM) staging system (e.g., united states joint committee for cancer (AJCC)) classification.

There are at least seven stages for lung cancer: stage (hidden), stage 0 (carcinoma in situ), stage I, stage II, stage IIIA, stage IIIB and stage IV. During the occult stage, the cancer cannot be seen by imaging or bronchoscopy. At stage 0, cancer cells were found in the inner wall of the airways.

In some aspects, the subject has stage 0 lung cancer.

In some aspects, the subject has stage I lung cancer. Stage I lung cancer is divided into stage IA and stage IB. In stage IA, the tumor is only in the lung and is 3 cm or less. In stage IB, the cancer has not spread to the lymph nodes and one or more of the following are true: 1) Tumors are greater than 3 cm but not greater than 5 cm; 2) The cancer has spread to the main bronchi and is at least 2 cm below the location where the trachea connects with the bronchi; 3) Cancer has spread to the innermost layer of the membrane covering the lung; or 4) that part of the lung has collapsed or progressed to pneumonia (inflammation of the lung) in the area where the trachea connects with the bronchi.

In some aspects, the subject has stage II lung cancer. Stage II is divided into stage IIA and stage IIB. In stage IIA, the cancer has spread to the lymph nodes or has not spread to the lymph nodes. If the cancer has spread to the lymph nodes, the cancer may have spread only to lymph nodes on the same side of the chest as the tumor, with the lymph nodes in the lung or near the bronchi, and one or more of the following is true: 1) The tumor is not more than 5 cm; 2) The cancer has spread to the main bronchi and is at least 2 cm below the location where the trachea connects with the bronchi; 3) Cancer has spread to the innermost layer of the membrane covering the lung; or 4) that part of the lung has collapsed or progressed to pneumonia (inflammation of the lung) in the area where the trachea connects with the bronchi. If the cancer has not spread to the lymph nodes, and one or more of the following are true: 1) Tumors are greater than 5 cm but not greater than 7 cm; 2) The cancer has spread to the main bronchi and is at least 2 cm below the location where the trachea connects with the bronchi; 3) Cancer has spread to the innermost layer of the membrane covering the lung; or 4) that part of the lung has collapsed or progressed to pneumonia (inflammation of the lung) in the area where the trachea connects with the bronchi, the tumor is also considered as stage IIA. In stage IIB, the cancer has spread to the lymph nodes or has not spread to the lymph nodes. If the cancer has spread to the lymph nodes, the cancer may have spread only to lymph nodes on the same side of the chest as the tumor, with the lymph nodes in the lung or near the bronchi, and one or more of the following is true: 1) Tumors are greater than 5 cm but not greater than 7 cm; 2) The cancer has spread to the main bronchi and is at least 2 cm below the location where the trachea connects with the bronchi; 3) Cancer has spread to the innermost layer of the membrane covering the lung; or 4) that part of the lung has collapsed or progressed to pneumonia (inflammation of the lung) in the area where the trachea connects with the bronchi. If the cancer has not spread to the lymph nodes, and one or more of the following are true: 1) The tumor is larger than 7 cm; 2) Cancer has spread to the main bronchi (and at least 2 cm below the location where the trachea connects with the bronchi), the chest wall, the diaphragm, or nerves controlling the diaphragm; 3) The membrane that the cancer has spread to the surrounding of the heart or the inner layer of the chest wall; 4) The entire lung has collapsed or progressed to pneumonia (inflammation of the lung); or 5) the presence of one or more individual tumors in the same lobe, then the tumor is also considered stage IIB.

In some aspects, the subject has stage III lung cancer. Stage IIIA is divided into 3 parts. These 3 parts are based on 1) tumor size; 2) The location of the tumor and 3) which (if any) lymph nodes are afflicted with cancer. In the first type of IIIA stage, the cancer has spread to the lymph nodes on the same side of the chest as the tumor, and the lymph nodes with cancer enter the lung near the sternum or bronchi. In addition: 1) The tumor may be of any size; 2) A portion of the lung (where the trachea connects with the bronchi) or the entire lung may have collapsed or developed into pneumonia (inflammation of the lung); 3) One or more individual tumors may be present in the same lobe; and 4) the cancer may have spread to any of the following: a) the area of the main bronchi but not the bronchi that connect to the bronchi, b) the chest wall, c) the septum and nerves that control the septum, d) the membrane around the lungs or the inner layer of the chest wall, e) the membrane around the heart. In the second type of IIIA stage, the cancer has spread to the lymph nodes on the same side of the chest as the tumor, and the lymph nodes with cancer are in the lung or near the bronchi. In addition: 1) The tumor may be of any size; 2) The entire lung may have collapsed or developed into pneumonia (inflammation of the lung); 3) One or more individual tumors may be present in any lung lobe with cancer; and 4) the cancer may have spread to any of the following: a) the area of the main bronchi but not the bronchi, b) the chest wall, c) the diaphragm and nerves controlling the diaphragm, d) the membrane around the lungs or inner layer of the chest wall, e) the heart or the membrane around the heart, f) the main blood vessels leading to or from the heart, g) the trachea, h) the oesophagus, i) the nerves controlling the larynx (larynx), j) the sternum (sternum/chest bone) or the spine, or k) the carina (location of the trachea connected to the bronchi). In the third type of IIIA stage, the cancer has not spread to the lymph nodes, the tumor may be of any size, and the cancer has spread to any of the following: a) the heart, b) the main vessels leading to or from the heart, c) the trachea, d) the esophagus, e) the nerves controlling the larynx, f) the sternum or spine, or g) the carina (where the trachea connects to the bronchi). Stage IIIB is divided into 2 parts, depending on 1) the size of the tumor, 2) the location of the tumor found, and 3) which lymph nodes have cancer. In the first type of IIIB stage, the cancer has spread to lymph nodes located on the breast opposite the tumor. In addition, 1) the tumor can be of any size; 2) A portion of the lung (where the trachea connects with the bronchi) or the entire lung may have collapsed or developed into pneumonia (inflammation of the lung); 3) One or more individual tumors may be present in any lung lobe with cancer; and 4) the cancer may have spread to any of the following: a) a main bronchus, b) a chest wall, c) a diaphragm and nerves controlling the diaphragm, d) a membrane surrounding the lungs or inner layer of the chest wall, e) a heart or a membrane surrounding the heart, f) a main blood vessel leading to or from the heart, g) a trachea, h) an esophagus, i) nerves controlling the larynx, j) a sternum or spine, or k) a carina (where the trachea connects with a bronchus). In the second type of IIIB stage, the cancer has spread to lymph nodes on the same side of the breast as the tumor. Lymph nodes with cancer are near the sternum (sternum/chest bone) or at the location where the bronchi enter the lungs. In addition, 1) the tumor can 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) the main vessels leading to or from the heart, c) the trachea, d) the esophagus, e) the nerves controlling the larynx, f) the sternum or spine, or g) the carina (where the trachea connects to the bronchi).

In some aspects, the subject has 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) One or more tumors are present in both lungs; 2) Cancer is found in fluids surrounding the lungs or heart; and 3) the cancer has spread to other parts of the body, such as the brain, liver, adrenal gland, kidney or bone.

In some aspects, the lung cancer is Small Cell Lung Cancer (SCLC). In some aspects, the stage of SCLC is determined by TNM staging. In some aspects, unlike TNM staging, SCLC is classified as either limited or extensive. The limited stage SCLC is limited to one lung and/or regional lymph node. Extensive staging SCLC is found in distant sites of both lungs and/or body.

In some aspects, the lung cancer is non-small cell lung cancer (NSCLC). NSCLC includes NSCLC with "non-specific" (NOS) histology, NSCLC with squamous histology (SQ), and NSCLC with non-squamous histology (NSQ, including adenocarcinoma, large cell, and undifferentiated carcinoma). In some aspects, the NSCLC has squamous histology. In some aspects, the NSCLC has non-squamous histology.

Surgery (i.e., surgical excision), radiation Therapy (RT), and chemotherapy are three ways commonly used to treat NSCLC patients. As a class, NSCLC is relatively insensitive to chemotherapy and RT compared to small cell cancers. In general, surgical excision provides the best cure opportunity for patients with stage I or II disease, and chemotherapy is commonly used both pre-operatively and post-operatively. RT may also be used as an adjuvant therapy, a primary topical therapy, or as a palliative therapy for patients with incurable NSCLC. Patients with advanced or metastatic disease (e.g., stage IV NSCLC) with good Physical Status (PS) may benefit from chemotherapy.

Specific targeted therapies have also been developed for the treatment of advanced or metastatic NSCLC in subjects with sensitizing mutations in the genes of the Epidermal Growth Factor Receptor (EGFR), anaplastic Lymphoma Kinase (ALK), ROS-1, neurotrophin receptor tyrosine kinase (NTRK), and B-fast accelerating fibrosarcoma proto-oncogene (BRAF, e.g., BRAF V600E mutation).

In some aspects, the subject has a EGFR, ALK, NTRK, ROS-1 or BRAF mutation that is sensitive to targeted inhibitor therapy.

In some aspects, the subject is free of EGFR, ALK, NTRK, ROS-1 or BRAF mutations that are sensitive to targeted inhibitor therapy.

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

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

In some aspects, one or more immune cells in tumor tissue from the patient do not express PD-1 (i.e., tumor tissue from the patient is PD-1 negative). In some aspects, the tumor tissue is PD-1 negative when less than about 1% of the immune cells express PD-1.

In some aspects, one or more tumor cells in tumor tissue from the patient do not express PD-L1 (i.e., tumor tissue from the patient is PD-L1 negative). In some aspects, the tumor tissue is PD-L1 negative when less than about 1% of the tumor cells express PD-L1.

In some aspects, LAG-3, PD-1, and/or PD-L1 expression in tumor tissue of a subject is determined from a test tissue sample. In some aspects, the test tissue sample includes, but is not limited to, any clinically relevant tissue sample, such as a tumor biopsy, core biopsy, incision biopsy, resection biopsy, surgical specimen, fine needle aspirate, or a sample of bodily fluid (e.g., blood, plasma, serum, lymph, ascites, cyst fluid, or urine). In some aspects, the test tissue sample is from a primary tumor. In some aspects, the test tissue sample is from a metastasis. In some aspects, the test tissue samples are taken at multiple time points (e.g., before treatment, during treatment, and/or after treatment). In some aspects, the test tissue samples are from different locations in the subject, e.g., from a primary tumor and from metastasis.

In some aspects, the test tissue sample is a paraffin-embedded fixed tissue sample. In some aspects, the test tissue sample is a formalin-fixed paraffin embedded (FFPE) tissue sample. In some aspects, the test tissue sample is a fresh tissue (e.g., tumor) sample. In some aspects, the test tissue sample is a frozen tissue sample. In some aspects, the test tissue sample is a Freshly Frozen (FF) tissue (e.g., tumor) sample. In some aspects, the test tissue sample is a cell isolated from a fluid. In some aspects, the test tissue sample comprises Circulating Tumor Cells (CTCs). In some aspects, the test tissue sample comprises tumor-infiltrating lymphocytes (TILs). In some aspects, the test tissue sample comprises tumor cells and tumor-infiltrating lymphocytes (TILs). In some aspects, the test tissue sample comprises circulating lymphocytes. In some aspects, the test tissue sample is an archived tissue sample. In some aspects, the test tissue sample is an archived tissue sample with a known history of diagnosis, treatment, and/or outcome. In some aspects, the sample is a tissue mass. In some aspects, the test tissue sample is a dispersed cell. In some aspects, the sample size is from about 1 cell to about 1 x 10 ⁶ Individual cells or more. In some aspects, the sample size is from about 1 cell to about 1 x 10 ⁵ Individual cells. In some aspects, the sample is of the sizeFrom about 1 cell to about 10,000 cells. In some aspects, the sample size is from about 1 cell to about 1,000 cells. In some aspects, the sample size is from about 1 cell to about 100 cells. In some aspects, the sample size is from about 1 cell to about 10 cells. In some aspects, the sample size is a single cell.

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

In some aspects, LAG-3, PD-1 and/or PD-L1 expression is assessed by performing an assay to detect the presence of LAG-3, PD-1 and/or PD-L1 polypeptides, respectively. In some aspects, 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.

LAG-3 antagonists

LAG-3 antagonists for use in the methods of the present disclosure include, but are not limited to, LAG-3 binding agents and soluble LAG-3 polypeptides. LAG-3 binding agents include antibodies that specifically bind LAG-3 (i.e., "anti-LAG-3 antibodies"). As used herein, the term "LAG-3 antagonist" is interchangeable with the term "LAG-3 inhibitor".

In some aspects, the LAG-3 antagonist is an anti-LAG-3 antibody.

Antibodies that bind to LAG-3 have been disclosed, for example, in International publication No. WO/2015/042246; and U.S. publication nos. 2014/0093511 and 2011/0150892, each of which is incorporated herein by reference in its entirety.

An exemplary LAG-3 antibody useful in the present disclosure is 25F7 (described in U.S. publication No. 2011/0150892). Another exemplary LAG-3 antibody useful in the present disclosure is BMS-986016 (Rala Li Shan antibody). In some aspects, anti-LAG-3 antibodies useful in the present disclosure cross-compete with 25F7 or BMS-986016. In another aspect, anti-LAG-3 antibodies useful in the present disclosure bind to the same epitope as 25F7 or BMS-986016. In some aspects, the anti-LAG-3 antibody comprises six CDRs of 25F7 or BMS-986016.

Other art-recognized anti-LAG-3 antibodies that may be used in the methods of the present disclosure include IMP731 (H5L 7 BW) described in US 2011/007033, MK-4280 (28G-10, fei Weize Li Shan antibody), burova E et al, j.immunother. Cancer (2016) described in WO 2016028672 and U.S. publication 2020/0055938; 4 (supplement 1): P195 and REGN3767 (furilimab) described in U.S. patent No. 10,358,495, humanized BAP050, GSK2831781, described in WO 2017/019894, IMP-701 (LAG 525; erla Li Shan antibody), aLAG3 (0414), aLAG3 (0416), sym022, TSR-033, TSR-075, xmAb841 (previous XmAb 22841), MGD013 (topolimab), BI754111, FS118, P13B 02-30, AVA-017, age 6, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007 and ABL501. These and other anti-LAG-3 antibodies useful in the claimed invention can be found, for example: US 10,188,730, WO 2016/028672, WO 2017/106129, WO2017/062888, WO 2009/044273, WO 2018/069500, WO 2016/126858, WO 2014/179664, WO 2016/200782, WO 2015/200119, WO 2017/019846, WO 2017/198741, WO 2017/220555, WO 2017/220569, WO 2018/071500, WO 2017/015560, WO 2017/025498, WO 2017/087589, WO 2017/087901, WO 2018/083087, WO 2017/149743, WO 2017/9995, US 2017/0260271, WO 2017/086367, WO 2017/086419, WO 2018/034227, WO 2018/185046, WO 2018/042170, WO 19/011088, WO 201208180, WO 2012084/208180, WO 2010189 and WO 201018730. The contents of each of these references are incorporated by reference in their entirety.

anti-LAG-3 antibodies that can be used in the methods of the present disclosure also include isolated antibodies that specifically bind to human LAG-3 and cross-compete with any anti-LAG-3 antibody disclosed herein (e.g., a rale Li Shan antibody) for binding to human LAG-3. In some aspects, the anti-LAG-3 antibody binds to the same epitope as any anti-LAG-3 antibody described herein (e.g., a rayleigh Li Shan antibody).

In some aspects, antibodies that cross-compete with any anti-LAG-3 antibody disclosed herein (e.g., a rally Li Shan antibody) for binding to human LAG-3 or bind to the same epitope region as any anti-LAG-3 antibody disclosed herein are monoclonal antibodies. For administration to a human subject, these cross-competing antibodies are chimeric, engineered or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies may be prepared and isolated by methods well known in the art.

The ability of antibodies to cross-compete for binding to an antigen indicates that these antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region. These cross-competing antibodies are expected to have very similar functional properties to the reference antibody (e.g., the rayleigh Li Shan antibody) due to their binding to the same epitope region. They can be readily identified in standard binding assays (such as Biacore assays, ELISA assays or flow cytometry) based on their ability to cross-compete for antibodies (see, e.g., WO 2013/173223).

anti-LAG-3 antibodies that can be used in the methods of the present disclosure also include antigen-binding portions of any of the full-length antibodies described above. It is well documented that the antigen binding function of an antibody can be performed by fragments of a full length antibody.

In some aspects, the anti-LAG-3 antibody is a full-length antibody.

In some aspects, the anti-LAG-3 antibody is BMS-986016 (rap Li Shan antibody), IMP731 (H5L 7 BW), MK4280 (28G-10, fei Weize Li Shan antibody), REGN3767 (furilimab), GSK2831781, humanized BAP050, IMP-701 (LAG 525, ela Li Shan antibody), aLAG3 (0414), aLAG3 (0416), sym022, TSR-033, TSR-075, xmAb841 (XmAb 22841), MGD013 (topolimab), BI754111, FS118, P13B 02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or an antigen binding portion thereof.

In some aspects, the anti-LAG-3 antibody is a rale Li Shan antibody.

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO. 3 and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO. 4.

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

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 3 and 4, respectively.

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs 1 and 2, respectively.

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs 21 and 2, respectively.

In some aspects, the anti-LAG-3 antibody is MGD013 (terpolimumab), which is bispecific PD-1 x LAG-3DART. In some aspects, the topolimab is administered intravenously at a dose of about 300mg or about 600mg about every 2 or 3 weeks. In some aspects, the topolimab is administered intravenously at a dose of about 300mg about every 2 weeks. In some aspects, the topolimab is administered intravenously at a dose of about 600mg about every 3 weeks.

In some aspects, the anti-LAG-3 antibody is REGN3767 (furilimumab). In some aspects, the furazalide is administered intravenously at a dose of about 1mg/kg, about 3mg/kg, about 10mg/kg, or about 20mg/kg about every 3 weeks. In some aspects, the furazalizumab is administered intravenously at a dose of about 1600mg about once every 3 weeks. In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO. 25 and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO. 26.

In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising: (a) A heavy chain variable region CDR1 comprising the sequence shown in SEQ ID NO 27; (b) A heavy chain variable region CDR2 comprising the sequence shown in SEQ ID NO. 28; (c) A heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO. 29; (d) A light chain variable region CDR1 comprising the sequence shown in SEQ ID NO. 30; (e) A light chain variable region CDR2 comprising the sequence shown in SEQ ID NO. 31; and (f) a light chain variable region CDR3 comprising the sequence shown in SEQ ID NO. 32.

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 25 and 26, respectively.

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs 23 and 24, respectively.

In some aspects, the anti-LAG-3 antibody is LAG525 (erla Li Shan antibody). In some aspects, the erla Li Shan antibody is administered intravenously at a dose of about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, or about 1300mg about once every 2, 3, or 4 weeks.

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO. 47 and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO. 49.

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO 48 and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO 50.

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

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 47 and 49, respectively.

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 48 and 50, respectively.

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs 43 and 45, respectively.

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs 44 and 46, respectively.

In some aspects, the anti-LAG-3 antibody is MK4280 (Fei Weize Li Shan antibody). In some aspects, fei Weize Li Shan antibodies are administered intravenously at a dose of about 7mg, about 21mg, about 70mg, about 210mg, about 700mg, or about 800mg about once every 3 weeks or about once every 6 weeks. In some aspects, fei Weize Li Shan antibody is administered intravenously at a dose of about 200mg about every 3 weeks. In some aspects, fei Weize Li Shan antibody is administered intravenously at a dose of about 800mg about every 6 weeks. In some aspects, fei Weize Li Shan antibody is administered intravenously at a dose of about 800mg on day 1, then about once every 3 weeks. In some aspects, fei Weize Li Shan antibodies are administered for up to 35 cycles. In some aspects, fei Weize Li Shan antibody is administered intravenously at a dose of about 800mg for up to 35 cycles at day 1 of a three week cycle for about 30 minutes.

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

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

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOS 69 and 70, respectively.

In some aspects, the methods of the present disclosure include anti-LAG-3 antibodies comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs 67 and 68, respectively.

In some aspects, the LAG-3 antagonist is a soluble LAG-3 polypeptide. In some aspects, the soluble LAG-3 polypeptide is a fusion polypeptide, e.g., a fusion protein comprising an extracellular portion of LAG-3. In some aspects, the soluble LAG-3 polypeptide is a LAG-3-Fc fusion polypeptide that is capable of binding to MHC class II. In some aspects, the soluble LAG-3 polypeptide comprises a ligand binding fragment of a LAG-3 extracellular domain. In some aspects, 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 to SEQ ID No. 22. In some aspects, the soluble LAG-3 polypeptide further comprises a half-life extending moiety. In some aspects, the half-life extending moiety comprises an immunoglobulin constant region or portion thereof, an immunoglobulin binding polypeptide, an immunoglobulin G (IgG), an Albumin Binding Polypeptide (ABP), a PAS moiety, a HES moiety, XTEN, a pegylated moiety, an Fc region, or any combination thereof. In some aspects, the soluble LAG-3 polypeptide is IMP321 (etimod a). See, e.g., brignone C et al, j.immunol. (2007); 179:4202-4211 and WO2009/044273. In some aspects, etimod a is administered at a dose of about 30 mg. In some aspects, etimod a is administered subcutaneously at a dose of about 30mg about every 2 weeks.

In some aspects, anti-LAG-3 antibodies are used to determine LAG-3 expression. In some aspects, anti-LAG-3 antibodies are selected for their ability to bind LAG-3 in formalin-fixed, paraffin-embedded (FFPE) tissue samples. In some aspects, the anti-LAG-3 antibody is capable of binding to LAG-3 in frozen tissue. In some aspects, the anti-LAG-3 antibodies are capable of distinguishing between membrane-bound, cytoplasmic, and/or soluble forms of LAG-3.

In some aspects, the anti-LAG-3 antibodies useful for determining, detecting and/or quantifying LAG-3 expression according to the methods disclosed herein are 17B4 mouse IgG1 anti-human LAG-3 monoclonal antibodies. See, e.g., matsuzaki, J et al, PNAS (2010); 107:7875.

In some aspects, the anti-LAG-3 antibody is administered intravenously for about 30 minutes.

In some aspects, the LAG-3 antagonist is administered in a flat dose.

In some aspects, the LAG-3 antagonist is administered in a weight-based dose.

In some aspects, a LAG-3 antagonist as described herein is administered as monotherapy, i.e., the LAG-3 antagonist is not administered in combination with one or more additional therapeutic agents.

In some aspects, a LAG-3 antagonist as described herein is administered as a combination therapy, i.e., the LAG-3 antagonist is administered in combination with one or more additional therapeutic agents and/or anti-cancer therapies.

II.B. combination therapy

The additional therapeutic agent and/or anti-cancer therapy may include any known therapeutic agent or anti-cancer therapy, including standard care in the art for treating subjects with lung cancer. In some aspects, the LAG-3 antagonist is combined with NCCN for the treatment of NSCLCA combination of therapeutic agents and/or therapies described in (c). See, for example, therapeutic agents and therapies described in the following documents:https://www.cancertherapyadvisor.com/home/cancer-topics/ lung-cancer/lung-cancer-treatment-regimens-landing-page/non-small-cell-lung- cancer-treatment-regimens/last visit was 10 months 23 days 2020.

II.B.1. Anticancer therapies

In some aspects, the additional anti-cancer therapy comprises surgery, radiation therapy, chemotherapy, immunotherapy, or any combination thereof. In some aspects, the additional anti-cancer therapy comprises chemotherapy, including any of the chemotherapeutic agents disclosed herein. In some aspects, the chemotherapy comprises platinum-containing dual-drug chemotherapy.

In some aspects, the PDCT comprises a platinum agent in combination with a nucleoside analog, an antimetabolite, a taxane, a vinca alkaloid, or a topoisomerase inhibitor.

In some aspects, the platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, liposomal platinum, or phenanthriplatin.

In some aspects, the nucleoside analog is cytarabine, gemcitabine, lamivudine, entecavir, or telbivudine. In some aspects, the nucleoside analog is gemcitabine.

In some aspects, the antimetabolite is capecitabine, cladribine, clofarabine, cytarabine, fluorouridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pennisetum, pralatrexed, or thioguanine. In some aspects, the antimetabolite is pemetrexed.

In some aspects, the taxane is paclitaxel, albumin-bound paclitaxel (also referred to as nanoparticle albumin-bound paclitaxel), docetaxel, or carbopaclitaxel.

In some aspects, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincamine alcohol, vinri dine, or vinbunting. In some aspects, the vinca alkaloid is vinorelbine or vinblastine.

In some aspects, the topoisomerase inhibitor is etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin. In some aspects, the topoisomerase inhibitor is etoposide. In some aspects, the topoisomerase inhibitor is irinotecan.

In some aspects, the PDCT is administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, or about 24 weeks.

In some aspects, the PDCT is administered for about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8 cycles about every three weeks. In some aspects, the PDCT is administered for about 1, about 2, about 3, about 4, about 5, or about 6 cycles about every three weeks. In some aspects, the PDCT is administered for about 1, about 2, about 3, or about 4 cycles every three weeks.

In some aspects, the PDCT is administered for up to about 4, about 5, or about 6 three week periods. In some aspects, the PDCT is administered for up to about 4 three week periods.

In some aspects, the platinum agent is cisplatin. In some aspects, cisplatin is added at about 25mg/m ² To about 150mg/m ² About 50mg/m ² To about 100mg/m ² About 75mg/m ² To about 100mg/m ² Or about 75mg/m ² To about 80mg/m ² Is administered at a dose of (a). In some aspects, cisplatin is added at about 50mg/m 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/m ² About 85mg/m ² About 90mg/m ² About 95mg/m ² Or about 100mg/m ² Is administered at a dose of (a). In some aspects, cisplatin is administered intravenously for about 60 minutes. In some aspects, cisplatin is administered on day 1 of a three week period for up to about 4, about 5, or about 6 periods.

In some aspects, the platinum agent is carboplatin. In some aspects, carboplatin is administered at a dose having an area under the target concentration-time curve (AUC) of about 1 mg/mL-min to about 10 mg/mL-min. In some aspects, carboplatin is administered at a dose of about 1 mg/mL-min, about 2 mg/mL-min, about 3 mg/mL-min, about 4 mg/mL-min, about 5 mg/mL-min, about 6 mg/mL-min, about 7 mg/mL-min, about 8 mg/mL-min, about 9 mg/mL-min, or about 10 mg/mL-min of the target AUC. In some aspects, carboplatin is administered at a dose of about 2mg/ml·min for the target AUC. In some aspects, carboplatin is administered at a dose of about 5mg/ml·min for the target AUC. In some aspects, carboplatin is administered at a dose of about 6mg/ml·min for the target AUC. In some aspects, carboplatin is administered intravenously for about 30 minutes. In some aspects, carboplatin is administered on day 1 of a three week period for up to about 4, about 5, or about 6 periods.

The carboplatin dose may be calculated according to methods known in the art. In some aspects, carboplatin dose is calculated using the following calvet formula (Calvert formula):

carboplatin dose (mg) =target aucx (CrCl [ mL/min ] +25).

Creatine clearance (CrCl) calculations in the calfute formula may be determined using the colk croft-Gao Erte formula (Cockcroft-Gault formula):

kokekoff-Gao Erte crcl= [ (140-age) x (body weight (kg)) x (0.85 (female)) ]/(72 xcr).

The formula of Kekrofet-Gao Erte includes the subject's recent body weight (kg) and recent serum creatinine (Cr) concentration (mg/dL). In some aspects, if a result of >125mL/min is obtained by calculating CrCl by the formula of Kekrofet-Gao Erte, then CrCl is calculated by an alternative formula according to the institutional standards or has an upper limit of 125mL/min.

In some aspects, the PDCT comprises cisplatin or carboplatin in combination with gemcitabine, paclitaxel, albumin-bound paclitaxel, docetaxel, pemetrexed, vinorelbine, vinblastine, etoposide, or irinotecan.

In some aspects, the PDCT comprises cisplatin or carboplatin in combination with gemcitabine. In some aspects, gemcitabine is administered at about 1,000mg/m ² To about 1,250mg/m ² Is administered at a dose of (a). In some aspects, gemcitabine is administered at about 1,000mg/m ² About 1,050mg/m ² About 1,100mg/m ² About 1,150mg/m ² About 1,200mg/m ² Or about 1,250mg/m ² Is administered at a dose of (a). In some aspects, the gemcitabine is administered intravenously for about 30 minutes. In some aspects, gemcitabine is administered on days 1, 8, and 15 of a three week cycle for up to about 4, about 5, or about 6 cycles. In some aspects, gemcitabine is administered on days 1 and 8 of a three week cycle for up to about 4, about 5, or about 6 cycles. In some aspects, aThe PDCT comprises intravenous administration at a dose of about 1,000mg/m on days 1 and 8 of a three week cycle ² To about 1.250mg/m ² For about 30 minutes for about 4 to about 6 cycles, and an intravenous administration dose of about 75mg/m on day 1 of each cycle ² To about 80mg/m ² About 60 minutes. In some aspects, the PDCT comprises intravenous administration at a dose of about 1,000mg/m on days 1, 8, and 15 of a three week cycle ² For about 30 minutes, for about 4 to about 6 cycles, and intravenously administering carboplatin at a dose of about 5mg/ml·min for a target AUC on day 1 of each cycle for about 30 minutes.

In some aspects, the PDCT comprises cisplatin or a combination of carboplatin and paclitaxel. In some aspects, paclitaxel is administered at about 45mg/m ² To about 200mg/m ² Is administered at a dose of (a). In some aspects, paclitaxel is administered at the following doses: about 45mg/m ² About 50mg/m ² About 55mg/m ² About 60mg/m ² About 65mg/m ² About 70mg/m ² About 75mg/m ² About 80mg/m ² About 85mg/m ² About 90mg/m ² About 95mg/m ² About 100mg/m ² About 105mg/m ² About 110mg/m ² About 115mg/m ² About 120mg/m ² About 125mg/m ² About 130mg/m ² About 135mg/m ² About 140mg/m ² About 145mg/m ² About 150mg/m ² 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 about 200mg/m ² . In some aspects, paclitaxel is administered intravenously for about 60 minutes to about 180 minutes. In some aspects, the PDCT comprises an intravenous administration dose of about 200mg/m on day 1 of a three week period ² For about 180 minutes for about 4 to about 6 cycles, and at 1 st of each cycleThe daily intravenous administration dose is about 75mg/m ² To about 80mg/m ² About 60 minutes. In some aspects, the PDCT comprises an intravenous administration dose of about 135mg/m on day 1 of a three week period ² For about 180 minutes for about 4 to about 6 cycles, and intravenous administration at a dose of about 75mg/m on day 1 of each cycle ² About 60 minutes. In some aspects, the PDCT comprises an intravenous administration dose of about 200mg/m on day 1 of a three week period ² For about 4 to about 6 cycles, and intravenously administering carboplatin at a dose of about 6mg/ml·min for a target AUC for about 30 minutes on day 1 of each cycle. In some aspects, the PDCT comprises an intravenous administration dose of about 45mg/m on day 1 of a week period ² To about 50mg/m ² For about 60 minutes for about 7 cycles, and intravenously administering carboplatin at a dose of about 2 mg/mL/min for a target AUC on day 1 of each cycle for about 30 minutes.

In some aspects, the PDCT comprises cisplatin or carboplatin in combination with albumin-bound paclitaxel. In some embodiments, albumin-bound paclitaxel is administered at about 100mg/m ² Is administered at a dose of (a). In some aspects, the albumin-bound paclitaxel is administered intravenously for about 30 minutes. In some aspects, the PDCT comprises an intravenous administration dose of about 100mg/m on days 1, 8, and 15 of a three week cycle ² Albumin-bound paclitaxel for about 30 minutes for about 4 cycles, and intravenous administration at about 75mg/m on day 1 of each cycle ² To about 80mg/m ² About 60 minutes. In some aspects, the PDCT comprises an intravenous administration dose of about 100mg/m on days 1, 8, and 15 of a three week cycle ² Albumin-bound paclitaxel for about 30 minutes for about 4 to about 6 cycles, and carboplatin at a dose of about 6mg/ml·min for about 30 minutes at the target AUC was administered intravenously on day 1 of each cycle.

In some aspects, the PDCT comprises cisplatin or a combination of carboplatin and docetaxel. In some embodiments, docetaxel is administered at about 75mg/m ² Is administered at a dose of (a). In some aspects, willDocetaxel was administered intravenously for about 60 minutes. In some aspects, the PDCT comprises a dose of about 75mg/m administered intravenously on day 1 of a three week period ² About 60 minutes for about 4 to about 6 cycles, and intravenous administration at about 75mg/m on day 1 of each cycle ² About 60 minutes. In some aspects, the PDCT comprises a dose of about 75mg/m administered intravenously on day 1 of a three week period ² About 60 minutes for about 4 to about 6 cycles, and intravenously administering carboplatin at a dose of about 6mg/ml·min for a target AUC on day 1 of each cycle for about 30 minutes.

In some aspects, the PDCT comprises cisplatin or a combination of carboplatin and pemetrexed. In some embodiments, pemetrexed is added at about 500mg/m ² Is administered at a dose of (a). In some aspects, pemetrexed is administered intravenously for about 10 minutes. In some aspects, the PDCT comprises an intravenous administration dose of about 500mg/m on day 1 of a three week period ² Is maintained for about 4 to about 6 cycles for about 10 minutes, and is administered intravenously at a dose of about 75mg/m on day 1 of each cycle ² About 60 minutes. In some aspects, the PDCT comprises an intravenous administration dose of about 500mg/m on day 1 of a three week period ² Is continued for about 3 cycles for about 10 minutes and is administered intravenously at a dose of about 75mg/m on day 1 of each cycle ² About 60 minutes. In some aspects, the PDCT comprises an intravenous administration dose of about 500mg/m on day 1 of a three week period ² For about 60 minutes, for about 4 to about 6 cycles, and intravenously administering carboplatin at a dose of about 6mg/ml·min for a target AUC on day 1 of each cycle for about 30 minutes. In some aspects, the PDCT comprises an intravenous administration dose of about 500mg/m on day 1 of a three week period ² For about 60 minutes, for about 4 to about 6 cycles, and intravenously administering carboplatin at a dose of about 5mg/ml·min for a target AUC on day 1 of each cycle for about 30 minutes.

In some aspects, the PDCT comprises cisplatin or a combination of carboplatin and etoposide. In some aspects, etoposide is present at about 50mg/m ² To about 100mg/m ² Is administered at a dose of (a). In some aspects, etoposide is administered intravenously for about 30 minutes to about 60 minutes. In some aspects, the PDCT comprises administering intravenously at a dose of about 100mg/m on days 1-3 of a three week period ² For about 60 minutes for about 4 to about 6 cycles, and intravenous administration at a dose of about 100mg/m on day 1 of each cycle ² About 60 minutes. In some aspects, the PDCT comprises administering intravenously at a dose of about 100mg/m on days 1-3 of a four week period ² For about 60 minutes for about 4 cycles, and intravenous administration at a dose of about 100mg/m on day 1 of each cycle ² About 60 minutes. In some aspects, the PDCT comprises administering intravenously at a dose of about 50mg/m on days 1-5 of a four week period ² For about 60 minutes for about 2 cycles, and intravenous administration at about 50mg/m on day 1 and day 8 of each cycle ² About 60 minutes. In some aspects, the PDCT comprises administering intravenously at a dose of about 100mg/m on days 1-3 of a three week period ² For about 30 minutes, for about 4 to about 6 cycles, and intravenously administering carboplatin at a dose of about 5mg/ml·min for a target AUC on day 1 of each cycle for about 30 minutes.

In some aspects, the PDCT comprises cisplatin and vinorelbine. In some aspects, vinorelbine is added at about 25mg/m ² To about 30mg/m ² Is administered at a dose of (a). In some aspects, vinorelbine is administered intravenously for about 5 minutes to about 10 minutes. In some aspects, the PDCT comprises an intravenous administration dose of about 25mg/m on day 1 and day 8 of a three week cycle ² To about 30mg/m ² About 5 minutes to about 10 minutes for about 4 cycles, and intravenous administration at day 1 of each cycle at a dose of about 75mg/m ² To about 80mg/m ² About 60 minutes. In some aspects, the PDCT comprises intravenous administration at a dose of about 25mg/m on days 1, 8, 15, and 22 of a four week cycle ² About 5 minutes to about 10 minutes for about 4 cycles, and intravenous administration at about 50mg +. m ² About 60 minutes. In some aspects, the PDCT comprises intravenous administration at a dose of about 30mg/m on days 1, 8, 15, and 22 of a four week cycle ² About 5 minutes to about 10 minutes for about 4 cycles, and intravenous administration at a dose of about 100mg/m on day 1 of each cycle ² About 60 minutes.

In some aspects, the PDCT comprises cisplatin and vinblastine. In some aspects, vinblastine is added at about 5mg/m ² Is administered at a dose of (a). In some aspects, the vinblastine is administered intravenously for about 5 minutes to about 10 minutes. In some aspects, the PDCT comprises intravenous administration at a dose of about 5mg/m on days 1, 8, 15, 22, and 29 of a 35 day cycle ² About 5 minutes to about 10 minutes, and intravenous administration at about 100mg/m on days 1 and 29 of the cycle ² About 60 minutes.

In some aspects, the PDCT is combined with bevacizumab (also known as) And (3) combined application. In some aspects, bevacizumab is administered intravenously at a dose of about 15mg/kg on day 1 of a three week cycle for about 6 cycles, paclitaxel is administered at about 200mg/m on day 1 of each cycle ² Is administered intravenously for about 180 minutes and carboplatin is administered intravenously at a dose of about 6 mg/mL-min for a target AUC on day 1 of each cycle for about 30 minutes. In some aspects, bevacizumab is administered intravenously at a dose of about 15mg/kg for about 4 to about 6 cycles on day 1 of the three week cycle, pemetrexed at about 500mg/m on day 1 of each cycle ² Is administered intravenously for about 10 minutes and carboplatin is administered intravenously at a dose of about 6 mg/mL-min for a target AUC on day 1 of each cycle for about 30 minutes. In some aspects, bevacizumab is administered intravenously at a dose of about 7.5mg/kg for about 4 to about 6 cycles on day 1 of the three week cycle, pemetrexed is administered at about 500mg/m on day 1 of each cycle ² Is administered intravenously for about 10 minutes at a dose of about 75mg/m on day 1 of each cycle ² Is administered intravenously for about 60 minutes.

II.B.2. therapeutic agents

In some aspects, the additional therapeutic agent comprises an anticancer agent. In some aspects, the anti-cancer agent comprises a tyrosine kinase inhibitor, an anti-angiogenesis agent, a checkpoint inhibitor, a checkpoint stimulant, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topoisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof.

In some aspects, the tyrosine kinase inhibitor comprises sorafenib (e.g., sorafenib tosylate, also known as) Lenvatinib (e.g. lenvatinib mesylate, also known as +.>) Regorafenib (e.g.) >) Cabozitinib (e.g. cabozitinib S-malate, also called +.>) Sunitinib (e.g. sunitinib malate, also known as +.>) Brinib, li Nifa Ni, pemettinib (also known as PEMAZYRE) ^TM ) Everolimus (also known as +.>Or->) Gefitinib (/ -)>Molecular TKI of EGFR), imatinib (e.g., imatinib mesylate), lapatinib (e.g., lapatinib xylene sulfonate, also known as +.>) Nilotinib (e.g., nilotinib hydrochloride, also known as +.>) Pazopanib (e.g. pazopanib hydrochloride, also called +.>) Tamrolimus (also known as +.>) Erlotinib (e.g., erlotinib hydrochloride, also known as +.>Molecular TKI of EGFR), afatinib (/ -for EGFR)>Molecular TKI for EGFR), dactylinib (>Molecular TKI for EGFR), octreotide (/ -for EGFR>Molecular TKI for EGFR), ai Leti ni (/ -for EGFR)>Small molecule TKI for ALK), ceritinib (>Small molecule TKI of ALK and ROS-1), bujitinib (++>Small molecule TKI for ALK), crizotinib (+.>Small molecule TKI of ALK and ROS-1), lolatinib (+.>Small molecule TKI of ALK and ROS-1), emtrictinib @, andsmall molecule TKI of ROS-1 and NTRK), dabrafenib (++>Small molecule TKI for BRAF), trametinib (/ -for BRAF>Small molecule TKI of BRAF), dimension Mo Feini (/ -for BRAF >Small molecule TKI for BRAF), larotinib (>A small molecule TKI of NTRK) or any combination thereof.

In some aspects, the anti-angiogenic agent comprises an inhibitor of Vascular Endothelial Growth Factor (VEGF), VEGF receptor (VEGFR), platelet Derived Growth Factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase (Tie) receptor having Ig-like and EGF-like domains, hepatocyte Growth Factor (HGF), tyrosine protein kinase Met (C-Met), C lectin family 14 member a (CLEC 14A), polyprotein 2 (MMRN 2), shock protein 70-1A (HSP 70-1A), epidermal Growth Factor (EGF), EGFR, or any combination thereof. In some aspects, the anti-angiogenic agent comprises bevacizumab (also known as) Ramucirumab (also known as +.>) Abelmoschus (also known asOr->) Tanibiumab, olamab (also known as LARTRUVO ^TM ) Pravastatin Su Shan, AMG780, MEDI3617, vannooxymab, rituximab, non-pratutuzumab, TAK-701, onatuzumab, ematuzumab, or any combination thereof.

In some aspects, the anti-angiogenic agent is bevacizumab. In some aspects, bevacizumab is administered at a dose of about 15 mg/kg. In some aspects, bevacizumab is administered at a dose of about 15mg/kg on day 1 of a three week cycle.

In some aspects, the checkpoint stimulators include agonists of B7-1, B7-2, CD28, 4-1BB (CD 137), 4-1BBL, GITR, an induced T cell costimulatory agent (ICOS), ICOS-L, OX40, OX40L, CD, CD27, CD40, death receptor 3 (DR 3), CD28H, or any combination thereof.

In some aspects, the chemotherapeutic agent comprises an alkylating agent, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, a hormone or hormone modulator, a protein tyrosine kinase inhibitor, an epidermal growth factor inhibitor, a proteasome inhibitor, other neoplastic agents, or any combination thereof.

In some aspects, the immunotherapeutic agent comprises a drug that binds to EGFR (e.g., cetuximab) ALK, ROS-1, NTRK, BRAF, ICOS, CD137 (4-1 BB), CD134 (OX 40), NKG2A, CD, CD96, GITR, herpes Virus Entry Mediator (HVEM), PD-1, PD-L1, CTLA-4, BTLA, TIM-3, A2aR, killer lectin-like receptor G1 (KLRG-1), natural killer cell receptor 2B4 (CD 244), CD160, TIGIT, VISTA, KIR, TGF beta, IL-10, IL-8, B7-H4, fas ligand,Antibodies that specifically bind CSF1R, CXCR, mesothelin, CEACAM-1, CD52, HER2, MICA, MICB, or any combination thereof.

In some aspects, the platinum agent comprises cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin (e.g., triplatin tetranitrate), liposomal platinum, phenanthreneplatinum, or any combination thereof.

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

In some aspects, the taxane comprises paclitaxel, albumin-bound paclitaxel (i.e., nanoparticle albumin-bound paclitaxel), docetaxel, carbopaclitaxel, or any combination thereof.

In some aspects, the taxane comprises paclitaxel. In some aspects, paclitaxel is administered at about 200mg/m ² To about 225mg/m ² Is administered intravenously for about 180 minutes on day 1 of a three week period for about 4 to about 6 cycles. In some aspects, paclitaxel is administered at about 80mg/m ² Is administered intravenously on days 1, 8, and 15 of a four week cycle for about 60 minutes for about 4 to about 6 cycles.

In some aspects, the taxane comprises albumin-bound paclitaxel. In some aspects, albumin-bound paclitaxel is administered at about 260mg/m ² Is administered intravenously on day 1 of a three week cycle for about 4 to about 6 cycles. In some aspects, albumin-bound paclitaxel is administered at about 125mg/m ² Is administered intravenously on days 1, 8, and 15 of a four week cycle for about 30 minutes for about 4 to about 6 cycles.

In some aspects, the taxane comprises docetaxel. In some aspects, docetaxel is administered at about 75mg/m ² Is administered intravenously for about 60 minutes on day 1 of a three week cycle. In some aspects, docetaxel is administered at about 75mg/m ² Is administered intravenously for about 4 to about 6 cycles on day 1 of a three week cycle for about 60 minutes.

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

In some aspects, the nucleoside analog is gemcitabine. In some aspects, gemcitabine is administered at about 1,000mg/m ² To about 1,250mg/m ² Is administered intravenously on days 1, 8 and 15 of a four week cycle for about 30 minutes. In some aspects, gemcitabine is administered at about 1,000mg/m ² To about 1,250mg/m ² Is administered intravenously on days 1, 8, and 15 of a four week cycle for about 30 minutes for about 4 to about 6 cycles. In some aspects, gemcitabine is administered at about 1,250mg/m ² Is administered intravenously for about 30 minutes on days 1 and 8 of a three week cycle. In some aspects, gemcitabine is administered at about 1,250mg/m ² Is administered intravenously for about 30 minutes on days 1 and 8 of a three week cycle for about 4 to about 6 cycles.

In some aspects, the antimetabolite comprises capecitabine, cladribine, clofarabine, cytarabine, fluorouridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pennisetum, pralatrexed, thioguanine, or any combination thereof.

In some aspects, the antimetabolite is pemetrexed. In some aspects, pemetrexed is added at about 500mg/m ² Is administered intravenously about 10 minutes on day 1 of a three week cycle. In some aspects, pemetrexed is added at about 500mg/m ² Is administered intravenously on day 1 of a three week cycle for about 4 to about 6 cycles.

In some aspects, the topoisomerase inhibitor comprises etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, camptothecin, or any combination thereof.

In some aspects, the anthracycline is doxorubicin, daunomycin, epirubicin, idarubicin, or any combination thereof.

In some aspects, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincamine alcohol, vinri dine, vinbunting, or any combination thereof.

In some aspects, the anticancer agent comprises gemcitabine and docetaxel. In some aspects, gemcitabine is administered at about 1,000mg/m ² To about 1,250mg/m ² Is administered intravenously for about 30 minutes on days 1 and 8 of a three week cycle for about 4 to about 6 cycles, and docetaxel is administered at about 85mg/m ² Is administered intravenously at day 8 of each cycle for about 30 minutes to about 60 minutes.

In some aspects, the anti-cancer agent comprises gemcitabine and vinorelbine. In some aspects, gemcitabine is administered at about 1,000mg/m ² Is administered intravenously for about 30 minutes on days 1 and 8 of a three week cycle for about 4 to about 6 cycles, and vinorelbine is administered at about 25mg/m ² Is administered intravenously on days 1 and 8 of each cycle for about 5 minutes to about 10 minutes.

In some aspects, the anti-cancer agent comprises ramucirumab and docetaxel. In some aspects, ramucirumab is administered intravenously at a dose of about 10mg/kg for about 60 minutes on day 1 of the three week cycle, and docetaxel is administered at about 75mg/m ² Is administered intravenously on day 1 of each cycle for about 60 minutes.

In some aspects, the anti-cancer agent comprises bevacizumab and pemetrexed. In some aspects, bevacizumab is administered intravenously at a dose of about 7.5mg/kg to about 15mg/kg for about 10 minutes on day 1 of a three week cycle, and pemetrexed is administered at about 500mg/m ² Is administered intravenously on day 1 of each cycle for about 10 minutes.

II.B.3. Checkpoint inhibitors

In some aspects, the anti-cancer agent administered as an additional therapeutic agent in the methods of the present disclosure is a checkpoint inhibitor.

In some aspects, the checkpoint inhibitors include inhibitors of the programmed death protein-1 (PD-1) pathway, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, T cell immunoglobulin and ITIM domain (TIGIT) inhibitors, T cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B and T cell lymphocyte attenuator (BTLA) inhibitors, T cell activated V domain Ig inhibitor (VISTA) inhibitors, indoleamine 2, 3-dioxygenase (IDO) inhibitors (e.g., indoleamine 2, 3-dioxygenase 1 (IDO 1) inhibitors, ai Kaduo span (INCB 24360), natamod (GDC-0919) or Lin Luosi he (BMS-986205), including Lin Luosi his salts, such as, for example, methanesulfonic acid Lin Luosi he), nicotinamide adenine dinucleotide phosphate oxidase subtype 2 (NOX 2) inhibitors, killer cell immunoglobulin-like receptor (KIR) inhibitors, adenosine A2a receptor (A2 aR) inhibitors, transforming growth factor beta (TGF-beta) inhibitors, phosphoinositide 3-kinase (PI 3K) inhibitors, CD47 inhibitors, CD48 inhibitors, CD73 inhibitors, CD113 inhibitors, sialic acid binding immunoglobulin-like lectin-7 (SIGLEC-7) inhibitors, sigc-9 inhibitors, SIGLEC-15 inhibitors, glucocorticoid-induced TNFR-related protein (GITR) inhibitors, galectin-1 inhibitors, galectin-9 inhibitors, carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1) inhibitors, G protein coupled receptor 56 (GPR 56) inhibitors, glycoprotein A repeat dominant (GARP) inhibitors, 2B4 inhibitors, programmed death protein-1 homolog (PD 1H) inhibitors, leukocyte-related immunoglobulin-like receptor 1 (LAIR 1) inhibitors, or any combination thereof.

In some aspects, the checkpoint inhibitor is administered in a flat dose.

In some aspects, the dose of the checkpoint inhibitor 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, or every twelve weeks.

In some aspects, each dose of the LAG-3 antagonist and/or the checkpoint inhibitor is administered in a constant amount.

In some aspects, each dose of the LAG-3 antagonist and/or the checkpoint inhibitor is administered in a different amount. For example, in some aspects, the maintenance (or subsequent) dose of the LAG-3 antagonist and/or the checkpoint inhibitor may be greater than or equal to the loading dose administered for the first time. In some aspects, the maintenance dose of the LAG-3 antagonist and/or the checkpoint inhibitor may be lower than or equal to the loading dose.

Inhibitors of the II.B.3.a.PD-1 pathway

In some aspects, checkpoint inhibitors for use in methods of the present disclosure include PD-1 pathway inhibitors.

In some aspects, the PD-1 pathway inhibitor is a PD-1 inhibitor and/or a PD-L1 inhibitor.

In some aspects, the PD-1 inhibitor and/or PD-L1 inhibitor is a small molecule.

In some aspects, the PD-1 inhibitor and/or PD-L1 inhibitor is a millamolecule.

In some aspects, the PD-1 inhibitor and/or PD-L1 inhibitor is a macrocyclic peptide.

In certain aspects, the PD-1 inhibitor and/or PD-L1 inhibitor is BMS-986189.

In some aspects, the PD-1 inhibitor is an inhibitor disclosed in international publication No. WO 2014/151634, which is incorporated herein by reference in its entirety.

In some aspects, the PD-1 inhibitor is incmsa 00012 (Insight Pharmaceuticals).

In some aspects, the PD-1 inhibitors include a combination of an anti-PD-1 antibody disclosed herein and a PD-1 small molecule inhibitor.

In some aspects, the PD-L1 inhibitor comprises a millamole having the formula shown in formula (I):

wherein R is ¹ -R ¹³ Is an amino acid side chain, R ^a -R ⁿ Is hydrogen, methyl or forms a ring with an adjacent R group, and R ¹⁴ is-C (O) NHR ¹⁵ Wherein R is ¹⁵ Is a hydrogen or glycine residue optionally substituted with additional glycine residues and/or tails that may improve pharmacokinetic properties. In some aspects, the PD-L1 inhibitor comprises a compound disclosed in international publication No. WO 2014/151634, which is incorporated herein by reference in its entirety. In some aspects, the PD-L1 inhibitor comprises a compound disclosed in: international publication Nos. WO 2016/039749, WO 2016/149551, WO 2016/077518, WO 2016/100285, WO 2016/100608, WO 2016/126646, WO 2016/057624, WO 2017/151830, WO 2017/1768608, WO 2018/085750, WO 2018/237153 or WO 2019/070643, each of which is incorporated herein by reference in its entirety.

In some aspects, the PD-L1 inhibitor comprises a small molecule PD-L1 inhibitor disclosed in: international publication nos. WO 2015/034820, WO 2015/160641, WO 2018/044963, WO 2017/066227, WO 2018/009505, WO 2018/183171, WO 2018/118848, WO 2019/147662, or WO 2019/169123, each of which is incorporated herein by reference in its entirety.

In some aspects, the PD-1 pathway inhibitor is a soluble PD-L2 polypeptide. In some aspects, the soluble PD-L2 polypeptide is a fusion polypeptide. In some aspects, the soluble PD-L2 polypeptide comprises a ligand binding fragment of a PD-L2 extracellular domain. In some aspects, the soluble PD-L2 polypeptide further comprises a half-life extending moiety. In some aspects, the half-life extending moiety comprises an immunoglobulin constant region or portion thereof, an immunoglobulin binding polypeptide, an immunoglobulin G (IgG), an Albumin Binding Polypeptide (ABP), a PAS moiety, a HES moiety, XTEN, a pegylated moiety, an Fc region, or any combination thereof. In some aspects, the soluble PD-L2 polypeptide is AMP-224 (see, e.g., US 2013/0017199).

II.B.3.a.i. anti-PD-1 antibodies

anti-PD-1 antibodies known in the art may be used in the methods of the present disclosure. Various human monoclonal antibodies that specifically bind to PD-1 with high affinity have been 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 been demonstrated to exhibit one or more of the following characteristics: (a) At 1x 10 ^-7 M or less K _D Binding to human PD-1 as determined by surface plasmon resonance using a Biacore biosensor system; (b) does not substantially bind to human CD28, CTLA-4 or ICOS; (c) Increasing T cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay; (d) increasing interferon-gamma production in the MLR assay; (e) increasing IL-2 secretion in the MLR assay;(f) Binding to human PD-1 and cynomolgus PD-1; (g) inhibiting the binding of PD-L1 and/or PD-L2 to PD-1; (h) stimulating an antigen-specific memory response; (i) stimulating an antibody response; and (j) inhibiting tumor cell growth in vivo. anti-PD-1 antibodies useful in the present disclosure include monoclonal antibodies that specifically bind to human PD-1 and exhibit at least one, in some aspects at least five, of the foregoing characteristics.

Other anti-PD-1 monoclonal antibodies that can be used in the methods of the present disclosure have been described, for example, in the following: us patent numbers 6,808,710, 7,488,802, 8,168,757 and 8,354,509, us publication numbers 2016/0272708, and PCT publication numbers WO 2012/145493, WO 2008/156712, WO 2015/112900, WO 2012/145493, WO 2015/112800, WO 2014/206107, WO 2015/35606, WO 2015/085847, WO 2014/179664, WO 2017/020291, WO 2017/020858, WO 2016/197367, WO 2017/0245515, WO 2017/025051, WO 2017/123557, WO 2016/106159, WO 2014/194302, WO 2017/040790, WO 2017/133540, WO 2017/132827, WO 2017/024665, WO 2017/025016, WO 2017/1067, WO 2017/19846, WO 2017/0202465, WO 2017/025016, WO 2017/1335, and WO 2017/540 are each incorporated by reference in its entirety.

anti-PD-1 antibodies that can be used in the methods of the present disclosure include nivolumab (also known as5C4, BMS-936558, MDX-1106 and ONO-4538), pembrolizumab (Merck; also called +.>Palbociclizumab (lambrolizumab) and MK3475; see WO 2008/156712), PDR001 (Novartis; also known as swabber; see WO 2015/112900 and U.S. patent No. 9,683,048), MEDI-0680 (AstraZeneca; also known as AMP-514; see WO 2012/145493), TSR-042 (Tesaro Biopharmaceutical; also known as ANB011 or rituximab; see WO 2014/179664), ciminopril Li Shan (Regeneron; also called +.>Or REGN2810; see WO 2015/112800 and U.S. patent No. 9,987,500), JS001 (TAIZHOU JUNSHI PHARMA; also known as terep Li Shan antibody; see Si-Yang Liu et al, J.Hematol. Oncol.10:136 (2017)), PF-06801591 (Pfizer; also known as saran Li Shan resistance; US 2016/0159905), BGB-a317 (Beigene; also known as tirelizumab; see WO 2015/35606 and US 2015/0079209), BI 754091 (Boehringer Ingelheim; see Zettl M et al, cancer.res. (2018); 78 (13 journal) abstract 4558), incsshr 1210 (Jiangsu Hengrui Medicine; also known as SHR-1210 or Carilizumab; see WO 2015/085847; si-Yang Liu et al, J.Hematol. Oncol.10:136 (2017)), GLS-010 (Wuxi/Harbin Gloria Pharmaceuticals; also known as WBP3055; see Si-Yang Liu et al, J.Hematol. Oncol.10:136 (2017)), AM-0001 (Armo), STI-1110 (Sorrento Therapeutics; see WO 2014/194302), AGEN2034 (agalus; see WO 2017/040790), MGA012 (macrogenetics; see WO 2017/19846), BCD-100 (Biocad; kaplon et al, mAbs10 (2): 183-203 (2018), IBI308 (Innovent; also known as Xindi Li Shan antibody; see WO 2017/024465, WO 2017/025016, WO 2017/132825 and WO 2017/133540), and SSI-361 (Lyvgen Biopharma Holdings Limited, US 2018/0346569).

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

In some aspects, an antibody that cross-competes with any anti-PD-1 antibody disclosed herein (e.g., nivolumab) for binding to human PD-1 or binds to the same epitope region as any anti-PD-1 antibody disclosed herein is a monoclonal antibody. For administration to a human subject, these cross-competing antibodies are chimeric, engineered or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies may be prepared and isolated by methods well known in the art.

anti-PD-1 antibodies that can be used in the methods of the present disclosure also include antigen-binding portions of any of the full-length antibodies described above.

anti-PD-1 antibodies that can be used in the methods of the present disclosure 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 effects of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-1 "antibody" includes an antigen-binding portion or fragment that binds to the PD-1 receptor and exhibits similar functional properties as an intact antibody in terms of inhibiting ligand binding and up-regulating the immune system. In certain aspects, the anti-PD-1 antibody, or antigen-binding portion thereof, cross-competes with nivolumab for binding to human PD-1.

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

In some aspects, the anti-PD-1 antibodies are formulated for intravenous administration.

In some aspects, the anti-PD-1 antibody is administered intravenously for about 30 minutes.

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

In some aspects, the nivolumab is administered at a flat dose of about 240mg about every 2 weeks. In some aspects, the nivolumab is administered at a flat dose of about 240mg about once every 3 weeks. In some aspects, the nivolumab is administered at a flat dose of about 360mg about once every 3 weeks. In some aspects, the nivolumab is administered at a flat dose of about 480mg about once every 4 weeks.

In some aspects, the nivolumab is administered intravenously at a dose of about 240mg for about 30 minutes on day 1 of a two week cycle.

In some aspects, the nivolumab is administered intravenously at a dose of about 480mg for about 30 minutes on day 1 of the four week cycle.

In some aspects, the methods of the present disclosure include anti-PD-1 antibodies comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO. 13 and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO. 14.

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

In some aspects, the methods of the present disclosure include anti-PD-1 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 13 and 14, respectively.

In some aspects, the methods of the present disclosure include anti-PD-1 antibodies comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs 11 and 12, respectively.

In some aspects, the methods of the present disclosure comprise a combination of a rapa Li Shan antibody and nivolumab.

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

In some aspects, the methods of the present disclosure include: (a) An anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences shown 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 shown 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 shown 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 shown in SEQ ID No. 18, SEQ ID No. 19, and SEQ ID No. 20, respectively.

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

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

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

In some aspects, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 (S228P) antibody directed against human cell surface receptor PD-1. Pembrolizumab is described, for example, in U.S. patent nos. 8,354,509 and 8,900,587.

In some aspects, pembrolizumab is administered at a flat dose of about 200mg about once every 2 weeks. In some aspects, pembrolizumab is administered at a flat dose of about 200mg about once every 3 weeks. In some aspects, pembrolizumab is administered at a flat dose of about 400mg about once every 6 weeks. In some aspects, pembrolizumab is administered at a flat dose of about 300mg about once every 4-5 weeks.

In some aspects, pembrolizumab is administered intravenously on day 1 at a dose of about 200mg, then about once every 3 weeks. In some aspects, pembrolizumab is administered for up to 35 cycles. In some aspects, pembrolizumab is administered intravenously at a dose of about 200mg for up to 35 cycles at day 1 of a three week cycle for about 30 minutes.

In some aspects, pemetrexed is administered intravenously at a dose of about 200mg for up to 35 cycles at day 1 of a three week cycle, and pemetrexed is administered at about 500mg/m at day 1 of each cycle ² Is administered intravenously for about 10 minutes, followed by about 500mg/m on day 1 of a three week cycle ² Is administered intravenously. In some embodiments, the maintenance therapy continues until disease progression or unacceptable toxicity.

In some aspects, pemetrexed is administered intravenously at a dose of about 200mg for about 30 minutes on day 1 of a three week cycle for about 4 to about 6 cycles, pemetrexed is administered at about 500mg/m on day 1 of each cycle ² Is administered intravenously for about 10 minutes and carboplatin is administered intravenously at a dose of about 5 mg/mL-min for a target AUC on day 1 of each cycle for about 30 minutes.

In some aspects, pemetrexed is administered intravenously at a dose of about 200mg for about 30 minutes on day 1 of a three week cycle for about 4 to about 6 cycles, pemetrexed is administered at about 500mg/m on day 1 of each cycle ² Is administered intravenously for about 10 minutes at a dose of about 75mg/m on day 1 of each cycle ² Is administered intravenously for about 60 minutes.

In one placeIn some aspects, pembrolizumab is administered intravenously at a dose of about 200mg for about 30 minutes on day 1 of a three week cycle for about 4 cycles, and albumin-bound paclitaxel is administered at about 100mg/m on days 1, 8, and 15 of each cycle ² Is administered intravenously for about 30 minutes and carboplatin is administered intravenously at a dose of about 6 mg/mL-min for a target AUC on day 1 of each cycle for about 30 minutes.

In some aspects, pembrolizumab is administered intravenously at a dose of about 200mg on day 1 of a three week cycle for about 4 cycles, paclitaxel is administered at about 200mg/m on day 1 of each cycle ² Is administered intravenously for about 180 minutes and carboplatin is administered intravenously at a dose of about 6 mg/mL-min for a target AUC on day 1 of each cycle for about 30 minutes.

In some aspects, pembrolizumab is administered intravenously at a dose of about 200mg on day 1 of a three week cycle for about 4 cycles, and albumin-bound paclitaxel is administered at about 100mg/m on days 1, 8, and 15 of each cycle ² Is administered intravenously for about 30 minutes at a dose of about 75mg/m on day 1 of each cycle ² To about 80mg/m ² Is administered intravenously for about 60 minutes.

In some aspects, pembrolizumab is administered intravenously at a dose of about 200mg on day 1 of a three week cycle for about 4 cycles, paclitaxel is administered at about 200mg/m on day 1 of each cycle ² Is administered intravenously for about 180 minutes at a dose of about 75mg/m on day 1 of each cycle ² To about 80mg/m ² Is administered intravenously for about 60 minutes.

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

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

In some aspects, the methods of the present disclosure include anti-PD-1 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 79 and 80, respectively.

In some aspects, the methods of the present disclosure include anti-PD-1 antibodies comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs 77 and 78, respectively.

In some aspects, the methods of the present disclosure include a Fei Weize Li Shan antibody in combination with pembrolizumab. In some aspects, 800mg of Fei Weize Li Shan antibody and 200mg of pembrolizumab are administered intravenously on day 1, then about once every 3 weeks. In some aspects, the combination of Fei Weize Li Shan antibody and pembrolizumab is administered for up to 35 cycles. In some aspects, 800mg of Fei Weize Li Shan antibody and 200mg of pembrolizumab are administered intravenously on day 1 of a three week cycle for about 30 minutes for up to 35 cycles.

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

In some aspects, the methods of the present disclosure include: (a) An anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences shown 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 shown 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 shown 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 shown in SEQ ID No. 84, SEQ ID No. 85, and SEQ ID No. 86, respectively.

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

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

In some aspects, the anti-PD-1 antibody is a cimiput Li Shan antibody (REGN 2810). The siegesbeck Li Shan antibody is described, for example, in WO 2015/112800 and U.S. patent No. 9,987,500.

In some aspects, the cimetidine Li Shan antibody is administered intravenously at a dose of about 3mg/kg or about 350mg about every 3 weeks.

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

In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising: (a) A heavy chain variable region CDR1 comprising the sequence shown in SEQ ID NO 37; (b) A heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO 38; (c) A heavy chain variable region CDR3 comprising the sequence shown in SEQ ID NO 39; (d) A light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO. 40; (e) A light chain variable region CDR2 comprising the sequence shown in SEQ ID NO. 41; and (f) a light chain variable region CDR3 comprising the sequence of SEQ ID NO. 42.

In some aspects, the methods of the present disclosure include anti-PD-1 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 35 and 36, respectively.

In some aspects, the methods of the present disclosure include anti-PD-1 antibodies comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs 33 and 34, respectively.

In some aspects, the methods of the present disclosure comprise a combination of furazamab and a cemipramine Li Shan antibody.

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

In some aspects, the methods of the present disclosure include: (a) An anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences shown 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 shown 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 shown 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 shown in SEQ ID No. 40, SEQ ID No. 41, and SEQ ID No. 42, respectively.

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

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

In some aspects, the anti-PD-1 antibody is swabber antibody (PDR 001). Stadalimumab is described, for example, in WO 2015/112900 and U.S. Pat. No. 9,683,048.

In some aspects, the swabbing is administered intravenously at a dose of about 300mg about every 3 weeks or at a dose of 400mg about every 4 weeks.

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

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

In some aspects, the methods of the present disclosure include anti-PD-1 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 59 and 60, respectively.

In some aspects, the methods of the present disclosure include anti-PD-1 antibodies comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs 57 and 58, respectively.

In some aspects, the methods of the present disclosure comprise a combination of an ela Li Shan antibody and a swabbing antibody. In some aspects, the elas Li Shan antibody is administered intravenously at a dose of about 400mg about every three weeks, and the swadazumab is administered intravenously at a dose of about 300mg about every 3 weeks. In some aspects, the elas Li Shan antibody is administered intravenously at a dose of about 600mg about once every four weeks, and the swadazumab is administered intravenously at a dose of about 400mg about once every 4 weeks.

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

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

In some aspects, the methods of the present disclosure include: (a) An anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences shown 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 shown 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 shown 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 shown in SEQ ID No. 64, SEQ ID No. 65, and SEQ ID No. 66, respectively.

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

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

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

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

Provided herein is a method of treating a human subject having lung cancer, the method comprising administering to the subject: (a) an anti-LAG-3 antibody, and (b) an anti-PD-1 antibody.

In some aspects, the method further comprises administering PDCT to the subject.

Provided herein is a method of treating a human subject having stage IV or recurrent NSCLC with squamous histology, the method comprising administering to the subject: (a) an anti-LAG-3 antibody, (b) an anti-PD-1 antibody, and (c) PDCT.

Provided herein is a method of treating a human subject having stage IV or recurrent NSCLC with non-squamous histology, the method comprising administering to the subject: (a) an anti-LAG-3 antibody, (b) an anti-PD-1 antibody, and (c) PDCT.

The anti-LAG-3 antibody and the anti-PD-1 antibody may be administered in any dose or combination of doses described herein.

In some aspects, the dose of the anti-LAG-3 antibody is 80mg.

In some aspects, the dose of the anti-LAG-3 antibody is 160mg.

In some aspects, the dose of the anti-LAG-3 antibody is 360mg.

In some aspects, the dose of the anti-LAG-3 antibody is 480mg.

In some aspects, the dose of the anti-LAG-3 antibody is 720mg.

In some aspects, the dose of the anti-LAG-3 antibody is 800mg.

In some aspects, the dose of the anti-LAG-3 antibody is 960mg.

In some aspects, the dose of the anti-PD-1 antibody is 200mg.

In some aspects, the dose of the anti-PD-1 antibody is 240mg.

In some aspects, the dose of the anti-PD-1 antibody is 360mg.

In some aspects, the dose of the anti-PD-1 antibody is 480mg.

In some aspects, the dose of the anti-LAG-3 antibody is 80mg and the dose of the anti-PD-1 antibody is 240mg.

In some aspects, the dose of the anti-LAG-3 antibody is 160mg and the dose of the anti-PD-1 antibody is 480mg.

In some aspects, the dose of the anti-LAG-3 antibody is 360mg and the dose of the anti-PD-1 antibody is 360mg.

In some aspects, the dose of the anti-LAG-3 antibody is 480mg and the dose of the anti-PD-1 antibody is 480mg.

In some aspects, the dose of the anti-LAG-3 antibody is 720mg and the dose of the anti-PD-1 antibody is 360mg.

In some aspects, the dose of the anti-LAG-3 antibody is 800mg and the dose of the anti-PD-1 antibody is 200mg.

In some aspects, the dose of the anti-LAG-3 antibody is 960mg and the dose of the anti-PD-1 antibody is 480mg.

Provided herein is a method of treating a human subject having lung cancer, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 360 mg; and (b) an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence shown in SEQ ID NO. 13 and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence shown in SEQ ID NO. 14 at a dose of about 360mg.

Provided herein is a method of treating a human subject having lung cancer, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 720 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14.

Provided herein is a method of treating a human subject having stage IV or recurrent NSCLC with squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 360 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) Carboplatin at a dose of about 6 mg/mL-min in area under the target concentration-time curve, and (ii) at a dose of about 200mg/m ² Wherein the method is first line therapy.

Provided herein is a method of treating a human subject having stage IV or recurrent NSCLC with squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 720 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) Carboplatin at a dose of about 6 mg/mL-min in area under the target concentration-time curve, and (ii) at a dose of about 200mg/m ² Wherein the method is first line therapy.

Provided herein is a method of treating a human subject having stage IV or recurrent NSCLC with squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 360 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) Carboplatin at a dose of about 6 mg/mL-min in area under the target concentration-time curve, and (ii) at a dose of about 100mg/m ² Albumin-bound paclitaxel, wherein the method is first line therapy.

Provided herein is a method of treating a human subject having stage IV or recurrent NSCLC with squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 720 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) Carboplatin at a dose of about 6 mg/mL-min in area under the target concentration-time curve, and (ii) at a dose of about 100mg/m ² Albumin-bound paclitaxel, wherein the method is first line therapy.

Provided herein is a method of treating a human subject having stage IV or recurrent NSCLC with non-squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence shown in SEQ ID NO. 3 at a dose of about 360mg CDR1, CDR2 and CDR3 domains of the 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 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) Carboplatin at a target concentration-time curve area of about 5 mg/mL-min or about 6 mg/mL-min, and (ii) at a dose of about 500mg/m ² Wherein the method is first line therapy.

Provided herein is a method of treating a human subject having stage IV or recurrent NSCLC with non-squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 720 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) Carboplatin at a target concentration-time curve area of about 5 mg/mL-min or about 6 mg/mL-min, and (ii) at a dose of about 500mg/m ² Wherein the method is first line therapy.

Provided herein is a method of treating a human subject having stage IV or recurrent NSCLC with non-squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 360 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) The dosage is about 75mg/m ² Cisplatin of (C), and(ii) The dosage is about 500mg/m ² Wherein the method is first line therapy.

Provided herein is a method of treating a human subject having stage IV or recurrent NSCLC with non-squamous histology, the method comprising administering to the subject: (a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 720 mg; (b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14; (c) PDCT, comprising: (i) The dosage is about 75mg/m ² And (ii) a dose of about 500mg/m ² Wherein the method is first line therapy.

In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are administered about once every three weeks. In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are administered on day 1 of a three week cycle.

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

In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are administered intravenously from a single iv bag for about 30 minutes.

In some aspects, PDCT is administered every three weeks. In some aspects, the PDCT is administered for up to about 4 cycles in a three week cycle.

In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are administered prior to PDCT.

In some aspects, the PDCT comprises carboplatin and paclitaxel. In some aspects, paclitaxel is administered for about 180 minutes on day 1 of each cycle followed by carboplatin administered intravenously on day 1 of each cycle for about 30 minutes. In some aspects, the NSCLC has squamous histology.

In some aspects, the PDCT comprises carboplatin and albumin-bound paclitaxel. In some aspects, the albumin-bound paclitaxel is administered for about 30 minutes on days 1, 8, and 15 of each cycle, followed by intravenous administration of carboplatin for about 30 minutes on day 1 of each cycle. In some aspects, the NSCLC has squamous histology.

In some aspects, the PDCT comprises carboplatin and pemetrexed. In some aspects, pemetrexed is administered for about 10 minutes on day 1 of each cycle followed by carboplatin administered intravenously on day 1 of each cycle for about 30 minutes. In some aspects, pemetrexed is administered to a disease-stable or responsive subject at a maintenance dose alone or in combination with an anti-LAG-3 and an anti-PD-1 antibody after about 4 three weeks of PDCT administration. In some aspects, the maintenance dose of pemetrexed is 500mg/m ² . In some aspects, the maintenance dose is administered on day 1 of a three week period. In some aspects, the maintenance dose is continued until disease progression or unacceptable toxicity. In some aspects, the NSCLC has non-squamous histology.

In some aspects, the PDCT comprises cisplatin and pemetrexed. In some aspects, pemetrexed is administered for about 10 minutes on day 1 of each cycle followed by cisplatin being administered intravenously on day 1 of each cycle for about 30 minutes. In some aspects, pemetrexed is administered to a disease-stable or responsive subject at a maintenance dose alone or in combination with an anti-LAG-3 and an anti-PD-1 antibody about 4 cycles after PDCT administration. In some aspects, the maintenance dose of pemetrexed is 500mg/m ² . In some aspects, the maintenance dose is administered on day 1 of a three week period. In some aspects, the maintenance dose is continued until disease progression or unacceptable toxicity. In some aspects, the NSCLC has non-squamous histology.

II.B.3.a.ii. anti-PD-L1 antibodies

anti-PD-L1 antibodies known in the art may be used in the methods of the present disclosure. Can be used in the present disclosureExamples of anti-PD-L1 antibodies in the compositions and methods of (a) include the antibodies disclosed in U.S. patent No. 9,580,507. The anti-PD-L1 human monoclonal antibodies disclosed in us patent No. 9,580,507 have been demonstrated to exhibit one or more of the following characteristics: (a) At 1x 10 ^-7 M or less K _D Binding to human PD-L1 as determined by surface plasmon resonance using the Biacore biosensor system; (b) Increasing T cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay; (c) increasing interferon-gamma production in the MLR assay; (d) increasing IL-2 secretion in an MLR assay; (e) stimulating an antibody response; and (f) reversing the effect of the T regulatory cells on T cell effector cells and/or dendritic cells. anti-PD-L1 antibodies useful in the present disclosure include monoclonal antibodies that specifically bind to human PD-L1 and exhibit at least one, in some aspects at least five, of the foregoing characteristics.

anti-PD-L1 antibodies that may be used in the methods of the present disclosure include BMS-936559 (also known as 12A4, MDX-1105; see, e.g., U.S. Pat. No. 7,943,743 and WO 2013/173223), alemtuzumab (Roche; also known asMPDL3280A, RG7446; see US 8,217,149; see also Herbst et al (2013) J Clin Oncol 31 (journal): 3000), cerstuzumab (AstraZeneca; also known as IMFINZI ^TM MEDI-4736; see WO 2011/066389), avermectin (Pfizer; also called +.>MSB-0010718C; see WO 2013/079174), STI-1014 (Sorrento; see WO 2013/181634), CX-072 (Cytomx; see WO 2016/14991), KN035 (3D Med/Alphamab; see Zhang et al, cell discovery.7:3 (month 3 of 2017), LY3300054 (Eli Lilly Co.; see, e.g., WO 2017/034916), BGB-A333 (BeiGene; see Desai et al, J CO 36 (15 supplement): TPS3113 (2018)), ICO 36, FAZ053 (Novartis), and CK-301 (Checkpoint Therapeutics; see Gorelik et al, AACR: abstract 4606 (month 4 of 2016)).

anti-PD-L1 antibodies that can be used in the methods of the present disclosure also include isolated antibodies that specifically bind to human PD-L1 and cross-compete with any anti-PD-L1 antibody disclosed herein (e.g., alemtuzumab, dimarvaluzumab, and/or avistuzumab) for binding to human PD-L1. In some aspects, the anti-PD-L1 antibody binds to the same epitope as any anti-PD-L1 antibody described herein (e.g., alemtuzumab, cerstuzumab, and/or avermectin). In certain aspects, antibodies that cross-compete with any of the anti-PD-L1 antibodies disclosed herein (e.g., alemtuzumab, dimaruzumab, and/or avistuzumab) for binding to human PD-L1 or bind to the same epitope region as any of the anti-PD-L1 antibodies disclosed herein are monoclonal antibodies. For administration to a human subject, these cross-competing antibodies are chimeric, engineered or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies may be prepared and isolated by methods well known in the art.

anti-PD-L1 antibodies that can be used in the methods of the present disclosure also include antigen-binding portions of any of the full-length antibodies described above.

anti-PD-L1 antibodies that can be used in the methods of the present disclosure are antibodies that bind to PD-L1 with high specificity and affinity, block binding of PD-1, and inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-L1 "antibody" includes an antigen-binding portion or fragment that binds to PD-L1 and exhibits similar functional properties as an intact antibody in terms of inhibiting receptor binding and up-regulating the immune system. In certain aspects, the anti-PD-L1 antibody or antigen-binding portion thereof cross-competes with alemtuzumab, cerstuzumab, and/or avermectin for binding to human PD-L1.

In some aspects, in any of the methods disclosed herein, the anti-PD-1 antibody is replaced with an anti-PD-L1 antibody.

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

In some aspects, the PD-L1 antibody is an alte Li Zhushan antibody. The alemtuzumab is a fully humanized IgG1 monoclonal anti-PD-L1 antibody. In some aspects, the atu Li Zhushan antibody is administered at a flat dose of about 800mg about every 2 weeks. In some aspects, the atu Li Zhushan antibody is administered at a flat dose of about 840mg about every 2 weeks.

In some aspects, the atu Li Zhushan antibody is administered intravenously at a dose of about 1,200mg on day 1 of the three week cycle.

In some aspects, the atu Li Zhushan antibody is administered intravenously at a dose of about 1,200mg on day 1 of a three week cycle, and the bevacizumab is administered at a dose of about 15mg/kg on day 1 of each cycle.

In some aspects, the alemtuzumab is administered intravenously at a dose of about 1,200mg for about 4 to about 6 cycles on day 1 of the three week cycle, the bevacizumab is administered at a dose of about 15mg/kg on day 1 of each cycle, the paclitaxel is administered at about 200mg/m on day 1 of each cycle ² Is administered intravenously for about 180 minutes and carboplatin is administered intravenously at a dose of about 6 mg/mL-min for a target AUC on day 1 of each cycle for about 30 minutes.

In some aspects, the PD-L1 antibody is cerulomumab. The divaruzumab is a human IgG1 kappa monoclonal anti-PD-L1 antibody. In some aspects, the divaruzumab is administered at a dose of about 10mg/kg about once every 2 weeks. In some aspects, the dimaruzumab is administered at a dose of about 10mg/kg about once every 2 weeks for up to 12 months. In some aspects, the dimvaluzumab is administered about once every 2 weeks at a flat dose of about 800 mg/kg. In some aspects, the dimvaluzumab is administered at a flat dose of about 1200mg/kg about once every 3 weeks.

In some aspects, the PD-L1 antibody is avilamab. Avermectin is a human IgG1 lambda monoclonal anti-PD-L1 antibody. In some aspects, the avermectin is administered at a flat dose of about 800mg about once every 2 weeks.

Inhibitors of CTLA-4

In some aspects, the checkpoint inhibitors disclosed herein include CTLA-4 inhibitors. In some aspects, the CTLA-4 inhibitor is an anti-CTLA-4 antibody.

anti-CTLA-4 antibodies that can be used in the methods of the present disclosure bind to human CTLA-4 and disrupt CTLA-4 interaction with human B7 receptor. Since the interaction of CTLA-4 with B7 transduces a signal that causes inactivation of T cells carrying CTLA-4 receptor, disruption of the interaction effectively induces, enhances or extends activation of such T cells, thereby inducing, enhancing or extending an immune response.

Human monoclonal antibodies that specifically bind to CTLA-4 with high affinity have been disclosed in U.S. patent No. 6,984,720. Other anti-CTLA-4 monoclonal antibodies have been described, for example, in the following: U.S. Pat. nos. 5,977,318, 6,051,227, 6,682,736 and 7,034,121, and international publication nos. WO 2012/12244, WO 2007/113648, WO 2016/196237 and WO 2000/037504, each of which is incorporated herein by reference in its entirety. The anti-CTLA-4 human monoclonal antibody disclosed in us patent No. 6,984,720 has been demonstrated to exhibit one or more of the following characteristics: (a) At least about 10 ⁷ M ^-1 Or about 10 ⁹ M ^-1 Or about 10 ¹⁰ M ^-1 To 10 ¹¹ M ^-1 Or higher equilibrium association constant (K _a ) The reflected binding affinity specifically binds to human CTLA-4 as determined by Biacore analysis; (b) Kinetic association constant (k) _a ) At least about 10 ³ About 10 ⁴ Or about 10 ⁵ m ^-1 s ^-1 The method comprises the steps of carrying out a first treatment on the surface of the (c) Kinetic dissociation constant (k) _d ) At least about 10 ³ About 10 ⁴ Or about 10 ⁵ m ^-1 s ^-1 The method comprises the steps of carrying out a first treatment on the surface of the And (d) inhibiting CTLA-4 and B7-1 (CD 80) and B7-2 (CD 86) binding. anti-CTLA-4 antibodies useful in the present disclosure include monoclonal antibodies that specifically bind to human CTLA-4 and exhibit at least one, at least two, or at least three of the foregoing characteristics.

anti-CTLA-4 antibodies that can be used in the methods of the present disclosure include ipilimumab (also known as MDX-010, 10D1; see U.S. patent No. 6,984,720), MK-1308 (Merck), AGEN-1884 (agalus inc; see WO 2016/196237) and trimethoprim (AstraZeneca; also known as tiximumab, CP-675,206; see WO 2000/037504 and Ribas, update Cancer Ther.2 (3): 133-39 (2007).

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

In some aspects, antibodies that cross-compete with any of the anti-CTLA-4 antibodies disclosed herein (e.g., ipilimumab and/or tremelimumab) for binding to human CTLA-4 or bind to the same epitope region as any of the anti-CTLA-4 antibodies disclosed herein are monoclonal antibodies. For administration to a human subject, these cross-competing antibodies are chimeric, engineered or humanized or human antibodies.

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

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

In some aspects, the anti-CTLA-4 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments,scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

In some aspects, the anti-CTLA-4 antibody is ipilimumab. Ipilimumab is a fully human IgG1 monoclonal antibody that blocks binding of CTLA-4 to its B7 ligand, thereby stimulating T cell activation. In some aspects, ipilimumab is administered at a dose of about 3mg/kg about once every 3 weeks. In some aspects, ipilimumab is administered at a dose of about 10mg/kg about once every 3 weeks. In some aspects, ipilimumab is administered at a dose of about 10mg/kg about once every 12 weeks. In some aspects, the ipilimumab is administered in four doses. In some aspects, ipilimumab is administered on day 1 of each cycle.

II.B.4. Therapies for sensitizing mutations

In some aspects, the methods of the disclosure include treating a subject having a mutation that is sensitive to targeted inhibitor therapy, e.g., a sensitizing mutation in a gene (e.g., EGFR, ALK, ROS-1, NTRK, or BRAF). Such methods may further comprise administering a targeted inhibitor of the mutant gene to a subject having such mutation, including standard care therapies, suffering from NSCLC.

In some aspects, the methods of the disclosure include first line therapy for a subject with advanced or metastatic NSCLC having sensitized EGFR mutations, the therapy comprising administering afatinib (e.g., 40mg, orally once per day), erlotinib (e.g., 150mg, orally once per day), dactinib (e.g., 45mg, orally once per day), gefitinib (e.g., 250mg, orally once per day), or octtinib (e.g., 80mg, orally once per day) to the subject.

In some aspects, the methods of the disclosure include a two-wire or three-wire therapy for a subject with advanced or metastatic NSCLC having sensitized EGFR mutations, the therapy comprising administering afatinib and cetuximab to the subject (e.g., orally administering 40mg of afatinib once daily on days 1-14 of a 2 week cycle Nib and taken orally 500mg/m once on day 1 ² Cetuximab) or octreotide (e.g., 80mg, orally administered once a day).

In some aspects, the methods of the present disclosure include a first-line, second-line, or third-line therapy for a subject with advanced or metastatic NSCLC having a sensitized ALK mutation (e.g., ALK rearrangement), the therapy comprising administering Ai Leti ni (e.g., 600mg, orally twice daily), bujitinib (e.g., orally twice daily for a 4-week period, orally 90mg once daily on days 1-7, orally 180mg once daily on days 8-28, followed by orally 180mg once daily on days 29-56), ceritinib (e.g., 450mg, orally once daily), or crizotinib (e.g., orally 250mg, orally twice daily) to the subject.

In some aspects, the methods of the disclosure include a two-wire or three-wire therapy for a subject with advanced or metastatic NSCLC having a sensitized ALK mutation (e.g., ALK rearrangement), the therapy comprising administering to the subject loratidine (e.g., 100mg, orally once per day).

In some aspects, the methods of the present disclosure include first line therapy for a subject with advanced or metastatic NSCLC having sensitized ROS-1 mutations (e.g., ROS-1 rearrangement), the therapy comprising administering to the subject ceritinib (e.g., 450mg, orally once per day), crizotinib (e.g., 250mg, orally once per day), or emtrictinib (e.g., 600mg, orally once per day). In some aspects, the methods of the present disclosure include standard caretwo-wire or three-wire therapy for a subject with advanced or metastatic NSCLC having sensitized ROS-1 mutations (e.g., ROS-1 rearrangement), wherein the standard caretherapy comprises administering to the subject loratidine (e.g., 100mg, orally once per day).

In some aspects, the methods of the present disclosure include a first-line, second-line, or third-line therapy for a subject with advanced or metastatic NSCLC having a sensitized BRAF mutation (e.g., BRAF V600E), the therapy comprising administering to the subject dabrafenib (e.g., 150mg, twice daily oral), dabrafenib, and trametinib (e.g., 150mg, twice daily oral, and once daily oral 2mg of trametinib), or vitamin Mo Feini (e.g., 960mg, once daily oral).

In some aspects, the methods of the disclosure include a first-line, second-line, or third-line therapy for a subject with advanced or metastatic NSCLC having a sensitized NTRK mutation (e.g., NTRK gene fusion), the therapy comprising administering emtrictinib (e.g., 600mg, orally once per day) or larotinib (e.g., 100mg, orally twice per day) to the subject.

III pharmaceutical composition

The therapeutic agents of the present disclosure may constitute compositions, e.g., pharmaceutical compositions containing an inhibitor, antibody, and/or agent as disclosed herein, and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.

In some aspects, the carrier containing the compositions of inhibitors, antibodies, and/or medicaments as disclosed herein is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). In some aspects, the carrier is suitable for parenteral, e.g., oral administration. In some aspects, the subcutaneous injection is Halozyme Therapeutics-basedDrug delivery techniques (see U.S. Pat. No. 7,767,429, which is incorporated herein by reference in its entirety). />The use of a co-formulation of antibodies with recombinant human hyaluronidase (rHuPH 20) eliminates the traditional limitation of the volume of biologicals and drugs that can be delivered subcutaneously due to the extracellular matrix (see U.S. Pat. No. 7,767,429). The pharmaceutical compositions of the present disclosure may comprise one or more pharmaceutically acceptable salts, antioxidants, aqueous and non-aqueous carriers, and/or adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents.In some aspects, the pharmaceutical compositions used in the present disclosure may further comprise recombinant human hyaluronidase (e.g., rHuPH 20).

Treatment continues as long as clinical benefit is observed or until unacceptable toxicity or disease progression occurs. The dosage and frequency will vary depending on the half-life of the inhibitor, antibody and/or agent in the subject. In general, human antibodies exhibit the longest half-life, followed by humanized, chimeric, and non-human antibodies. The dosage and frequency of administration may vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, relatively low doses are typically administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the remainder of their lives. In therapeutic applications, it is sometimes desirable to administer relatively high doses at relatively short intervals until the progression of the disease is reduced or terminated, and preferably until the patient exhibits a partial or complete improvement in the symptoms of the disease. Thereafter, a prophylactic regimen can be administered to the patient.

The actual dosage level of the active ingredient (i.e., inhibitor, antibody, and/or agent) in the pharmaceutical compositions of the present disclosure may be varied in order to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without undue toxicity to the patient. The selected dosage level will depend on a variety of pharmacokinetic factors including the activity of the particular composition of the present disclosure employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health and past medical history of the patient being treated, and like factors well known in the medical arts. The compositions of the present disclosure may be administered via one or more routes of administration using one or more of a variety of methods well known in the art. As the skilled artisan will appreciate, the route and/or mode of administration will vary depending on the desired result.

Provided herein is a pharmaceutical composition comprising an anti-LAG-3 antibody and an anti-PD-1 antibody as described herein, at any dose or combination of doses described herein.

In some aspects, the pharmaceutical composition is for treating a human subject having lung cancer as described herein.

In some aspects, methods for treating a human subject having lung cancer as described herein comprise administering a pharmaceutical composition as described herein.

In some aspects, the pharmaceutical composition comprises a dose of the rella Li Shan antibody and a dose of the anti-PD-1 antibody as described herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cimaprevin Li Shan, or swabber. In some aspects, the anti-PD-1 antibody is nivolumab.

In some aspects, the pharmaceutical composition comprises a dose of Fei Weize Li Shan antibody and a dose of an anti-PD-1 antibody as described herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cimaprevin Li Shan, or swabber. In some aspects, the anti-PD-1 antibody is pembrolizumab.

In some aspects, the pharmaceutical composition comprises a dose of the furazamab and a dose of an anti-PD-1 antibody as described herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cimaprevin Li Shan, or swabber. In some aspects, the anti-PD-1 antibody is a cimetidine Li Shan antibody.

In some aspects, the pharmaceutical composition comprises a dose of an ela Li Shan antibody and a dose of an anti-PD-1 antibody as described herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cimaprevin Li Shan, or swabber. In some aspects, the anti-PD-1 antibody is swabber.

In some aspects, the pharmaceutical composition comprises the following ratio of anti-LAG-3 antibody to anti-PD-1 antibody: about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1.

In some aspects, the pharmaceutical composition comprises an anti-LAG-3 antibody to an anti-PD-1 antibody in a ratio of about 1:3.

In some aspects, the pharmaceutical composition comprises an anti-LAG-3 antibody to an anti-PD-1 antibody in a ratio of about 1:1

In some aspects, the pharmaceutical composition comprises an anti-LAG-3 antibody to an anti-PD-1 antibody in a ratio of about 2:1.

In some aspects, the pharmaceutical composition comprises an anti-LAG-3 antibody to an anti-PD-1 antibody in a ratio of about 4:1.

In some aspects of the present invention, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the pharmaceutical composition is about 20mg/mL, about 25mg/mL, about 30mg/mL, about 35mg/mL, about 40mg/mL, about 45mg/mL, about 50mg/mL, about 55mg/mL, about 60mg/mL, about 65mg/mL, about 70mg/mL, about 75mg/mL, about 80mg/mL, about 85mg/mL, about 90mg/mL, about 95mg/mL, about 100mg/mL, about 105mg/mL, about 110mg/mL, about 115mg/mL, about 120mg/mL, about 125mg/mL, about 130mg/mL, about 135mg/mL, about 140mg/mL, about 145mg/mL, about 150mg/mL, about 155mg/mL, about 160mg/mL, about 165mg/mL, about 170mg/mL, about 175mg/mL, about 180mg/mL about 185mg/mL, about 190mg/mL, about 195mg/mL, about 200mg/mL, about 205mg/mL, about 210mg/mL, about 215mg/mL, about 220mg/mL, about 225mg/mL, about 230mg/mL, about 235mg/mL, about 240mg/mL, about 245mg/mL, about 250mg/mL, about 255mg/mL, about 260mg/mL, about 265mg/mL, about 270mg/mL, about 275mg/mL, about 280mg/mL, about 285mg/mL, about 290mg/mL, about 295mg/mL, about 300mg/mL, about 305mg/mL, about 310mg/mL, about 315mg/mL, about 320mg/mL, about 325mg/mL, about 330mg/mL, about 335mg/mL, about 340mg/mL, about 345mg/mL, about 350mg/mL, about 355mg/mL, about 360mg/mL, about, about 365mg/mL, about 370mg/mL, about 375mg/mL, about 380mg/mL, about 385mg/mL, about 390mg/mL, about 395mg/mL, about 400mg/mL, 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 360mg about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 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 1010mg, about 1020mg, about 1030mg, about 1040mg, about 1050mg, about 1060mg, about 1070mg, about 1080mg, about 1090mg, about 1100mg, about 1110mg, about 1120mg, about 1130mg, about 1140mg, about 1150mg, about 1160mg, about 1170mg, about 1180mg about 1190mg, about 1200mg, about 1210mg, about 1220mg, about 1230mg, about 1240mg, about 1250mg, about 1260mg, about 1270mg, about 1280mg, about 1290mg, about 1300mg, about 1310mg, about 1320mg, about 1330mg, about 1340mg, about 1350mg, about 1360mg, about 1370mg, about 1380mg, about 1390mg, about 1400mg, about 1410mg, about 1420mg, about 1430mg, about 1440mg, about 1450mg, about 1460mg, about 1470mg, about 1480mg, about 1490mg, about 1500mg, about 1510mg, about 1520mg, about 1530mg, about 1540mg, about 1550mg, about 1560mg, about 1570mg, about 1580mg, about 1590mg, about 1600mg, about 1610mg, about 1620mg, about 1630mg, about 1640mg, about 1650mg, about 1660mg, about 1670mg, about 1680mg, about 1690mg, about 1700mg, about 1710mg, about 1720mg, about 1730mg, about 1740mg, about 1750mg, about 1760mg, about 1770mg, or about 1780mg.

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

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

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

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

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

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

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

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

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

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

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

In some aspects of the present invention, the pharmaceutical composition comprises about 10mg/mL, about 12.5mg/mL, about 15mg/mL, about 17.5mg/mL, about 20mg/mL, about 22.5mg/mL, about 25mg/mL, about 27.5mg/mL, about 30mg/mL, about 32.5mg/mL, about 35mg/mL, about 37.5mg/mL, about 40mg/mL, about 42.5mg/mL, about 45mg/mL, about 47.5mg/mL, about 50mg/mL, about 55mg/mL, about 60mg/mL, about 65mg/mL, about 70mg/mL, about 75mg/mL, about 80mg/mL, about 85mg/mL, about 90mg/mL, about 95mg/mL, about 100mg/mL, about 105mg/mL, about 110mg/mL, about 115mg/mL, about 120mg/mL, about 50mg/mL about 125mg/mL, 130mg/mL, about 135mg/mL, about 140mg/mL, about 145mg/mL, about 150mg/mL, about 155mg/mL, about 160mg/mL, about 165mg/mL, about 170mg/mL, about 175mg/mL, about 180mg/mL, about 185mg/mL, about 190mg/mL, about 195mg/mL, about 200mg/mL, about 7mg, about 21mg, about 40mg, about 70mg, about 80mg, about 160mg, about 200mg, about 210mg, about 300mg, about 400mg, about 480mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, about 960mg, about 1000mg, about 1100mg, about 1200mg or about 1300mg of anti-LAG-3 antibody. In some aspects of the present invention, the pharmaceutical composition comprises about 5mg/mL, about 10mg/mL, about 12.5mg/mL, about 15mg/mL, about 17.5mg/mL, about 20mg/mL, about 22.5mg/mL, about 25mg/mL, about 27.5mg/mL, about 30mg/mL, about 32.5mg/mL, about 35mg/mL, about 37.5mg/mL, about 40mg/mL, about 42.5mg/mL, about 45mg/mL, about 47.5mg/mL, about 50mg/mL, about 55mg/mL, about 60mg/mL, about 65mg/mL, about 70mg/mL, about 75mg/mL, about 80mg/mL, about 85mg/mL, about 90mg/mL, about 95mg/mL, about 100mg/mL about 105mg/mL, about 110mg/mL, about 115mg/mL, about 120mg/mL, about 125mg/mL, 130mg/mL, about 135mg/mL, about 140mg/mL, about 145mg/mL, about 150mg/mL, about 155mg/mL, about 160mg/mL, about 165mg/mL, about 170mg/mL, about 175mg/mL, about 180mg/mL, about 185mg/mL, about 190mg/mL, about 195mg/mL, about 200mg/mL, about 10mg, about 40mg, about 100mg, about 200mg, about 240mg, about 300mg, about 350mg, about 360mg, about 400mg or about 480mg of the anti-PD-1 antibody.

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

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

In some aspects, the pharmaceutical composition comprises about 75mg/mL of the anti-LAG-3 antibody and about 75mg/mL of the anti-PD-1 antibody.

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

In some aspects, the pharmaceutical composition comprises about 80mg of the anti-LAG-3 antibody and about 240mg of the anti-PD-1 antibody.

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

In some aspects, the pharmaceutical composition comprises about 360mg of the anti-LAG-3 antibody and about 360mg of the anti-PD-1 antibody.

In some aspects, the pharmaceutical composition comprises about 480mg of the anti-LAG-3 antibody and about 480mg of the anti-PD-1 antibody.

In some aspects, the pharmaceutical composition comprises about 720mg of the anti-LAG-3 antibody and about 360mg of the anti-PD-1 antibody.

In some aspects, the pharmaceutical composition comprises about 800mg of the anti-LAG-3 antibody and about 200mg of the anti-PD-1 antibody.

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

In some aspects, the pharmaceutical composition comprises about 5mM to about 50mM histidine, about 50mM to about 300mM sucrose, about 5 μm to about 1mM diethylenetriamine pentaacetic acid (DTPA) or ethylenediamine tetraacetic acid (EDTA), and about 0.001% to about 1% (w/v) polysorbate or poloxamer (e.g., polysorbate 80 (PS 80), polysorbate 20 (PS 20), poloxamer 188 (PX 188), or any combination thereof).

In some aspects, the pharmaceutical composition comprises about 20mM histidine, about 250mM sucrose, about 50 μmdtpa, and 0.05% PS80.

In some aspects, the pH of the pharmaceutical composition is about 5 to about 6.5. In some aspects, the pH is about 5.3 to about 6.3. In some aspects, the pH is 5.8. In some aspects, the pH is 5.7.

Provided herein is a vial, syringe, or iv bag comprising a pharmaceutical composition as described herein. In some aspects, the present disclosure includes an automatic injector comprising a pharmaceutical composition described herein.

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

IV. kit

Kits for treating a human subject having lung cancer comprising any of the antibodies, therapeutic agents, and/or anti-cancer therapies described herein are also within the scope of the invention.

Kits typically comprise a label that indicates the intended use of the kit contents and instructions for use. The term "label" includes any writing or recording material supplied on or with or otherwise accompanying the kit.

Provided herein is a kit for treating a human subject having lung cancer, the kit comprising: (a) a dose of an anti-LAG-3 antibody; (b) a dose of an anti-PD-1 antibody; and (c) instructions for using the anti-LAG-3 antibody and the anti-PD-1 antibody in a method of treating a human subject with lung cancer.

The anti-LAG-3 antibody and the anti-PD-1 antibody may be provided in any dose or combination of doses described herein.

In some aspects, the kit comprises a dose of the rana Li Shan antibody and a dose of an anti-PD-1 antibody as described herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cimaprevin Li Shan, or swabber. In some aspects, the anti-PD-1 antibody is nivolumab.

In some aspects, the kit comprises a dose of Fei Weize Li Shan antibody and a dose of an anti-PD-1 antibody as described herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cimaprevin Li Shan, or swabber. In some aspects, the anti-PD-1 antibody is pembrolizumab.

In some aspects, the kit comprises furazamab and an anti-PD-1 antibody as described herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cimaprevin Li Shan, or swabber. In some aspects, the anti-PD-1 antibody is a cimetidine Li Shan antibody.

In some aspects, the kit comprises an ela Li Shan antibody and an anti-PD-1 antibody as described herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cimaprevin Li Shan, or swabber. In some aspects, the anti-PD-1 antibody is swabber.

In some aspects, the kit comprises the following ratios of anti-LAG-3 antibody to anti-PD-1 antibody: about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1.

In some aspects, the kit comprises an anti-LAG-3 antibody to an anti-PD-1 antibody in a ratio of about 1:3.

In some aspects, the kit comprises an anti-LAG-3 antibody to an anti-PD-1 antibody in a ratio of about 1:1

In some aspects, the kit comprises an anti-LAG-3 antibody to an anti-PD-1 antibody in a ratio of about 2:1.

In some aspects, the kit comprises an anti-LAG-3 antibody to an anti-PD-1 antibody in a ratio of about 4:1.

In some aspects of the present invention, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the kit is about 20mg/mL, about 25mg/mL, about 30mg/mL, about 35mg/mL, about 40mg/mL, about 45mg/mL, about 50mg/mL, about 55mg/mL, about 60mg/mL, about 65mg/mL, about 70mg/mL, about 75mg/mL, about 80mg/mL, about 85mg/mL, about 90mg/mL, about 95mg/mL, about 100mg/mL, about 105mg/mL, about 110mg/mL, about 115mg/mL, about 120mg/mL, about 125mg/mL, about 130mg/mL, about 135mg/mL, about 140mg/mL, about 145mg/mL, about 150mg/mL, about 155mg/mL, about 160mg/mL, about 165mg/mL, about 170mg/mL, about 175mg/mL, about 180mg/mL about 185mg/mL, about 190mg/mL, about 195mg/mL, about 200mg/mL, about 205mg/mL, about 210mg/mL, about 215mg/mL, about 220mg/mL, about 225mg/mL, about 230mg/mL, about 235mg/mL, about 240mg/mL, about 245mg/mL, about 250mg/mL, about 255mg/mL, about 260mg/mL, about 265mg/mL, about 270mg/mL, about 275mg/mL, about 280mg/mL, about 285mg/mL, about 290mg/mL, about 295mg/mL, about 300mg/mL, about 305mg/mL, about 310mg/mL, about 315mg/mL, about 320mg/mL, about 325mg/mL, about 330mg/mL, about 335mg/mL, about 340mg/mL, about 345mg/mL, about 350mg/mL, about 355mg/mL, about 360mg/mL, about, about 365mg/mL, about 370mg/mL, about 375mg/mL, about 380mg/mL, about 385mg/mL, about 390mg/mL, about 395mg/mL, about 400mg/mL, 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 360mg about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 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 1010mg, about 1020mg, about 1030mg, about 1040mg, about 1050mg, about 1060mg, about 1070mg, about 1080mg, about 1090mg, about 1100mg, about 1110mg, about 1120mg, about 1130mg, about 1140mg, about 1150mg, about 1160mg, about 1170mg, about 1180mg about 1190mg, about 1200mg, about 1210mg, about 1220mg, about 1230mg, about 1240mg, about 1250mg, about 1260mg, about 1270mg, about 1280mg, about 1290mg, about 1300mg, about 1310mg, about 1320mg, about 1330mg, about 1340mg, about 1350mg, about 1360mg, about 1370mg, about 1380mg, about 1390mg, about 1400mg, about 1410mg, about 1420mg, about 1430mg, about 1440mg, about 1450mg, about 1460mg, about 1470mg, about 1480mg, about 1490mg, about 1500mg, about 1510mg, about 1520mg, about 1530mg, about 1540mg, about 1550mg, about 1560mg, about 1570mg, about 1580mg, about 1590mg, about 1600mg, about 1610mg, about 1620mg, about 1630mg, about 1640mg, about 1650mg, about 1660mg, about 1670mg, about 1680mg, about 1690mg, about 1700mg, about 1710mg, about 1720mg, about 1730mg, about 1740mg, about 1750mg, about 1760mg, about 1770mg, or about 1780mg.

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

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

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

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

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

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

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

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

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

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

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

In some aspects of the present invention, the kit comprises about 10mg/mL, about 12.5mg/mL, about 15mg/mL, about 17.5mg/mL, about 20mg/mL, about 22.5mg/mL, about 25mg/mL, about 27.5mg/mL, about 30mg/mL, about 32.5mg/mL, about 35mg/mL, about 37.5mg/mL, about 40mg/mL, about 42.5mg/mL, about 45mg/mL, about 47.5mg/mL, about 50mg/mL, about 55mg/mL, about 60mg/mL, about 65mg/mL, about 70mg/mL, about 75mg/mL, about 80mg/mL, about 85mg/mL, about 90mg/mL, about 95mg/mL, about 100mg/mL, about 105mg/mL, about 110mg/mL, about 115mg/mL, about 120mg/mL, about 125mg/mL, about 130mg/mL, about 135mg/mL, about 140mg/mL, about 145mg/mL, about 150mg/mL, about 155mg/mL, about 160mg/mL, about 165mg/mL, about 170mg/mL, about 175mg/mL, about 180mg/mL, about 185mg/mL, about 190mg/mL, about 195mg/mL, about 200mg/mL, about 7mg, about 21mg, about 40mg, about 70mg, about 80mg, about 160mg, about 200mg, about 210mg, about 300mg, about 400mg, about 480mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, about 960mg, about 1000mg, about 1100mg, about 1200mg or about 1300mg of anti-LAG-3 antibody. In some aspects of the present invention, the kit comprises about 5mg/mL, about 10mg/mL, about 12.5mg/mL, about 15mg/mL, about 17.5mg/mL, about 20mg/mL, about 22.5mg/mL, about 25mg/mL, about 27.5mg/mL, about 30mg/mL, about 32.5mg/mL, about 35mg/mL, about 37.5mg/mL, about 40mg/mL, about 42.5mg/mL, about 45mg/mL, about 47.5mg/mL, about 50mg/mL, about 55mg/mL, about 60mg/mL, about 65mg/mL, about 70mg/mL, about 75mg/mL, about 80mg/mL, about 85mg/mL, about 90mg/mL, about 95mg/mL, about 100mg/mL about 105mg/mL, about 110mg/mL, about 115mg/mL, about 120mg/mL, about 125mg/mL, 130mg/mL, about 135mg/mL, about 140mg/mL, about 145mg/mL, about 150mg/mL, about 155mg/mL, about 160mg/mL, about 165mg/mL, about 170mg/mL, about 175mg/mL, about 180mg/mL, about 185mg/mL, about 190mg/mL, about 195mg/mL, about 200mg/mL, about 10mg, about 40mg, about 100mg, about 200mg, about 240mg, about 300mg, about 350mg, about 360mg, about 400mg or about 480mg of the anti-PD-1 antibody.

In some aspects, the kit comprises about 12.5mg/mL of anti-LAG-3 antibody and about 37.5mg/mL of anti-PD-1 antibody.

In some aspects, the kit comprises about 20mg/mL of the anti-LAG-3 antibody and about 5mg/mL of the anti-PD-1 antibody.

In some aspects, the kit comprises about 75mg/mL of anti-LAG-3 antibody and about 75mg/mL of anti-PD-1 antibody.

In some aspects, the kit comprises about 100mg/mL of anti-LAG-3 antibody and about 50mg/mL of anti-PD-1 antibody.

In some aspects, the kit comprises about 80mg of the anti-LAG-3 antibody and about 240mg of the anti-PD-1 antibody.

In some aspects, the kit comprises about 160mg of the anti-LAG-3 antibody and about 480mg of the anti-PD-1 antibody.

In some aspects, the kit comprises about 360mg of the anti-LAG-3 antibody and about 360mg of the anti-PD-1 antibody.

In some aspects, the kit comprises about 480mg of the anti-LAG-3 antibody and about 480mg of the anti-PD-1 antibody.

In some aspects, the kit comprises about 720mg of the anti-LAG-3 antibody and about 360mg of the anti-PD-1 antibody.

In some aspects, the kit comprises about 800mg of the anti-LAG-3 antibody and about 200mg of the anti-PD-1 antibody.

In some aspects, the kit comprises about 960mg of the anti-LAG-3 antibody and about 480mg of the anti-PD-1 antibody.

Provided herein is a kit for treating a human subject having lung cancer, the kit comprising: (a) 360mg of anti-LAG-3 antibody; (b) 360mg of anti-PD-1 antibody; and (c) instructions for using the anti-LAG-3 antibody and the anti-PD-1 antibody in a method of treating a human subject with lung cancer.

Provided herein is a kit for treating a human subject having lung cancer, the kit comprising: (a) 720mg of an anti-LAG-3 antibody; (b) 360mg of anti-PD-1 antibody; and (c) instructions for using the anti-LAG-3 antibody and the anti-PD-1 antibody in a method of treating a human subject with lung cancer.

Provided herein is a kit for treating a human subject having lung cancer, the kit comprising: (a) an anti-LAG-3 antibody; (b) an anti-PD-1 antibody; and (c) preparing each antibody in an amount of 360mg and instructions for using the antibodies in a method for treating a human subject having lung cancer.

Provided herein is a kit for treating a human subject having lung cancer, the kit comprising: (a) an anti-LAG-3 antibody; (b) an anti-PD-1 antibody; and (c) preparing said LAG-3 antibody and said PD-1 antibody in amounts of 720mg and 360mg, respectively, and instructions for using said antibodies in a method for treating a human subject having lung cancer.

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

In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are packaged in separate unit dosage forms.

In some aspects, 40mg of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 80mg of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 160mg of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 360mg of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 480mg of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 720mg of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 800mg of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 960mg of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 12.5mg/mL of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 20mg/mL of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 50mg/mL of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 75mg/mL of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 100mg/mL of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 130mg/mL of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 150mg/mL of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 175mg/mL of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 200mg/mL of the anti-LAG-3 antibody is provided in a unit dosage form.

In some aspects, 10mg of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 40mg of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 100mg of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 200mg of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 240mg of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 360mg of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 480mg of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 5mg/mL of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 10mg/mL of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 37.5mg/mL of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 50mg/mL of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 75mg/mL of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 100mg/mL of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 175mg/mL of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, 200mg/mL of the anti-PD-1 antibody is provided in a unit dosage form.

In some aspects, the unit dosage form comprises about 5mM to about 50mM histidine, about 50mM to about 300mM sucrose, about 5 μm to about 1mM diethylenetriamine pentaacetic acid (DTPA) or ethylenediamine tetraacetic acid (EDTA), and about 0.001% to about 1% (w/v) polysorbate or poloxamer (e.g., polysorbate 80 (PS 80), polysorbate 20 (PS 20), poloxamer 188 (PX 188), or any combination thereof.

In some aspects, the unit dosage form comprises about 20mM histidine, about 250mM sucrose, about 50 μmdtpa, and 0.05% PS80.

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

In some aspects, the unit dosage form is a vial, syringe, or iv bag. In some aspects, the unit dosage form is an auto-injector. In some aspects, the unit dosage form is a vial comprising a stopper and a seal. In some aspects, the total volume in the vial is about 5mL, about 6mL, about 7mL, about 8mL, about 9mL, about 10mL, about 11mL, about 12mL, about 13mL, about 14mL, about 15mL, about 16mL, about 17mL, about 18mL, about 19mL, or about 20mL

In some aspects, the kit provides instructions for intravenous administration of the anti-LAG-3 antibody and/or the anti-PD-1 antibody for about 30 minutes.

In some aspects, the kit further comprises a therapeutic agent for one or more PDCT as disclosed herein. In some aspects, the therapeutic agent for one or more PDCT is carboplatin and paclitaxel, carboplatin and albumin-bound paclitaxel, carboplatin and pemetrexed, and/or cisplatin and pemetrexed. In some aspects, the therapeutic agent is carboplatin, cisplatin, paclitaxel, albumin-bound paclitaxel, and pemetrexed.

All references cited above and all references cited herein are incorporated by reference in their entirety.

The following examples are provided by way of illustration and not by way of limitation.

Examples

Example 1

Combination of anti-LAG-3 antibodies and anti-PD-1 antibodies for use in the treatment of lung cancer

A multicenter randomized trial ("study a") will evaluate the efficacy and safety of the combination of nal Wu Shankang garela Li Shan antibody with chemotherapy compared to that of the combination of nivolumab with chemotherapy in adults with untreated stage IV or recurrent non-small cell lung cancer (NSCLC). The study will be performed in 2 parts: part 1, site and subject set blind dose safety confirmation; and part 2, double blind random control.

Another multicenter randomized trial ("study B") will evaluate the efficacy and safety of nal Wu Shankang gariraterol Li Shan anti-combination with chemotherapy compared to pembrolizumab in adults with untreated stage IV or recurrent NSCLC.

Patient inclusion/exclusion criteria

Patients will be male and female adults ≡18 years of age or local legal ages selected based on the following eligibility criteria: (1) A Squamous (SQ) or non-squamous (NSQ) histologically confirmed metastatic NSCLC with stage IV a/B (as defined by the 8 th international lung cancer classification study conference) or recurrent disease following multimodal therapy for locally advanced disease; (2) Diseases measurable by computed tomography or magnetic resonance imaging according to RECIST v1.1 criteria, wherein radiation tumor assessment is performed within 28 days prior to random grouping; (3) No previous systemic anti-cancer treatment as primary therapy for advanced or metastatic disease was administered; (4) ECOG ps.ltoreq.1 at screening and acknowledging prior to random grouping; (5) an expected lifetime of at least 3 months at first administration; (6) Core biopsies, punch biopsies, excising biopsies or formalin-fixed paraffin-embedded tissue blocks of surgical specimens obtained during screening or prior to recruitment (within 3 months of enrollment if stored at 2 ℃ -8 ℃ or within 2 months of enrollment if stored at ambient temperature and without intervening systemic anti-cancer therapy between acquisition and enrollment), containing sufficient tissue to cut tumor tissue into 20 sections or a minimum of 20 unstained slides; and (6) PD-L1 and LAG-3 Immunohistochemical (IHC) results during the screening period prior to random grouping (LAG-3 expression on immune cells and PD-L1 expression on tumor cells will be measured using an analytically validated assay).

Previously definitive radiotherapy for locally advanced disease is allowed as long as the last administration of chemotherapy or radiation therapy (based on the last administration) occurs at least 6 months prior to recruitment. Previous adjuvant or neoadjuvant chemotherapy for early stage lung cancer is allowed if completed at least 6 months before study treatment begins. Previous palliative radiotherapy for non-Central Nervous System (CNS) lesions must be completed at least 2 weeks prior to treatment. Participants with symptomatic tumor lesions at baseline who may need to be on palliative radiation therapy within 4 weeks of the first treatment are strongly encouraged to receive palliative radiation therapy prior to treatment.

The key exclusion criteria will be: (1) pregnant or lactating women; (2) Participants with EGFR, ALK, or ROS-1 mutations that are sensitive to available targeted inhibitor therapies (all participants with NSQ histology must have been tested for EGFR, ALK, or ROS-1 mutation status; participants with NSQ histology and unknown EGFR, ALK, or ROS-1 status are excluded); (3) Participants with known BRAF V600E mutations that are sensitive to available targeted inhibitor therapies (participants with unknown or indeterminate BRAF mutation status are eligible); (4) Participants with untreated central nervous system metastasis; (5) Participants with leptomeningeal metastasis (cancerous meningitis); (6) Recruiting a concurrent malignancy in need of treatment for the first 2 years or having a past history of malignancy activity (i.e., participants with past history of malignancy are eligible if treatment is completed at least 2 years prior to enrollment and the participants have no signs of disease); (7) Participants with active, known or suspected autoimmune disease; (8) Previous treatments with anti-PD-1 antibodies, anti-PD-L2 antibodies, anti-LAG-3 antibodies or anti-CTLA-4 antibodies or any other antibody or drug specifically targeting a T cell costimulatory or checkpoint pathway; and (9) participants with a history of myocarditis.

Study A design

Partial 1-dose safety validation

Up to about 120 qualified participants were randomly grouped into experimental groups a or B at 1:1. Random groupings were stratified according to histology (SQ compared to NSQ NSCLC).

Group A: 360mg of nal Wu Shankang +Ruila Li Shan anti 720mg Q3W+4 cycles of histological-based PDCT are administered every three weeks (Q3W).

Group B: nawuzumab 360mg Q3W+Raela Li Shan against 360mg Q3W+4 cycles of histological-based PDCT.

Histology-based PDCT is as follows:

NSQ: area under carboplatin concentration-time curve (AUC) of 5 or 6 or cisplatin 75mg/m ² +pemetrexed 500mg/m ² (maintenance with pemetrexed is allowed after completion of the PDCT cycle).

SQ: carboplatin AUC6+ paclitaxel 200mg/m ² Or nanoparticle albumin-bound paclitaxel (i.e., albumin-bound paclitaxel) 100mg/m ² 。

The na Wu Shankang garila Li Shan antibody will be administered blindly to the site and subject, while PDCT will be administered as an open label.

The safety and tolerability of na Wu Shankang garila Li Shan against the combination of 720mg and PDCT was evaluated and the safety profile was confirmed. The rayleigh Li Shan anti-360 mg q3w dose in group B was evaluated to generate additional safety data at this dose level.

Safety data for part 1 will be evaluated after all treated participants have been followed for at least 12 weeks. In addition, using bayesian continuous monitoring, the proportion of treatment-related adverse events (TRAEs) that resulted in discontinuation within 12 weeks of the first dose was monitored for each group individually.

Partial 2-efficacy and safety

Part 2 will be a double blind randomized controlled trial that will further evaluate the efficacy and safety of the combination of na Wu Shankang and rila Li Shan anti-plus chemotherapy compared to nivolumab plus chemotherapy. Recruitment in study part 2 can begin only after the safety of the na Wu Shankang garila Li Shan antibody and PDCT was confirmed in study part 1. At this point, participants who were being screened and found to be eligible will be randomly grouped at 1:1 into either experimental group C or control group D. The recruitment will end when approximately 400 participants are randomly grouped. The stratification factors of the random groupings in part 2 were PD-L1 levels (. Gtoreq.1% versus <1% [ including unquantifiable (NQ) ]), LAG-3 expression levels (. Gtoreq.1% versus <1% [ including NQ ]), histology (SQ versus NSQ), and gender (male versus female).

Group C: nawuzumab 360mg Q3W+Raela Li Shan against 720mg or 360mg Q3W+4 cycles of histology-based PDCT.

Group D: nivolumab 360mg q3w+placebo q3w+4 cycles of histological-based PDCT.

Histology-based PDCT was as described for part 1 of the present study.

All participants will be treated until progression, intolerant toxicity occurs, consent is withdrawn, or the study is completed, whichever occurs first. If clinical benefit to the participants has been confirmed, continuous safety and tumor assessments will guide the decision to conduct additional cycles of study therapy to the participants.

Participants were allowed to continue to study treatment until any of the following occurs for the first time: (1) Progressive disease defined by RECIST v1.1 unless participants meet treatment criteria beyond progression; (2) Clinical deterioration, indicating that no further benefit from treatment is possible; (3) intolerance to therapy; or (4) the participants met the criteria for discontinuing study treatment.

Administration of immunotherapy

Participants will receive masked nal Wu Shankang and rale Li Shan antibodies, followed by chemotherapy on day 1 of every 3 week cycle. In groups a, B and C, nivolumab will be co-administered with rila Li Shan antibody in a single iv bag for 30 minutes. To maintain blindness, group D participants will also receive nivolumab+placebo intravenously (5% glucose or 0.9% saline solution) within 30 minutes. On completion of 4 cycles of chemotherapy, participants not experiencing disease progression will continue to receive immunotherapy Q3W starting on day 1 of the next cycle. Dose escalation or reduction of immunotherapy is not allowed.

Chemotherapy administration

Of all 4 study groups, the 4-cycle histological-based PDCT options selected by the investigator will be administered on day 1 of Q3W. Participants with NSQ histology may also receive 500mg/m alone on day 1 of every 3 week period ² Pemetrexed is optionally maintained on therapy until disease progression or unacceptable toxicity.

For PDCT with paclitaxel and arborvitae, participants will receive 200mg/m paclitaxel as 180 min intravenous infusion on day 1 of the 3 week cycle ² Carboplatin was then received as an AUC 6 dose or as a dose according to local prescription information in the form of a 30 minute IV infusion. The infusion time may follow local institutional standards.

For PDCT with nanoparticle albumin-conjugated paclitaxel and carboplatin, participants will receive 100mg/m of nanoparticle albumin-conjugated paclitaxel as 30 min intravenous infusions on day 1, day 8, and day 15 of each 21 day cycle ² . Carboplatin at AUC 6 dose or at doses according to local prescription information was administered as a 30 minute intravenous infusion immediately after administration of nanoparticulate albumin-bound paclitaxel on day 1 of every 3 week period. The infusion time may follow local institutional standards.

For PDCT with pemetrexed and cisplatin, participants will receive a dose of 500mg/m at day 1 as a 10 minute intravenous infusion ² Is 75mg/m in infusion according to local standard practice on day 1 of the 3 week treatment cycle ² For up to 4 cycles. Cisplatin will be administered to the participants at least 30 minutes after the end of pemetrexed infusion.

For PDCT with pemetrexed and carboplatin, participants will receive a dose of 500mg/m at day 1 as a 10 minute intravenous infusion ² Followed by an AUC 5 or 6 dose of carboplatin as a 30 minute intravenous infusion on day 1 of a 3 week treatment cycle for up to 4 cycles.

Participants with NSQ histology who allowed disease stabilization or response received 500mg/m alone after cycle 4 of chemotherapy ² Pemetrexed acts as a maintenance therapy until disease progression or unacceptable toxicity.

Study B design

Study B will be a double blind randomized controlled trial that will further evaluate the safety and efficacy of the combination of na Wu Shankang and rila Li Shan anti-plus chemotherapy compared to pembrolizumab plus chemotherapy. Up to about 670 qualified participants were randomly grouped into experimental group a or control group B at 1:1. Random groupings will be stratified according to histology (SQ versus NSQ NSCLC), PD-L1 levels (> 1% versus <1% [ including unquantifiable (NQ) ]), LAG-3 expression levels (> 1% versus <1% [ including NQ ]), and gender (male versus female).

Group A: nawuzumab 360mg Q3W+Raela Li Shan against 720mg+4 cycles of histological-based PDCT.

Group B: pembrolizumab 200mg qd3w+4 cycles of histological-based PDCT.

Histology-based PDCT was as described for part 1 of study a.

All participants will be treated until progression, intolerant toxicity occurs, consent is withdrawn or for 2 years, whichever occurs first. The scan will last 1 year at Q6W and then at Q12W until there is progress or disruption of the study.

Immunotherapy and chemotherapy administration will proceed in a similar manner to study a.

Example 2

Clinical Activity of a combination of an anti-LAG-3 antibody and an anti-PD-1 antibody in patients with lung cancer

The combination of anti-LAG-3 antibody (ralston Li Shan antibody) with anti-PD-1 antibody (nivolumab) was evaluated as a first line treatment for NSCLC.

Tumor tissue samples were obtained from each patient for determination of LAG-3 expression. Based on that LAG-3 expression in the tissue sample is greater than or equal to 1% or less than 1%, patients are respectively stratified into LAG-3 expressive or non-expressive ones.

Patients were treated with 80mg of rila Li Shan antibody once every 2 weeks in combination with 240mg of nivolumab once every 2 weeks.

The Best Overall Response (BOR) for all subjects whose response was assessed is summarized in table 1. Objective Response Rate (ORR) is defined as the proportion of subjects treated based on Blind Independent Clinical Review (BICR) assessment according to RECIST 1.1 criteria, BOR being either Complete Response (CR) or Partial Response (PR). The bilateral 95% accurate confidence interval was determined by the kronet-pearson method.

Table 1: optimal overall reaction summary

(A) Reaction of only confirmation

DCR (12W) =disease control rate=cr+pr+sd, +.gtoreq.12 weeks

Sequence(s)

SEQ ID NO. 1 heavy chain amino acid sequence; anti-LAG-3 mAb (BMS-986016)

QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNP

SLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSSAS

TKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP

PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSV

LTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV

MHEALHNHYTQKSLSLSLGK

SEQ ID NO. 2 light chain amino acid sequence; anti-LAG-3 mAb (BMS-986016)

EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPAR

FSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIKRTVAAPSVFIFPPSD

EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK

ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO. 3 heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (BMS-986016)

QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNP

SLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSS

SEQ ID NO. 4 light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (BMS-986016)

EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPAR

FSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIK

SEQ ID NO. 5 heavy chain CDR1 amino acid sequence; anti-LAG-3 mAb (BMS-986016)

DYYWN

SEQ ID NO. 6 heavy chain CDR2 amino acid sequence; anti-LAG-3 mAb (BMS-986016)

EINHRGSTNSNPSLKS

The heavy chain CDR3 amino acid sequence of SEQ ID NO. 7; anti-LAG-3 mAb (BMS-986016)

GYSDYEYNWFDP

8 light chain CDR1 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (BMS-986016)

RASQSISSYLA

The light chain CDR2 amino acid sequence of SEQ ID NO. 9; anti-LAG-3 mAb (BMS-986016)

DASNRAT

SEQ ID NO. 10 light chain CDR3 amino acid sequence; anti-LAG-3 mAb (BMS-986016)

QQRSNWPLT

11 heavy chain amino acid sequence of SEQ ID NO; anti-PD-1 mAb (BMS-936558)

QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYA

DSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVF

PLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT

VPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTL

MISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQD

WLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFY

PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHN

HYTQKSLSLSLGK

SEQ ID NO. 12 light chain amino acid sequence; anti-PD-1 mAb (BMS-936558)

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPAR

FSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSD

EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLLSKA

DYEKHKVYACEVTHQGLSSPVTKSFNRGEC

13 heavy chain variable region (VH) amino acid sequence of SEQ ID NO; anti-PD-1 mAb (BMS-936558)

QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYA

DSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS

14 light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (BMS-936558)

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPAR

FSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK

15 heavy chain CDR1 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (BMS-936558)

NSGMH

16 heavy chain CDR2 amino acid sequences of SEQ ID NO; anti-PD-1 mAb (BMS-936558)

VIWYDGSKRYYADSVKG

17 heavy chain CDR3 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (BMS-936558)

NDDY

18 light chain CDR1 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (BMS-936558)

RASQSVSSYLA

The amino acid sequence of the light chain CDR2 of SEQ ID NO. 19; anti-PD-1 mAb (BMS-936558)

DASNRAT

20 light chain CDR3 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (BMS-936558)

QQSSNWPRT

The heavy chain amino acid sequence of SEQ ID NO. 21; anti-LAG-3 mAb without terminal lysine (BMS-986016)

QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNP

SLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSSAS

TKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP

PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSV

LTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLT

CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV

MHEALHNHYTQKSLSLSLG

SEQ ID NO. 22 lymphocyte activation gene 3 protein amino acid sequence (Chiren, NP-002277)

MWEAQFLGLLFLQPLWVAPVKPLQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGV

TWQHQPDSGPPAAAPGHPLAPGPHPAAPSSWGPRPRRYTVLSVGPGGLRSGRLPLQPRVQL

DERGRQRGDFSLWLRPARRADAGEYRAAVHLRDRALSCRLRLRLGQASMTASPPGSLRASD

WVILNCSFSRPDRPASVHWFRNRGQGRVPVRESPHHHLAESFLFLPQVSPMDSGPWGCILT

YRDGFNVSIMYNLTVLGLEPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPGGGP

DLLVTGDNGDFTLRLEDVSQAQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGSPGSLGK

LLCEVTPVSGQERFVWSSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYF

TELSSPGAQRSGRAPGALPAGHLLLFLILGVLSLLLLVTGAFGFHLWRRQWRPRRFSALEQ

GIHPPQAQSKIEELEQEPEPEPEPEPEPEPEPEPEQL

23 heavy chain amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (REGN 3767)

QVQLVESGGGVVQPGRSLRLSCVASGFTFSSYGMHWVRQAPGKGLEWVAIIWYDGSNKYY

ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCASVATSGDFDYYGMDVWGQGTTVT

VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL

QSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGP

SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS

TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM

TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ

EGNVFSCSVMHEALHNHYTQKSLSLSLGK

24 light chain amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (REGN 3767)

EIVLTQSPATLSLSPGERTTLSCRASQRISTYLAWYQQKPGQAPRLLIYDASKRATGIPA

RFSGSGSGTGFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKRTVAAPSVFIFPP

SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT

LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

25 heavy chain variable region (VH) amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (REGN 3767)

QVQLVESGGGVVQPGRSLRLSCVASGFTFSSYGMHWVRQAPGKGLEWVAIIWYDGSNKYY

ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCASVATSGDFDYYGMDVWGQGTTVT

VSS

26 light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (REGN 3767)

EIVLTQSPATLSLSPGERTTLSCRASQRISTYLAWYQQKPGQAPRLLIYDASKRATGIPA

RFSGSGSGTGFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK

27 heavy chain CDR1 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (REGN 3767)

GFTFSSYG

28 heavy chain CDR2 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (REGN 3767)

IWYDGSNK

29 heavy chain CDR3 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (REGN 3767)

ASVATSGDFDYYGMDV

30 light chain CDR1 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (REGN 3767)

QRISTY

31 light chain CDR2 amino acid sequence; anti-LAG-3 mAb (REGN 3767)

DAS

32 light chain CDR3 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (REGN 3767)

QQRSNWPLT

33 heavy chain amino acid sequence of SEQ ID NO; anti-PD-1 mAb (REGN 2810)

EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDTYF

ADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSSAST

KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLF

PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV

SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV

SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF

SCSVMHEALHNHYTQKSLSLSLGK

34 light chain amino acid sequence of SEQ ID NO; anti-PD-1 mAb (REGN 2810)

DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAASSLHGGVPS

RFSGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFGPGTVVDFRRTVAAPSVFIFPP

SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT

LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

35 heavy chain variable region (VH) amino acid sequence of SEQ ID NO; anti-PD-1 mAb (REGN 2810)

EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDTYF

ADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSS

36 light chain variable region (VL) amino acid sequence of SEQ ID NO; anti-PD-1 mAb (REGN 2810)

DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAASSLHGGVPS

RFSGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFGPGTVVDFR

37 heavy chain CDR1 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (REGN 2810)

GFTFSNFG

38 heavy chain CDR2 amino acid sequences of SEQ ID NO; anti-PD-1 mAb (REGN 2810)

ISGGGRDT

39 heavy chain CDR3 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (REGN 2810)

VKWGNIYFDY

40 light chain CDR1 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (REGN 2810)

LSINTF

The light chain CDR2 amino acid sequence of SEQ ID NO. 41; anti-PD-1 mAb (REGN 2810)

AAS

The light chain CDR3 amino acid sequence of SEQ ID NO. 42; anti-PD-1 mAb (REGN 2810)

QQSSNTPFT

43 heavy chain amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (LAG 525)

QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTT

VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA

VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFL

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ

FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ

EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS

RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

The heavy chain amino acid sequence of SEQ ID NO. 44; anti-LAG-3 mAb (LAG 525)

QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTT

VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA

VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFL

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ

FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ

EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS

RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

45 light chain amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (LAG 525)

DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPS

RFSGSGSGTEFTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPP

SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT

LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

46 light chain amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (LAG 525)

DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPP

RFSGSGYGTDFTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPP

SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT

LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

The heavy chain variable region (VH) amino acid sequence of SEQ ID NO. 47; anti-LAG-3 mAb (LAG 525)

QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTT

VTVSS

48 heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (LAG 525)

QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTY

ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTT

VTVSS

49 light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (LAG 525)

DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPS

RFSGSGSGTEFTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK

SEQ ID NO. 50 light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (LAG 525)

DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPP

RFSGSGYGTDFTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK

The amino acid sequence of the heavy chain CDR1 of SEQ ID NO. 51; anti-LAG-3 mAb (LAG 525)

NYGMN

52 heavy chain CDR2 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (LAG 525)

WINTDTGEPTYADDFKG

53 heavy chain CDR3 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (LAG 525)

NPPYYYGTNNAEAMDY

54 light chain CDR1 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (LAG 525)

SSSQDISNYLN

55 light chain CDR2 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (LAG 525)

YTSTLHL

56 light chain CDR3 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (LAG 525)

QQYYNLPWT

57 heavy chain amino acid sequence of SEQ ID NO; anti-PD-1 mAb (PDR 001)

EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNF

DEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSAST

KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLF

PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV

SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV

SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF

SCSVMHEALHNHYTQKSLSLSLG

58 light chain amino acid sequence of SEQ ID NO; anti-PD-1 mAb (PDR 001)

EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTR

ESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPS

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS

LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

59 heavy chain variable region (VH) amino acid sequence of SEQ ID NO; anti-PD-1 mAb (PDR 001)

EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNF

DEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS

60 light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (PDR 001)

EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTR

ESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK

61 heavy chain CDR1 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (PDR 001)

TYWMH

The heavy chain CDR2 amino acid sequence of SEQ ID NO. 62; anti-PD-1 mAb (PDR 001)

NIYPGTGGSNFDEKFKN

63 heavy chain CDR3 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (PDR 001)

WTTGTGAY

64 light chain CDR1 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (PDR 001)

KSSQSLLDSGNQKNFLT

65 light chain CDR2 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (PDR 001)

WASTRES

The light chain CDR3 amino acid sequence of SEQ ID NO. 66; anti-PD-1 mAb (PDR 001)

QNDYSYPYT

67 heavy chain amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (MK 4280)

QMQLVQSGPEVKKPGTSVKVSCKASGYTFTDYNVDWVRQARGQRLEWIGDINPNDGGTIYAQKFQERVTITVDKSTSTAYMELSSLRSEDTAVYYCARNYRWFGAMDHWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

68 light chain amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (MK 4280)

DIVMTQTPLSLSVTPGQPASISCKASQSLDYEGDSDMNWYLQKPGQPPQLLIYGASNLESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQSTEDPRTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

69 heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (MK 4280)

QMQLVQSGPEVKKPGTSVKVSCKASGYTFTDYNVDWVRQARGQRLEWIGDINPNDGGTIYAQKFQERVTITVDKSTSTAYMELSSLRSEDTAVYYCARNYRWFGAMDHWGQGTTVTVSS

The light chain variable region (VL) amino acid sequence of SEQ ID NO. 70; anti-LAG-3 mAb (MK 4280)

DIVMTQTPLSLSVTPGQPASISCKASQSLDYEGDSDMNWYLQKPGQPPQLLIYGASNLESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQSTEDPRTFGGGTKVEIK

71 heavy chain CDR1 amino acid sequence; anti-LAG-3 mAb (MK 4280)

DYNVD

72 heavy chain CDR2 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (MK 4280)

DINPNDGGTIYAQKFQE

73 heavy chain CDR3 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (MK 4280)

NYRWFGAMDH

74 light chain CDR1 amino acid sequences of SEQ ID NO; anti-LAG-3 mAb (MK 4280)

KASQSLDYEGDSDMN

75 light chain CDR2 amino acid sequence of SEQ ID NO; anti-LAG-3 mAb (MK 4280)

GASNLES

76 light chain CDR3 amino acid sequence; anti-LAG-3 mAb (MK 4280)

QQSTEDPRT

77 heavy chain amino acid sequence of SEQ ID NO; anti-PD-1 mAb (MK 3475)

QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

78 light chain amino acid sequence of SEQ ID NO; anti-PD-1 mAb (MK 3475)

EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

79 heavy chain variable region (VH) amino acid sequence of SEQ ID NO; anti-PD-1 mAb (MK 3475)

QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS

80 light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (MK 3475)

EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK

81 heavy chain CDR1 amino acid sequences of SEQ ID NO; anti-PD-1 mAb (MK 3475)

NYYMY

82 heavy chain CDR2 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (MK 3475)

GINPSNGGTNFNEKFKN

83 heavy chain CDR3 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (MK 3475)

RDYRFDMGFDY

84 light chain CDR1 amino acid sequence; anti-PD-1 mAb (MK 3475)

RASKGVSTSGYSYLH

85 light chain CDR2 amino acid sequence of SEQ ID NO; anti-PD-1 mAb (MK 3475)

LASYLES

86 light chain CDR3 amino acid sequence; anti-PD-1 mAb (MK 3475)

QHSRDLPLT

SEQUENCE LISTING

<110> Bai Shi Guibao Co

<120> LAG-3 antagonist therapy for lung cancer

<130> 3338.240PC02

<150> US 63/110,210

<151> 2020-11-05

<150> US 63/104,744

<151> 2020-10-23

<160> 86

<170> PatentIn version 3.5

<210> 1

<211> 447

<212> PRT

<213> Artificial Sequence

<220>

<223> Heavy Chain Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016)

<400> 1

Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Tyr

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Arg Gly Ser Thr Asn Ser Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Leu Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Phe Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 2

<211> 214

<212> PRT

<213> Artificial Sequence

<220>

<223> Light Chain Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016)

<400> 2

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 3

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-LAG-3

mAb (BMS-986016)

<400> 3

Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Tyr

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Arg Gly Ser Thr Asn Ser Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Leu Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Phe Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 4

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> Light Chain Variable Region (VL) Amino Acid Sequence; Anti-LAG-3

mAb (BMS-986016)

<400> 4

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys

100 105

<210> 5

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Heavy Chain CDR1 Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016)

<400> 5

Asp Tyr Tyr Trp Asn

1 5

<210> 6

<211> 16

<212> PRT

<213> Artificial Sequence

<220>

<223> Heavy Chain CDR2 Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016)

<400> 6

Glu Ile Asn His Arg Gly Ser Thr Asn Ser Asn Pro Ser Leu Lys Ser

1 5 10 15

<210> 7

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Heavy Chain CDR3 Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016)

<400> 7

Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro

1 5 10

<210> 8

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Light Chain CDR1 Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016)

<400> 8

Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Ala

1 5 10

<210> 9

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Light Chain CDR2 Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016)

<400> 9

Asp Ala Ser Asn Arg Ala Thr

1 5

<210> 10

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Light Chain CDR3 Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016)

<400> 10

Gln Gln Arg Ser Asn Trp Pro Leu Thr

1 5

<210> 11

<211> 440

<212> PRT

<213> Artificial Sequence

<220>

<223> Heavy Chain Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558)

<400> 11

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser

115 120 125

Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp

130 135 140

Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr

145 150 155 160

Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr

165 170 175

Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys

180 185 190

Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp

195 200 205

Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

210 215 220

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

225 230 235 240

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

245 250 255

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

260 265 270

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

275 280 285

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

290 295 300

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

305 310 315 320

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

325 330 335

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr

340 345 350

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

355 360 365

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

370 375 380

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

385 390 395 400

Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

405 410 415

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

420 425 430

Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 12

<211> 213

<212> PRT

<213> Artificial Sequence

<220>

<223> Light Chain Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558)

<400> 12

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala

180 185 190

Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe

195 200 205

Asn Arg Gly Glu Cys

210

<210> 13

<211> 113

<212> PRT

<213> Artificial Sequence

<220>

<223> Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-PD-1 (BMS-936558)

<400> 13

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 14

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> Light Chain Variable Region (VL) Amino Acid Sequence; Anti-PD-1

mAb (BMS-936558)

<400> 14

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 15

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Heavy Chain CDR1 Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558)

<400> 15

Asn Ser Gly Met His

1 5

<210> 16

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Heavy Chain CDR2 Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558)

<400> 16

Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 17

<211> 4

<212> PRT

<213> Artificial Sequence

<220>

<223> Heavy Chain CDR3 Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558)

<400> 17

Asn Asp Asp Tyr

1

<210> 18

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Light Chain CDR1 Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558)

<400> 18

Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala

1 5 10

<210> 19

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Light Chain CDR2 Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558)

<400> 19

Asp Ala Ser Asn Arg Ala Thr

1 5

<210> 20

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Light Chain CDR3 Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558)

<400> 20

Gln Gln Ser Ser Asn Trp Pro Arg Thr

1 5

<210> 21

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> Heavy Chain Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016)

<400> 21

Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Tyr

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Arg Gly Ser Thr Asn Ser Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Leu Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Phe Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440 445

<210> 22

<211> 525

<212> PRT

<213> Artificial Sequence

<220>

<223> Lymphocyte Activation Gene 3 Protein Amino Acid Sequence

<400> 22

Met Trp Glu Ala Gln Phe Leu Gly Leu Leu Phe Leu Gln Pro Leu Trp

1 5 10 15

Val Ala Pro Val Lys Pro Leu Gln Pro Gly Ala Glu Val Pro Val Val

20 25 30

Trp Ala Gln Glu Gly Ala Pro Ala Gln Leu Pro Cys Ser Pro Thr Ile

35 40 45

Pro Leu Gln Asp Leu Ser Leu Leu Arg Arg Ala Gly Val Thr Trp Gln

50 55 60

His Gln Pro Asp Ser Gly Pro Pro Ala Ala Ala Pro Gly His Pro Leu

65 70 75 80

Ala Pro Gly Pro His Pro Ala Ala Pro Ser Ser Trp Gly Pro Arg Pro

85 90 95

Arg Arg Tyr Thr Val Leu Ser Val Gly Pro Gly Gly Leu Arg Ser Gly

100 105 110

Arg Leu Pro Leu Gln Pro Arg Val Gln Leu Asp Glu Arg Gly Arg Gln

115 120 125

Arg Gly Asp Phe Ser Leu Trp Leu Arg Pro Ala Arg Arg Ala Asp Ala

130 135 140

Gly Glu Tyr Arg Ala Ala Val His Leu Arg Asp Arg Ala Leu Ser Cys

145 150 155 160

Arg Leu Arg Leu Arg Leu Gly Gln Ala Ser Met Thr Ala Ser Pro Pro

165 170 175

Gly Ser Leu Arg Ala Ser Asp Trp Val Ile Leu Asn Cys Ser Phe Ser

180 185 190

Arg Pro Asp Arg Pro Ala Ser Val His Trp Phe Arg Asn Arg Gly Gln

195 200 205

Gly Arg Val Pro Val Arg Glu Ser Pro His His His Leu Ala Glu Ser

210 215 220

Phe Leu Phe Leu Pro Gln Val Ser Pro Met Asp Ser Gly Pro Trp Gly

225 230 235 240

Cys Ile Leu Thr Tyr Arg Asp Gly Phe Asn Val Ser Ile Met Tyr Asn

245 250 255

Leu Thr Val Leu Gly Leu Glu Pro Pro Thr Pro Leu Thr Val Tyr Ala

260 265 270

Gly Ala Gly Ser Arg Val Gly Leu Pro Cys Arg Leu Pro Ala Gly Val

275 280 285

Gly Thr Arg Ser Phe Leu Thr Ala Lys Trp Thr Pro Pro Gly Gly Gly

290 295 300

Pro Asp Leu Leu Val Thr Gly Asp Asn Gly Asp Phe Thr Leu Arg Leu

305 310 315 320

Glu Asp Val Ser Gln Ala Gln Ala Gly Thr Tyr Thr Cys His Ile His

325 330 335

Leu Gln Glu Gln Gln Leu Asn Ala Thr Val Thr Leu Ala Ile Ile Thr

340 345 350

Val Thr Pro Lys Ser Phe Gly Ser Pro Gly Ser Leu Gly Lys Leu Leu

355 360 365

Cys Glu Val Thr Pro Val Ser Gly Gln Glu Arg Phe Val Trp Ser Ser

370 375 380

Leu Asp Thr Pro Ser Gln Arg Ser Phe Ser Gly Pro Trp Leu Glu Ala

385 390 395 400

Gln Glu Ala Gln Leu Leu Ser Gln Pro Trp Gln Cys Gln Leu Tyr Gln

405 410 415

Gly Glu Arg Leu Leu Gly Ala Ala Val Tyr Phe Thr Glu Leu Ser Ser

420 425 430

Pro Gly Ala Gln Arg Ser Gly Arg Ala Pro Gly Ala Leu Pro Ala Gly

435 440 445

His Leu Leu Leu Phe Leu Ile Leu Gly Val Leu Ser Leu Leu Leu Leu

450 455 460

Val Thr Gly Ala Phe Gly Phe His Leu Trp Arg Arg Gln Trp Arg Pro

465 470 475 480

Arg Arg Phe Ser Ala Leu Glu Gln Gly Ile His Pro Pro Gln Ala Gln

485 490 495

Ser Lys Ile Glu Glu Leu Glu Gln Glu Pro Glu Pro Glu Pro Glu Pro

500 505 510

Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Gln Leu

515 520 525

<210> 23

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767)

<400> 23

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ile Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Gln Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Val Ala Thr Ser Gly Asp Phe Asp Tyr Tyr Gly Met Asp Val

100 105 110

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val

195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys

210 215 220

Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro

225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp

260 265 270

Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys

405 410 415

Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440 445

Lys

<210> 24

<211> 214

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767)

<400> 24

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Thr Thr Leu Ser Cys Arg Ala Ser Gln Arg Ile Ser Thr Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Lys Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 25

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-LAG-3

mAb (REGN3767)

<400> 25

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ile Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Gln Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Val Ala Thr Ser Gly Asp Phe Asp Tyr Tyr Gly Met Asp Val

100 105 110

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 26

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Variable Region (VL) Amino Acid Sequence; Anti-LAG-3

mAb (REGN3767)

<400> 26

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Thr Thr Leu Ser Cys Arg Ala Ser Gln Arg Ile Ser Thr Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Lys Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 27

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR1 Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767)

<400> 27

Gly Phe Thr Phe Ser Ser Tyr Gly

1 5

<210> 28

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR2 Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767)

<400> 28

Ile Trp Tyr Asp Gly Ser Asn Lys

1 5

<210> 29

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR3 Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767)

<400> 29

Ala Ser Val Ala Thr Ser Gly Asp Phe Asp Tyr Tyr Gly Met Asp Val

1 5 10 15

<210> 30

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR1 Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767)

<400> 30

Gln Arg Ile Ser Thr Tyr

1 5

<210> 31

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR2 Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767)

<400> 31

Asp Ala Ser

1

<210> 32

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR3 Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767)

<400> 32

Gln Gln Arg Ser Asn Trp Pro Leu Thr

1 5

<210> 33

<211> 444

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Amino Acid Sequence; Anti-PD-1 mAb (REGN2810)

<400> 33

Glu Val Gln Leu Leu Glu Ser Gly Gly Val Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe

20 25 30

Gly Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Ser Gly Gly Gly Arg Asp Thr Tyr Phe Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Gly Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Val Lys Trp Gly Asn Ile Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro

210 215 220

Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

290 295 300

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

325 330 335

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 34

<211> 214

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Amino Acid Sequence; Anti-PD-1 mAb (REGN2810)

<400> 34

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Ser Ile Thr Ile Thr Cys Arg Ala Ser Leu Ser Ile Asn Thr Phe

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu His Gly Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Thr Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Asn Thr Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Val Val Asp Phe Arg Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 35

<211> 117

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-PD-1

mAb (REGN2810)

<400> 35

Glu Val Gln Leu Leu Glu Ser Gly Gly Val Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe

20 25 30

Gly Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Ser Gly Gly Gly Arg Asp Thr Tyr Phe Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Gly Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Val Lys Trp Gly Asn Ile Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 36

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Variable Region (VL) Amino Acid Sequence; Anti-PD-1

mAb (REGN2810)

<400> 36

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Ser Ile Thr Ile Thr Cys Arg Ala Ser Leu Ser Ile Asn Thr Phe

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu His Gly Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Thr Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Asn Thr Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Val Val Asp Phe Arg

100 105

<210> 37

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR1 Amino Acid Sequence; Anti-PD-1 mAb (REGN2810)

<400> 37

Gly Phe Thr Phe Ser Asn Phe Gly

1 5

<210> 38

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR2 Amino Acid Sequence; Anti-PD-1 mAb (REGN2810)

<400> 38

Ile Ser Gly Gly Gly Arg Asp Thr

1 5

<210> 39

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR3 Amino Acid Sequence; Anti-PD-1 mAb (REGN2810)

<400> 39

Val Lys Trp Gly Asn Ile Tyr Phe Asp Tyr

1 5 10

<210> 40

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR1 Amino Acid Sequence; Anti-PD-1 mAb (REGN2810)

<400> 40

Leu Ser Ile Asn Thr Phe

1 5

<210> 41

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR2 Amino Acid Sequence; Anti-PD-1 mAb (REGN2810)

<400> 41

Ala Ala Ser

1

<210> 42

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR3 Amino Acid Sequence; Anti-PD-1 mAb (REGN2810)

<400> 42

Gln Gln Ser Ser Asn Thr Pro Phe Thr

1 5

<210> 43

<211> 451

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Amino Acid Sequence; Anti-LAG-3 mAb (LAG525)

<400> 43

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Leu Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr

115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser

130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

165 170 175

Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser

180 185 190

Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys

195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu

210 215 220

Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu

225 230 235 240

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

245 250 255

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

260 265 270

Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

275 280 285

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr

290 295 300

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

305 310 315 320

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser

325 330 335

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

340 345 350

Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val

355 360 365

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

370 375 380

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

385 390 395 400

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr

405 410 415

Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val

420 425 430

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

435 440 445

Ser Leu Gly

450

<210> 44

<211> 451

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Amino Acid Sequence; Anti-LAG-3 mAb (LAG525)

<400> 44

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Leu Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr

115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser

130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

165 170 175

Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser

180 185 190

Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys

195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu

210 215 220

Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu

225 230 235 240

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

245 250 255

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

260 265 270

Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

275 280 285

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr

290 295 300

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

305 310 315 320

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser

325 330 335

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

340 345 350

Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val

355 360 365

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

370 375 380

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

385 390 395 400

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr

405 410 415

Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val

420 425 430

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

435 440 445

Ser Leu Gly

450

<210> 45

<211> 214

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Amino Acid Sequence; Anti-LAG-3 mAb (LAG525)

<400> 45

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ser Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Thr Leu His Leu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Asn Leu Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 46

<211> 214

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Amino Acid Sequence; Anti-LAG-3 mAb (LAG525)

<400> 46

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ser Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Thr Leu His Leu Gly Ile Pro Pro Arg Phe Ser Gly

50 55 60

Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser

65 70 75 80

Glu Asp Ala Ala Tyr Tyr Phe Cys Gln Gln Tyr Tyr Asn Leu Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 47

<211> 125

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-LAG-3

mAb (LAG525)

<400> 47

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Leu Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 48

<211> 125

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-LAG-3

mAb (LAG525)

<400> 48

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Leu Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met

100 105 110

Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 49

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Variable Region (VL) Amino Acid Sequence; Anti-LAG-3

mAb (LAG525)

<400> 49

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ser Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Thr Leu His Leu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Asn Leu Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 50

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Variable Region (VL) Amino Acid Sequence; Anti-LAG-3

mAb (LAG525)

<400> 50

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ser Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Thr Leu His Leu Gly Ile Pro Pro Arg Phe Ser Gly

50 55 60

Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Ile Glu Ser

65 70 75 80

Glu Asp Ala Ala Tyr Tyr Phe Cys Gln Gln Tyr Tyr Asn Leu Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 51

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR1 Amino Acid Sequence; Anti-LAG-3 mAb (LAG525)

<400> 51

Asn Tyr Gly Met Asn

1 5

<210> 52

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR2 Amino Acid Sequence; Anti-LAG-3 mAb (LAG525)

<400> 52

Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys

1 5 10 15

Gly

<210> 53

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR3 Amino Acid Sequence; Anti-LAG-3 mAb (LAG525)

<400> 53

Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met Asp Tyr

1 5 10 15

<210> 54

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR1 Amino Acid Sequence; Anti-LAG-3 mAb (LAG525)

<400> 54

Ser Ser Ser Gln Asp Ile Ser Asn Tyr Leu Asn

1 5 10

<210> 55

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR2 Amino Acid Sequence; Anti-LAG-3 mAb (LAG525)

<400> 55

Tyr Thr Ser Thr Leu His Leu

1 5

<210> 56

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR3 Amino Acid Sequence; Anti-LAG-3 mAb (LAG525)

<400> 56

Gln Gln Tyr Tyr Asn Leu Pro Trp Thr

1 5

<210> 57

<211> 443

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Amino Acid Sequence; Anti-PD-1 mAb (PDR001)

<400> 57

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Thr Tyr

20 25 30

Trp Met His Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asn Ile Tyr Pro Gly Thr Gly Gly Ser Asn Phe Asp Glu Lys Phe

50 55 60

Lys Asn Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Trp Thr Thr Gly Thr Gly Ala Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro

210 215 220

Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

290 295 300

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

325 330 335

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440

<210> 58

<211> 220

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Amino Acid Sequence; Anti-PD-1 mAb (PDR001)

<400> 58

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ala Pro Arg Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr

65 70 75 80

Ile Ser Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Asn

85 90 95

Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp

115 120 125

Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn

130 135 140

Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu

145 150 155 160

Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp

165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr

180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser

195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

<210> 59

<211> 117

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-PD-1

mAb (PDR001)

<400> 59

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Thr Tyr

20 25 30

Trp Met His Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Asn Ile Tyr Pro Gly Thr Gly Gly Ser Asn Phe Asp Glu Lys Phe

50 55 60

Lys Asn Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Trp Thr Thr Gly Thr Gly Ala Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 60

<211> 113

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Variable Region (VL) Amino Acid Sequence; Anti-PD-1

mAb (PDR001)

<400> 60

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ala Pro Arg Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr

65 70 75 80

Ile Ser Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Asn

85 90 95

Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys

<210> 61

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR1 Amino Acid Sequence; Anti-PD-1 mAb (PDR001)

<400> 61

Thr Tyr Trp Met His

1 5

<210> 62

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR2 Amino Acid Sequence; Anti-PD-1 mAb (PDR001)

<400> 62

Asn Ile Tyr Pro Gly Thr Gly Gly Ser Asn Phe Asp Glu Lys Phe Lys

1 5 10 15

Asn

<210> 63

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR3 Amino Acid Sequence; Anti-PD-1 mAb (PDR001)

<400> 63

Trp Thr Thr Gly Thr Gly Ala Tyr

1 5

<210> 64

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR1 Amino Acid Sequence; Anti-PD-1 mAb (PDR001)

<400> 64

Lys Ser Ser Gln Ser Leu Leu Asp Ser Gly Asn Gln Lys Asn Phe Leu

1 5 10 15

Thr

<210> 65

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR2 Amino Acid Sequence; Anti-PD-1 mAb (PDR001)

<400> 65

Trp Ala Ser Thr Arg Glu Ser

1 5

<210> 66

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR3 Amino Acid Sequence; Anti-PD-1 mAb (PDR001)

<400> 66

Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr

1 5

<210> 67

<211> 446

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Amino Acid Sequence; Anti-LAG-3 mAb (MK4280)

<400> 67

Gln Met Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Thr

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Asn Val Asp Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Asp Ile Asn Pro Asn Asp Gly Gly Thr Ile Tyr Ala Gln Lys Phe

50 55 60

Gln Glu Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Tyr Arg Trp Phe Gly Ala Met Asp His Trp Gly Gln Gly

100 105 110

Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val

260 265 270

Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 68

<211> 218

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Amino Acid Sequence; Anti-LAG-3 mAb (MK4280)

<400> 68

Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ala Ser Gln Ser Leu Asp Tyr Glu

20 25 30

Gly Asp Ser Asp Met Asn Trp Tyr Leu Gln Lys Pro Gly Gln Pro Pro

35 40 45

Gln Leu Leu Ile Tyr Gly Ala Ser Asn Leu Glu Ser Gly Val Pro Asp

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser

65 70 75 80

Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Ser Thr

85 90 95

Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 69

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-LAG-3

mAb (MK4280)

<400> 69

Gln Met Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Thr

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Asn Val Asp Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Asp Ile Asn Pro Asn Asp Gly Gly Thr Ile Tyr Ala Gln Lys Phe

50 55 60

Gln Glu Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Tyr Arg Trp Phe Gly Ala Met Asp His Trp Gly Gln Gly

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 70

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Variable Region (VL) Amino Acid Sequence; Anti-LAG-3

Anti-LAG-3 mAb (MK4280)

<400> 70

Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ala Ser Gln Ser Leu Asp Tyr Glu

20 25 30

Gly Asp Ser Asp Met Asn Trp Tyr Leu Gln Lys Pro Gly Gln Pro Pro

35 40 45

Gln Leu Leu Ile Tyr Gly Ala Ser Asn Leu Glu Ser Gly Val Pro Asp

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser

65 70 75 80

Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Ser Thr

85 90 95

Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 71

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR1 Amino Acid Sequence; Anti-LAG-3 mAb (MK4280)

<400> 71

Asp Tyr Asn Val Asp

1 5

<210> 72

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR2 Amino Acid Sequence; Anti-LAG-3 mAb (MK4280)

<400> 72

Asp Ile Asn Pro Asn Asp Gly Gly Thr Ile Tyr Ala Gln Lys Phe Gln

1 5 10 15

Glu

<210> 73

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR3 Amino Acid Sequence; Anti-LAG-3 mAb (MK4280)

<400> 73

Asn Tyr Arg Trp Phe Gly Ala Met Asp His

1 5 10

<210> 74

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR1 Amino Acid Sequence; Anti-LAG-3 mAb (MK4280)

<400> 74

Lys Ala Ser Gln Ser Leu Asp Tyr Glu Gly Asp Ser Asp Met Asn

1 5 10 15

<210> 75

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR2 Amino Acid Sequence; Anti-LAG-3 mAb (MK4280)

<400> 75

Gly Ala Ser Asn Leu Glu Ser

1 5

<210> 76

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR3 Amino Acid Sequence; Anti-LAG-3 mAb (MK4280)

<400> 76

Gln Gln Ser Thr Glu Asp Pro Arg Thr

1 5

<210> 77

<211> 447

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Amino Acid Sequence; Anti-PD-1 mAb (MK3475)

<400> 77

Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe

50 55 60

Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 78

<211> 218

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Amino Acid Sequence; Anti-PD-1 mAb (MK3475)

<400> 78

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser

20 25 30

Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg

85 90 95

Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 79

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-PD-1

mAb (MK3475)

<400> 79

Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe

50 55 60

Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 80

<211> 111

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain Variable Region (VL) Amino Acid Sequence; Anti-PD-1

mAb (MK3475)

<400> 80

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser

20 25 30

Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg

85 90 95

Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 81

<211> 5

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR1 Amino Acid Sequence; Anti-PD-1 mAb (MK3475)

<400> 81

Asn Tyr Tyr Met Tyr

1 5

<210> 82

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR2 Amino Acid Sequence; Anti-PD-1 mAb (MK4280)

<400> 82

Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe Lys

1 5 10 15

Asn

<210> 83

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> Heavy Chain CDR3 Amino Acid Sequence; Anti-PD-1 mAb (MK3475)

<400> 83

Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr

1 5 10

<210> 84

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR1 Amino Acid Sequence; Anti-PD-1 mAb (MK3475)

<400> 84

Arg Ala Ser Lys Gly Val Ser Thr Ser Gly Tyr Ser Tyr Leu His

1 5 10 15

<210> 85

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR2 Amino Acid Sequence; Anti-PD-1 mAb (MK3475)

<400> 85

Leu Ala Ser Tyr Leu Glu Ser

1 5

<210> 86

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> Light Chain CDR3 Amino Acid Sequence; Anti-PD-1 mAb (MK3475)

<400> 86

Gln His Ser Arg Asp Leu Pro Leu Thr

1 5

Claims

1. A method of treating a human subject having lung cancer, the method comprising administering to the subject a lymphocyte activating gene-3 (LAG-3) antagonist and platinum-containing dual drug chemotherapy (PDCT).

2. The method of claim 1, wherein the method is first line therapy.

3. The method of claim 1, wherein the method is two-wire therapy.

4. The method of claim 1, wherein the method is trilinear therapy.

5. The method of claim 3 or 4, wherein the subject has progressed on a prior therapy.

6. The method of any one of claims 1-5, wherein the lung cancer recurs after multi-mode therapy for locally advanced lung cancer.

7. The method of any one of claims 1-6, wherein the subject has not received prior systemic therapy for cancer, the subject has not received prior systemic therapy for lung cancer, or the subject has not received prior systemic therapy for advanced or metastatic lung cancer.

8. The method of any one of claims 1-7, wherein the subject is primary treated for prior immunooncology, the subject is primary treated for prior immunooncology for lung cancer, or the lung cancer is primary treated for prior immunooncology.

9. The method of any one of claims 1-8, wherein the lung cancer is unresectable, advanced, recurrent, and/or metastatic.

10. The method of any one of claims 1-9, wherein the subject has stage IV lung cancer.

11. The method of any one of claims 1-10, wherein the lung cancer is small cell lung cancer.

12. The method of any one of claims 1-10, wherein the lung cancer is non-small cell lung cancer (NSCLC).

13. The method of claim 12, wherein the NSCLC has squamous or non-squamous histology.

14. The method of any one of claims 1-13, wherein one or more immune cells in tumor tissue from the subject express LAG-3.

15. The method of claim 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 the immune cells express LAG-3.

16. The method of claim 14 or 15, wherein at least about 1% of the immune cells express LAG-3.

17. The method of any one of claims 1-16, wherein one or more tumor cells in tumor tissue from the subject express PD-L1.

18. The method of claim 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.

19. The method of claim 17 or 18, wherein at least about 1% of the tumor cells express PD-L1.

20. The method of any one of claims 14-16, wherein the immune cells are tumor infiltrating lymphocytes.

21. The method of claim 20, wherein the tumor-infiltrating lymphocyte is CD8 ⁺ And (3) cells.

22. The method of any one of claims 1-21, wherein the LAG-3 antagonist is an anti-LAG-3 antibody.

23. The method of claim 22, wherein the anti-LAG-3 antibody is a full length antibody.

24. The method of claim 22 or 23, wherein the anti-LAG-3 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody.

25. The method of claim 24, wherein the multispecific antibody is a amphipathic retargeting antibody (DART), DVD-Ig, or bispecific antibody.

26. The method of claim 22, wherein the anti-LAG-3 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments, scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

27. The method of any one of claims 22-26, wherein the anti-LAG-3 antibody is BMS-986016 (rap Li Shan antibody), IMP731 (H5L 7 BW), MK4280 (28G-10, fei Weize Li Shan antibody), REGN3767 (furiximab), GSK2831781, humanized BAP050, IMP-701 (LAG 525, ela Li Shan antibody), aLAG3 (0414), aLAG3 (0416), sym022, TSR-033, TSR-075, xmAb841 (XmAb 22841), MGD013 (teporimab), BI754111, FS118, P13B 02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or an antigen binding portion thereof.

28. The method of any one of claims 22-27, 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.

29. The method of any one of claims 22-28, wherein the anti-LAG-3 antibody comprises:

(a) A heavy chain variable region CDR1 comprising the sequence shown in SEQ ID NO. 5;

(b) A heavy chain variable region CDR2 comprising the sequence shown in SEQ ID NO. 6;

(c) A heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO. 7;

(d) A light chain variable region CDR1 comprising the sequence shown in SEQ ID NO. 8;

(e) A light chain variable region CDR2 comprising the sequence shown in SEQ ID NO 9; and

(f) Light chain variable region CDR3 comprising the sequence shown in SEQ ID NO. 10.

30. The method of any one of claims 22-29, wherein the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 3 and 4, respectively.

31. The method of any one of claims 22-25 and 27-30, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs 1 and 2, respectively.

32. The method of any one of claims 22-25 and 27-30, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs 21 and 2, respectively.

33. The method of any one of claims 1-21, wherein the LAG-3 antagonist is a soluble LAG-3 polypeptide.

34. The method of claim 33, wherein the soluble LAG-3 polypeptide is a fusion polypeptide.

35. The method of claim 33 or 34, wherein the soluble LAG-3 polypeptide comprises a ligand binding fragment of a LAG-3 extracellular domain.

36. The method of claim 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 to SEQ ID No. 22.

37. The method of any one of claims 33-36, wherein the soluble LAG-3 polypeptide further comprises a half-life extending moiety.

38. The method of claim 37, wherein the half-life extending moiety comprises an immunoglobulin constant region or portion thereof, an immunoglobulin binding polypeptide, an immunoglobulin G (IgG), an Albumin Binding Polypeptide (ABP), a PAS moiety, a HES moiety, XTEN, a pegylated moiety, an Fc region, or any combination thereof.

39. The method of any one of claims 33-38, wherein the soluble LAG-3 polypeptide is IMP321 (etimod a).

40. The method of any one of claims 1-39, wherein the LAG-3 antagonist is formulated for intravenous administration.

41. The method of any one of claims 1-40, wherein the LAG-3 antagonist is administered in a flat dose.

42. The method of any one of claims 1-41, wherein the LAG-3 antagonist is administered at a dose of: at least about 0.25mg to about 2000mg, about 0.25mg to about 1600mg, about 0.25mg to about 1200mg, about 0.25mg to about 800mg, about 0.25mg to about 400mg, about 0.25mg to about 100mg, about 0.25mg to about 50mg, about 0.25mg to about 40mg, about 0.25mg to about 30mg, about 0.25mg to about 20mg, about 20mg to about 2000mg, about 20mg to about 1600mg, about 20mg to about 1200mg, about 20mg to about 800mg, about 20mg to about 400mg, about 20mg to about 100mg, about 100mg to about 2000mg, about 100mg to about 1800mg, about 100mg to about 1600mg, about 100mg to about 1400mg, about 100mg to about 1200mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 400mg to about 400mg, about 400mg to about 2000mg, about 400mg to about 400mg, about 400mg to about 400mg, or about 400mg to about 400 mg.

43. The method of any one of claims 1-42, wherein the LAG-3 antagonist is administered at a dose of: about 0.25mg, about 0.5mg, about 0.75mg, about 1mg, about 1.25mg, about 1.5mg, about 1.75mg, about 2mg, about 2.25mg, about 2.5mg, about 2.75mg, about 3mg, about 3.25mg, about 3.5mg, about 3.75mg, about 4mg, about 4.25mg, about 4.5mg, about 4.75mg, about 5mg, about 5.25mg, about 5.5mg, about 5.75mg, about 6mg, about 6.25mg, about 6.5mg, about 6.75mg, about 7mg, about 7.25mg, about 7.5mg, about 7.75mg, about 8mg, about 8.25mg, about 8.5mg, about 8.75mg, about 9mg, about 9.5mg, about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, 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 850mg 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 1180mg, about 1200mg, about 1240mg, about 1280mg, about 1300mg, about 1340mg, about 1380mg, about 1400mg, about 1440mg, about 1480mg, about 1500mg, about 1540mg, about 1580mg, about 1600mg, about 1640mg, about 1680mg, about 1700mg, about 1740mg, about 1780mg, about 1800mg, about 1840mg, about 1880mg, about 1900mg, about 1940mg, about 1980mg, or about 2000mg.

44. The method of any one of claims 1-40, wherein the LAG-3 antagonist is administered in a weight-based dose.

45. The method of any one of claims 1-40 or 44, wherein the LAG-3 antagonist is administered at a dose of: about 0.003mg/kg to about 25mg/kg, about 0.003mg/kg to about 20mg/kg, about 0.003mg/kg to about 15mg/kg, about 0.003mg/kg to about 5mg/kg, about 0.003mg/kg to about 1mg/kg, about 0.003mg/kg to about 0.9mg/kg, about 0.003mg/kg to about 0.8mg/kg, about 0.003mg/kg to about 0.7mg/kg, about 0.003mg/kg to about 0.6mg/kg, about 0.003mg/kg to about 0.5mg/kg, about 0.003mg/kg to about 0.4mg/kg, about 0.003mg/kg to about 0.3mg/kg, about 0.003mg/kg to about 0.2mg/kg, about 0.003mg/kg to about 0.1mg/kg, about 25mg/kg to about 1mg to about 25mg/kg, about 1mg to about 25mg/kg to about 15mg/kg, about 1mg to about 25mg/kg, about 15mg to about 5mg/kg to about 25mg/kg, about 25mg to about 15 mg/kg.

46. The method of any one of claims 1-40 or 44-45, wherein the LAG-3 antagonist is administered at a dose of: about 0.003mg/kg, about 0.004mg/kg, about 0.005mg/kg, about 0.006mg/kg, about 0.007mg/kg, about 0.008mg/kg, about 0.009mg/kg, about 0.01mg/kg, about 0.02mg/kg, about 0.03mg/kg, about 0.04mg/kg, about 0.05mg/kg, about 0.06mg/kg, about 0.07mg/kg, about 0.08mg/kg, about 0.09mg/kg, about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 0.6mg/kg, about 0.7mg/kg, about 0.8mg/kg, about 0.9mg/kg about 1.0mg/kg, about 2.0mg/kg, about 3.0mg/kg, about 4.0mg/kg, about 5.0mg/kg, about 6.0mg/kg, about 7.0mg/kg, about 8.0mg/kg, about 9.0mg/kg, about 10.0mg/kg, about 11.0mg/kg, about 12.0mg/kg, about 13.0mg/kg, about 14.0mg/kg, about 15.0mg/kg, about 16.0mg/kg, about 17.0mg/kg, about 18.0mg/kg, about 19.0mg/kg, about 20.0mg/kg, about 21.0mg/kg, about 22.0mg/kg, about 23.0mg/kg, about 24.0mg/kg or about 25.0mg/kg.

47. The method of any one of claims 41-46, wherein the dose is administered about once every week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, about once every eight weeks, about once every nine weeks, about once every ten weeks, or about once every twelve weeks.

48. The method of any one of claims 1-47, wherein the PDCT comprises a platinum agent in combination with a nucleoside analog, an antimetabolite, a taxane, a vinca alkaloid, or a topoisomerase inhibitor.

49. The method of claim 48, wherein the platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, liposomal platinum, or phenanthreneplatinum.

50. The method of claim 48 or 49, wherein the platinum agent is cisplatin.

51. The method of claim 48 or 49, wherein the platinum agent is carboplatin.

52. The method of any one of claims 48-51, wherein the nucleoside analog is cytarabine, gemcitabine, lamivudine, entecavir, or telbivudine.

53. The method of claim 52, wherein the nucleoside analog is gemcitabine.

54. The method of any one of claims 48-51, wherein the antimetabolite is capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pravastatin, pramipexole, or thioguanine.

55. The method of claim 54, wherein the antimetabolite is pemetrexed.

56. The method of any one of claims 48-51, wherein the taxane is paclitaxel, albumin-bound paclitaxel, docetaxel, or cabazitaxel.

57. The method of any one of claims 48-51, wherein said vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincamine alcohol, vinri dine, or vinbunting.

58. The method of claim 57, wherein the vinca alkaloid is vinorelbine or vinblastine.

59. The method of any one of claims 48-51, wherein the topoisomerase inhibitor is etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin.

60. The method of claim 59, wherein the topoisomerase inhibitor is etoposide.

61. The method of claim 59, wherein the topoisomerase inhibitor is irinotecan.

62. The method of any one of claims 1-49, wherein the PDCT comprises cisplatin or carboplatin in combination with gemcitabine, pemetrexed, paclitaxel, albumin-bound paclitaxel, docetaxel, vinorelbine, vinblastine, etoposide, or irinotecan.

63. The method of any one of claims 1-49, wherein the PDCT comprises cisplatin or carboplatin in combination with paclitaxel or albumin-bound paclitaxel.

64. The method of any one of claims 1-49, wherein the PDCT comprises cisplatin or a combination of carboplatin and pemetrexed.

65. The method of any one of claims 1-64, further comprising administering to the subject an additional therapeutic agent.

66. The method of claim 65, wherein the additional therapeutic agent comprises an anticancer agent.

67. The method of claim 66, wherein the anti-cancer agent comprises a tyrosine kinase inhibitor, an anti-angiogenic agent, a checkpoint inhibitor, a checkpoint stimulant, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topoisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof.

68. The method of claim 67, wherein the tyrosine kinase inhibitor comprises afatinib, erlotinib, dactinib, gefitinib, octtinib, ai Leti ni, buntinib, ceritinib, crizotinib, lolatin, emtrictinib, dabrafenib, trimetinib, vitamin Mo Feini, lartinib, or any combination thereof.

69. The method of claim 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 (Tie) receptor having Ig-like and EGF-like domains, hepatocyte Growth Factor (HGF), tyrosine protein kinase Met (C-Met), C-lectin family 14 member a (CLEC 14A), polyprotein 2 (MMRN 2), shock protein 70-1A (HSP 70-1A), epidermal Growth Factor (EGF), EGF receptor (EGFR), or any combination thereof.

70. The method of claim 67 or 69, wherein the anti-angiogenic agent comprises bevacizumab, ramucirumab, albespride, taniriumab, olamumab, nevacizumab Su Shan, AMG780, MEDI3617, vannooximab, rituximab, non-trastuzumab, TAK-701, onatuzumab, ematuzumab, or any combination thereof.

71. The method of claim 67, wherein the step of, wherein the checkpoint inhibitor comprises a programmed death protein-1 (PD-1) pathway inhibitor, a cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor, a T cell immunoglobulin and ITIM domain (TIGIT) inhibitor, a T cell immunoglobulin and mucin domain protein-3 (TIM-3) inhibitor, a TIM-1 inhibitor, a TIM-4 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a B and T cell lymphocyte attenuator (BTLA) inhibitor, a T cell activated V domain Ig inhibitor (VISTA) inhibitor, an indoleamine 2, 3-dioxygenase (IDO) inhibitor, a nicotinamide adenine dinucleotide phosphate oxidase subtype 2 (NOX 2) inhibitor, a killer cell immunoglobulin-like receptor (KIR) inhibitor, an adenosine A2a receptor (A2 aR) inhibitor, a transforming growth factor beta (TGF-beta) inhibitor, a phosphoinositide 3-kinase (PI 3K) inhibitor, a CD47 inhibitor, a CD48 inhibitor, a CD73, a CD113, a sialog-7-sik inhibitor, a galectin-7 (SIEC-7), a GLEC-9-like protein-1, a galectin-related hormone-1, a galectin-15, a galectin-related hormone-receptor (GLEC-1), a galectin-9-related antigen, a galectin-1-related antigen, a galban-15 A G protein coupled receptor 56 (GPR 56) inhibitor, a glycoprotein a repeat dominant (GARP) inhibitor, a 2B4 inhibitor, a programmed death protein-1 homolog (PD 1H) inhibitor, a leukocyte associated immunoglobulin-like receptor 1 (LAIR 1) inhibitor, or any combination thereof.

72. The method of any one of claims 67 or 71, wherein the checkpoint inhibitor comprises a PD-1 pathway inhibitor.

73. The method of claim 71 or 72, wherein the PD-1 pathway inhibitor is an anti-PD-1 antibody and/or an anti-PD-L1 antibody.

74. The method of any one of claims 71-73, wherein the PD-1 pathway inhibitor is an anti-PD-1 antibody.

75. The method of claim 73 or 74, wherein the anti-PD-1 antibody is a full length antibody.

76. The method of any one of claims 73-75, wherein the anti-PD-1 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody.

77. The method of claim 76, wherein the multispecific antibody is a DART, DVD-Ig, or bispecific antibody.

78. The method of claim 73 or 74, wherein the anti-PD-1 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments, scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

79. The method of any one of claims 73-78, wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, PDR001 (swabber), MEDI-0680, TSR-042, cimiput Li Shan antibody, JS001, PF-06801591, BGB-a317, BI 754091, INCSHR1210, GLS-010, AM-001, STI-1110, age 2034, MGA012, BCD-100, IBI308, SSI-361, or comprises an antigen-binding portion thereof.

80. The method of any one of claims 73-79, 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.

81. The method of any one of claims 73-80, wherein the anti-PD-1 antibody comprises:

(a) A heavy chain variable region CDR1 comprising the sequence shown in SEQ ID NO. 15;

(b) A heavy chain variable region CDR2 comprising the sequence shown in SEQ ID NO. 16;

(c) A heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID No. 17;

(d) A light chain variable region CDR1 comprising the sequence shown in SEQ ID NO. 18;

(e) A light chain variable region CDR2 comprising the sequence shown in SEQ ID NO. 19; and

(f) Light chain variable region CDR3 comprising the sequence shown in SEQ ID NO. 20.

82. The method of any one of claims 73-81, wherein the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 13 and 14, respectively.

83. The method of any one of claims 73-77 or 79-82, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs 11 and 12, respectively.

84. The method of claim 71 or 72, wherein the PD-1 pathway inhibitor is a soluble PD-L2 polypeptide.

85. The method of claim 84, wherein the soluble PD-L2 polypeptide is a fusion polypeptide.

86. The method of claim 84 or 85, wherein the soluble PD-L2 polypeptide comprises a ligand binding fragment of a PD-L2 extracellular domain.

87. The method of any one of claims 84-86, wherein the soluble PD-L2 polypeptide further comprises a half-life extending moiety.

88. The method of claim 87, wherein the half-life extending moiety comprises an immunoglobulin constant region or portion thereof, an immunoglobulin binding polypeptide, an immunoglobulin G (IgG), an Albumin Binding Polypeptide (ABP), a PAS moiety, a HES moiety, XTEN, a pegylated moiety, an Fc region, or any combination thereof.

89. The method of any one of claims 84-88, wherein the soluble PD-L2 polypeptide is AMP-224.

90. The method of any one of claims 71-73, wherein the PD-1 pathway inhibitor is an anti-PD-L1 antibody.

91. The method of claim 73 or 90, wherein the anti-PD-L1 antibody is a full-length antibody.

92. The method of any one of claims 73 or 90-91, wherein the anti-PD-L1 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody.

93. The method of claim 92, wherein the multispecific antibody is a DART, DVD-Ig, or bispecific antibody.

94. The method of claim 73 or 90, wherein the anti-PD-L1 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments, scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

95. The method of any one of claims 73 or 91-94, wherein the anti-PD-L1 antibody is BMS-936559, alemtuzumab, dimvaluzumab, aviuzumab, STI-1014, CX-072, KN035, LY3300054, BGB-a333, ICO 36, FAZ053, CK-301, or comprises an antigen-binding portion thereof.

96. The method of claim 71 or 72, wherein the PD-1 pathway inhibitor is BMS-986189.

97. The method of any one of claims 67 or 71-96, wherein the checkpoint inhibitor comprises a CTLA-4 inhibitor.

98. The method of claim 97, wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody.

99. The method of claim 98, wherein the anti-CTLA-4 antibody is a full-length antibody.

100. The method of any one of claims 97-99, wherein the anti-CTLA-4 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody.

101. The method of claim 100, wherein the multispecific antibody is a DART, DVD-Ig, or bispecific antibody.

102. The method of claim 98, wherein the anti-CTLA-4 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments, scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

103. The method of any one of claims 98-102, wherein the anti-CTLA-4 antibody is ipilimumab, tremelimumab, MK-1308, AGEN-1884, or comprises an antigen-binding portion thereof.

104. The method of any one of claims 67 or 71-103, wherein the checkpoint inhibitor is formulated for intravenous administration.

105. The method of any one of claims 67 or 71-104, wherein said LAG-3 antagonist and said checkpoint inhibitor are formulated separately.

106. The method of claim 105, wherein when the checkpoint inhibitor comprises more than one checkpoint inhibitor, each checkpoint inhibitor is formulated separately.

107. The method of any one of claims 67 or 71-104, wherein said LAG-3 antagonist and said checkpoint inhibitor are formulated together.

108. The method of claim 107, wherein when the checkpoint inhibitor comprises more than one checkpoint inhibitor, two or more checkpoint inhibitors are formulated together.

109. The method of claim 105 or 106, wherein the checkpoint inhibitor is administered prior to the LAG-3 antagonist.

110. The method of claim 105 or 106, wherein the LAG-3 antagonist is administered prior to the checkpoint inhibitor.

111. The method of any one of claims 105-108, wherein the LAG-3 antagonist and the checkpoint inhibitor are administered concurrently.

112. The method of any one of claims 67 or 71-111, wherein the checkpoint inhibitor is administered in a flat dose.

113. The method of any one of claims 67 or 71-112, wherein the checkpoint inhibitor is administered at a dose of: at least about 0.25mg to about 2000mg, about 0.25mg to about 1600mg, about 0.25mg to about 1200mg, about 0.25mg to about 800mg, about 0.25mg to about 400mg, about 0.25mg to about 100mg, about 0.25mg to about 50mg, about 0.25mg to about 40mg, about 0.25mg to about 30mg, about 0.25mg to about 20mg, about 20mg to about 2000mg, about 20mg to about 1600mg, about 20mg to about 1200mg, about 20mg to about 800mg, about 20mg to about 400mg, about 20mg to about 100mg, about 100mg to about 2000mg, about 100mg to about 1800mg, about 100mg to about 1600mg, about 100mg to about 1400mg, about 100mg to about 1200mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 400mg to about 400mg, about 400mg to about 2000mg, about 400mg to about 400mg, about 400mg to about 400mg, or about 400mg to about 400 mg.

114. The method of any one of claims 67 or 71-113, wherein the checkpoint inhibitor is administered at a dose of: about 0.25mg, about 0.5mg, about 0.75mg, about 1mg, about 1.25mg, about 1.5mg, about 1.75mg, about 2mg, about 2.25mg, about 2.5mg, about 2.75mg, about 3mg, about 3.25mg, about 3.5mg, about 3.75mg, about 4mg, about 4.25mg, about 4.5mg, about 4.75mg, about 5mg, about 5.25mg, about 5.5mg, about 5.75mg, about 6mg, about 6.25mg, about 6.5mg, about 6.75mg, about 7mg, about 7.25mg, about 7.5mg, about 7.75mg, about 8mg, about 8.25mg, about 8.5mg, about 8.75mg, about 9mg, about 9.5mg, about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, 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 850mg 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 1180mg, about 1200mg, about 1240mg, about 1280mg, about 1300mg, about 1340mg, about 1380mg, about 1400mg, about 1440mg, about 1480mg, about 1500mg, about 1540mg, about 1580mg, about 1600mg, about 1640mg, about 1680mg, about 1700mg, about 1740mg, about 1780mg, about 1800mg, about 1840mg, about 1880mg, about 1900mg, about 1940mg, about 1980mg, or about 2000mg.

115. The method of any one of claims 67 or 71-111, wherein the checkpoint inhibitor is administered in a weight-based dose.

116. The method of any one of claims 67, 71-111, or 115, wherein the checkpoint inhibitor is administered at a dose of: about 0.003mg/kg to about 25mg/kg, about 0.003mg/kg to about 20mg/kg, about 0.003mg/kg to about 15mg/kg, about 0.003mg/kg to about 5mg/kg, about 0.003mg/kg to about 1mg/kg, about 0.003mg/kg to about 0.9mg/kg, about 0.003mg/kg to about 0.8mg/kg, about 0.003mg/kg to about 0.7mg/kg, about 0.003mg/kg to about 0.6mg/kg, about 0.003mg/kg to about 0.5mg/kg, about 0.003mg/kg to about 0.4mg/kg, about 0.003mg/kg to about 0.3mg/kg, about 0.003mg/kg to about 0.2mg/kg, about 0.003mg/kg to about 0.1mg/kg, about 25mg/kg to about 1mg to about 25mg/kg, about 1mg to about 25mg/kg to about 15mg/kg, about 1mg to about 25mg/kg, about 15mg to about 5mg/kg to about 25mg/kg, about 25mg to about 15 mg/kg.

117. The method of any one of claims 67, 71-111, or 115-116, wherein the checkpoint inhibitor is administered at a dose of: about 0.003mg/kg, about 0.004mg/kg, about 0.005mg/kg, about 0.006mg/kg, about 0.007mg/kg, about 0.008mg/kg, about 0.009mg/kg, about 0.01mg/kg, about 0.02mg/kg, about 0.03mg/kg, about 0.04mg/kg, about 0.05mg/kg, about 0.06mg/kg, about 0.07mg/kg, about 0.08mg/kg, about 0.09mg/kg, about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 0.6mg/kg, about 0.7mg/kg, about 0.8mg/kg, about 0.9mg/kg about 1.0mg/kg, about 2.0mg/kg, about 3.0mg/kg, about 4.0mg/kg, about 5.0mg/kg, about 6.0mg/kg, about 7.0mg/kg, about 8.0mg/kg, about 9.0mg/kg, about 10.0mg/kg, about 11.0mg/kg, about 12.0mg/kg, about 13.0mg/kg, about 14.0mg/kg, about 15.0mg/kg, about 16.0mg/kg, about 17.0mg/kg, about 18.0mg/kg, about 19.0mg/kg, about 20.0mg/kg, about 21.0mg/kg, about 22.0mg/kg, about 23.0mg/kg, about 24.0mg/kg or about 25.0mg/kg.

118. The method of any one of claims 112-117, wherein the dose is administered about once every week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, about once every eight weeks, about once every nine weeks, about once every ten weeks, or about once every twelve weeks.

119. A method of treating a human subject having lung cancer, the method comprising administering to the subject:

(a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 360 mg; and

(b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14.

120. A method of treating a human subject having lung cancer, the method comprising administering to the subject:

(a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 720 mg;

121. The method of claim 119 or 120, wherein the method is first line therapy.

122. The method of claim 119 or 120, wherein the method is two-wire therapy.

123. The method of claim 119 or 120, wherein the method is trilinear therapy.

124. The method of claim 122 or 123, wherein the subject has progressed on a prior therapy.

125. The method of any one of claims 119-124, wherein the lung cancer is unresectable, advanced, recurrent, and/or metastatic.

126. The method of any one of claims 119-125, wherein the subject has stage IV lung cancer.

127. The method of any one of claims 119-126, wherein the lung cancer is small cell lung cancer.

128. The method of any one of claims 119-126, wherein the lung cancer is non-small cell lung cancer (NSCLC).

129. The method of claim 128, wherein the NSCLC has squamous or non-squamous histology.

130. The method of any one of claims 119-129, further comprising administering PDCT.

131. The method of claim 130, wherein the PDCT comprises a platinum agent in combination with a nucleoside analog, an antimetabolite, a taxane, a vinca alkaloid, or a topoisomerase inhibitor.

132. The method of claim 131, wherein the platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, liposomal platinum, or phenanthreneplatinum.

133. The method of claim 131 or 132, wherein the platinum agent is cisplatin.

134. The method of claim 131 or 132, wherein the platinum agent is carboplatin.

135. The method of any one of claims 131-134, wherein the nucleoside analog is cytarabine, gemcitabine, lamivudine, entecavir, or telbivudine.

136. The method of claim 135, wherein the nucleoside analog is gemcitabine.

137. The method of any one of claims 131-134, wherein the antimetabolite is capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pravastatin, pramipexole, or thioguanine.

138. The method of claim 137, wherein the antimetabolite is pemetrexed.

139. The method of any one of claims 131-134, wherein the taxane is paclitaxel, albumin bound paclitaxel, docetaxel, or cabazitaxel.

140. The method of any one of claims 131-134, wherein the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincamine alcohol, vinri dine, or vinbunting.

141. The method of claim 140, wherein the vinca alkaloid is vinorelbine or vinblastine.

142. The method of any one of claims 131-134, wherein the topoisomerase inhibitor is etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin.

143. The method of claim 142, wherein the topoisomerase inhibitor is etoposide.

144. The method of claim 142, wherein the topoisomerase inhibitor is irinotecan.

145. The method of any one of claims 130-132, wherein the PDCT comprises cisplatin or carboplatin in combination with gemcitabine, pemetrexed, paclitaxel, albumin-bound paclitaxel, docetaxel, vinorelbine, vinblastine, etoposide, or irinotecan.

146. The method of any of claims 130-132, wherein the PDCT comprises cisplatin or carboplatin in combination with paclitaxel or albumin-bound paclitaxel.

147. The method of any of claims 130-132, wherein the PDCT comprises cisplatin or a combination of carboplatin and pemetrexed.

148. A method of treating a human subject having stage IV or recurrent NSCLC with squamous histology, the method comprising administering to the subject:

(a) An anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 3, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 4 at a dose of about 360 mg;

(b) An anti-PD-1 antibody at a dose of about 360mg comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID No. 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID No. 14;

(c) PDCT, comprising:

(i) Carboplatin at a dose of about 6 mg/mL-min in area under the target concentration-time curve, and

(ii) The dosage is about 200mg/m ² Is used for the preparation of paclitaxel,

wherein the method is first line therapy.

149. A method of treating a human subject having stage IV or recurrent NSCLC with squamous histology, the method comprising administering to the subject:

(c) PDCT, comprising:

(ii) The dosage is about 200mg/m ² Is used for the preparation of paclitaxel,

wherein the method is first line therapy.

150. A method of treating a human subject having stage IV or recurrent NSCLC with squamous histology, the method comprising administering to the subject:

(c) PDCT, comprising:

(ii) The dosage is about 100mg/m ² Albumin-bound paclitaxel of (a) and (b),

wherein the method is first line therapy.

151. A method of treating a human subject having stage IV or recurrent NSCLC with squamous histology, the method comprising administering to the subject:

(c) PDCT, comprising:

(ii) The dosage is about 100mg/m ² Albumin-bound paclitaxel of (a) and (b),

wherein the method is first line therapy.

152. A method of treating a human subject having stage IV or recurrent NSCLC with non-squamous histology, the method comprising administering to the subject:

(c) PDCT, comprising:

(i) Carboplatin at a target concentration-time curve area of about 5 mg/mL-min or about 6 mg/mL-min, and

(ii) The dosage is about 500mg/m ² Is characterized in that the pemetrexed is a solid,

wherein the method is first line therapy.

153. A method of treating a human subject having stage IV or recurrent NSCLC with non-squamous histology, the method comprising administering to the subject:

(c) PDCT, comprising:

wherein the method is first line therapy.

154. A method of treating a human subject having stage IV or recurrent NSCLC with non-squamous histology, the method comprising administering to the subject:

(c) PDCT, comprising:

(i) The dosage is about 75mg/m ² Cisplatin of (a) and (b)

wherein the method is first line therapy.

155. A method of treating a human subject having stage IV or recurrent NSCLC with non-squamous histology, the method comprising administering to the subject:

(c) PDCT, comprising:

(i) The dosage is about 75mg/m ² Cisplatin of (a) and (b)

wherein the method is first line therapy.

156. The method of any one of claims 119-155, wherein the lung cancer recurs after multi-mode therapy for locally advanced lung cancer.

157. The method of any one of claims 119-156, wherein the subject has not received prior systemic therapy for cancer, the subject has not received prior systemic therapy for lung cancer, or the subject has not received prior systemic therapy for advanced or metastatic lung cancer.

158. The method of any one of claims 119-157, wherein the subject is primary treated for prior immunooncology, the subject is primary treated for prior immunooncology for lung cancer, or the lung cancer is primary treated for prior immunooncology.

159. The method of any one of claims 119-158, wherein one or more immune cells in tumor tissue from the subject express LAG-3.

160. The method of claim 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 the immune cells express LAG-3.

161. The method of claim 159 or 160, wherein at least about 1% of the immune cells express LAG-3.

162. The method of any one of claims 119-161, wherein one or more tumor cells in tumor tissue from the subject express PD-L1.

163. The method of claim 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 the tumor cells express PD-L1.

164. The method of claim 162 or 163, wherein at least about 1% of the tumor cells express PD-L1.

165. The method of any of claims 159-161, wherein the immune cell is a tumor infiltrating lymphocyte.

166. The method of claim 165, wherein the tumor-infiltrating lymphocyte is CD8 ⁺ And (3) cells.

167. The method of any one of claims 119-166, wherein:

(a) The anti-LAG-3 antibody comprises a heavy chain variable region CDR1, CDR2 and CDR3 comprising the sequences shown in SEQ ID NO:5, SEQ ID NO:6 and SEQ ID NO:7, respectively, and a light chain variable region CDR1, CDR2 and CDR3 comprising the sequences shown 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 comprising the sequences shown 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 shown in SEQ ID NO. 18, SEQ ID NO. 19 and SEQ ID NO. 20, respectively.

168. The method of any one of claims 119-167, wherein the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 3 and 4, respectively, and the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 13 and 14, respectively.

169. The method of any one of claims 119-168, wherein the anti-LAG-3 antibody and/or the anti-PD-1 antibody is a full-length antibody.

170. The method of any one of claims 119-169, wherein the anti-LAG-3 antibody and/or anti-PD-1 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody.

171. The method of claim 170, wherein the multispecific antibody is a DART, DVD-Ig, or bispecific antibody.

172. The method of claims 119-168, wherein the anti-LAG-3 antibody and/or anti-PD-1 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments, scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

173. The method of any one of claims 119-171, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs 1 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs 11 and 12, respectively.

174. The method of any one of claims 119-171, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID nos. 21 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID nos. 11 and 12, respectively.

175. The method of any one of claims 119-174, further comprising administering to the subject an additional therapeutic agent.

176. The method of claim 175, wherein the additional therapeutic agent comprises an anticancer agent.

177. The method of claim 176, wherein the anti-cancer agent comprises a tyrosine kinase inhibitor, an anti-angiogenic agent, a checkpoint inhibitor, a checkpoint stimulant, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topoisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof.

178. The method of claim 177, wherein the tyrosine kinase inhibitor is afatinib, erlotinib, dactinib, gefitinib, octtinib, ai Leti ni, buntinib, ceritinib, crizotinib, lolatin, emtrictinib, dabrafenib, trimetinib, vitamin Mo Feini, lartinib, or any combination thereof.

179. The method of claim 177, 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 (Tie) receptor having Ig-like and EGF-like domains, hepatocyte Growth Factor (HGF), tyrosine protein kinase Met (C-Met), C-lectin family 14 member a (CLEC 14A), polyprotein 2 (MMRN 2), shock protein 70-1A (HSP 70-1A), epidermal Growth Factor (EGF), EGF receptor (EGFR), or any combination thereof.

180. The method of claim 177 or 179, wherein the anti-angiogenic agent comprises bevacizumab, ramucirumab, albespride, taniriumab, olamumab, nevacizumab Su Shan, AMG780, MEDI3617, vannooximab, rituximab, non-trastuzumab, TAK-701, onatuzumab, ematuzumab, or any combination thereof.

181. The method according to claim 177, wherein the checkpoint inhibitor comprises a programmed death protein-1 (PD-1) pathway inhibitor, a cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor, a T cell immunoglobulin and ITIM domain (TIGIT) inhibitor, a T cell immunoglobulin and mucin domain protein-3 (TIM-3) inhibitor, a TIM-1 inhibitor, a TIM-4 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a B and T cell lymphocyte attenuator (BTLA) inhibitor, a T cell activated V domain Ig inhibitor (VISTA) inhibitor, an indoleamine 2, 3-dioxygenase (IDO) inhibitor, a nicotinamide adenine dinucleotide phosphate oxidase subtype 2 (NOX 2) inhibitor, a killer cell immunoglobulin-like receptor (KIR) inhibitor, an adenosine A2a receptor (A2 aR) inhibitor, a transforming growth factor beta (TGF-beta) inhibitor, a phosphoinositide 3-kinase (PI 3K) inhibitor, a CD47 inhibitor, a CD48 inhibitor, a CD73, a CD113, a sialog-7-sik inhibitor, a galectin-7 (SIEC-7), a GLEC-9-like protein-1, a galectin-related hormone-1, a galectin-15, a galectin-related hormone-receptor (GLEC-1), a galectin-9-related antigen, a galectin-1-related antigen, a galban-15 A G protein coupled receptor 56 (GPR 56) inhibitor, a glycoprotein a repeat dominant (GARP) inhibitor, a 2B4 inhibitor, a programmed death protein-1 homolog (PD 1H) inhibitor, a leukocyte associated immunoglobulin-like receptor 1 (LAIR 1) inhibitor, or any combination thereof.

182. The method of claim 181, wherein the PD-1 pathway inhibitor is an anti-PD-L1 antibody.

183. The method of claim 182, wherein the anti-PD-L1 antibody is a full-length antibody.

184. The method of claim 181 or 182, wherein the anti-PD-L1 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody.

185. The method of claim 184, wherein the multispecific antibody is a DART, DVD-Ig, or bispecific antibody.

186. The method of claim 182, wherein the anti-PD-L1 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments, scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

187. The method of any one of claims 182-186, wherein the anti-PD-L1 antibody is BMS-936559, alemtuzumab, divaruzumab, aviuzumab, STI-1014, CX-072, KN035, LY3300054, BGB-a333, ICO 36, CK-301, or comprises an antigen-binding portion thereof.

188. The method of claim 182, wherein the PD-1 pathway inhibitor is BMS-986189.

189. The method of any one of claims 177 or 181, wherein the checkpoint inhibitor comprises a CTLA-4 inhibitor.

190. The method of claim 189, wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody.

191. The method of claim 190, wherein the anti-CTLA-4 antibody is a full-length antibody.

192. The method of claim 190 or 191, wherein the anti-CTLA-4 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody.

193. The method of claim 192, wherein the multispecific antibody is a DART, DVD-Ig, or bispecific antibody.

194. The method of claim 190, wherein the anti-CTLA-4 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments, scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

195. The method of any one of claims 190-194, wherein the anti-CTLA-4 antibody is ipilimumab, tremelimumab, MK-1308, AGEN-1884, or comprises an antigen-binding portion thereof.

196. The method of any one of claims 119-195, wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are formulated for intravenous administration.

197. The method of any one of claims 181-196, wherein the checkpoint inhibitor is formulated for intravenous administration.

198. The method of any one of claims 119-197, wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are formulated separately.

199. The method of any one of claims 119-197, wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are formulated together.

200. The method of any one of claims 119-198, wherein the anti-PD-1 antibody is administered prior to the anti-LAG-3 antibody.

201. The method of any one of claims 119-198, wherein the anti-LAG-3 antibody is administered prior to the anti-PD-1 antibody.

202. The method of any one of claims 119-199, wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are administered in parallel.

203. The method of any one of claims 119-202, wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are administered about once every three weeks.

204. The method of claim 203, wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are administered on day 1 of a three week cycle.

205. The method of claim 203 or 204, wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are administered intravenously from a single iv bag for about 30 minutes.

206. The method of any one of claims 130-205, wherein the PDCT is administered every three weeks.

207. The method of claim 206, wherein the PDCT is administered for up to about 4 three week periods.

208. A pharmaceutical composition comprising (a) 360mg of an anti-LAG-3 antibody and (b) 360mg of an anti-PD-1 antibody.

209. A pharmaceutical composition comprising (a) 360mg of an anti-LAG-3 antibody and (b) 720mg of an anti-PD-1 antibody.

210. The pharmaceutical composition of claim 208 or 209, wherein:

(a) The anti-LAG-3 antibody comprises CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence shown in SEQ ID NO. 3 and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence shown in SEQ ID NO. 4, and

(b) The anti-PD-1 antibodies comprise CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence shown in SEQ ID NO. 13 and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence shown in SEQ ID NO. 14.

211. The pharmaceutical composition of any one of claims 208-210, wherein:

212. The pharmaceutical composition of any one of claims 208-211, wherein the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 3 and 4, respectively, and the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs 13 and 14, respectively.

213. The pharmaceutical composition of any one of claims 208-212, wherein the anti-LAG-3 antibody and/or the anti-PD-1 antibody is a full-length antibody.

214. The pharmaceutical composition of any one of claims 208-213, wherein the anti-LAG-3 antibody and/or anti-PD-1 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody.

215. The pharmaceutical composition of claim 214, wherein the multispecific antibody is a DART, DVD-Ig, or bispecific antibody.

216. The pharmaceutical composition of claims 208-212, wherein the anti-LAG-3 antibody and/or anti-PD-1 antibody is F (ab') ₂ Fragments, fab' fragments, fab fragments, fv fragments, scFv fragments, dsFv fragments, dAb fragments or single chain binding polypeptides.

217. The pharmaceutical composition of any one of claims 208-215, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs 1 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs 11 and 12, respectively.

218. The pharmaceutical composition of any one of claims 208-215, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID nos. 21 and 2, respectively, and the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID nos. 11 and 12, respectively.

219. A kit for treating a human subject having lung cancer, the kit comprising:

(a) 360mg of anti-LAG-3 antibody;

(b) 360mg of anti-PD-1 antibody; and

(c) Instructions for using the anti-LAG-3 antibody and the anti-PD-1 antibody in a method of treating a human subject having lung cancer.

220. A kit for treating a human subject having lung cancer, the kit comprising:

(a) 720mg of an anti-LAG-3 antibody;

(b) 360mg of anti-PD-1 antibody; and