Combination of a pd-1 inhibitor and a lag-3 inhibitor for enhancing efficacy in the treatment of lung cancer

Abstract

The present disclosure provides methods for treating or inhibiting the growth of lung cancer in a subject in need thereof, comprising administering a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody or antigen-binding fragment thereof) in combination with a PD-1 inhibitor (e.g., an anti-PD-1 antibody or antigen-binding fragment thereof). In certain embodiments, the administration of the PD-1 inhibitor enhances the efficacy of the LAG-3 inhibitor in inhibiting the growth of lung cancer. In certain embodiments, the administration of the PD-1 inhibitor and the LAG-3 inhibitor in combination with a platinum doublet chemotherapy enhances efficacy in treating lung cancer. In certain embodiments, following the administration of the PD-1 inhibitor and the LAG-3 inhibitor in combination with a platinum doublet chemotherapy, surgery to resect the cancer and adjuvant therapy, including further administration of the PD-1 inhibitor and the LAG-3 inhibitor, can be performed.

Description

Technical Field

[0001] This disclosure provides compositions for treating lung cancer, including inhibitors of LAG-3 and PD-1, and methods for treating lung cancer.

[0002] sequence list A formal copy of the sequence list and the specification were submitted electronically through the Patent Center. The contents of the electronic sequence list (11616WO01_Sequence_Listing_ST26.xml; size: 28,672 bytes; and creation date: November 14, 2024) are incorporated herein by reference in their entirety. Background Technology

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

[0004] Similar to PD-1, lymphocyte activation gene-3 (LAG-3) negatively regulates T-cell activity. LAG-3 (also known as CD223) is a 503-amino acid transmembrane protein receptor expressed on activated CD4 and CD8 T cells, γδ T cells, natural killer T cells, B cells, natural killer cells, plasmacytoid dendritic cells, and regulatory T cells. LAG-3 is a member of the immunoglobulin (Ig) superfamily. The primary function of LAG-3 is to attenuate immune responses. Binding of LAG-3 to MHC class II molecules leads to the delivery of negative signals to LAG-3-expressing cells and downregulation of antigen-dependent CD4 and CD8 T cell responses. LAG-3 negatively regulates the ability of T cells to proliferate, produce cytokines, and lyse target cells, a process known as T cell “exhaustion.” LAG-3 has also been reported to play a role in enhancing the function of regulatory T (Treg) cells (Pardoll 2012, Nature Reviews Cancer 12: 252-264).

[0005] Because both PD-1 and LAG-3 play important roles in tumor immunity, they are ideal targets for immunotherapy. Simultaneous targeting of LAG-3 and PD-1 (including in anti-PD-1 resistant tumors) may lead to objective responses across several tumor types in patients. Summary of the Invention

[0006] This disclosure relates to methods for treating lung cancer and methods for inhibiting tumor growth.

[0007] This document provides methods for treating, improving at least one symptom or indication of lung cancer, or inhibiting lung cancer in subjects. A method according to this disclosure comprises administering to a subject in need a therapeutically effective amount of an antibody specifically binding to programmed death protein 1 (PD-1) or an antigen-binding fragment thereof, in combination with a therapeutically effective amount of an antibody specifically binding to LAG-3 or an antigen-binding fragment thereof. In the methods disclosed herein, inhibition achieved with combination therapy is more effective than administration of either antibody as a monotherapy.

[0008] This document provides methods for treating lung cancer or inhibiting lung cancer growth and / or metastasis in subjects. Methods according to this disclosure include administering to a subject in need a therapeutically effective amount of an antibody specifically binding to programmed death protein 1 (PD-1) or an antigen-binding fragment thereof, in combination with a therapeutically effective amount of an antibody specifically binding to LAG-3 or an antigen-binding fragment thereof. In the methods disclosed herein, inhibition achieved with combination therapy is more effective than administration of either antibody as a monotherapy.

[0009] This article also provides methods for treating or inhibiting lung cancer growth, which involve administering the following to subjects in need: (a) An antibody or antigen-binding fragment thereof that specifically binds to programmed death protein 1 (PD-1); and (b) Antibodies or antigen-binding fragments thereof that specifically bind to lymphocyte activation gene-3 (LAG-3). The subject had advanced, untreated lung cancer in which, as determined by immunohistochemistry, PD-L1 was expressed in ≥50% of cancer cells.

[0010] In some cases, lung cancer is unresectable. In some cases, it is locally advanced. In some cases, it is metastatic.

[0011] Subjects can be selected based on one or more of the following criteria: ● (i) The subject must be at least 18 years old; ● (ii) Subjects have stage IIIB or IIIC non-squamous or squamous histological non-small cell lung cancer (NSCLC) and are not candidates for surgical resection or radical chemoradiotherapy; ● (iii) Subjects have stage IV non-squamous or squamous histological NSCLC (metastatic disease) and have not received prior systemic therapy for recurrent or metastatic NSCLC; ● (iv) Subjects have at least one radiographically measurable lesion as determined by computed tomography (CT) or magnetic resonance imaging (MRI) according to RECIST 1.1 criteria; ● (v) Subjects with an Eastern Cooperative Oncology Group (ECOG) performance status ≤1; and ● (vi) The subject has adequate organ and bone marrow function.

[0012] In some embodiments, a dose of the anti-PD-1 antibody or its antigen-binding fragment comprises 50 mg to 1500 mg, or about 100 mg, or about 200 mg, or about 300 mg, or about 350 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, or about 1100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg. In some embodiments, a dose of the anti-PD-1 antibody or its antigen-binding fragment comprises 350 mg.

[0013] In some embodiments, a dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 50 mg to 8000 mg, or about 100 mg, or about 200 mg, or about 300 mg, or about 350 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, or about 1100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg, or about 1600 mg, or about 2000 mg, or about 2500 mg, or about 3000 mg, or about 4000 mg, or about 5000 mg, or about 6000 mg, or about 7000 mg, or about 8000 mg. In some embodiments, a dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 400 mg. In some implementations, a dose of the anti-LAG-3 antibody or its antigen-binding fragment contains 1600 mg.

[0014] In some implementations, immunohistochemistry is used to determine that lung cancer expresses PD-L1 in ≥55%, ≥60%, ≥65%, ≥70%, or ≥75% of cancer cells.

[0015] In some implementations, ≥1% LAG3 is present in the cancerous tissue.

[0016] In some embodiments, the anti-LAG-3 antibody or its antigen-binding fragment is administered before, simultaneously with, or after the anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the anti-LAG-3 antibody or its antigen-binding fragment is administered on the same day as the anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the anti-LAG-3 antibody or its antigen-binding fragment is administered as a co-infusion with the anti-PD-1 antibody or its antigen-binding fragment.

[0017] In some implementations, two or more doses of anti-LAG-3 antibody or its antigen-binding fragment are administered in combination with two or more doses of anti-PD-1 antibody or its antigen-binding fragment.

[0018] In some implementations, each dose of the anti-PD-1 antibody or its antigen-binding fragment contains 350 mg.

[0019] In some implementations, the dose of the anti-LAG-3 antibody or its antigen-binding fragment is between 50 mg and 8000 mg.

[0020] In some implementations, each dose of the anti-LAG-3 antibody or its antigen-binding fragment contains 1600 mg.

[0021] In some implementations, each dose of the anti-LAG-3 antibody or its antigen-binding fragment contains 400 mg.

[0022] In some embodiments, each dose of the anti-PD-1 antibody or its antigen-binding fragment contains 200 mg, 250 mg, or 350 mg, and each dose of the anti-LAG-3 antibody or its antigen-binding fragment contains 400 mg, 800 mg, 1000 mg, 1400 mg, or 1600 mg.

[0023] In some embodiments, each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered 0.5 to 12 weeks after the preceding dose. In some embodiments, each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered 0.5 to 12 weeks after the preceding dose. In some embodiments, each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered every six weeks. In some embodiments, each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered every six weeks. In some embodiments, each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered every three weeks. In some embodiments, each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered every three weeks.

[0024] Antibodies can be administered intravenously, subcutaneously, or intraperitoneally.

[0025] In some respects, the methods described herein produce therapeutic effects selected from groups consisting of: delayed cancer growth, reduced cancer cell number, cancer regression, increased survival, partial response, and complete response. In some respects, cancer growth is delayed by at least 10 days compared to untreated subjects. In some respects, cancer growth is inhibited by at least 50% compared to untreated subjects. In some respects, cancer growth is inhibited by at least 20% compared to subjects receiving either antibody as a monotherapy. In some respects, this inhibition is more effective than receiving either antibody as a monotherapy.

[0026] In some aspects, the methods provided herein also include administering an additional therapeutic agent or therapy to the subject. In some embodiments, the additional therapy is radiation. In some embodiments, the additional therapy is surgery. In some embodiments, the additional therapy is the administration of a therapeutic agent. Additive therapy agents can be selected from the following groups: cancer vaccines, PD-L1 inhibitors, CTLA-4 inhibitors, TIM3 inhibitors, BTLA inhibitors, TIGIT inhibitors, CD47 inhibitors, CD28 agonists, CD38 inhibitors, indoleamine-2,3-dioxygenase (IDO) inhibitors, vascular endothelial growth factor (VEGF) antagonists, angiopoietin-2 (Ang2) inhibitors, transforming growth factor β (TGFβ) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, antibodies against tumor-specific antigens, BCG vaccine, granulocyte-macrophage colony-stimulating factor, oncolytic viruses, cytotoxins, interleukin-6 receptor (IL-6R) inhibitors, interleukin-4 receptor (IL-4R) inhibitors, IL-10 inhibitors, IL-2, IL-7, IL-21, IL-12, IL-15, antibody-drug conjugates, GITR agonists, 4-1BB agonists, and anti-inflammatory drugs.

[0027] According to the method provided herein, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (HCDR1, HCDR2, and HCDR3) of the heavy chain variable region (HCVR) and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the light chain variable region (LCVR), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0028] In some respects, the anti-PD-1 antibody contains the HCVR amino acid sequence of SEQ ID NO: 1 and the LCVR amino acid sequence of SEQ ID NO: 2.

[0029] In some respects, the anti-PD-1 antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10.

[0030] According to the method provided herein, the anti-LAG-3 antibody or its antigen-binding fragment comprises the heavy chain CDRs (HCDR1, HCDR2, and HCDR3) of HCVR and the three light chain CDRs (LCDR1, LCDR2, and LCDR3) of LCVR, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; HCDR3 comprises the amino acid sequence of SEQ ID NO: 15; LCDR1 comprises the amino acid sequence of SEQ ID NO: 16; LCDR2 comprises the amino acid sequence of SEQ ID NO: 17; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 18.

[0031] In some respects, the anti-LAG3 antibody contains the HCVR amino acid sequence of SEQ ID NO: 11 and the LCVR amino acid sequence of SEQ ID NO: 12.

[0032] In some respects, the anti-LAG-3 antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 19 and a light chain containing the amino acid sequence of SEQ ID NO: 20.

[0033] In some embodiments, the method includes administering to a subject (a) 350 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2, and (b) 400 mg or 1600 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 11 / 12. Administration may be performed every 3 weeks; administration may be performed every 6 weeks.

[0034] This article provides a method for treating or inhibiting lung cancer growth, which involves administering the following to subjects in need: (a) An antibody or its antigen-binding fragment that specifically binds to programmed death protein 1 (PD-1); (b) An antibody or its antigen-binding fragment that specifically binds to lymphocyte activation gene-3 (LAG-3); and (c) Platinum-based double chemotherapy; The participants had advanced, untreated lung cancer.

[0035] Platinum-based doublet chemotherapy can be any combination of such chemotherapy used by clinicians in cancer treatment. In some implementations, platinum-based doublet chemotherapy is selected from a group consisting of: paclitaxel, carboplatin, cisplatin, gemcitabine, and pemetrexed.

[0036] In some implementations, the lung cancer is unresectable. In some implementations, the lung cancer is locally advanced. In some implementations, the lung cancer is metastatic.

[0037] In some respects, subjects were further selected based on one or more of the following: ● (i) Must be at least 18 years old; ● (ii) Having stage IIIB or IIIC non-squamous or squamous histological non-small cell lung cancer (NSCLC) and not a candidate for surgical resection or radical chemoradiotherapy; ● (iii) Having stage IV non-squamous or squamous histological NSCLC (metastatic disease) and not having received prior systemic therapy for recurrent or metastatic NSCLC; ● (iv) Having at least one radiographically measurable lesion as determined by computed tomography (CT) or magnetic resonance imaging (MRI) according to RECIST 1.1 criteria; ● (v) Eastern Cooperative Oncology Group (ECOG) performance status ≤1; and ● (vi) Proper organ and bone marrow function.

[0038] This document provides methods for treating, improving at least one symptom or indication of lung cancer, or inhibiting lung cancer growth in subjects. Methods according to this aspect of the disclosure include: (i) Selecting subjects with resectable lung cancer; and (ii) administering neoadjuvant therapy to the subject, the neoadjuvant therapy comprising: (a) An antibody or its antigen-binding fragment that specifically binds to programmed death protein 1 (PD-1); (b) An antibody or its antigen-binding fragment that specifically binds to lymphocyte activation gene-3 (LAG-3); and (c) Platinum-based dual chemotherapy.

[0039] In some respects, lung cancer is non-squamous or squamous histological non-small cell lung cancer (NSCLC) of stage II to IIIB (N2).

[0040] In some respects, lung cancer is newly diagnosed, meaning it is either untreated or newly diagnosed.

[0041] In some respects, participants were further selected based on one or more of the following criteria: ● (i) Must be at least 18 years old; ● (ii) There is no evidence of distant migration; ● (iii) Evaluable PD-L1 IHC results; ● (iv) Eastern Cooperative Oncology Group (ECOG) performance status ≤1; and ● (v) Adequate kidney, liver, and bone marrow function.

[0042] In some embodiments, each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered 0.5 to 12 weeks after the immediate preceding dose. In some embodiments, each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered 0.5 to 12 weeks after the immediate preceding dose. In some embodiments, each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered every six weeks. In some embodiments, each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered every six weeks. In some embodiments, each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered every three weeks. In some embodiments, each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered every three weeks. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered to the subject every three weeks for up to 15 weeks. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered to the subject every three weeks for up to 12 weeks. In some embodiments, the anti-LAG-3 antibody or its antigen-binding fragment is administered to the subject every three weeks for up to 15 weeks. In some implementations, the subject is administered an anti-LAG-3 antibody or its antigen-binding fragment every three weeks for up to 12 weeks. In some implementations, the subject is administered chemotherapy every three weeks for up to 15 weeks. In some implementations, the subject is administered chemotherapy every three weeks for up to 12 weeks.

[0043] Radiographic evaluation of the cancer may be performed after treatment, such as after neoadjuvant therapy. In some respects, the subject undergoes surgery to remove the cancer. In some respects, radiographic evaluation of the cancer is performed after the subject undergoes surgery to remove the cancer. In some respects, surgery occurs 1 to 10 weeks after administration of anti-PD-1 antibody or its antigen-binding fragment, 1 to 10 weeks after administration of anti-LAG-3 antibody or its antigen-binding fragment, and / or 1 to 10 weeks after administration of chemotherapy. In some respects, surgery occurs 1 to 6 weeks after administration of anti-PD-1 antibody or its antigen-binding fragment, 1 to 6 weeks after administration of anti-LAG-3 antibody or its antigen-binding fragment, and / or 1 to 6 weeks after administration of chemotherapy.

[0044] In some embodiments, the method further includes administering adjuvant therapy to the subject comprising an anti-PD-1 antibody or its antigen-binding fragment and / or an anti-LAG-3 antibody or its antigen-binding fragment. In some aspects, the anti-PD-1 antibody or its antigen-binding fragment and / or the anti-LAG-3 antibody or its antigen-binding fragment are administered every three to 45 weeks.

[0045] In some embodiments, a dose of the anti-PD-1 antibody or its antigen-binding fragment comprises 50 mg to 1500 mg, or about 100 mg, or about 200 mg, or about 300 mg, or about 350 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, or about 1100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg. In some embodiments, a dose of the anti-PD-1 antibody or its antigen-binding fragment comprises 350 mg.

[0046] In some embodiments, a dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 50 mg to 8000 mg, or about 100 mg, or about 200 mg, or about 300 mg, or about 350 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, or about 1100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg, or about 1600 mg, or about 2000 mg, or about 2500 mg, or about 3000 mg, or about 4000 mg, or about 5000 mg, or about 6000 mg, or about 7000 mg, or about 8000 mg. In some embodiments, a dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 400 mg. In some implementations, a dose of the anti-LAG-3 antibody or its antigen-binding fragment contains 1600 mg.

[0047] In some implementations, subjects showed ≥1% LAG3 in cancerous tissue.

[0048] In some implementations, subjects showed <1%, 1% to 49%, ≥50% to <75%, or ≥75% PD-L1 in cancer tissue.

[0049] In some embodiments, the anti-LAG-3 antibody or its antigen-binding fragment is administered on the same day as the anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the anti-LAG-3 antibody or its antigen-binding fragment is administered as a co-infusion with the anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, chemotherapy is administered after the anti-PD-1 antibody or its antigen-binding fragment and / or the anti-LAG-3 antibody or its antigen-binding fragment. In some embodiments, chemotherapy is administered before the anti-PD-1 antibody or its antigen-binding fragment and / or the anti-LAG-3 antibody or its antigen-binding fragment. In some embodiments, chemotherapy is administered on the same day as the anti-PD-1 antibody or its antigen-binding fragment and / or the anti-LAG-3 antibody or its antigen-binding fragment.

[0050] As provided herein, two or more doses of anti-LAG-3 antibody or its antigen-binding fragment may be administered in combination with two or more doses of anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, each dose of anti-PD-1 antibody or its antigen-binding fragment comprises 350 mg. In some embodiments, each dose of anti-LAG-3 antibody or its antigen-binding fragment is between 50 mg and 8000 mg. In some embodiments, each dose of anti-LAG-3 antibody or its antigen-binding fragment comprises 1600 mg. In some embodiments, each dose of anti-LAG-3 antibody or its antigen-binding fragment comprises 400 mg. In some embodiments, each dose of anti-PD-1 antibody or its antigen-binding fragment comprises 200 mg, 250 mg, or 350 mg, and each dose of anti-LAG-3 antibody or its antigen-binding fragment comprises 400 mg, 800 mg, 1000 mg, 1400 mg, or 1600 mg.

[0051] In some embodiments, each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered 0.5 to 12 weeks after the preceding dose. In some embodiments, each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered 0.5 to 12 weeks after the preceding dose. In some embodiments, each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered every six weeks. In some embodiments, each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered every six weeks. In some embodiments, each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered every three weeks. In some embodiments, each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered every three weeks.

[0052] Antibodies can be administered intravenously, subcutaneously, or intraperitoneally.

[0053] According to the methods described herein, treatment produces therapeutic effects selected from groups comprising: delayed cancer growth, reduced cancer cell number, cancer regression, increased survival, partial response, and complete response. In some respects, cancer growth is delayed by at least 10 days compared to untreated subjects. In some respects, cancer growth is inhibited by at least 50% compared to untreated subjects. In some respects, cancer growth is inhibited by at least 20% compared to subjects receiving either antibody as a monotherapy. In some respects, this inhibition is more effective than receiving either antibody as a monotherapy.

[0054] According to the method provided herein, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (HCDR1, HCDR2, and HCDR3) of the heavy chain variable region (HCVR) and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the light chain variable region (LCVR), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0055] In some respects, the anti-PD-1 antibody contains the HCVR amino acid sequence of SEQ ID NO: 1 and the LCVR amino acid sequence of SEQ ID NO: 2.

[0056] In some respects, the anti-PD-1 antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10.

[0057] According to the method provided herein, the anti-LAG-3 antibody or its antigen-binding fragment comprises the heavy chain CDRs (HCDR1, HCDR2, and HCDR3) of HCVR and the three light chain CDRs (LCDR1, LCDR2, and LCDR3) of LCVR, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; HCDR3 comprises the amino acid sequence of SEQ ID NO: 15; LCDR1 comprises the amino acid sequence of SEQ ID NO: 16; LCDR2 comprises the amino acid sequence of SEQ ID NO: 17; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 18.

[0058] In some embodiments, the anti-LAG3 antibody comprises the HCVR amino acid sequence of SEQ ID NO: 11 and the LCVR amino acid sequence of SEQ ID NO: 12.

[0059] In some embodiments, the anti-LAG-3 antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 19 and a light chain containing the amino acid sequence of SEQ ID NO: 20.

[0060] In some embodiments, the methods provided herein include administering to a subject (a) 350 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2, and (b) 400 mg or 1600 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 11 / 12. The administration steps can be performed as needed, either every 3 weeks or every 6 weeks.

[0061] In some implementations, the anti-PD-1 antibody is cimiprilmab.

[0062] In some implementations, the anti-LAG-3 antibody is fianlimab.

[0063] Other implementation methods will become apparent upon referring to the following detailed description. Attached Figure Description

[0064] Figure 1 A flowchart of the research process for Example 1 is described.

[0065] Figure 2 A flowchart of the research process for Example 2 is described.

[0066] Figure 3 A flowchart of the research process for Example 3 is described. Detailed Implementation

[0067] It should be understood that the present invention is not limited to the specific methods and experimental conditions described, as such methods and conditions can vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the invention will be limited only by the appended claims.

[0068] Unless otherwise defined, 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 invention pertains. When referring to a specifically enumerated numerical value, the term “about” as used herein means that the value may vary by no more than 1% from the enumerated value. For example, the expression “about 100” as used herein includes 99 and 101 and all values ​​between them (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0069] As used herein, the term "antibody" includes immunoglobulin molecules and their multimers (e.g., IgM) comprising four polypeptide chains (two heavy (H) chains and two light (L) chains) linked together by disulfide bonds. In a typical antibody, each heavy chain contains a heavy chain variable region (abbreviated herein as HCVR or V). H ) and the heavy-chain constant region. The heavy-chain constant region contains three structural domains: C H1 C H2 and C H3 Each light chain contains a light chain variable region (abbreviated as LCVR or V in this document). L The light chain constant region contains a structural domain (C) and a light chain constant region. L1 V H District and V L The region can be further subdivided into highly variable regions known as complementary determinant regions (CDRs), which are interspersed with more conservative regions known as frame regions (FRs). Each V H and V L It consists of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of this disclosure, the FRs of the anti-IL-4R antibody (or its antigen-binding portion) may be identical to the human germline sequence, or may be natural or artificially modified. The common amino acid sequence may be defined based on the parallel analysis of two or more CDRs.

[0070] The term "antibody" as used herein also includes the antigen-binding fragment of a complete antibody molecule. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc., as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from whole antibody molecules, for example, using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding variable and optionally constant antibody domains. Such DNA is known and / or readily available from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or using molecular biology techniques, for example, to align one or more variable and / or constant domains into suitable conformations, or to introduce codons, generate cysteine ​​residues, modify, add, or delete amino acids, etc.

[0071] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) the smallest recognition unit consisting of amino acid residues of a hypervariable region of a mimicking antibody (e.g., a separated complementarity-determining region (CDR), such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. The term “antigen-binding fragment” as used herein also encompasses other engineered molecules such as domain-specific antibodies, single-domain antibodies, domain-deficient antibodies, chimeric antibodies, CDR-transplanted antibodies, dimers, triplets, tetramers, microsomes, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains.

[0072] Antigen-binding fragments of antibodies typically include at least one variable domain. Variable domains can have any size or amino acid composition and will generally include at least one CDR adjacent to or aligned with one or more frame sequences. In the presence of V... H Domain and V L In the antigen-binding fragment associated with the structural domain, V H and V L The domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer and contain V. H -V H V H -V L or V L -V LDimer. Alternatively, the antigen-binding fragment of the antibody may contain monomer V. H or V L Structural domain.

[0073] In some embodiments, the antigen-binding fragment of the antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of the variable and constant domains that may be found within the antigen-binding fragment of the antibody disclosed herein include: (i) V H -C H1 (ii) V H -C H2 (iii) V H -C H3 (iv) V H -C H1 -C H2 ;(v) V H -C H1 -C H2 -C H3 ;(vi) V H -C H2 -C H3 ;(vii) V H -C L (viii) V L -C H1 ;(ix) V L -C H2 ;(x) V L -C H3 ;(xi) V L -C H1 -C H2 ;(xii) V L -C H1 -C H2 -C H3 (xiii) V L -C H2 -C H3 ; and (xiv) V L -C L In any configuration of the variable and constant domains (including any of the exemplary configurations listed above), the variable and constant domains may be directly connected to each other or linked via complete or partial hinge regions or linking regions. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids, resulting in a flexible or semi-flexible connection between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, the antigen-binding fragment of the antibody disclosed herein may comprise each other and / or one or more monomers V H or VL Homodimers or heterodimers (or other polymers) of any of the above-described variable and constant domain configurations of non-covalently associated domains (e.g., via disulfide bonds).

[0074] The term "antibody" as used herein also includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies typically comprise at least two distinct variable domains, each capable of specifically binding to a single antigen or a different epitope on the same antigen. Any form of multispecific antibody can be applied to the cases of the antibodies or antigen-binding fragments of antibodies disclosed herein using conventional techniques available in the art. For example, this disclosure includes methods involving the use of bispecific antibodies, wherein one arm of an immunoglobulin is specific for PD-1 or LAG-3 or fragments thereof, and the other arm of the immunoglobulin is specific for or conjugated to a second therapeutic target. Exemplary bispecific forms that may be used in the context of this disclosure include, but are not limited to: for example, scFv-based or biantibody-based bispecific forms, IgG-scFv fusion proteins, dual variable region (DVD)-Ig, tetrageneous hybridomas, knock-in-hole structures, common light chains (e.g., common light chains with knock-in-hole structures, etc.), CrossMab, CrossFab fragments, chain exchange engineered domain (SEED) antibodies, leucine zippers, Duobody, IgG1 / IgG2, bifunctional Fab fragments (DAF)-IgG and Mab 2 Bispecific forms (for a review of the aforementioned forms, see, for example, Klein et al. 2012, mAbs 4:6, 1-11 and references cited therein). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugations, for example, where site-specific antibody-oligonucleotide conjugates are generated using non-natural amino acids with orthogonal chemical reactivity, and then these antibody-oligonucleotide conjugates are self-assembled into multimeric complexes with defined composition, valence state, and geometry. (See, for example, Kazane et al., J. Am. Chem. Soc. [Electronic publication date: December 4, 2012]).

[0075] The antibodies used in the methods of this disclosure may be human antibodies. The term "human antibody" as used herein is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies of this disclosure may, for example, include amino acid residues in the CDR, and specifically in CDR3, that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random mutagenesis or site-specific mutagenesis, or by in vivo somatic mutations). However, the term "human antibody" as used herein is not intended to include antibodies in which a CDR sequence derived from another mammalian species (such as a mouse) has been grafted onto a human frame sequence.

[0076] The antibodies used in the methods of this disclosure may be recombinant human antibodies. As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, produced, or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells (further described below), antibodies isolated from recombinant human antibody combinatorial libraries (further described below), antibodies isolated from transgenic animals (e.g., mice) relative to the human immunoglobulin gene (see, for example, Taylor et al., (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, produced, or isolated by any other means involving splicing a human immunoglobulin gene sequence into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using animals transgenic against human Ig sequences, in vivo somatic cell mutagenesis), and therefore the V of the recombinant antibody is... H and V L The amino acid sequence of the region is, although it originates from human lineage V H and V L Sequences and related sequences that may not naturally exist within the human antibody germline library in vivo.

[0077] While any methods and materials similar to or equivalent to those described herein may be used in the practice of this disclosure, exemplary methods and materials are described hereafter. All publications mentioned herein are incorporated herein by reference in their entirety.

[0078] General Method Standard methods in molecular biology are described in Sambrook, Fritsch, and Maniatis (1982 and 1989, 2nd edition; 2001, 3rd edition) *Molecular Cloning, A Laboratory Manual*, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Sambrook and Russell (2001) *Molecular Cloning*, 3rd edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; and Wu (1993) *Recombinant DNA*, Vol. 217, Academic Press, San Diego, California. Standard methods also appear in Ausbel. et al. (2001) Current Protocols in Molecular Biology, Volumes 1–4, John Wiley and Sons, Inc. New York, NY. This book describes cloning and DNA mutagenesis in bacterial cells (Volume 1), cloning in mammalian cells and yeast (Volume 2), glycoconjugates and protein expression (Volume 3), and bioinformatics (Volume 4).

[0079] Protein purification methods include immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization, as described in (Coligan) wait people (2000) Current Protocols in Protein Science, Volume 1, John Wiley and Sons, Inc., New York. Describes chemical analysis, chemical modification, post-translational modification, fusion protein production, and protein glycosylation (see...). For example Coligan et al. (2000) Current Protocols in Protein Science, Volume 2, JohnWiley and Sons, Inc., New York; Ausubel et al.(2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, NY, pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, Mo., pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, NJ, pp. 384-391. Describes the generation, purification, and fragmentation of polyclonal and monoclonal antibodies (Coligan...). et al. (2001) Current Protocols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Harlow and Lane, ibid. Standard techniques for characterizing ligand / receptor interactions are available (see above). For example Coligan et al. (2001) Current Protocols in Immunology, Volume 4, John Wiley, Inc., New York.

[0080] Monoclonal antibodies, polyclonal antibodies, and humanized antibodies can be prepared (see...) For example , Sheperd and Dean (eds. 2000) Monoclonal Antibodies, Oxford Univ. Press, New York, NY; Kontermann and Dubel (eds. 2001) Antibody Engineering, Springer-Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 139-243; Carpenter et al.(2000) J. Immunol. 165:6205; He et al. (1998) J. Immunol. 160:1029; Tang et al. (1999) J. Biol. Chem. 274:27371-27378; Baca et al. (1997) J. Biol. Chem. 272:10678-10684; Chothia et al. (1989) Nature 342:877-883; Foote and Winter (1992) J. Mol. Biol. 224:487-499; U.S. Patent No. 6,329,511.

[0081] Alternatives to humanization include using human antibody libraries presented on bacteriophages or human antibody libraries from transgenic mice (Vaughan). et al. (1996) Nature Biotechnol. 14:309-314; Barbas (1995) NatureMedicine 1:837-839; Mendez et al. (1997) Nature Genetics 15:146-156; Hoogenboom and Chames (2000) Immunol. Today 21:371-377; Barbas et al. (2001) Phage Display: ALaboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Kay et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, Calif.; de Bruin et al. (1999) Nature Biotechnol. 17:397-399). Describes single-chain antibodies and bifunctional antibodies (see...). For example Malecki et al. (2002) Proc. Natl. Acad. Sci. USA 99:213-218; Conrath et al.(2001) J. Biol. Chem. 276:7346-7350; Desmyter et al. (2001) J. Biol. Chem. 276:26285-26290; Hudson and Kortt (1999) J. Immunol. Methods 231:177-189; and U.S. Patent No. 4,946,778). Bifunctional antibodies are provided (see...). For example Mack et al. (1995) Proc. Natl. Acad. Sci. USA 92:7021-7025; Carter (2001) J. Immunol. Methods 248:7-15; Volkel et al. (2001) Protein Engineering 14:815-823; Segal et al. (2001) J. Immunol. Methods 248:1-6; Brennan et al. (1985) Science229:81-83; Raso et al. (1997) J. Biol. Chem. 272:27623; Morrison (1985) Science229:1202-1207; Traunecker et al. (1991) EMBO J. 10:3655-3659; and U.S. Patents 5,932,448, 5,532,210, and 6,129,914. Fully human antibodies can also be developed in genetically engineered mice such as VelociMouse. See, for example, DeChiara. et al. , Producing fully ES cell-derived mice from eight-cell stage embryo injections, Methods Enzymol, 476:285-94 (2010); Dechiara et al.VelociMouse: fully ES cell-derived F0-generation mice obtained from the injection of ES cells into eight-cell-stage embryos. Methods MolBiol, 530:311-24 (2009); U.S. Patent Nos. 7,576,259, 7,659,442 or 7,294,754, and US2008 / 0078000A1.

[0082] Antigen purification is generally not required for antibody production. Animals can be immunized with cells carrying the antigen of interest. Subsequently, spleen cells can be isolated from the immunized animal, and these spleen cells can be fused with myeloma cell lines to generate fusion tumors (see [link to relevant documentation]). example like Meyaard et al. (1997) Immunity 7:283-290; Wright et al. (2000) Immunity 13:233-242; Preston et al. Same as above; Kaithamana et al. (1999) J. Immunol. 163:5157-5164).

[0083] Antibodies can bind to For example Small drug molecules, enzymes, liposomes, polyethylene glycol (PEG). Antibodies are suitable for therapeutic, diagnostic, kit, or other purposes, and include conjugations to... For example Dyes, radioactive isotopes, enzymes, or metals ( For example Antibodies with colloidal gold (see For example Le Doussal et al. (1991) J. Immunol. 146:169-175; Gibellini et al. (1998) J. Immunol. 160:3891-3898; Hsing and Bishop (1999) J. Immunol. 162:2804-2811; Everts et al. (2002) J. Immunol. 168:883-889).

[0084] Methods for flow cytometry, including fluorescence-activated cell sorting (FACS), are available (see, for example, Owens). et al.(1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, NJ; Givan (2001) Flow Cytometry, 2nd edition, Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). used as For example Fluorescent reagents suitable for modifying nucleic acids (including nucleic acid primers and probes), peptides, and antibodies are available for diagnostic purposes (Molecular Probes (2003) Catalogue, MolecularProbes, Inc., Eugene, Oreg.; Sigma-Aldrich (2003) Catalogue, St. Louis, Mo.).

[0085] Describe the standard immune system histological methods (see For example , edited by Muller-Harmelink (1986) HumanThymus: Histopathology and Pathology, Springer Verlag, New York, NY; Hiatt wait people (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Phila, Pa.; Louis et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, NY.

[0086] Used for determination For example Software packages and databases for antigen fragments, leader sequences, protein folds, functional domains, glycosylation sites, and sequence alignment are available (see [link]). For example, GenBank, Vector NTI® Suite (Informax, Inc., Bethesda, Md.); GCG Wisconsin Package (Accelrys, Inc., San Diego, Calif.); DeCypher® (TimeLogic Corp., Crystal Bay, Nev.); Menne et al. (2000)Bioinformatics 16: 741-742; Menne et al. (2000) Bioinformatics Applications Note16:741-742; Wren et al. (2002) Comput. Methods Programs Biomed. 68:177-181; von Heijne (1983) Eur. J. Biochem. 133:17-21; von Heijne (1986) Nucleic Acids Res. 14:4683-4690).

[0087] PD-1 inhibitors According to certain exemplary embodiments of this disclosure, the method includes administering a therapeutically effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof. The term "PD-1" refers to programmed death-1 protein, a T-cell co-inhibitory molecule, also known as CD279. The full-length amino acid sequence of PD-1 is available in GenBank under accession number NP_005009.2. PD-1 is a member of the CD28 / CTLA-4 / ICOS family of T-cell co-inhibitory molecules. PD-1 is a 288-amino acid protein with an extracellular N-terminal domain (which is IgV-like), a transmembrane domain, and an intracellular domain containing an immunoreceptor tyrosine inhibitory (ITIM) motif and an immunoreceptor tyrosine switching (ITSM) motif (Chattopadhyay et al., 2009, Immunol. Rev.). The PD-1 receptor has two ligands—PD-ligand-1 (PD-L1) and PD-L2.

[0088] PD-L1 is a 290-amino acid protein with an extracellular IgV-like domain, a transmembrane domain, and a highly conserved intracellular domain (approximately 30 amino acids). PD-L1 is constitutively expressed on a variety of cell types, including antigen-presenting cells (e.g., dendritic cells, macrophages, and B cells) and on both hematopoietic and non-hematopoietic cells (e.g., vascular endothelial cells, pancreatic islets, and immune-immune sites). PD-L1 is also expressed on various tumor cells, virus-infected cells, and autoimmune tissues, and is a component of the immunosuppressive microenvironment (Ribas 2012, NEJM 366: 2517-2519).

[0089] PD-1 inhibitors include antibodies and their antigen-binding fragments, as well as other substances that specifically bind to PD-1 and antagonize one or more of its biological activities. For example (peptides and small molecules). Molecules that specifically bind to PD-1 may be referred to as "anti-PD-1". In embodiments of this disclosure, a PD-1 inhibitor is an antibody or antigen-binding fragment thereof that binds to PD-L1 or PD-L2.

[0090] In embodiments of this disclosure, the PD-1 inhibitor is an antibody or antigen-binding fragment thereof as described in US 9,987,500.

[0091] According to certain embodiments, the antibodies used in the methods of this disclosure specifically bind to PD-1. The term "specific binding," etc., means that the antibody or its antigen-binding fragment forms a relatively stable complex with the antigen under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, etc. For example, as used in the context of this disclosure, antibodies that "specifically bind" PD-1 include, as measured in a surface plasmon resonance assay, at concentrations of less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM. D Antibodies that bind to PD-1 or a portion thereof. However, isolated antibodies that specifically bind to human PD-1 may be cross-reactive with other antigens, such as PD-1 molecules from other (non-human) species.

[0092] According to certain exemplary embodiments of this disclosure, an anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR) containing any amino acid sequence of an anti-PD-1 antibody listed in U.S. Patent No. 9,987,500.

[0093] In some exemplary embodiments, the anti-PD-1 antibody or its antigen-binding fragment used in the methods of this disclosure comprises a heavy chain complementarity-determining region (HCDR) of a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity-determining region (LCDR) of a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 2. According to some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 contains the amino acid sequence of SEQ ID NO: 3; HCDR2 contains the amino acid sequence of SEQ ID NO: 4; HCDR3 contains the amino acid sequence of SEQ ID NO: 5; LCDR1 contains the amino acid sequence of SEQ ID NO: 6; LCDR2 contains the amino acid sequence of SEQ ID NO: 7; and LCDR3 contains the amino acid sequence of SEQ ID NO: 8. In other embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises an HCVR containing SEQ ID NO: 1 and an LCVR containing SEQ ID NO: 2. In some embodiments, the method of this disclosure includes using an anti-PD-1 antibody, wherein the antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-PD-1 antibody comprises a light chain containing the amino acid sequence of SEQ ID NO: 10. An exemplary antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 2 is a fully human anti-PD-1 antibody called REGN2810 (cimiprilmab, LIBTAYO®).

[0094] According to certain exemplary embodiments, the methods of this disclosure include the use of REGN2810 or a bioequivalent thereof. As used herein, the term "bioequivalent" means an anti-PD-1 antibody or PD-1 binding protein, or a fragment thereof that is a pharmaceutical equivalent or substitute, whose rate of absorption and / or extent of absorption does not show a significant difference from that of REGN2810 when administered at the same molar dose (single or multiple doses) under similar experimental conditions. In the context of this disclosure, the term refers to an antigen-binding protein that binds to PD-1 and does not have clinically significant differences from REGN2810 in terms of its safety, purity, and / or potency.

[0095] Other anti-PD-1 antibodies that may be used in the context of the methods disclosed herein include, for example, antibodies known in the art and referred to as nivolumab (US Patent No. 8,008,449), pembrolizumab (US Patent No. 8,354,509), MEDI0608 (US Patent No. 8,609,089), pidilizumab (US Patent No. 8,686,119), or any of the anti-PD-1 antibodies described in US Patent Nos. 6,808,710, 7,488,802, 8,168,757, 8,354,509, 8,779,105, or 8,900,587. In embodiments of this disclosure, PD-1 inhibitors are described in any of the following: US 20110008369, US 20130017199, US 20130022595, WO2006121168, WO20091154335, WO2012145493, WO2013014668, WO2009101611, EP2262837, and EP2504028.

[0096] LAG-3 inhibitors The term "LAG-3" refers to the lymphocyte activation gene-3 protein, an immune checkpoint receptor or T-cell co-inhibitory molecule, also known as CD223. The full-length amino acid sequence of LAG-3 is available in GenBank under accession number NP_002277.4. LAG-3 is a member of the immunoglobulin (Ig) superfamily. LAG-3 is a 503-amino acid type I transmembrane protein with four extracellular Ig-like domains D1 through D4, and is expressed on activated T cells, natural killer cells, B cells, plasmacytoid dendritic cells, and regulatory T cells. The LAG-3 receptor binds to MHC class II molecules present on antigen-presenting cells (APCs).

[0097] As used in this article, the term "T cell co-inhibitory molecule" refers to ligands and / or receptors that regulate immune responses through T cell activation or inhibition. The term "T cell co-inhibitory molecule" is also known as T cell co-signaling molecules and includes, but is not limited to: programmed death-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), B and T lymphocyte attenuators (BTLA), CD-28, 2B4, LY108, T cell immunoglobulin and mucin 3 (TIM3), T cell immune receptor with immunoglobulin and ITIM (TIGIT, also known as VSIG9), leukocyte-associated immunoglobulin-like receptor 1 (LAIR1, also known as CD305), inducible T cell co-stimulatory molecule (ICOS, also known as CD278), T cell activation V-domain Ig repressor (VISTA), and CD160.

[0098] LAG-3 inhibitors include antibodies and their antigen-binding fragments, as well as other substances that specifically bind to LAG-3 and antagonize LAG-3 with one or more biological activities. For example (peptides and small molecules). Molecules that specifically bind to LAG-3 can be called "anti-LAG-3".

[0099] In embodiments of this disclosure, the LAG-3 inhibitor is an antibody or antigen-binding fragment thereof as described in US 20170101472.

[0100] According to certain embodiments, the antibodies used in the methods of this disclosure specifically bind to LAG-3. The term "specific binding," etc., means that the antibody or its antigen-binding fragment forms a relatively stable complex with the antigen under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, etc. For example, as used in the context of this disclosure, antibodies that "specifically bind" to LAG-3 include those, as measured in a surface plasmon resonance assay, at concentrations of less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM. D Antibodies that bind to LAG-3 or a portion thereof. However, isolated antibodies that specifically bind to human LAG-3 may be cross-reactive with other antigens, such as LAG-3 molecules from other (non-human) species.

[0101] According to certain exemplary embodiments of this disclosure, an anti-LAG-3 antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR), wherein the anti-LAG-3 antibody or its antigen-binding fragment comprises any amino acid sequence of an anti-LAG-3 antibody as set forth in US 20170101472.

[0102] In some exemplary embodiments, the anti-LAG-3 antibody or its antigen-binding fragment used in the methods of this disclosure comprises a heavy chain complementarity-determining region (HCDR) of a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 11 and a light chain complementarity-determining region (LCDR) of a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 12. According to some embodiments, the anti-LAG-3 antibody or its antigen-binding fragment comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 contains the amino acid sequence of SEQ ID NO: 13; HCDR2 contains the amino acid sequence of SEQ ID NO: 14; HCDR3 contains the amino acid sequence of SEQ ID NO: 15; LCDR1 contains the amino acid sequence of SEQ ID NO: 16; LCDR2 contains the amino acid sequence of SEQ ID NO: 17; and LCDR3 contains the amino acid sequence of SEQ ID NO: 18. In other embodiments, the anti-LAG-3 antibody or its antigen-binding fragment comprises an HCVR containing SEQ ID NO: 11 and an LCVR containing SEQ ID NO: 12. In some embodiments, the method of this disclosure includes using an anti-LAG-3 antibody, wherein the antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-LAG-3 antibody comprises a light chain containing the amino acid sequence of SEQ ID NO: 20. An exemplary antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 11 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 12 is a fully human anti-LAG-3 antibody called REGN3767, i.e., fianlimab.

[0103] According to certain exemplary embodiments, the methods of this disclosure include the use of REGN3767 or a bioequivalence thereof. As used herein, the term "bioequivalence" refers to an anti-LAG-3 antibody or LAG-3 binding protein, or a fragment thereof that is a pharmaceutical equivalent or substitute, whose absorption rate and / or extent does not show significant difference from that of REGN3767 when administered at the same molar dose (single or multiple doses) under similar experimental conditions. In the context of this disclosure, the term refers to an antigen-binding protein that binds to LAG-3 and does not have clinically significant differences from REGN3767 in terms of safety, purity, and / or potency.

[0104] Other anti-LAG-3 antibodies that may be used in the context of the methods disclosed herein include, for example, those known in the art and referred to as relatlimab (US 20110150892), LAG525 (WO2017 / 037203), GSK2831781 (US 2016 / 0017037), and Sym022. Antibodies as described in (WO2018 / 069500), INCAGN02385 (US20180127499), or in US Patent / Publication Nos. 5976877, 6143273, 6197524, 8551481, 20110070238, 20110150892, 20130095114, 20140093511, 20140127226, 20140286935, and in WO95 / 30750, WO Any of the anti-LAG-3 antibodies described in 97 / 03695, WO98 / 58059, WO2004 / 078928, WO2008 / 132601, WO2010 / 019570, WO2014 / 008218, EP0510079B1, EP0758383B1, EP0843557B1, EP0977856B1, EP1897548B2, EP2142210A1 and EP2320940B1.

[0105] Methods for treating lung cancer or inhibiting lung cancer metastasis This disclosure includes methods for treating, improving, or reducing the severity of at least one symptom or indication of lung cancer, or inhibiting lung cancer growth in subjects. Methods according to this aspect include administering to a subject in need a combination of an antibody specifically binding to PD-1 or an antigen-binding fragment thereof and an antibody specifically binding to LAG-3 or an antigen-binding fragment thereof. In some aspects, the method includes administering to a subject in need a therapeutically effective amount of an antibody specifically binding to PD-1 or an antigen-binding fragment thereof and a therapeutically effective amount of an antibody specifically binding to LAG-3 or an antigen-binding fragment thereof. As used herein, the term "treatment," etc., means relief of symptoms, temporary or permanent elimination of the cause of symptoms, delay or inhibition of lung cancer growth, reduction of lung cancer cell load or tumor burden, promotion of lung cancer regression, causing lung cancer shrinkage, necrosis, and / or disappearance, prevention of lung cancer recurrence, and / or increase in the survival duration of a subject.

[0106] As used herein, the term "subject in need" refers to a human or non-human mammal exhibiting one or more symptoms or indications of lung cancer, and / or diagnosed with lung cancer and requiring treatment for lung cancer. In many embodiments, the term "subject" may be used interchangeably with the term "patient." For example, a human subject may be diagnosed with primary or metastatic lung cancer and / or one or more symptoms or indications, including but not limited to, enlarged lymph nodes, abdominal swelling, chest pain / tightness, unexplained weight loss, fever, night sweats, persistent fatigue, loss of appetite, splenomegaly, and pruritus. In specific embodiments, this term includes human subjects with unresectable locally advanced or metastatic lung cancer who require treatment. In some embodiments, the human subject has not previously received systemic treatment for advanced disease. In some embodiments, this term includes human subjects with resectable stage II to IIIB (N2) non-small cell lung cancer who require treatment.

[0107] In some cases, subjects with locally advanced or metastatic lung cancer are selected based on one or more of the following criteria: ● (i) Must be at least 18 years old; ● (ii) Having stage IIIB or IIIC non-squamous or squamous histological non-small cell lung cancer (NSCLC) and not a candidate for surgical resection or radical chemoradiotherapy; ● (iii) Having stage IV non-squamous or squamous histological NSCLC (metastatic disease) and not having received prior systemic therapy for recurrent or metastatic NSCLC; ● (iv) Having at least one radiographically measurable lesion as determined by computed tomography (CT) or magnetic resonance imaging (MRI) according to RECIST 1.1 criteria; ● (v) Eastern Cooperative Oncology Group (ECOG) performance status ≤1; and ● (vi) Proper organ and bone marrow function.

[0108] In some cases, subjects with resectable stage II to IIIB (N2) NSCLC are selected based on one or more of the following criteria: (i) Be at least 18 years of age (or, in accordance with specific national regulations, the legal age for adults to consent to participate in clinical research); (ii) Newly diagnosed, histologically confirmed, fully resectable stage II to IIIB (N2) NSCLC; (iii) For patients with evidence of mediastinal lymph node enlargement on imaging, mediastinal lymph node sampling is required; (iv) There is no evidence of distant migration; (v) Evaluable PD-L1 IHC results; (vi) ECOG fitness level ≤ 1; and (vii) Proper organ and bone marrow function.

[0109] The phrase "subjects in need" also includes subjects at risk of developing lung cancer, such as those with a family history of lung cancer, those who have had lung cancer in the past, or those with a compromised immune system. In some cases, subjects may be resistant to or inadequately respond to previous treatments, or have experienced a relapse after previous treatment.

[0110] In some embodiments, the methods provided herein can be used to treat patients exhibiting elevated levels of one or more cancer-related biomarkers (e.g., PD-L1 or LAG-3). For example, the method of the present invention includes administering a therapeutically effective amount of a combination of an anti-LAG-3 antibody and an anti-PD-1 antibody to a patient with elevated LAG-3 and / or PD-L1 levels. In one embodiment, the method of the present invention is used for lung cancer patients selected based on PD-L1 expression in cancer tissue comprising lung cancer cells and tumor-infiltrating immune cells. In some embodiments, the method of the present invention is used to treat lung cancer patients selected based on PD-L1 expression in cancer tissue and / or immune cells of <1%, 1% to 49%, 50%, ≥50%, ≥50% to <75%, ≥75%, or ≥80%. In one embodiment, the method of the present invention is used for patients with lung cancer selected based on LAG-3 expression in cancer tissue comprising lung cancer cells and tumor-infiltrating immune cells. In some embodiments, the method of the present invention is used to treat lung cancer patients in which the patient exhibits ≥1% LAG-3 expression in cancer tissue and / or immune cells. Methods for determining LAG-3 or PD-L1 expression in cancer tissues and / or tumor-associated immune cells are well known in the art. In some embodiments, LAG-3 or PD-L1 expression in tumor tissues is determined by any assay known in the art, such as by ELISA or by immunohistochemistry (IHC) (e.g., as described in He et al. 2017, J. Thoracic Oncol. 12: 814-823; WO2016124558 or WO2016191751). In some embodiments, LAG-3 or PD-L1 expression is determined by quantifying RNA expression, e.g., by in situ hybridization or by RT-PCR. In some embodiments, LAG-3 expression is determined by imaging with labeled anti-LAG-3 antibodies, e.g., by immunopositron emission tomography or iPET [see, e.g., The Oncologist ,12: 1379 (2007); Journal of Nuclear Medicine, 52(8): 1171 (2011); U.S. Patent Application Publication 2018 / 0228926]. In some embodiments, PD-L1 expression is determined by imaging with labeled anti-PD-L1 antibodies, for example by immunopositron emission tomography or iPET (U.S. Patent Application Publication 2018 / 0161464). In some embodiments, PD-L1 expression is determined by a laboratory accredited by the College of American Pathologists (CAP) / Clinical Laboratory Improvement Amendments (CLIA) (or equivalent under local regulations). In some embodiments, PD-L1 expression is obtained using the VENTANA PD-L1 (SP263) assay.

[0111] In some implementations, the methods provided herein are used on subjects with cancer. The terms “tumor,” “cancer,” and “malignant tumor” are used interchangeably herein.

[0112] In some implementations, the cancer or tumor is lung cancer. Throughout this document, "tumor" or "cancer" includes lung cancer, for example, a tumor or cancer that is lung cancer, such as squamous or non-squamous non-small cell lung cancer (NSCLC). In some aspects, the lung cancer is unresectable locally advanced lung cancer. In some aspects, the lung cancer is metastatic lung cancer. In some aspects, the patient has not previously received systemic therapy for advanced disease. In some aspects, the patient has received prior systemic therapy.

[0113] According to certain embodiments, this disclosure includes methods for treating or delaying or inhibiting lung cancer growth. In some embodiments, this includes methods for promoting lung cancer regression. In some embodiments, this includes methods for reducing tumor cell burden or reducing tumor load. In some embodiments, this disclosure includes methods for preventing lung cancer recurrence. According to this aspect, the method includes sequentially administering a therapeutically effective amount of a combination of an anti-PD-1 antibody and an anti-LAG-3 antibody to a subject in need, wherein each antibody is administered to the subject in multiple doses, for example as part of a specific therapeutic dosing regimen. For example, the therapeutic dosing regimen may include administering one or more doses of the anti-PD-1 antibody to the subject at a frequency of approximately once daily, every two days, every three days, every four days, every five days, every six days, once weekly, every two weeks, every three weeks, every four weeks, once monthly, every six weeks, every two months, every three months, every four months, or less. In some implementations, the one or more doses of the anti-PD-1 antibody are administered in combination with one or more doses of a therapeutically effective amount of the anti-LAG-3 antibody, wherein the one or more doses of the anti-LAG-3 antibody are administered to the subject at a frequency of approximately once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, once every six weeks, once every two months, once every three months, once every four months, or less.

[0114] In some embodiments, this disclosure includes methods for inhibiting, delaying, or stopping lung cancer metastasis or invasion into peripheral organs. According to this aspect, the method includes administering a therapeutically effective amount of an anti-PD-1 antibody to a subject in need. In some embodiments, the anti-PD-1 antibody is administered in combination with an anti-LAG-3 antibody.

[0115] In specific embodiments, this disclosure provides methods for increasing antitumor efficacy or increasing lung cancer suppression. In some embodiments, the methods provide increased lung cancer suppression, for example, by about 20%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, or more than 80%, compared to subjects receiving either antibody as a monotherapy.

[0116] According to certain embodiments, the method provided herein includes administering a therapeutically effective amount of an anti-PD-1 antibody to a subject with lung cancer before, simultaneously with, or after administration of a therapeutically effective amount of an anti-LAG-3 antibody. In some aspects, the anti-PD-1 antibody may be administered approximately 1 day, more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, or more than 8 days prior to the anti-LAG-3 antibody. In some aspects, the anti-PD-1 antibody and the anti-LAG-3 antibody may be administered simultaneously, or at intervals not exceeding 30 minutes, 60 minutes, 2 hours, 3 hours, or 1 day.

[0117] In some embodiments, the methods provided herein include administering a therapeutically effective amount of an anti-PD-1 antibody or its antigen-binding fragment and a therapeutically effective amount of an anti-LAG-3 antibody or its antigen-binding fragment to a subject with lung cancer. In specific embodiments, the lung cancer is advanced or metastatic. In specific embodiments, the lung cancer is unresectable. In some embodiments, the subject is unresponsive to prior treatment or has experienced recurrence after prior treatment. Prior treatment may include surgery, radiation therapy and / or chemotherapy, or treatment with a PD-1 inhibitor, a PD-L1 inhibitor, and / or any other anticancer biological agent.

[0118] In some embodiments, the method of this disclosure includes administering a combination of an anti-PD-1 antibody and an anti-LAG-3 antibody to a subject in need as "first-line" treatment (e.g., initial treatment). In other embodiments, the combination of the anti-PD-1 antibody and the anti-LAG-3 antibody is administered as "second-line" treatment (e.g., after prior treatment). For example, the combination of the anti-PD-1 antibody and the anti-LAG-3 antibody is administered as "second-line" treatment to a subject who has relapsed after prior treatment (e.g., chemotherapy or rituximab).

[0119] In some embodiments, the methods of this disclosure are used to treat patients with minimal residual disease (MRD). Minimal residual disease (MRD) refers to a small number of cancer cells remaining in a patient's body during or after treatment, where the patient may or may not show symptoms or signs of the disease. Such residual cancer cells, if not eliminated, often lead to disease recurrence. This disclosure includes methods for inhibiting and / or eliminating residual cancer cells in a patient after an MRD test. MRD can be determined according to methods known in the art (e.g., MRD flow cytometry). According to this aspect of the disclosure, the method includes administering a combination of an anti-PD-1 antibody and an anti-LAG-3 antibody to a subject in need.

[0120] In some embodiments, the antibody may be administered in combination with therapies including chemotherapy, radiation, or surgery. The phrase "in combination with" as used herein means that the antibody is administered to the subject concurrently with, slightly earlier than, or slightly later than the administration of a third therapeutic agent. In relevant embodiments, this disclosure includes a method of administering a therapeutically effective amount of a combination of an anti-PD-1 antibody and an anti-LAG-3 antibody to a subject receiving a background anticancer treatment regimen. The background anticancer treatment regimen may include a course of treatment such as chemotherapy or radiation therapy. The combination of the anti-PD-1 antibody and the anti-LAG-3 antibody may be added to the background anticancer treatment regimen. In some embodiments, the antibody is added as part of a "background tapering" regimen, wherein the background anticancer treatment is gradually withdrawn from the subject over time (e.g., using a step-down approach) while the antibody is administered to the subject at a constant, escalating, or decreasing dose over time.

[0121] In some embodiments, the method of this disclosure includes administering a combination of a therapeutically effective amount of an anti-PD-1 antibody and a therapeutically effective amount of an anti-LAG-3 antibody to a subject in need, wherein the administration of the antibodies causes an increased inhibition of lung cancer growth. In some embodiments, lung cancer growth is inhibited by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80% compared to untreated subjects or subjects treated with either antibody as a monotherapy. In some embodiments, administration of the anti-PD-1 antibody and / or the anti-LAG-3 antibody to a subject results in an increased incidence of lung cancer regression, tumor shrinkage, and / or disappearance. In some embodiments, administration of the anti-PD-1 antibody and / or the anti-LAG-3 antibody causes a delay in lung cancer growth and development, for example, lung cancer growth may be delayed by about 3 days, more than 3 days, about 7 days, more than 7 days, at least 10 days, more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 1 year, more than 2 years, or more than 3 years compared to untreated subjects or subjects treated with either antibody as a monotherapy. In some embodiments, the combined administration of an anti-PD-1 antibody and an anti-LAG-3 antibody prevents lung cancer recurrence and / or prolongs the survival duration of subjects, for example, by extending survival duration by more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 12 months, more than 18 months, more than 24 months, more than 36 months, or more than 48 months compared to treatment-naïve subjects or subjects receiving either antibody as monotherapy. In some embodiments, the combined administration of the antibodies prolongs progression-free survival or overall survival. In some embodiments, the combined administration of an anti-PD-1 antibody and an anti-LAG-3 antibody increases the subject's response and duration of response, for example, by more than 2%, more than 3%, more than 4%, more than 5%, more than 6%, more than 7%, more than 8%, more than 9%, more than 10%, more than 20%, more than 30%, more than 40%, or more than 50%, compared to treatment-naïve subjects or subjects receiving either antibody as monotherapy. In some embodiments, administration of an anti-PD-1 antibody and / or an anti-LAG-3 antibody to a subject with lung cancer causes the complete disappearance of all signs of lung cancer cells (“complete response”). In some embodiments, administration of anti-PD-1 antibodies and / or anti-LAG-3 antibodies to a subject with lung cancer results in a reduction of lung cancer cells or tumor size of at least 30% or more (“partial response”). In some embodiments, administration of anti-PD-1 antibodies and / or anti-LAG-3 antibodies to a subject with lung cancer results in the complete or partial disappearance of lung cancer cells / lesions (including new measurable lesions). Reduction in lung cancer tumor size can be measured by any method known in the art, such as X-ray, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytological, histological, or molecular genetic analysis.In some respects, combining anti-PD-1 antibodies with anti-LAG-3 antibodies in a patient population resulted in more patients responding to treatment, longer responses to treatment, and / or deeper responses in patients who did respond to treatment, even if no more patients responded.

[0122] In some implementations, the combination of antibodies administered is safe and well-tolerated by patients, with no increase or only a tolerable increase in adverse side effects compared to patients receiving either antibody as a monotherapy.

[0123] Combination therapy According to certain embodiments, the method of this disclosure includes administering a combination of an anti-LAG-3 antibody and an anti-PD-1 antibody to a subject. In some embodiments, the method of this disclosure includes administering an antibody with additional or synergistic activity to treat lung cancer. The expression “combined with” as used herein means that the anti-LAG-3 antibody is administered before, after, or concurrently with the anti-PD-1 antibody. The term “combined with” also includes sequential or concurrent administration of the anti-PD-1 antibody and the anti-LAG-3 antibody. For example, when administered “before” the anti-LAG-3 antibody, the anti-PD-1 antibody may be administered more than 150 hours, about 150 hours, about 100 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the anti-LAG-3 antibody. When administered “following” the anti-LAG-3 antibody, the anti-PD-1 antibody may be administered approximately 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, or more than 72 hours after administration of the anti-LAG-3 antibody. Administering “simultaneously” with the anti-LAG-3 antibody means administering the anti-PD-1 antibody to the subject in a separate dosage form or as a single combined dose formulation containing both the anti-PD-1 and anti-LAG-3 antibodies within 5 minutes (before, after, or simultaneously with) the administration of the anti-LAG-3 antibody (e.g., within 5 minutes after the completion of the anti-LAG-3 antibody infusion). In some respects, the anti-PD-1 antibody and the anti-LAG-3 antibody are administered on the same day. In some cases, anti-PD-1 and anti-LAG-3 antibodies are administered as a combined infusion over 30 minutes.

[0124] Similarly, when administered in combination with chemotherapy agents (e.g., platinum-based dual chemotherapy regimens), anti-PD-1 antibodies, anti-LAG-3 antibodies, and chemotherapy agents can be administered individually, in combination with any other agent, or before, after, or simultaneously with any other agent.

[0125] In some implementations, the combination therapy includes a first therapy, such as neoadjuvant therapy, comprising administering to a subject in need an anti-PD-1 antibody or its antigen-binding fragment, an anti-LAG-3 antibody or its antigen-binding fragment, and a platinum-based double chemotherapy regimen, followed by adjuvant therapy, comprising administering to a subject in need an anti-PD-1 antibody or its antigen-binding fragment and an anti-LAG-3 antibody or its antigen-binding fragment. In some aspects, surgical resection of the cancer is performed after completion of neoadjuvant therapy. In some aspects, surgery is performed within 1 to 10 weeks after completion of neoadjuvant therapy. In some aspects, surgery is performed within 1 to 6 weeks after completion of neoadjuvant therapy. In some aspects, neoadjuvant therapy is administered every three weeks, for up to 15 weeks, or 12 weeks, or 9 weeks, or 6 weeks, or 3 weeks. In some cases, adjunctive therapy is administered every three weeks for up to 51 weeks, for example, up to 48 weeks, or 45 weeks, or 42 weeks, or 39 weeks, or 36 weeks, or 33 weeks, or 30 weeks, or 27 weeks, or 24 weeks, or 21 weeks, or 18 weeks, or 15 weeks, or 12 weeks, or 9 weeks, or 6 weeks, or three weeks.

[0126] In some embodiments, the methods provided herein include the administration of an adjunct therapeutic agent, wherein the adjunct therapeutic agent is an anticancer drug. As used herein, "anticancer drug" means any agent that can be used to treat cancer, including but not limited to cytotoxins and agents such as antimetabolites, alkylating agents, anthracyclines, antibiotics, antimitotic agents, procarbazine, hydroxyurea, asparaginase, corticosteroids, mitotane (O,P'-(DDD)), biologics (e.g., antibodies and interferons), and radiopharmaceuticals. "Cytoxin or cytotoxic agent" as used herein also refers to chemotherapeutic agents and means any agent that is harmful to cells. Examples include Taxol® (paclitaxel), temozolomide, cytochalasin B, bacitracin D, ethidium bromide, emetine, cisplatin, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracycline, mitoxantrone, photomycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and their analogues or homologues. In some embodiments, the methods provided herein include administering an additional therapeutic agent selected from the group consisting of: radiation, surgery, cancer vaccines, PD-L1 inhibitors (e.g., anti-PD-L1 antibodies), CD3 inhibitors, CTLA-4 inhibitors (e.g., ipilimumab), CD38 inhibitors, TIM3 inhibitors, BTLA inhibitors, TIGIT inhibitors, CD47 inhibitors, another T-cell co-inhibitor or ligand antagonist (e.g., antibodies against CD-28, 2B4, LY108, LAIR1, ICOS, CD160, or VISTA), indoleamine-2,3-dioxygenase (IDO) inhibitors, vascular endothelial growth factor (VEGF) antagonists [e.g., "VEGF-trap" such as aflibercept or as in U.S. Patent 7,087,Other VEGF-inhibiting fusion proteins shown in 411, or anti-VEGF antibodies or their antigen-binding fragments (e.g., bevacizumab or ranibizumab) or small molecule kinase inhibitors of the VEGF receptor (e.g., sunitinib, sorafenib, or pazopanib)], Ang2 inhibitors (e.g., nesvacumab), transforming growth factor β (TGFβ) inhibitors, epidermal growth factor receptor (EGFR) inhibitors (e.g., erlotinib, cetuximab), agonists of co-stimulatory receptors (e.g., agonists of glucocorticoid-induced TNFR-related proteins), tumor-specific antigens [e.g., CA9, CA125, melanoma-associated antigen 3], etc. Antibodies against MAGE3, carcinoembryonic antigen (CEA), CD28 agonists, GITR agonists, 4-1BB agonists, vimentin, tumor-M2-PK, prostate-specific antigen (PSA), mucin-1, MART-1, and CA19-9, vaccines (e.g., BCG, cancer vaccines), adjuvants that enhance antigen presentation (e.g., granulocyte-macrophage colony-stimulating factor), oncolytic viruses, cytotoxins, and chemotherapeutic agents (e.g., dacarbazine, temozolomide, cyclophosphamide, docetaxel, doxorubicin, daunorubicin, cisplatin, carboplatin, gemcitabine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, and vincristine). Radiation therapy, IL-6R inhibitors (e.g., sarilumab), IL-4R inhibitors (e.g., dupilumab), IL-10 inhibitors, cytokines (such as IL-2, IL-7, IL-12, IL-21, and IL-15), antibody-drug conjugates (ADCs) (e.g., anti-CD19-DM4 ADCs and anti-DS6-DM4 ADCs), chimeric antigen receptor T cells (e.g., CD19-targeting T cells) or other cell therapies, and anti-inflammatory drugs (e.g., corticosteroids and nonsteroidal anti-inflammatory drugs).

[0127] In some implementations, the methods described herein include administering an anti-LAG-3 antibody in combination with an anti-PD-1 antibody and platinum-based dual chemotherapy to produce a long-lasting antitumor response and / or improve survival in lung cancer patients. Illustratively, platinum-based dual chemotherapy includes, but is not limited to, paclitaxel / carboplatin, pemetrexed / cisplatin, gemcitabine / cisplatin, paclitaxel / cisplatin, and pemetrexed / carboplatin.

[0128] In some implementations, the methods provided herein include administering anti-PD-1 antibodies and anti-LAG-3 antibodies in combination with radiotherapy / chemotherapy or platinum-based dual chemotherapy to produce a long-lasting antitumor response and / or improve the survival of lung cancer patients.

[0129] In some embodiments, the methods of this disclosure include administering radiotherapy before, simultaneously with, or after administering anti-PD-1 and anti-LAG-3 antibodies to a lung cancer patient. For example, radiation therapy may be administered in one or more doses after administering one or more doses of the antibodies. In some embodiments, local radiotherapy may be administered to the lung cancer lesion before or after systemic administration of anti-PD-1 and / or anti-LAG-3 antibodies, i.e., in an adjuvant setting, to enhance the local immunogenicity of the patient's lung cancer (adjuvant radiation) and / or kill tumor cells (ablation radiation). In some embodiments, the antibodies may be administered in combination with radiotherapy and chemotherapeutic agents (e.g., temozolomide or cyclophosphamide) or VEGF antagonists (e.g., aflibercept). In some embodiments, the antibodies may be administered in combination with platinum-based dual chemotherapy.

[0130] Pharmaceutical composition and administration This document provides a method for administering a combination of an anti-PD-1 antibody and an anti-LAG-3 antibody to a subject, wherein the antibody is contained within a single or combined (single) pharmaceutical composition. The pharmaceutical compositions of this disclosure can be formulated using suitable carriers, excipients, and other agents that provide suitable delivery, tolerability, etc. Numerous suitable formulations are available in all the formulation collections known to pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, lipid-containing (cationic or anionic) vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorbable pastes, oil-in-water and water-in-oil emulsions, carbowax emulsions (polyethylene glycol of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al., “Compendium of excipients for parenteral formulations” PDA (1998) J Pharm Sci Technol 52:238-311.

[0131] Various delivery systems are known and can be used to administer the pharmaceutical compositions disclosed herein, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (see, for example, Wu et al., 1987, J. Biol. Chem. 262: 4429-4432). Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered via any convenient route, such as by infusion or bolus, by absorption through epithelial or mucosal skin linings (e.g., oral mucosa, rectal mucosa, and intestinal mucosa), and can be administered together with other bioactive agents.

[0132] The pharmaceutical compositions disclosed herein can be delivered subcutaneously or intravenously using standard needles and syringes. In one embodiment, the syringe is a pre-filled syringe. Alternatively, for subcutaneous delivery, pen-type delivery devices are readily applicable for delivering the pharmaceutical compositions disclosed herein. Such pen-type delivery devices can be reusable or disposable. Reusable pen-type delivery devices typically utilize replaceable cartridges containing the pharmaceutical composition. Once all the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen-type delivery device can then be reused. In disposable pen-type delivery devices, there are no replaceable cartridges. In fact, disposable pen-type delivery devices have a reservoir pre-filled with the pharmaceutical composition within the device. Once the pharmaceutical composition in the reservoir is emptied, the entire device is discarded.

[0133] In some cases, drug compositions can be delivered in controlled-release systems. In one embodiment, a pump can be used. In another embodiment, polymeric materials can be used; see Medical Applications of Controlled Release, Langer and Wise eds., 1974, CRC Pres., Boca Raton, Fla. In yet another embodiment, the controlled-release system can be placed near the target of the composition, thus requiring only a fraction of the systemic dose (see, for example, Goodson, 1984, in Medical Applications of Controlled Release, ibid., Vol. 2, pp. 115–138). Other controlled-release systems are discussed in a review in Langer, 1990, Science 249:1527–1533.

[0134] Injectable formulations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection, intravenous infusion, etc. These injectable formulations can be prepared by known methods. For example, injectable formulations can be prepared, for instance, by dissolving, suspending, or emulsifying the antibodies or their salts described above in a sterile aqueous or oily medium conventionally used for injection. Aqueous media for injection include, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, which can be used in combination with suitable solubilizers (such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (a polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc.]. Oily media include, for example, sesame oil, soybean oil, etc., which can be used in combination with solubilizers (such as benzyl benzoate, benzyl alcohol, etc.). The resulting injectable formulation is preferably filled into suitable ampoules.

[0135] Advantageously, the pharmaceutical compositions described above for oral or parenteral use are formulated into unit dose dosage forms suitable for the appropriate dosage of the active ingredient. Such unit dose dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0136] Application plan This disclosure includes methods of administering anti-PD-1 antibodies to subjects at a frequency of approximately four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less (providing a therapeutic response is achieved). In some embodiments, this disclosure includes methods of administering anti-LAG-3 antibodies to subjects at a frequency of approximately four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less (providing a therapeutic response is achieved). In some embodiments, the method involves administering a combination of anti-PD-1 and anti-LAG-3 antibodies at a frequency of approximately four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every nine weeks, once every twelve weeks, or less (providing a therapeutic response is achieved).

[0137] According to certain embodiments of this disclosure, multiple doses of a combination of anti-PD-1 antibody and anti-LAG-3 antibody can be administered to a subject over a defined time period. A method according to this aspect of the disclosure includes sequentially administering one or more doses of a combination of anti-PD-1 antibody and one or more doses of anti-LAG-3 antibody to a subject. As used herein, “sequentially administering” means administering each dose of antibody to a subject at different time points, such as on different days separated by predetermined intervals (e.g., hours, days, weeks, or months). This disclosure includes a method comprising sequentially administering a single initial dose of anti-PD-1 antibody to a patient, followed by one or more second doses of anti-PD-1 antibody, and optionally subsequently administering one or more third doses of anti-PD-1 antibody. In some embodiments, the method further includes sequentially administering a single initial dose of anti-LAG-3 antibody to a patient, followed by one or more second doses of anti-LAG-3 antibody, and optionally subsequently administering one or more third doses of anti-LAG-3 antibody.

[0138] According to certain embodiments of this disclosure, multiple doses of anti-PD-1 antibody and anti-LAG-3 antibody may be administered to a subject over a defined time period. A method according to this aspect of the disclosure includes sequentially administering multiple doses of anti-PD-1 antibody and anti-LAG-3 antibody to a subject. As used herein, “sequentially administering” means administering each dose of the combination of anti-PD-1 antibody and anti-LAG-3 antibody to the subject at different time points, such as on different days at predetermined intervals (e.g., hours, days, weeks, or months).

[0139] According to certain embodiments of this disclosure, subjects may be administered multiple doses of anti-LAG-3 antibody for months or years, every 3 or 6 weeks, followed by administration of a combination of anti-PD-1 antibody and anti-LAG-3 antibody for months or years. In some aspects, the anti-LAG-3 antibody dose differs from that of monotherapy versus combination therapy. In some aspects, the anti-LAG-3 antibody dose is the same whether administered as monotherapy or in combination with an anti-PD-1 antibody.

[0140] The terms “initial dose,” “second dose,” and “third dose” refer to the time sequence of administration. Therefore, the “initial dose” is the dose administered at the start of the treatment regimen (also known as the “baseline dose”); the “second dose” is the dose administered after the initial dose; and the “third dose” is the dose administered after the second dose. The initial, second, and third doses may all contain the same amount of antibody (anti-PD-1 antibody or anti-LAG-3 antibody). However, in some embodiments, the amounts contained in the initial, second, and / or third doses may differ from each other during treatment (e.g., up- or down-adjusted as appropriate). In some embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered at the start of the treatment regimen as a “loading dose,” followed by subsequent doses administered at a lower frequency (e.g., a “maintenance dose”). For example, an anti-PD-1 antibody may be administered to a patient with lung cancer at a loading dose of about 1-20 mg / kg, followed by one or more maintenance doses of about 3 mg / kg of the patient's body weight.

[0141] In one exemplary embodiment of this disclosure, each second and / or third dose is administered 1 / 2 to 14 weeks (e.g., 1 / 2, 1 / 2, 1 / 2, 1 / 2, 3, 1 / 2, 4, 1 / 2, 5, 1 / 2, 6, 1 / 2, 7, 8, 8 / 2, 9, 9 / 2, 10, 10 / 2, 11 / 2, 12 / 2, 13, 13 / 2, 14, 14 / 2 or more weeks) immediately following the previous dose. The phrase “immediately following the previous dose” as used herein means, in a sequence of multiple administrations, the dose of anti-PD-1 antibody (and / or anti-LAG-3 antibody) administered to the patient when there is no intervention dose prior to the next dose in the sequence.

[0142] Methods according to some aspects may include administering any number of two- and / or three-dose doses of anti-PD-1 antibody (and / or anti-LAG-3 antibody) to a patient. For example, in some embodiments, only a single two-dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) two-dose doses are administered to the patient. Similarly, in some embodiments, only a single three-dose dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) three-dose doses are administered to the patient.

[0143] In embodiments involving multiple second doses, each second dose may be administered at the same frequency as the other second doses. For example, each second dose may be administered to the patient 1 to 2 weeks or 3 weeks immediately following the previous dose. Similarly, in embodiments involving multiple third doses, each third dose may be administered at the same frequency as the other third doses. For example, each third dose may be administered to the patient 2 to 4 weeks (e.g., 3 weeks) immediately following the previous dose. Alternatively, the frequency of second and / or third doses administered to the patient may vary during the treatment regimen. The physician may also adjust the frequency of administration during treatment as needed by each patient following clinical examination.

[0144] In some implementations, one or more doses of anti-PD-1 antibody and / or anti-LAG-3 antibody are administered at a higher frequency (twice a week, once a week, or once every 2 weeks) as an “induction dose” at the start of the treatment regimen, followed by subsequent doses (“consolidation dose” or “maintenance dose”) at a lower frequency (e.g., once every 4 to 12 weeks).

[0145] In some embodiments, this document covers the concurrent administration of anti-PD-1 antibody and anti-LAG-3 antibody, with the anti-LAG-3 antibody administered at a different dose at a similar or different frequency relative to the anti-PD-1 antibody. In some embodiments, the anti-LAG-3 antibody is administered before, after, or concurrently with the anti-PD-1 antibody. In some embodiments, the anti-LAG-3 antibody and anti-PD-1 antibody are administered as a single-dose formulation (co-infusion).

[0146] This disclosure also includes methods for treating lung cancer by sequentially administering a combination of anti-LAG-3 antibody and anti-PD-1 antibody to a patient. In some embodiments, the method of the present invention includes administering one or more doses of anti-LAG-3 antibody, followed by administering one or more doses of anti-PD-1 antibody. In some embodiments, the method of the present invention includes administering a single dose of anti-LAG-3 antibody, followed by administering one or more doses of anti-PD-1 antibody. In some embodiments, one or more doses of about 0.1 mg / kg to about 50 mg / kg of anti-LAG-3 antibody may be administered, followed by administering one or more doses of about 0.1 mg / kg to about 20 mg / kg of anti-PD-1 antibody to inhibit tumor growth in a patient with lung cancer and / or prevent lung cancer recurrence. In some embodiments, one or more doses of about 50 mg to about 8000 mg of anti-LAG-3 antibody may be administered, followed by administering one or more doses of about 50 mg to about 1500 mg of anti-PD-1 antibody to inhibit lung cancer growth in a patient with lung cancer and / or prevent lung cancer recurrence. In some implementations, administering one or more doses of anti-LAG-3 antibody followed by one or more doses of anti-PD-1 antibody results in increased anti-tumor efficacy (e.g., greater inhibition of lung cancer growth and increased prevention of lung cancer recurrence compared to untreated subjects or subjects receiving either antibody as a monotherapy).

[0147] dose The amount of anti-PD-1 antibody and / or anti-LAG-3 antibody administered to a subject according to the methods of this disclosure is generally a therapeutically effective amount. As used herein, the phrase “therapeutically effective amount” refers to the amount of antibody (anti-PD-1 antibody or anti-LAG-3 antibody) that produces or has one or more of the following therapeutic effects: (a) reducing the severity or duration of lung cancer symptoms; (b) inhibiting lung cancer growth, or increasing lung cancer cell necrosis, lung cancer tumor shrinkage, and / or lung cancer tumor disappearance; (c) delaying lung cancer growth and development; (d) inhibiting, delaying, or stopping lung cancer metastasis; (e) preventing lung cancer growth and recurrence; (f) increasing the survival of a subject with lung cancer; and / or (g) reducing the use or need for conventional anticancer therapies (e.g., reducing or eliminating the use of chemotherapeutic agents or cytotoxic agents) compared to untreated subjects or subjects receiving either antibody as a monotherapy.

[0148] In the case of anti-PD-1 antibodies, the effective therapeutic dose can be from about 0.05 mg to about 1500 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 3... 20mg, approximately 330mg, approximately 340mg, approximately 350mg, approximately 360mg, approximately 370mg, approximately 380mg, approximately 390mg, approximately 400mg, approximately 410mg, approximately 420mg, approximately 430mg, approximately 440mg, approximately 450mg, approximately 460mg, approximately 470mg, approximately 480mg, approximately 490mg, approximately 500mg, approximately 510mg, approximately 520mg Anti-PD-1 antibody in doses of approximately 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg. In some embodiments, 350 mg of anti-PD-1 antibody is administered. In some embodiments, 1050 mg of anti-PD-1 antibody is administered.

[0149] In the case of anti-LAG-3 antibodies, the effective therapeutic dose can be from approximately 10 mg to approximately 8000 mg, for example, approximately 10 mg, approximately 20 mg, approximately 50 mg, approximately 70 mg, approximately 100 mg, approximately 120 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 700 mg, approximately 800 mg, approximately 900 mg, approximately 1000 mg, etc. Anti-LAG-3 antibody in doses of approximately 1050 mg, 1100 mg, 1500 mg, 1600 mg, 1700 mg, 2000 mg, 2050 mg, 2100 mg, 2200 mg, 2500 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3200 mg, 4000 mg, 5000 mg, 6000 mg, 7000 mg, or 8000 mg.

[0150] The amount of anti-PD-1 antibody or anti-LAG-3 antibody contained in each dose can be expressed in milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). In some embodiments, the anti-PD-1 antibody or anti-LAG-3 antibody used in the methods of this disclosure may be administered to the subject at a dose of about 1 mg / kg of subject body weight to about 50 mg / kg of subject body weight. For example, the anti-PD-1 antibody may be administered at a dose of about 0.1 mg / kg of patient body weight to about 20 mg / kg of patient body weight. The anti-LAG-3 antibody may be administered at a dose of about 0.1 mg / kg of patient body weight to about 50 mg / kg of patient body weight.

[0151] Example The following examples are provided to provide a complete disclosure and description of how to prepare and use the methods and compositions of this disclosure to those skilled in the art, and are not intended to limit the scope of the disclosure as the inventors believe it to be. Efforts have been made to ensure the accuracy of the figures used (e.g., amounts, temperatures, etc.), but some experimental errors and biases should be taken into account. Unless otherwise specified, parts are parts by weight, molecular weights are average molecular weights, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure. The compositions and methods set forth in the examples form part of this disclosure.

[0152] Therapeutic monoclonal antibodies (mAbs) targeting immunosuppressive receptors (e.g., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] and programmed cell death 1 [PD-1]) have shown remarkable clinical activity in several tumor types with acceptable benefit-risk ratios (Topalian, 2014) (Wolchok, 2013) (Larkin, 2015a) (Baksh, 2015). However, sustained responses have only been achieved in a small number of patients, suggesting that combination approaches may be needed to overcome tumor immunosuppressive mechanisms (Topalian, 2012).

[0153] Antibodies against inhibitory receptor lymphocyte activation gene 3 (LAG-3) represent an attractive potential therapeutic strategy to enhance the immune response to cancer, particularly in combination with antibodies that block PD-1. LAG-3 binds to major histocompatibility complex class II (MHC II) on antigen-presenting cells and is upregulated on activated CD4+ and CD8+ T cells upon T cell receptor binding. It negatively regulates T cell proliferation, activation, and the production of pro-inflammatory cytokines (Maçon-Lemaître, 2005). Multiple reports have demonstrated that a majority of PD-1-positive CD8+ and CD4+ tumor-infiltrating lymphocytes co-express LAG-3, suggesting a dominant role for PD-1 in regulating anti-tumor T cell responses and a direct role for LAG-3 in suppressing the activity of PD-1-expressing T cell subsets (Woo, 2012). Early clinical data indicate that lung cancer patients who have previously received anti-PD-1 therapy but have progressed can respond to simultaneous blockade of LAG-3 and PD-1 (Ascierto, 2017).

[0154] In the following examples, the antibody (REGN3767 (INN: fumarimab), an antibody that blocks the LAG-3 receptor, which inhibits T-cell suppression mediated by LAG-3 / MHCII, was tested in combination with cimiprimab (REGN2810), an antibody that blocks the PD-1 receptor, which inhibits T-cell suppression mediated by PD-1 / programmed death-ligand 1 (PD-L1). LIBTAYO® (cimiprimab is known as cimiprimab rwlc in the United States) has been approved by multiple health authorities for the treatment of patients with various tumor types.

[0155] Example 1: A phase 2 / 3 double-blind clinical trial of anti-LAG3 (REGN3767; fuamilimab) and anti-PD-1 (REGN2810; cimiprimab) combined with cimiprimab monotherapy as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC) whose tumors express PD-L1 ≥50%. This phase 2 / 3 study evaluated the combination of fumarazumab and cimiprimab versus cimiprimab monotherapy in first-line patients with stage IIIB, IIIC, or IV squamous or non-squamous NSCLC who had tumors expressing PD-L1 in ≥50% of tumor cells, lacked mutations that could be targeted by approved targeted therapies, and were ineligible for radical chemoradiotherapy.

[0156] Purpose The primary objective of the phase 2 study was to evaluate, by blinded independent central review (BICR), the objective response rate (ORR) of the combination of 1600 mg and 400 mg cimiprimab and fuamilumab as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC) whose tumors expressed programmed death cell ligand-1 (PD-L1) in ≥50% of tumor cells.

[0157] The secondary objectives of the Phase 2 study included the following: ● Evaluate the safety and tolerability of the combination of cimiprimab and fumarazumab compared to cimiprimab monotherapy.

[0158] ● Evaluate the additional antitumor activity of the combination of cimiprimab and fumarazumab compared to cimiprimab monotherapy using ORR, disease control rate (DCR), time to tumor response (TTR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS) obtained by BICR.

[0159] ● Evaluate patient-reported outcomes of the combination of cimiprimab and fuamilumab compared to cimiprimab monotherapy (via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core Version 30 [EORTC QLQ-C30], Lung Cancer 13 [EORTC QLQ-LC13] and EQ-5D 5L scale [EQ-5D-5L]).

[0160] ● To evaluate patient-reported fatigue status as measured by fatigue severity and interference with routine or daily activities in the Patient-Reported Outcomes Common Terminology Standard (PRO-CTCAE) compared to cimiprimab monotherapy in combination of cimiprimab and fumarlimab.

[0161] ● Characterize the pharmacokinetics (PK) of fumarazumab and cimiprimab.

[0162] ● Evaluate the immunogenicity of fumarazumab and cimiprimab.

[0163] The primary objective of the phase 3 study was to compare overall survival (OS) of cimiprimab and fuamilumab versus cimiprimab monotherapy.

[0164] The secondary objectives of the Phase 3 study included the following: ● Evaluate the safety and tolerability of the combination of cimiprimab and fumarazumab compared to cimiprimab monotherapy.

[0165] ● Evaluate the additional antitumor activity of the combination of cimiprimab and fuamilumab with cimiprimab monotherapy, as measured by ORR, DCR, TTR, DOR, and PFS, and by BICR.

[0166] ● Evaluate patient-reported outcomes of the combination of cimiprimab and fuamilumab compared to cimiprimab monotherapy (via EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L).

[0167] ● Evaluate patient-reported fatigue status and interference items in PRO-CTCAE as measured by fatigue severity in the combination of cimiprimab and fuamilimab compared to cimiprimab alone.

[0168] ● Characterize the pharmacokinetic (PK) performance of franbizumab and cimiprimab.

[0169] ● Evaluate the immunogenicity of fumarazumab and cimiprimab.

[0170] Research Design This is a randomized, double-blind, multicenter phase 2 / 3 study comparing cimiprimab in combination with two different doses of fumarlimab versus cimiprimab monotherapy in patients aged 18 years or older with stage IIIB, IIIC, or IV squamous or non-squamous NSCLC who were treatment-naïve and whose tumors expressed PD-L1 in ≥50% of tumor cells, lacked mutations that could be targeted by approved targeted therapies, and were ineligible for curative chemoradiotherapy. The upper limit for squamous NSCLC patients was ≤50% of the total sample size.

[0171] To be enrolled in this study, patients must have advanced, treatment-naïve NSCLC and PD-L1 expression in ≥50% of tumor cells (see inclusion criteria below).

[0172] The study was divided into two phases: Phase 2 and Phase 3.

[0173] During the second phase of treatment, patients were randomly assigned to one of three treatment groups in a 1:1:1 ratio: ● Group A: Furamimab (1600mg) + Cimiprimab (350mg) intravenously every 3 weeks (Q3WIV) ● Group B: Furamimab (400mg) + Cimiprimab (350mg) Q3W IV ● Group C: Cimiprilmab (350 mg) + Saline / Glucose Placebo Q3W IV Enrollment may be paused between Phase 2 and Phase 3, depending on the timing of the dose selection decision in the Phase 2 portion. All data during Phase 2 will be monitored to determine the optimal fumarimab dose for Phase 3 of NSCLC. Based on Phase 2 data (including ORR), a decision will be made regarding which dose of fumarimab (1600 mg, in Phase 3, or 400 mg, in Phase 3, compared to treatment group C (cimiprilmab (350 mg) + saline / glucose placebo Q3W IV) will be used in Phase 3.

[0174] In phase 3, patients were randomly assigned to one of two treatment groups (treatment group A or treatment group B and treatment group C) at a 1:1 ratio.

[0175] The research flowchart is presented in Figure 1 middle.

[0176] Approximately 850 patients were enrolled. In Phase 2, 150 patients were randomly assigned in a 1:1:1 ratio to Group A (50 patients), Group B (50 patients), and Group C (50 patients). In Phase 3, 700 patients were randomly assigned in a 1:1 ratio to one of the two treatment groups.

[0177] To be enrolled in this study, patients must have advanced, treatment-naïve NSCLC and PD-L1 must be expressed in ≥50% of tumor cells.

[0178] Patients were randomly assigned and stratified histologically (non-squamous vs. squamous). The upper limit for squamous NSCLC patients was ≤50% of the total sample size.

[0179] Patients continued treatment for up to 108 weeks, or until they experienced an intolerable adverse event (AE), disease progression, death, or the patient and / or physician decided to discontinue study treatment. All patients had a post-treatment follow-up period. After the last follow-up visit, patients were contacted by telephone every 3 months to investigate their survival.

[0180] Efficacy was assessed using tumor imaging and RECIST 1.1. The first radiation oncology assessment occurred 9 weeks after study treatment and was performed every 9 weeks in the first year and every 12 weeks thereafter (if applicable). Radiation oncology assessment was performed before BICR assessment for progressive disease as defined by RECIST 1.1, withdrawal of consent, death, or initiation of another anticancer therapy.

[0181] Safety was continuously monitored throughout the study. Clinical safety and laboratory monitoring were conducted throughout the treatment and follow-up periods. Samples were also collected for biomarker evaluation throughout the treatment and follow-up periods.

[0182] Inclusion criteria Adult patients aged ≥18 years (or the legal age of consent to participate in a clinical study according to national regulations) with advanced, treatment-naïve NSCLC, whose tumors were confirmed by immunohistochemical (IHC) evaluation to have ≥50% PD-L1 expression. Given the higher incidence of lung cancer in patients of African descent, the focus is on patients of African descent.

[0183] After evaluating the Phase 2 data and before the start of the Phase 3 portion of the study, a revised protocol will be released to address any Phase 3-specific eligibility criteria issues.

[0184] Patients must meet the following criteria to be eligible for inclusion in this study: 1. (i) Men and women aged 18 years or older (or the legal age of consent to participate in clinical studies according to specific national regulations).

[0185] 2. Patients with stage IIIB or IIIC non-squamous or squamous histological NSCLC who are not candidates for surgical resection or radical chemoradiotherapy or are in stage IV (metastatic disease) and have not received prior systemic therapy for recurrent or metastatic NSCLC.

[0186] 3. Formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples are available for archiving or research purposes, with no interventional therapy between biopsy collection and screening.

[0187] Biopsy Site Guidelines: a. Archived or fresh biopsy is acceptable.

[0188] b. FFPE tissue blocks must be ≤6 months old; however, unstained slides (archived or recent) of tumor samples must be ≤2 weeks after preparation. For patients with local EGFR, ALK, and ROS1 results available, at least 10 slides or equivalent block volumes are required. For patients without local EGFR, ALK, or ROS1 results available, at least 19 slides or equivalent block volumes are required.

[0189] c. Biopsies should be taken from metastatic or recurrent sites that have not previously been irradiated. Bone biopsies are permissible if there is no decalcification.

[0190] i. Exceptions: Primary lung tumors may be used if the primary lung tumor remains in situ and other metastatic sites are inaccessible (brain) or unusable, or if biopsy would put the patient at risk.

[0191] 4. For enrollment in the Phase 2 portion of this study, patients should have PD-L1 levels ≥50% as determined by a laboratory accredited by the College of American Pathologists (CAP) / Clinical Laboratory Improvement Amendments (CLIA) (or equivalent under local regulations). If PD-L1 IHC results are unavailable prior to obtaining informed consent from the patient, PD-L1 IHC results should be obtained during screening using the VENTANA PD-L1 (SP263) assay. For enrollment in the Phase 3 portion of this study, patients should have PD-L1 expression in ≥50% of their tumor cells stained using the VENTANA PD-L1 (SP263) assay performed by a central laboratory.

[0192] 5. At least one radiographically measurable lesion, as determined by computed tomography (CT) or magnetic resonance imaging (MRI), according to RECIST 1.1 criteria. If there is documented disease progression (radiographically) at that site, the target lesion may be located in a previously irradiated area.

[0193] 6. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.

[0194] 7. Proper organ and bone marrow function.

[0195] (i) Hemoglobin ≥ 9.0 g / dL (ii) Absolute neutrophil count (ANC) ≥ 1.5 × 10⁻⁶ 9 / L (iii) Platelet count ≥100,000 / mm 3 (iv) Glomerular filtration rate (GFR) > 30 mL / min / 1.73 m 2 (v) Total bilirubin ≤1.5 × upper limit of normal (ULN) (except for patients diagnosed with clinically confirmed Gilbert's syndrome if liver metastases are ≤3 × ULN). (vi) If liver metastasis occurs, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3×ULN or ≤5×ULN. (vii) Alkaline phosphatase (ALP) ≤2.5×ULN (or ≤5.0×ULN if liver or bone metastases) (viii) The criteria of Hy's law are not met (ALT > 3 × ULN and bilirubin > 2 × ULN).

[0196] 8. Willing and able to cooperate in completing outpatient visits and research-related procedures.

[0197] 9. Provide a signed informed consent form.

[0198] 10. Able to understand and complete research-related questionnaires.

[0199] Exclusion criteria Patients meeting any of the following criteria were excluded from the study: 1. Never smoked, defined as a patient who has smoked ≤100 cigarettes in their lifetime.

[0200] 2. Active or untreated brain metastases or spinal cord compression. Patients are eligible if their central nervous system (CNS) metastases are adequately treated and they have neurologically recovered to baseline (excluding residual signs or symptoms related to CNS treatment) for at least 2 weeks prior to enrollment. Patients must discontinue (immunosuppressive doses) of corticosteroids.

[0201] 3. Patients with tumors that can target EGFR gene mutations, ALK gene translocations, or ROS1 fusions. For enrollment in the Phase 2 portion of the study, the genetic alteration status, as determined by a CAP / CLIA-accredited laboratory (or equivalently authorized under local regulations), should be available prior to screening. If the genetic alteration status is not available prior to obtaining informed consent from the patient, the genetic alteration status result should be obtained during screening.

[0202] 4. Patients who have had encephalitis, meningitis, or uncontrolled seizures within the year prior to enrollment.

[0203] 5. A history of the following conditions is acceptable: interstitial lung disease (e.g., idiopathic pulmonary fibrosis or organizing pneumonia), active non-infectious pneumonia requiring immunosuppressive doses of glucocorticoids for management, or pneumonia within the past 5 years. A history of radiation-induced pneumonia is permissible as long as the pneumonia resolved ≥6 months prior to enrollment.

[0204] 6. Known primary immunodeficiency, cellular immunodeficiency (e.g., DiGeorge syndrome, severe combined T-cell immunodeficiency [SCID]) or combined T-cell and B-cell immunodeficiency (e.g., T-cell and B-cell negative SCID, Wiskott-Aldrich syndrome, ataxia-telangiectasia, common variant immunodeficiency).

[0205] 7. Persistent or recent (within 2 years) evidence of significant autoimmune disease requiring systemic immunosuppressive therapy may indicate a risk of immune-mediated treatment-emergent adverse events (imTEAEs). Exclude patients with uncontrolled type 1 diabetes or uncontrolled adrenal insufficiency. The following conditions are not excluded: vitiligo, regressed childhood asthma, residual hypothyroidism requiring only hormone replacement therapy, or psoriasis not requiring systemic treatment.

[0206] 8. Patients requiring corticosteroid treatment (>10 mg prednisone / day or equivalent) within 14 days will be randomly assigned. Physiological replacement doses are permissible, even if they are >10 mg prednisone / day or equivalent, provided they are not administered for immunosuppressive purposes. Patients with clinically relevant systemic immunosuppression within the last 3 months prior to trial enrollment will be excluded. Inhaled or topical steroids are permitted if they are not used to treat autoimmune disorders.

[0207] 9. Another malignant tumor is progressing or requires treatment, except for non-melanoma skin cancer, cervical cancer in situ, or any other locally treated tumor that has received potentially curative treatment, and the patient is considered to have been in complete remission for at least 2 years prior to enrollment and does not require additional therapy during the study period.

[0208] 10. Known active hepatitis B (known positive result) or known hepatitis C (known positive result) and known quantitative hepatitis C virus (HCV) RNA result above the detection limit. Uncontrolled human immunodeficiency virus (HIV) infection, hepatitis B virus (HBV) or HCV infection; or a diagnosis of immunodeficiency (FDA).

[0209] Exceptions: a. HIV patients whose infection is under control (undetectable viral load and CD4 count above 350, whether spontaneous or generated while receiving a stable antiretroviral regimen) are allowed to be included.

[0210] b. Patients with HBV (hepatitis B surface antigen positive) whose infection is under control (serum hepatitis B virus DNA polymerase chain reaction [PCR] below the detection limit and who are receiving hepatitis B antiviral therapy) are allowed to be included.

[0211] c. Patients with HCV antibody-positive (HCV Ab+) whose infection has been controlled (spontaneous or as a response to a previously successful anti-HCV therapy, with undetectable HCV RNA by PCR) are allowed to be included.

[0212] 11. Documented or suspected persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients undergoing screening with documented or suspected SARS-CoV-2 may be included if they meet the following criteria: a. Recovery from COVID-19 (i.e., the resolution of all COVID-19-related symptoms and major clinical findings that could potentially affect patient safety), and i. It is recommended to perform two repeated COVID-19 PCR tests, or equivalent tests as recommended by the region, to confirm that the patient is negative for SARS-CoV-2.

[0213] ii. If a COVID-19 PCR test is not feasible, it is recommended to wait at least 3 months from the initial diagnosis.

[0214] 12. Active infections requiring systemic treatment within 14 days prior to randomization. Patients who have previously received systemic therapy are excluded, except for the following: a. If relapse or metastatic disease develops more than 6 months after completion of treatment, adjuvant or neoadjuvant platinum-based double chemotherapy (after surgery and / or radiotherapy) may be administered, provided that the toxicity has subsided to a CTCAE grade ≤1 or baseline, except for alopecia and peripheral neuropathy.

[0215] b. Anti-PD-(L)1, with or without LAG-3, as adjuvant or neoadjuvant therapy, provided that the last dose was >12 months prior to enrollment.

[0216] c. Previous exposure to other immunomodulatory or vaccine therapies as adjuvant or neoadjuvant therapy, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, provided that the last dose was >6 months prior to enrollment.

[0217] Note: At enrollment, immune-mediated adverse events (AEs) must have regressed to a CTCAE grade ≤1 or baseline. Prior control with hormones or other non-immunosuppressive therapies is permitted for endocrine-immune AEs that have not regressed.

[0218] 14. Hypersensitivity to cimiprimab or any of its excipients, or contraindication of cimiprimab according to the approved local label.

[0219] 15. Receive the investigational drug or device within 30 days of enrollment or within 5 half-lives of the investigational drug or the investigational therapy (whichever is longer).

[0220] 16. Receive the live vaccine within 30 days of the planned start of drug research.

[0221] 17. Major surgery or major traumatic injury within 4 weeks prior to the first dose.

[0222] 18. Mental illness or substance abuse disorder known to interfere with participation in the study and / or the study requirements, including any illicit drugs currently in use.

[0223] 19. Pregnant or breastfeeding women.

[0224] 20. Sexually active men and women of fertility* who do not wish to use highly effective contraception before the first dose / start of the first treatment, during the study period, and for at least 6 months after the last dose. Highly effective contraception includes the stable use of ovulation-suppressing combination (estrogen and progestin) hormonal contraceptives (oral, vaginal, transdermal) or progestin-only hormonal contraceptives (oral, injectable, implantable) initiated for 2 or more menstrual cycles prior to screening; intrauterine devices (IUDs); intrauterine hormone-releasing systems (IUS); bilateral tubal ligation (blockage); partners who have undergone vasectomy; and / or abstinence. .

[0225] *Postmenopausal women must have stopped menstruating for at least 12 months to be considered infertile. Women who have undergone a confirmed hysterectomy do not need pregnancy testing or contraception.

[0226] Sexual abstinence is considered an effective approach only when defined as avoiding heterosexual intercourse throughout the entire period of risk associated with the study of treatment.

[0227] Regular abstinence (calendar, symptom-based basal body temperature, post-ovulation method), withdrawal (coitus interruptus), spermicide-only methods, and lactational amenorrhea (LAM) are unacceptable methods of contraception. Female and male condoms should not be used simultaneously.

[0228] Sexually active men and their partners must use highly effective contraception methods as described above. Men with a history of vasectomy do not require contraception.

[0229] 21. Patients admitted to an institution by order of a judicial or administrative authority are excluded from the study.

[0230] 22. Members of the research team at the clinical research center and / or their immediate family members, unless prior approval is obtained from the sponsor.

[0231] 23. Active or latent tuberculosis. In high-risk individuals, the latent period should be confirmed by the purified protein derivative (PPD) / QuantiFERON test, in accordance with local guidelines.

[0232] 24. Previous organ transplant history, including stem cell allogeneic transplantation.

[0233] 25. A history or current evidence of major cardiovascular disease within 6 months prior to study enrollment, including myocarditis, congestive heart failure (as defined by New York Heart Association functional classification III and IV), unstable angina, severe uncontrolled arrhythmia, and myocardial infarction.

[0234] 26. Patients with a history of myocarditis.

[0235] 27. At baseline, troponin T (TnT) or troponin I (TnI) >2 × institutional ULN. Patients with repeat TnT or TnI levels ≤1 × ULN within 24 hours are permissible if the levels are >1 to 2 × ULN. If TnT or TnI levels >1 to 2 × ULN within 24 hours, the subject may undergo cardiac evaluation and be considered for treatment. If repeat TnT or TnI levels <2 × ULN within 24 hours, the subject may undergo cardiac evaluation and be considered for treatment.

[0236] Dosage / Route of Administration / Dosage Regimen: The study treatment was prepared at the study site and administered in a blinded manner in an outpatient setting. Adult and adolescent patients received a combination infusion of the study drug every 3 weeks via intravenous infusion over 30 minutes (±10 minutes). Similarly, pembrolizumab and placebo were infused every 3 weeks via intravenous infusion over 30 minutes (±10 minutes).

[0237] Fumarimab and Cimiprimab (for combined infusion) Fumariumab 1600 mg was administered as a liquid in sterile single-use vials and given as a combined intravenous infusion every 3 weeks over 30 minutes (±10 minutes).

[0238] Fumariumab 400 mg was administered as a liquid in sterile single-use vials and given as a combined intravenous infusion every 3 weeks over 30 minutes (±10 minutes).

[0239] Cimiprimab 350 mg was administered as a liquid in sterile, single-use vials and given as a combined intravenous infusion every 3 weeks over 30 minutes (±10 minutes).

[0240] placebo For treatment group C (cimiprimab 350 mg + placebo), placebo refers to a prepared infusion solution remaining in the IV bag to replace fumarazumab, making it appear to be the same saline / glucose volume as the fumarazumab + cimiprimab infusion. The placebo (containing cimiprimab 350 mg) was administered via combined intravenous infusion over 30 minutes (±10 minutes).

[0241] Phase 2 The study investigated the optimal phase 3 dose of fambalimumab by combining it with intravenous infusion of cimiprimab every 3 weeks at doses of 400 mg and 1600 mg each, respectively.

[0242] Treatment Group A: Combination of fumizumab (higher dose) and cimiprimab: Patients received a combination of fumizumab 1600 mg (Q3W) and cimiprimab 350 mg (Q3W) via intravenous infusion over 30 minutes on day 1 of each cycle.

[0243] Treatment Group B: Combination of fumizumab (lower dose) and cimiprimab: Patients received a combination of fumizumab 400 mg (Q3W) and cimiprimab 350 mg (Q3W) via intravenous infusion over 30 minutes on day 1 of each cycle.

[0244] Treatment Group C: Cimiprimab monotherapy and placebo: Patients received a combination of cimiprimab 350 mg (Q3W) and placebo (Q3W) via intravenous infusion over 30 minutes on day 1 of each cycle.

[0245] Phase 3 The study investigated the combination of cimiprimab and fumarlimab at selected dose levels versus cimiprimab monotherapy, with overall survival (OS) as the primary endpoint.

[0246] Treatment Group A or B: Combination of fumizumab (selected dose) and cimiprimab: Patients received a combination of selected dose of fumizumab (Q3W) and cimiprimab 350 mg (Q3W) via intravenous infusion over 30 minutes on day 1 of each cycle.

[0247] Treatment Group C: Combination of cimiprimab and placebo: Patients received a combination of cimiprimab 350 mg (Q3W) and placebo (Q3W) via intravenous infusion over 30 minutes on day 1 of each cycle.

[0248] end For Phase 2, the primary endpoint was ORR assessed by BICR using RECIST 1.1 for up to 136 weeks. ORR was defined as the proportion of patients achieving a confirmed complete response (CR) or partial response (PR) of optimal overall response.

[0249] The secondary efficacy endpoint of Phase 2 is: ● ORR obtained using RECIST 1.1 lasted up to 136 weeks.

[0250] ● The disease control rate (DCR = CR + PR + stable disease [SD]) achieved through BICR lasted up to 136 weeks.

[0251] ● The TTR obtained through BICR is up to 136 weeks. TTR is defined as the time from randomization to the first response (based on the first recorded) in a patient with confirmed CR or PR.

[0252] ● DOR obtained through BICR is up to 5 years. DOR is defined as the time from the first response in CR or PR to the first radiographic progression or death from any cause in patients who have confirmed CR or PR.

[0253] ● PFS obtained through BICR, up to 5 years. PFS is defined as the time from random assignment to the date of first radiographic progression or death from any cause (whichever occurs earlier).

[0254] ● OS, up to 5 years, is defined as the period from random assignment to the date of death from any cause.

[0255] The secondary safety endpoint for Phase 2 was: ● Incidence of treatment-related adverse events (TEAEs), treatment-related TEAEs, serious adverse events (SAEs), adverse events of particular concern (AESIs), and immune-mediated adverse events (imAEs).

[0256] ● Events that interrupt or discontinue investigational drugs due to adverse events (TEAE, AESI, and imAE).

[0257] ● Mortality rate caused by TEAE.

[0258] ● Incidence of Level 3-4 laboratory abnormalities.

[0259] Phase 2 endpoints included assessing serum concentrations of cimiprimab and fumarazumab, as well as immunogenicity, as measured by anti-drug antibodies (ADA) and neutralizing antibodies against fumarazumab and cimiprimab (Nab).

[0260] Phase 2 patient-reported outcomes (PROs) include: ● Patient-reported overall health status (GHS) / quality of life (QoL) and physical function based on EORTC QLQC30, and changes in chest pain, dyspnea, and cough relative to baseline based on EORTC QLQLC13.

[0261] ● The time to the final deterioration of patient-reported GHS / QoL and physical function according to EORTC QLQ-C30, and chest pain, dyspnea, and cough, as well as the combination of these three symptoms, according to EORTC QLQ-LC13.

[0262] ● Changes in general health status relative to baseline as reported by patients using the EQ-5D-5L Visual Analogue Scale (VAS).

[0263] ● Based on the severity reported by patients in PRO-CTCAE and the change in the impact of fatigue on routine or daily activities relative to baseline.

[0264] For phase 3, the primary endpoint is OS, defined as the time from randomization to the date of all-cause mortality.

[0265] The secondary efficacy endpoints for Phase 3 were ORR, DCR, TTR, DOR, and PFS, obtained using RECIST 1.1 via BICR, lasting up to 136 weeks.

[0266] The secondary safety endpoint for Phase 3 is: ● Incidence of TEAE, treatment-related TEAE, SAE, AESI, and imAE.

[0267] ● Events that interrupt or discontinue investigational drugs due to adverse events (TEAE, AESI, and imAE).

[0268] ● Mortality rate caused by TEAE.

[0269] ● Incidence of Level 3-4 laboratory abnormalities.

[0270] Phase 3 endpoints included assessing serum concentrations of cimiprimab and fumarazumab, as well as immunogenicity, as measured by ADA and anti-fumarazumab and cimiprimab Nab.

[0271] Phase 3 patient-reported outcomes include: ● Patient-reported GHS / QoL and physical function based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC-QLQ-C30), and changes in chest pain, dyspnea, and cough relative to baseline based on the EORTC QLQ-LC13.

[0272] ● The time to the final deterioration of patient-reported GHS / QoL and physical function according to EORTC QLQ-C30, and chest pain, dyspnea, and cough, as well as the combination of these three symptoms, according to EORTC QLQ-LC13.

[0273] ● Changes in general health status relative to baseline as reported by patients with EQ-5D-5L VAS.

[0274] ● Based on the severity reported by patients in PRO-CTCAE and the change in the impact of fatigue on routine or daily activities relative to baseline.

[0275] Procedures and assessments Efficacy endpoints include antitumor activity assessed by diagnostic CT or MRI.

[0276] The safety and tolerability of the combination of fenpromazine and cimiprimazine were monitored through clinical evaluation of TEAE / imAE, SAE, and AESI, as well as through repeated measurements and clinical evaluation of vital signs (temperature, blood pressure, pulse, and respiration), physical examination, 12-lead electrocardiogram (ECG), and laboratory assessments, including standard hematological, chemical, urinalysis, and other laboratory tests (including serum cortisol and thyroid-stimulating hormone [TSH]).

[0277] Blood samples were collected from all patients to measure the levels of functional fuanlimumab and functional cimiprimab in serum, and to measure immunogenicity (the presence of ADA and Nab against fuanlimumab and cimiprimab in serum).

[0278] Exploratory pharmacodynamics and / or predictive and prognostic biomarkers associated with exposure to fumarlimab and cimiprimab treatments; clinical activity; and / or underlying disease can be investigated. Serum, plasma, peripheral blood mononuclear cells (PBMCs), genomic DNA (gDNA), soluble LAG-3, and tumor tissue can be collected.

[0279] result In patients with advanced NSCLC whose tumors express PD-L1 in ≥50% of tumor cells, the combination of fumarazumab (REGN3767, anti-LAG-3) and cimiprimab (Q3W) is expected to improve ORR and OS compared to cimiprimab plus placebo.

[0280] Example 2: A phase 2 / 3 randomized, double-blind study comparing cimiprimab (anti-LAG-3 antibody), cimiprimab (anti-PD-1 antibody), and chemotherapy as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) (regardless of PD-L1 expression level). This phase 2 / 3 study is a randomized, double-blind trial comparing cimiprimab (anti-LAG-3 antibody), cimiprimab (anti-PD-1 antibody), and chemotherapy as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) (regardless of PD-L1 expression levels).

[0281] Purpose The primary objective of this phase 2 study was to evaluate, using a blinded independent central review (BICR), the objective response rate (ORR) of 1600 mg and 400 mg fombrolizumab plus cimiprimab plus chemotherapy versus cimiprimab plus chemotherapy as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) (regardless of PD-L1 expression level). Chemotherapy typically consists of four cycles of platinum-based doublet chemotherapy.

[0282] The secondary objectives of Phase 2 include the following: ● Evaluate the safety and tolerability of fumarazumab + cimiprimab + chemotherapy compared to cimiprimab + chemotherapy.

[0283] ● Evaluate the other antitumor activities of fumarazumab plus cimiprimab plus chemotherapy compared to cimiprimab plus chemotherapy using ORR, disease control rate (DCR), time to tumor response (TTR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS) obtained by BICR.

[0284] ● Evaluate patient-reported outcomes of fumblymab + cimiprimab + chemotherapy versus cimiprimab + chemotherapy (via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core Version 30 [EORTC QLQ-C30], Lung Cancer 13 [EORTC QLQ-LC13] and EQ-5D 5L scale [EQ-5D-5L]).

[0285] ● To compare cimiprimab plus cimiprimab plus chemotherapy with cimiprimab plus chemotherapy, assess patient-reported fatigue status as measured by fatigue severity and interference with routine or daily activities in the Patient-Reported Outcomes Common Terminology Standard (PRO-CTCAE).

[0286] ● Characterize the pharmacokinetics (PK) of fumarazumab and cimiprimab.

[0287] ● Evaluate the immunogenicity of fumarazumab and cimiprimab.

[0288] The primary objective of this phase 3 study was to compare overall survival (OS) between fumarazumab plus cimiprimab plus chemotherapy and cimiprimab plus chemotherapy.

[0289] The secondary objectives of Phase 3 include the following: ● Evaluate the safety and tolerability of fumarazumab + cimiprimab + chemotherapy compared to cimiprimab + chemotherapy.

[0290] ● Evaluate the additional antitumor activities of fumarazumab + cimiprimab + chemotherapy and cimiprimab + chemotherapy as measured by BICR through ORR, DCR, TTR, DOR, and PFS, as well as by BICR.

[0291] ● Evaluate patient-reported outcomes (via EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L) of fumaritumab plus cimiprimab plus chemotherapy versus cimiprimab plus chemotherapy.

[0292] ● To evaluate patient-reported fatigue status and interference items in PRO-CTCAE as measured by fatigue severity, comparing fumarlimab + cimiprimab + chemotherapy with cimiprimab + chemotherapy.

[0293] ● Characterize the pharmacokinetic (PK) performance of franbizumab and cimiprimab.

[0294] ● Evaluate the immunogenicity of fumarazumab and cimiprimab.

[0295] Research Design This is a randomized, double-blind, multicenter phase 2 / 3 study comparing two different doses of fombimab versus cimiprimab plus chemotherapy with cimiprimab plus chemotherapy in patients with stage IIIB, IIIC, or IV treatment-naïve squamous or non-squamous NSCLC. These patients had tumor cells regardless of PD-L1 levels, lacked mutations that could be targeted by approved therapies, and were ineligible for radical chemoradiotherapy. Patients were stratified according to histology (squamous / non-squamous) and PD-L1 levels (<1% vs. 1%–49% vs. ≥50% to <75% vs. ≥75%†). In Phase 2, both researchers and patients were blinded regarding the treatment plan. The organizers maintained unblinding in Phase 2.

[0296] Phase 3 is blinded for investigators, patients, and the sponsor. The blinding rules for Phase 3 are clarified in subsequent protocol revisions before the start of the Phase 3 portion of the study.

[0297] During phase 2, fambalimumab was studied in combination with cimiprimab plus chemotherapy at doses of 400 mg and 1600 mg to determine the optimal phase 3 dose of fambalimumab. The safety and antitumor activity of these combinations of fambalimumab and cimiprimab plus chemotherapy were evaluated to select the optimal dose of fambalimumab for use in phase 3 NSCLC.

[0298] Phase 2: Patients were randomly assigned in a 1:1:1 double-blind ratio to receive one of three treatment options: ● Group A: Furamimab (1600mg) + Cimiprimab (350mg) + platinum-based double chemotherapy, administered intravenously (IV) every 3 weeks (Q3W). ● Group B: Furamimab (400mg) + Cimiprimab (350mg) + Platinum-based double chemotherapy Q3W IV ● Group C: Cimiprilmab (350mg) + platinum-based double chemotherapy + saline / glucose placebo (placebo) Q3WIV During Phase 3, fumarazab was studied in combination with cimiprimab plus chemotherapy at selected dose levels, with overall survival (OS) as the primary endpoint.

[0299] ● Phase 3: Patients are randomly assigned in a 1:1 double-blind ratio to receive one of two treatment options: ● Group A or Group B: Furamimab (selected dose) + Cimiprimab (350mg) + Platinum-based double chemotherapy Q3WIV ● Group C: Cimiprilmab (350mg) + platinum-based double chemotherapy + placebo Q3W IV Patients continued treatment for up to 108 weeks, or until they experienced an intolerable adverse event (AE), disease progression, death, or the patient and / or physician decided to discontinue study treatment. All patients had a post-treatment follow-up period. After the last follow-up visit, patients were contacted by telephone every 3 months to investigate their survival.

[0300] Approximately 150 patients with stage 2 disease and approximately 800 patients with stage 3 disease were enrolled in this study. The patients in the stage 2 and stage 3 portions of the study were separate and had no overlap.

[0301] Adult patients aged ≥18 years (or the legal age of consent to participate in a clinical study according to national regulations) with advanced, treatment-naïve NSCLC, whose tumors were confirmed by immunohistochemical (IHC) evaluation to have any PD-L1 and LAG-3 expression levels. Given the higher incidence of lung cancer in patients of African descent, the focus is on patients of African descent.

[0302] After evaluating the Phase 2 data and before the start of the Phase 3 portion of the study, a revised protocol will be released to address any Phase 3-specific eligibility criteria issues.

[0303] Inclusion criteria Patients must meet the following criteria to be eligible for inclusion in this study: 1. (i) Men and women aged 18 years or older (or the legal age of consent to participate in clinical studies according to specific national regulations).

[0304] 2. Patients with stage IIIB or IIIC non-squamous or squamous histological NSCLC who are not candidates for surgical resection or radical chemoradiotherapy or are in stage IV (metastatic disease) and have not received prior systemic therapy for recurrent or metastatic NSCLC.

[0305] 3. Formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples obtained from archives or studies are available, with no interventional therapy between biopsy collection and screening.

[0306] Biopsy Site Guidelines: ● Archived or fresh biopsy is acceptable.

[0307] ● FFPE tissue blocks must be ≤6 months old; however, unstained slides (archived or recent) of tumor samples must be ≤2 weeks after preparation. For patients with local EGFR, ALK, and ROS1 results available, at least 10 slides or equivalent block volumes are required. For patients without local EGFR, ALK, or ROS1 results available, at least 19 slides or equivalent block volumes are required.

[0308] ● Biopsies should be taken from previously un-irradiated metastatic or recurrent sites. Bone biopsies are permissible if decalcification is not observed. Exceptions: Primary lung tumor may be used if the primary lung tumor remains in situ and other metastatic sites are inaccessible (brain), or if a biopsy would put the patient at risk.

[0309] 4. For enrollment in the Phase 2 portion of this study, patients should have PD-L1 expression results (regardless of expression level) determined by a laboratory accredited by the College of American Pathologists (CAP) / Clinical Laboratory Improvement Amendments (CLIA) (or equivalent under local regulations). If PD-L1 IHC results are unavailable prior to the patient providing informed consent, PD-L1 IHC results should be obtained during screening using the VENTANA PD-L1 (SP263) assay at a central laboratory designated by the sponsor. For enrollment in the Phase 3 portion of this study, patients should have valid PD-L1 results (regardless of expression level) obtained using the VENTANA PD-L1 (SP263) assay performed at a central laboratory.

[0310] 5. According to RECIST 1.1 criteria, there is at least one radiographically measurable lesion on CT or MRI. If there is documented disease progression (radiographically) at that site, the target lesion may be located in a previously irradiated area.

[0311] 6. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.

[0312] 7. Appropriate organ and bone marrow function as defined below: ● Hemoglobin ≥ 9.0 g / dL ● Absolute neutrophil count (ANC) ≥ 1.5 × 10⁻⁶ 9 / L ● Platelet count ≥100,000 / mm3 ● Glomerular filtration rate (GFR) > 45 mL / min / 1.73 m 2 ● Total bilirubin ≤1.5 × upper limit of normal (ULN) (except for patients diagnosed with clinically confirmed Gilbert's syndrome if liver metastasis is ≤3 × ULN). ● If liver metastasis occurs, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels should be ≤3×ULN or ≤5×ULN. ● Alkaline phosphatase (ALP) ≤ 2.5 × ULN (or ≤ 5.0 × ULN if liver or bone metastases) ● Does not meet the criteria of Hay's Law (ALT > 3 × ULN and bilirubin > 2 × ULN).

[0313] 8. Willing and able to cooperate in completing outpatient visits and research-related procedures.

[0314] 9. Provide a signed informed consent form.

[0315] 10. Able to understand and complete research-related questionnaires.

[0316] Exclusion criteria Patients meeting any of the following criteria were excluded from the study: 1. Active or untreated brain metastases or spinal cord compression. Patients are eligible if their central nervous system (CNS) metastases are adequately treated and they have neurologically returned to baseline (excluding residual signs or symptoms related to CNS treatment) for at least 2 weeks prior to enrollment. Patients must discontinue (immunosuppressive doses) corticosteroid therapy (see Exclusion Criterion #7 for details on steroid discontinuation time).

[0317] 2. Patients with tumors that can target EGFR gene mutations, ALK gene translocations, or ROS1 fusions. For enrollment in the Phase 2 portion of the study, the genetic alteration status, as determined by a CAP / CLIA-accredited laboratory (or equivalently authorized under local regulations), should be available prior to screening. If the genetic alteration status is not available prior to the patient providing informed consent, the genetic alteration status result should be obtained during screening at a central laboratory designated by the sponsor.

[0318] 3. The patient had encephalitis, meningitis, or uncontrolled seizures within one year prior to enrollment.

[0319] 4. A history of the following conditions is acceptable: interstitial lung disease (e.g., idiopathic pulmonary fibrosis or organizing pneumonia), active non-infectious pneumonia requiring immunosuppressive doses of glucocorticoids, or pneumonia within the past 5 years. A history of radiation-induced pneumonia is permissible as long as the pneumonia resolved ≥6 months prior to enrollment.

[0320] 5. Known primary immunodeficiency, cellular immunodeficiency (e.g., DiGeorge syndrome, severe combined T-cell immunodeficiency [SCID]) or combined T-cell and B-cell immunodeficiency (e.g., T-cell and B-cell negative SCID, Wiscot-Aldrich syndrome, ataxia-telangiectasia, common variant immunodeficiency).

[0321] 6. Persistent or recent (within 2 years) evidence of significant autoimmune disease requiring systemic immunosuppressive therapy may indicate a risk of immune-mediated treatment-induced adverse events (imTEAEs). Exclude patients with uncontrolled type 1 diabetes or uncontrolled adrenal insufficiency. The following conditions are not excluded: vitiligo, regressed childhood asthma, residual hypothyroidism requiring only hormone replacement therapy, or psoriasis not requiring systemic treatment.

[0322] 7. Patients requiring corticosteroid treatment (>10 mg prednisone / day or equivalent) within 14 days will be randomly assigned. Physiological replacement doses are permissible, even if they are >10 mg prednisone / day or equivalent, provided they are not administered for immunosuppressive purposes. Patients with clinically relevant systemic immunosuppression within the last 3 months prior to trial enrollment will be excluded. Inhaled or topical steroids are permitted if they are not used to treat autoimmune disorders.

[0323] 8. Another malignant tumor is progressing or requires treatment, except for non-melanoma skin cancer, cervical cancer in situ, or any other locally treated tumor that has received potentially curative treatment, and the patient is considered to have been in complete remission for at least 2 years prior to enrollment and does not require additional therapy during the study period.

[0324] 9. Known active hepatitis B (known positive result) or known hepatitis C (known positive result) and known quantitative hepatitis C virus (HCV) RNA result above the detection limit. Uncontrolled human immunodeficiency virus (HIV) infection, hepatitis B virus (HBV) or HCV infection; or a diagnosis of immunodeficiency (FDA).

[0325] Exceptions: ● HIV patients whose infection is under control (undetectable viral load and CD4 count above 350, whether spontaneous or generated while receiving a stable antiretroviral regimen) are allowed to be included.

[0326] ● Patients with HBV (hepatitis B surface antigen positive) whose infection is under control (serum hepatitis B virus DNA polymerase chain reaction [PCR] below the detection limit and who are receiving hepatitis B antiviral therapy) are allowed to be included.

[0327] ● Patients with hepatitis C virus antibody-positive (HCV Ab+) whose infection is under control (either spontaneously or as a response to previously successful anti-HCV therapy, with undetectable HCV RNA by PCR) are allowed to be included.

[0328] 10. Documented or suspected persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients with documented or suspected SARS-CoV-2 who are being screened can be enrolled if they have recovered from COVID-19 (i.e., all COVID-19-related symptoms and major clinical findings that could potentially affect patient safety have subsided). ● It is recommended to perform two repeated COVID-19 PCR tests, or equivalent tests as recommended by the region, to confirm that the patient is negative for SARS-CoV-2.

[0329] ● If a COVID-19 PCR test is not feasible, it is recommended to wait at least 3 months from the initial diagnosis.

[0330] 11. Randomize active infections requiring systemic treatment within the preceding 14 days.

[0331] 12. Patients who have previously received systemic therapy are excluded, except for the following: ● If relapse or metastatic disease develops more than 6 months after completion of treatment, adjuvant or neoadjuvant platinum-based double chemotherapy (after surgery and / or radiotherapy) can be administered, provided that the toxicity has subsided to a CTCAE grade ≤1 or baseline, except for alopecia and peripheral neuropathy.

[0332] ● Anti-PD-(L)1, with or without LAG-3, can be used as adjuvant or neoadjuvant therapy, provided that the last dose was >12 months prior to enrollment.

[0333] ● Previous exposure to other immunomodulatory or vaccine therapies as adjuvant or neoadjuvant therapy, such as anti-CTLA-4 antibody, provided that the last dose was >6 months prior to enrollment.

[0334] Note: At enrollment, immune-mediated adverse events (AEs) must have regressed to a CTCAE grade ≤1 or baseline. Prior control with hormones or other non-immunosuppressive therapies is permitted for endocrine-immune AEs that have not regressed.

[0335] 13. Hypersensitivity to cimiprimab or any of its excipients, or contraindication of cimiprimab according to the approved local label.

[0336] 14. Receive the investigational drug or device within 30 days of enrollment or within 5 half-lives of the investigational drug or the therapy under investigation (whichever is longer).

[0337] 15. Receive the live vaccine within 30 days of the planned start of drug research.

[0338] 16. Major surgery or major traumatic injury within 4 weeks prior to the first dose.

[0339] 17. Mental illness or substance abuse disorder known to interfere with participation in the study and / or the study requirements, including any illicit drugs currently in use.

[0340] 18. Pregnant or breastfeeding women.

[0341] 19. Sexually active men and women of fertility* who do not wish to use highly effective contraception before the first dose / start of the first treatment, during the study period, and for at least 6 months after the last dose. Highly effective contraception includes the stable use of ovulation-suppressing combination (estrogen and progestin) hormonal contraceptives (oral, vaginal, transdermal) or progestin-only hormonal contraceptives (oral, injectable, implantable) initiated for 2 or more menstrual cycles prior to screening; intrauterine devices (IUDs); intrauterine hormone-releasing systems (IUS); bilateral tubal ligation (blockage); partners who have undergone vasectomy; and / or abstinence. .

[0342] ● *Postmenopausal women must have been menopausal for at least 12 months before their fertility potential is considered irreversible. Women who have undergone a confirmed hysterectomy do not require pregnancy testing or contraception.

[0343] ● Sexual abstinence is considered an effective approach only when defined as avoiding heterosexual intercourse throughout the entire period of risk associated with the study of treatment.

[0344] ● Periodic abstinence (calendar, ovulation, post-ovulation methods), withdrawal (coitus interruptus), spermicide-only methods, and lactogenic amenorrhea (LAM) are unacceptable methods of contraception. Female and male condoms should not be used simultaneously.

[0345] ● Sexually active men and their partners must use highly effective contraception methods as described above. Men with a history of vasectomy do not need contraception.

[0346] 20. Patients admitted to an institution by order of judicial or administrative authorities are excluded from the study.

[0347] 21. Members of the research team at the clinical research center and / or their immediate family members, unless prior approval is obtained from the sponsor.

[0348] 22. Active or latent tuberculosis. In high-risk individuals, the latent period should be confirmed by the purified protein derivative (PPD) / QuantiFERON test, in accordance with local guidelines.

[0349] 23. Previous organ transplant history, including stem cell allogeneic transplantation.

[0350] 24. Meets the comparison product contraindications listed in the local label.

[0351] 25. A history or current evidence of major cardiovascular disease within 6 months prior to study enrollment, including myocarditis, congestive heart failure (as defined by New York Heart Association functional classification III and IV), unstable angina, severe uncontrolled arrhythmia, and myocardial infarction.

[0352] 26. Patients with a history of myocarditis.

[0353] 27. At baseline, troponin T (TnT) or troponin I (TnI) >2 × institutional ULN. Patients with repeat TnT or TnI levels ≤1 × ULN within 24 hours are permissible if the levels are >1 to 2 × ULN. If TnT or TnI levels >1 to 2 × ULN within 24 hours, the subject may undergo cardiac evaluation and be considered for treatment. If repeat TnT or TnI levels <2 × ULN within 24 hours, the subject may undergo cardiac evaluation and be considered for treatment.

[0354] Dosage / Route of Administration / Dosage Regimen The study treatment was prepared by an unblinding pharmacist at the study site and administered in a blinded manner in an outpatient setting.

[0355] At each site, a designated unblinding pharmacist or other qualified individual is responsible for preparing the fumarlimab, cimiprimab, and placebo for administration. Detailed preparation and administration instructions are provided to the site in the pharmacy manual.

[0356] Platinum-based double chemotherapy should be obtained locally whenever possible. At each site, designate a pharmacist or other qualified individual to prepare the platinum-based double chemotherapy for administration according to local guidelines.

[0357] The placebo (saline / glucose) was obtained from the field.

[0358] All infusions for adults and adolescents were administered in an outpatient setting as 30-minute (±10-minute) IV infusions every 3 weeks.

[0359] Fumarimab and Cimiprimab (for combination / infusion administration) Fumariumab 1600 mg was administered as a liquid in sterile single-use vials and given as a combined intravenous infusion every 3 weeks over 30 minutes (±10 minutes).

[0360] Fumariumab 400 mg was administered as a liquid in sterile single-use vials and given as a combined intravenous infusion every 3 weeks over 30 minutes (±10 minutes).

[0361] Cimiprimab 350 mg was administered as a liquid in sterile, single-use vials and given as a combined intravenous infusion every 3 weeks over 30 minutes (±10 minutes).

[0362] Chemotherapy Chemotherapy was administered according to local prescribing information and practice guidelines. Prior to randomization, chemotherapy was assigned from one of the regimens shown in Table 1. The recommended administration sequence was a platinum-based doublet chemotherapy followed by a combination infusion of cimiprimab and fumarlimab or placebo.

[0363] Table 1: Platinum-based dual chemotherapy regimens The Phase 2 treatment group is as follows: ● Treatment Group A: Combination of fumarlimab (higher dose) + cimiprimab + chemotherapy Patients received a combination of 1600 mg fenpromazine (Q3W) and 350 mg cimiprimazine (Q3W) intravenously over 30 minutes on day 1 of each cycle, along with platinum-based double chemotherapy (Q3W), for a total of 4 cycles.

[0364] ● Treatment Group B: Combination of fumarazab (lower dose) plus cimiprimab and chemotherapy Patients received a combination of 400 mg fenpromazine (Q3W) and 350 mg cimiprimazine (Q3W) intravenously over 30 minutes on day 1 of each cycle, along with platinum-based double chemotherapy (Q3W), for a total of 4 cycles.

[0365] ● Treatment Group C: Cimiprimab + Chemotherapy + Placebo Patients received a combination of cimiprimab 350 mg administered via intravenous infusion over 30 minutes on day 1 of each cycle (Q3W) and placebo (Q3W) in combination with platinum-based double chemotherapy (Q3W), for a total of 4 cycles.

[0366] The Phase 3 treatment group is as follows: ● Treatment group A or B: Combination of fumarazab + cimiprimab + chemotherapy Patients received a combination of selected doses of fumarazumab (Q3W) and cimiprimab 350 mg (Q3W) in intravenous infusion over 30 minutes on day 1 of each cycle, along with platinum-based double chemotherapy (Q3W), for 4 cycles.

[0367] ● Treatment Group C: Cimiprimab + Chemotherapy + Placebo Patients received a combination of cimiprimab 350 mg administered via intravenous infusion over 30 minutes on day 1 of each cycle (Q3W) and placebo (Q3W) in combination with platinum-based double chemotherapy (Q3W), for a total of 4 cycles.

[0368] placebo For treatment group C (cimiprimab 350 mg + chemotherapy + placebo), placebo refers to the volume of prepared infusion solution left in the intravenous bag to replace fumarazumab and make it appear the same as the fumarazumab + cimiprimab infusion. The placebo (containing cimiprimab 350 mg) was administered as a combined intravenous infusion over 30 minutes (±10 minutes).

[0369] end The primary endpoint for Phase 2 was the overall response rate (ORR) over 136 weeks, as assessed by BICR using RECIST 1.1. ORR was defined as the proportion of patients who achieved a confirmed complete response (CR) or partial response (PR), representing the best overall response.

[0370] Secondary endpoints for Phase 2 include: effect ● ORR obtained using RECIST 1.1 lasted up to 136 weeks.

[0371] ● The DCR (CR+PR+stable condition [SD]) obtained through BICR lasted for up to 136 weeks.

[0372] ● The TTR obtained through BICR is up to 136 weeks. TTR is defined as the time from randomization to the first response (based on the first recorded) in a patient with confirmed CR or PR.

[0373] ● DOR obtained through BICR is up to 5 years. DOR is defined as the time from the first response in CR or PR to the first radiographic progression or death from any cause in patients who have confirmed CR or PR.

[0374] ● PFS obtained through BICR, up to 5 years. PFS is defined as the time from random assignment to the date of first radiographic progression or death from any cause (whichever occurs earlier).

[0375] ● OS is defined as the time from randomization to the date of all-cause mortality.

[0376] Security ● Incidence of treatment-related adverse events (TEAEs), treatment-related TEAEs, serious adverse events (SAEs), adverse events of particular concern (AESIs), and immune-mediated adverse events (imAEs).

[0377] ● Events that interrupt or discontinue investigational drugs due to adverse events (TEAE, AESI, and imAE).

[0378] ● Mortality rate caused by TEAE.

[0379] ● Incidence of Level 3-4 laboratory abnormalities.

[0380] Pharmacokinetics The endpoints included assessing serum concentrations of cimiprimab and fumarlimab.

[0381] Immunogenicity Endpoints included immunogenicity, measured by anti-drug antibody (ADA) and neutralizing antibodies (NAb) against fumarlimab and cimiprimab.

[0382] Patient-reported outcomes (PRO) ● Patient-reported overall health status (GHS) / quality of life (QoL) and physical function according to EORTC QLQC30, and changes in chest pain, dyspnea, and cough relative to baseline according to EORTC QLQ LC13.

[0383] ● The time to the final deterioration of patient-reported GHS / QoL and physical function according to EORTC QLQ-C30, and chest pain, dyspnea, and cough, as well as the combination of these three symptoms, according to EORTC QLQ-LC13.

[0384] ● Changes in general health status relative to baseline as reported by patients using the EQ-5D-5L Visual Analogue Scale (VAS).

[0385] ● Based on the severity reported by patients in PRO-CTCAE and the change in the impact of fatigue on routine or daily activities relative to baseline.

[0386] The primary endpoint in Phase 3 was overall survival (OS), defined as the time from randomization to the date of all-cause death.

[0387] The three secondary endpoints include: effect - ORR, DCR, TTR, DOR, and PFS obtained using RECIST 1.1 via BICR.

[0388] Security ● Incidence of TEAE, treatment-related TEAE, SAE, AESI, and imAE.

[0389] ● Events that interrupt or discontinue investigational drugs due to adverse events (TEAE, AESI, and imAE).

[0390] ● Mortality rate caused by TEAE ● Incidence of Level 3-4 laboratory abnormalities.

[0391] Pharmacokinetics - The concentrations of cimiprimab and fumarlimab in serum.

[0392] Immunogenicity - Immunogenicity, measured by NAb of ADA and anti-furanlimumab and cimiprimumab.

[0393] Patient-reported outcomes ● Patient-reported GHS / QoL and physical function based on EORTC QLQC30, and changes in chest pain, dyspnea, and cough relative to baseline based on EORTC QLQ-LC13.

[0394] ● The time to the final deterioration of patient-reported GHS / QoL and physical function according to EORTC QLQ-C30, and chest pain, dyspnea, and cough, as well as the combination of these three symptoms, according to EORTC QLQ-LC13.

[0395] ● Changes in general health status relative to baseline as reported by patients with EQ-5D-5L VAS.

[0396] ● Based on the severity reported by patients in PRO-CTCAE and the change in the impact of fatigue on routine or daily activities relative to baseline.

[0397] Procedures and assessments Efficacy endpoints included antitumor activity. Antitumor activity was assessed by computed tomography (CT) or magnetic resonance imaging (MRI) in all patients in the study.

[0398] The safety and tolerability of the combination of fenpromazine and cimiprimazine were monitored through clinical evaluation of TEAE / imAE, SAE, and AESI, as well as through repeated measurements and clinical evaluation of vital signs (temperature, blood pressure, pulse, and respiration), physical examination, 12-lead electrocardiogram (ECG), and laboratory assessments, including standard hematological, chemical, urinalysis, and other laboratory tests (including serum cortisol and thyroid-stimulating hormone [TSH]).

[0399] Blood samples were collected from all patients to measure the levels of functional fuanlimumab and functional cimiprimab in serum, and to measure immunogenicity (the presence of ADA and NAb against fuanlimumab and cimiprimab in serum).

[0400] Exploratory pharmacodynamics and / or predictive and prognostic biomarkers, clinical activity, and / or underlying disease associated with exposure to fumarlimab and cimiprilmab treatments can be investigated. Serum, plasma, peripheral blood mononuclear cells (PBMCs), genomic DNA (gDNA), soluble LAG-3, and tumor tissue should be collected. Other exploratory endpoints for phase 2 and phase 3 studies include: ● Tumor burden reduction achieved using RECIST 1.1 via BICR and investigator assessment until week 27. ● Tumor DNA / RNA sequencing and gene expression characterization ● Circulating tumor DNA levels before and after treatment ● Changes in serum biomarkers relative to baseline in each treatment group. Serum biomarkers include, but are not limited to, soluble LAG-3 and PD-L1 as measured by IHC in tumor tissue samples. ● Correlation between the above parameters and other biomarkers and clinical outcomes and treatment groups result In the phase 2 study, fumblymab plus cimiprimab plus chemotherapy was projected to demonstrate clinically meaningful antitumor activity (measured by ORR) compared to cimiprimab plus chemotherapy as first-line treatment in patients with advanced NSCLC (regardless of PD-L1 expression levels). Furthermore, the phase 2 data differentiated between two doses of fumblymab (400 mg and 1600 mg) and guided the selection of the optimal dose in phase 3.

[0401] In the phase 3 study, it is expected that cimiprimab plus cimiprimab plus chemotherapy will improve overall survival (OS) compared to cimiprimab plus chemotherapy in first-line treatment of patients with advanced NSCLC (regardless of PD-L1 expression level).

[0402] Example 3: A phase 2 perioperative study of fumarazumab plus cimiprimab plus chemotherapy versus cimiprimab plus chemotherapy in resectable early-stage NSCLC. This invention studies and evaluates the efficacy and safety of (I) fumarazumab plus cimiprimab plus chemotherapy versus (II) cimiprimab plus chemotherapy as perioperative treatment in patients with resectable stage II-IIIB (N2) NSCLC.

[0403] This phase 2 perioperative study provides in-depth insights into the clinical activity of (I) fombrolizumab plus cimiprimab plus chemotherapy in patients with resectable early-stage NSCLC, and provides a pathway for broader efforts to evaluate combination therapies for lung cancer. This study is exploring several other research questions, including: ● What side effects might occur when taking investigational drugs? ● The concentration of each research drug in the blood at different times ● Will the human body produce antibodies against the research drug (which could reduce the drug's effectiveness or cause side effects)? ● What impact might the administration of investigational drugs have on quality of life? Research Design A randomized, multicenter, double-blind, phase 2 perioperative study (NCT06161441) was conducted in patients with early, resectable stage II to IIIB (N2) squamous or non-squamous, surgically treated, newly diagnosed NSCLC who received neoadjuvant therapy followed by surgery and further adjuvant therapy. The study design is shown in [reference needed]. Figure 3 Eligible patients are treated with any of the four groups (A, B, or C) during the neoadjuvant therapy period for 1, 2, 3, or 4 cycles, followed by radiological restaging. Within 6 weeks of completing neoadjuvant therapy, patients undergo resection to remove any remaining cancer. Tumor status after treatment and resection is assessed using a residual tumor (R) classification: R0, no residual tumor; R1, minimal residual tumor; R2, grossly visible residual tumor. Residual tumor can be found in the primary tumor area, its regional lymph nodes, and / or distant sites. Patients with R0 or R1 tumor status receive adjuvant therapy; patients are assigned to any of the four groups (A, B, or C) for each allocation during neoadjuvant therapy, and may receive multiple cycles of adjuvant therapy.

[0404] All enrolled patients were stratified based on their clinical TNM stage at the time of randomization, according to stage II vs. III, histological characteristics (non-squamous vs. squamous), and PD-L1 expression (<1%, 1%–49%, ≥50%). The study was conducted at approximately 130 sites worldwide.

[0405] treat 180 patients were randomly assigned (1:1:1) to the following groups: New support period (maximum 4 cycles): ● Group A: Placebo + Cimiprimab 350mg IV every 3 weeks (Q3W) + Platinum-based double chemotherapy IV every 3 weeks (Q3W) ● Group B: High-dose fumarimab (1600mg) + cimiprimab 350mg IV Q3W + platinum-based double chemotherapy IV Q3W ● Group C: Low-dose fumarimab (400mg) + cimiprimab 350mg IV Q3W + platinum-based double chemotherapy IV Q3W Chemotherapy agents include pemetrexed (Alimta), paclitaxel (taxol), carboplatin (paraplatin), and cisplatin (platinol).

[0406] Adjuvant therapy (maximum 14 cycles): Following surgery, adjuvant therapy continues according to prior randomization, as shown below: ● Group A: Placebo + Cimiprilmab 350mg IV Q3W ● Group B: High-dose fumarlimab (1600mg) + cimiprimab 350mg IV Q3W ● Group C: Low-dose fumarimab (400mg) + cimiprimab 350mg IV Q3W Patients receive treatment for up to approximately 12 months (12 weeks of neoadjuvant therapy + 42 weeks of adjuvant therapy), or until disease relapse, unacceptable toxicity, patient decision, or investigator decision.

[0407] end The primary endpoint was pathological complete response (pCR) in tumor samples resected after treatment, assessed by blinded independent pathological examination (BIPR). Secondary endpoints included event-free survival (as assessed by the investigator), primary pathological response (MPR) obtained by BIPR, MPR (by local pathological review), tumor response to neoadjuvant therapy obtained by the investigator, safety and tolerability, pharmacokinetics, immunogenicity, incidence of surgery-related perioperative complications (within 90 days after surgery), and patient-reported outcomes.

[0408] Patient qualifications Eligible patients must be ≥18 years old (or the legal age of consent to participate in a clinical study according to national regulations) and newly diagnosed with completely resectable stage II to IIIB (N2) NSCLC.

[0409] Key inclusion criteria 1. ≥18 years of age (or the legal age for adults to participate in clinical research according to specific national regulations) 2. Newly diagnosed, histologically confirmed, completely resectable stage II to IIIB (N2) NSCLC 3. For patients with evidence of mediastinal lymph node enlargement on imaging, mediastinal lymph node sampling is required. 4. The disease status did not show evidence of distant metastasis documented in a comprehensive physical examination and imaging studies conducted within the 4 weeks prior to randomization. 5. Evaluable PD-L1 immunohistochemical (IHC) results 6. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 7. Adequate liver, kidney, and bone marrow function Key Exclusion Criteria 1. Evidence of any locally advanced unresectable or metastatic disease 2. The patient has a tumor with a known targetable epidermal growth factor receptor (EGFR) gene mutation or anaplastic lymphoma kinase (ALK) gene translocation. 3. Evidence of a persistent or recent (within the last 2 years) autoimmune disease requiring systemic treatment. 4. Uncontrolled infection with human immunodeficiency virus (HIV) or hepatitis B or C virus. 5. Systemic immunosuppression Randomized patients will be treated with anticancer therapies, including immunotherapy, chemotherapy, radiation therapy, or biotherapy, within the previous 3 years. Adjuvant hormone therapy during long-term remission of breast cancer or other hormone-sensitive cancers is permitted.

[0410] ● History of myocarditis ● Troponin T or Troponin I > 2 × upper limit of normal value ● A history or current evidence of significant (CTCAE grade ≥2) local or systemic infection requiring systemic antibiotic treatment within 2 weeks prior to the first dose of the investigational drug. result In a phase 2 perioperative study, it is anticipated that fumarazumab plus cimiprimab plus chemotherapy will demonstrate clinically meaningful antitumor activity compared to cimiprimab plus chemotherapy in patients with resectable early-stage (stage II to IIIB [N2]) NSCLC, as measured by pathological complete response (pCR) for up to 24 months and event-free survival (EFS) for up to 3 years in tumor samples resected after treatment.

[0411] This disclosure is not limited in scope to the specific embodiments described herein. In fact, various modifications to this disclosure will be apparent to those skilled in the art from the foregoing description and accompanying drawings, in addition to those described herein. Such modifications are intended to fall within the scope of the appended claims.

[0412] Table 2: Informal Sequence List

Claims

1. A method for treating or inhibiting lung cancer growth, the method comprising administering the following to a subject in need: (a) An antibody or antigen-binding fragment thereof that specifically binds to programmed death protein 1 (PD-1); and (b) Antibodies or antigen-binding fragments thereof that specifically bind to lymphocyte activation gene-3 (LAG-3). The subjects in the study had advanced, untreated lung cancer and, as determined by immunohistochemistry, the lung cancer expressed PD-L1 in ≥50% of cancer cells.

2. The method of claim 1, wherein the lung cancer is unresectable.

3. The method of any one of claims 1 or 2, wherein the lung cancer is locally advanced lung cancer.

4. The method of any one of claims 1 or 2, wherein the lung cancer is metastatic lung cancer.

5. The method of any one of claims 1 to 4, wherein the subject is further selected based on one or more of the following criteria: (i) Must be at least 18 years old; (ii) Having stage IIIB or IIIC non-squamous or squamous histological non-small cell lung cancer (NSCLC) and not a candidate for surgical resection or radical chemoradiotherapy; (iii) Having stage IV non-squamous or squamous histological NSCLC (metastatic disease) and not having received prior systemic therapy for recurrent or metastatic NSCLC; (iv) Having at least one radiographically measurable lesion as determined by computed tomography (CT) or magnetic resonance imaging (MRI) according to RECIST 1.1 criteria; (v) Eastern Cooperative Oncology Group (ECOG) performance status ≤1; and (vi) Proper organ and bone marrow function.

6. The method of any one of claims 1 to 5, wherein a dose of the anti-PD-1 antibody or its antigen-binding fragment comprises 50 mg to 1500 mg.

7. The method of any one of claims 1 to 6, wherein a dose of the anti-PD-1 antibody or its antigen-binding fragment comprises 350 mg.

8. The method of any one of claims 1 to 7, wherein a dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 50 mg to 8000 mg.

9. The method of any one of claims 1 to 8, wherein a dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 400 mg.

10. The method of any one of claims 1 to 8, wherein a dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 1600 mg.

11. The method of any one of claims 1 to 10, wherein the lung cancer expresses PD-L1 in ≥75% of cancer cells, as determined by immunohistochemistry.

12. The method of claim 11, wherein the subject shows ≥1% LAG3 in the cancerous tissue.

13. The method of any one of claims 1 to 12, wherein the anti-LAG-3 antibody or its antigen-binding fragment is administered before, simultaneously with or after the anti-PD-1 antibody or its antigen-binding fragment.

14. The method of any one of claims 1 to 13, wherein the anti-LAG-3 antibody or its antigen-binding fragment is administered on the same day as the anti-PD-1 antibody or its antigen-binding fragment.

15. The method of any one of claims 1 to 13, wherein the anti-LAG-3 antibody or its antigen-binding fragment is administered in combination with the anti-PD-1 antibody or its antigen-binding fragment as a co-infusion.

16. The method of any one of claims 1 to 15, wherein two or more doses of the anti-LAG-3 antibody or its antigen-binding fragment are administered in combination with two or more doses of the anti-PD-1 antibody or its antigen-binding fragment.

17. The method of claim 16, wherein each dose of the anti-PD-1 antibody or its antigen-binding fragment comprises 350 mg.

18. The method of claim 16 or 17, wherein each dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 50 mg to 8000 mg.

19. The method of any one of claims 16 to 18, wherein each dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 1600 mg.

20. The method of any one of claims 16 to 18, wherein each dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 400 mg.

21. The method of claim 16, wherein each dose of the anti-PD-1 antibody or its antigen-binding fragment comprises 200 mg, 250 mg, or 350 mg, and each dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 400 mg, 800 mg, 1000 mg, 1400 mg, or 1600 mg.

22. The method of any one of claims 16 to 21, wherein each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered 0.5 to 12 weeks after the immediately preceding dose.

23. The method of any one of claims 16 to 21, wherein each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered 0.5 to 12 weeks after the immediately preceding dose.

24. The method of any one of claims 16 to 21, wherein each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered once every six weeks.

25. The method of any one of claims 16 to 21, wherein each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered once every six weeks.

26. The method of any one of claims 16 to 21, wherein each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered once every three weeks.

27. The method of any one of claims 16 to 21, wherein each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered once every three weeks.

28. The method of any one of claims 1 to 27, wherein the antibody is administered intravenously, subcutaneously, or intraperitoneally.

29. The method of any one of claims 1 to 28, wherein the treatment produces a therapeutic effect selected from the group consisting of: delayed cancer growth, reduced number of cancer cells, cancer regression, increased survival, partial response, and complete response.

30. The method of claim 29, wherein cancer growth is delayed by at least 10 days compared to an untreated subject.

31. The method of claim 29, wherein the cancer growth is inhibited by at least 50% compared to an untreated subject.

32. The method of claim 29, wherein the cancer growth is inhibited by at least 20% compared to a subject who is given any antibody as a monotherapy.

33. The method of any one of claims 1 to 32, further comprising administering an additional therapeutic agent or therapy to the subject, wherein the additional therapeutic agent or therapy is selected from the group consisting of: radiation, surgery, chemotherapy agents, cancer vaccines, PD-L1 inhibitors, CTLA-4 inhibitors, TIM3 inhibitors, BTLA inhibitors, TIGIT inhibitors, CD47 inhibitors, CD28 agonists, CD38 inhibitors, indoleamine-2,3-dioxygenase (IDO) inhibitors, vascular endothelial growth factor (VEGF) antagonists, and angiopoietin-2. (Ang2) inhibitors, transforming growth factor β (TGFβ) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, antibodies against tumor-specific antigens, BCG vaccine, granulocyte-macrophage colony-stimulating factor, oncolytic viruses, cytotoxins, interleukin-6 receptor (IL-6R) inhibitors, interleukin-4 receptor (IL-4R) inhibitors, IL-10 inhibitors, IL-2, IL-7, IL-21, IL-12, IL-15, antibody-drug conjugates, GITR agonists, 4-1BB agonists, and anti-inflammatory drugs.

34. The method of any one of claims 1 to 33, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (HCDR1, HCDR2, and HCDR3) of the heavy chain variable region (HCVR) and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the light chain variable region (LCVR), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO:

8.

35. The method of claim 34, wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 1, and the LCVR comprises the amino acid sequence of SEQ ID NO:

2.

36. The method of any one of claims 1 to 35, wherein the anti-PD-1 antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

37. The method of any one of claims 1 to 36, wherein the anti-LAG-3 antibody or its antigen-binding fragment comprises a heavy chain CDR (HCDR1, HCDR2, and HCDR3) of HCVR and three light chain CDRs (LCDR1, LCDR2, and LCDR3) of LCVR, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; HCDR3 comprises the amino acid sequence of SEQ ID NO: 15; LCDR1 comprises the amino acid sequence of SEQ ID NO: 16; LCDR2 comprises the amino acid sequence of SEQ ID NO: 17; and LCDR3 comprises the amino acid sequence of SEQ ID NO:

18.

38. The method of claim 37, wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 11, and the LCVR comprises the amino acid sequence of SEQ ID NO:

12.

39. The method of any one of claims 1 to 38, wherein the anti-LAG-3 antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 19 and a light chain containing the amino acid sequence of SEQ ID NO:

20.

40. The method of any one of claims 1 to 39, wherein the inhibition is more effective than the administration of any antibody as a monotherapy.

41. The method of claim 1, wherein the method comprises administering to the subject (a) 350 mg of an anti-PD-1 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2 or an antigen-binding fragment thereof, and (b) 400 mg or 1600 mg of an anti-LAG-3 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 11 / 12 or an antigen-binding fragment thereof.

42. The method of claim 41, wherein the application is performed every 3 weeks.

43. The method of claim 41, wherein the application is performed every 6 weeks.

44. A method for treating or inhibiting lung cancer growth, said method comprising administering the following to a subject in need: (a) An antibody or its antigen-binding fragment that specifically binds to programmed death protein 1 (PD-1); (b) An antibody or its antigen-binding fragment that specifically binds to lymphocyte activation gene-3 (LAG-3); and (c) Platinum-based double chemotherapy; The subjects in question had advanced, untreated lung cancer.

45. The method of claim 44, wherein the lung cancer is unresectable.

46. ​​The method of any one of claims 44 or 45, wherein the lung cancer is locally advanced lung cancer.

47. The method of any one of claims 44 or 45, wherein the lung cancer is metastatic lung cancer.

48. The method of any one of claims 44 to 47, wherein the subject is further selected based on one or more of the following criteria: (i) Must be at least 18 years old; (ii) Having stage IIIB or IIIC non-squamous or squamous histological non-small cell lung cancer (NSCLC) and not a candidate for surgical resection or radical chemoradiotherapy; (iii) Having stage IV non-squamous or squamous histological NSCLC (metastatic disease) and not having received prior systemic therapy for recurrent or metastatic NSCLC; (iv) Having at least one radiographically measurable lesion as determined by computed tomography (CT) or magnetic resonance imaging (MRI) according to RECIST 1.1 criteria; (v) Eastern Cooperative Oncology Group (ECOG) performance status ≤1; and (vi) Proper organ and bone marrow function.

49. A method for treating or inhibiting lung cancer growth, the method comprising: (i) Select subjects with resectable lung cancer; as well as (ii) administering neoadjuvant therapy to the subject, the neoadjuvant therapy comprising: (a) An antibody or its antigen-binding fragment that specifically binds to programmed death protein 1 (PD-1); (b) An antibody or its antigen-binding fragment that specifically binds to lymphocyte activation gene-3 (LAG-3); and (c) Platinum-based dual chemotherapy.

50. The method of claim 49, wherein the lung cancer is a stage II to IIIB (N2) non-squamous or squamous histological non-small cell lung cancer (NSCLC).

51. The method of claim 49 or 50, wherein the subject is further selected based on one or more of the following criteria: (i) Must be at least 18 years old; (ii) There is no evidence of distant migration; (iii) Evaluable PD-L1 IHC results; (iv) Eastern Cooperative Oncology Group (ECOG) performance status ≤1; and (v) Adequate kidney, liver and bone marrow function.

52. The method of any one of claims 44 to 51, wherein a dose of the anti-PD-1 antibody or its antigen-binding fragment comprises 50 mg to 1500 mg.

53. The method of any one of claims 44 to 52, wherein a dose of the anti-PD-1 antibody or its antigen-binding fragment comprises 350 mg.

54. The method of any one of claims 44 to 53, wherein a dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 50 mg to 8000 mg.

55. The method of any one of claims 44 to 54, wherein a dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 400 mg.

56. The method of any one of claims 44 to 55, wherein a dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 1600 mg.

57. The method of any one of claims 44 to 56, wherein the platinum-based dual chemotherapy is selected from the group consisting of paclitaxel, carboplatin, cisplatin, gemcitabine, and pemetrexed.

58. The method of any one of claims 44 to 57, wherein the subject shows ≥1% LAG3 in the cancerous tissue.

59. The method of any one of claims 44 to 58, wherein the subject shows <1%, 1% to 49%, ≥50% to <75%, or ≥75% PD-L1 in the cancerous tissue.

60. The method of any one of claims 44 to 59, wherein the anti-LAG-3 antibody or its antigen-binding fragment is administered on the same day as the anti-PD-1 antibody or its antigen-binding fragment.

61. The method of any one of claims 44 to 59, wherein the anti-LAG-3 antibody or its antigen-binding fragment is administered in combination with the anti-PD-1 antibody or its antigen-binding fragment as a co-infusion.

62. The method of any one of claims 44 to 59, wherein the chemotherapy is administered after the anti-PD-1 antibody or its antigen-binding fragment and / or the anti-LAG-3 antibody or its antigen-binding fragment.

63. The method of any one of claims 44 to 59, wherein the chemotherapy is administered prior to the anti-PD-1 antibody or its antigen-binding fragment and / or the anti-LAG-3 antibody or its antigen-binding fragment.

64. The method of any one of claims 44 to 59, wherein the chemotherapy is administered on the same day as the anti-PD-1 antibody or its antigen-binding fragment and / or the anti-LAG-3 antibody or its antigen-binding fragment.

65. The method of any one of claims 44 to 59, wherein two or more doses of the anti-LAG-3 antibody or its antigen-binding fragment are administered in combination with two or more doses of the anti-PD-1 antibody or its antigen-binding fragment.

66. The method of claim 65, wherein each dose of the anti-PD-1 antibody or its antigen-binding fragment comprises 350 mg.

67. The method of claim 65 or 66, wherein each dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 50 mg to 8000 mg.

68. The method of any one of claims 65 to 67, wherein each dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 1600 mg.

69. The method of any one of claims 65 to 67, wherein each dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 400 mg.

70. The method of claim 65, wherein each dose of the anti-PD-1 antibody or its antigen-binding fragment comprises 200 mg, 250 mg, or 350 mg, and each dose of the anti-LAG-3 antibody or its antigen-binding fragment comprises 400 mg, 800 mg, 1000 mg, 1400 mg, or 1600 mg.

71. The method of any one of claims 65 to 70, wherein each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered 0.5 to 12 weeks after the immediately preceding dose.

72. The method of any one of claims 65 to 70, wherein each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered 0.5 to 12 weeks after the immediately preceding dose.

73. The method of any one of claims 65 to 70, wherein each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered once every six weeks.

74. The method of any one of claims 65 to 70, wherein each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered once every six weeks.

75. The method of any one of claims 65 to 70, wherein each dose of the anti-PD-1 antibody or its antigen-binding fragment is administered once every three weeks.

76. The method of any one of claims 65 to 70, wherein each dose of the anti-LAG-3 antibody or its antigen-binding fragment is administered once every three weeks.

77. The method of any one of claims 44 to 76, wherein the method comprises administering the anti-PD-1 antibody or its antigen-binding fragment to the subject every three weeks for up to 15 weeks.

78. The method of any one of claims 44 to 76, the method comprising administering the anti-PD-1 antibody or its antigen-binding fragment to the subject every three weeks for up to 12 weeks.

79. The method of any one of claims 44 to 78, wherein the method comprises administering the anti-LAG-3 antibody or its antigen-binding fragment every three weeks for up to 15 weeks.

80. The method of any one of claims 44 to 78, wherein the method comprises administering the anti-LAG-3 antibody or its antigen-binding fragment every three weeks for up to 12 weeks.

81. The method of any one of claims 44 to 80, wherein the method comprises administering chemotherapy once every three weeks for up to 15 weeks.

82. The method of any one of claims 44 to 80, wherein the method comprises administering chemotherapy once every three weeks for up to 12 weeks.

83. The method of any one of claims 44 to 82, wherein the cancer is radiologically evaluated after treatment.

84. The method of any one of claims 49 to 83, wherein the subject undergoes surgery to remove the cancer.

85. The method of claim 84, wherein the surgery occurs 1 to 10 weeks after administration of the anti-PD-1 antibody or its antigen-binding fragment, 1 to 10 weeks after administration of the anti-LAG-3 antibody or its antigen-binding fragment, and / or 1 to 10 weeks after administration of the chemotherapy.

86. The method of claim 84, wherein the surgery occurs 1 to 6 weeks after administration of the anti-PD-1 antibody or its antigen-binding fragment, 1 to 6 weeks after administration of the anti-LAG-3 antibody or its antigen-binding fragment, and / or 1 to 6 weeks after administration of the chemotherapy.

87. The method of claim 85 or claim 86, further comprising administering adjuvant therapy comprising the anti-PD-1 antibody or its antigen-binding fragment and / or the anti-LAG-3 antibody or its antigen-binding fragment.

88. The method of any one of claims 84 to 87, wherein the method comprises administering the anti-PD-1 antibody or its antigen-binding fragment and / or the anti-LAG-3 antibody or its antigen-binding fragment every three weeks for up to 45 weeks.

89. The method of any one of claims 44 to 88, wherein the antibody is administered intravenously, subcutaneously, or intraperitoneally.

90. The method of any one of claims 44 to 89, wherein the treatment produces a therapeutic effect selected from the group consisting of: delayed cancer growth, reduced number of cancer cells, cancer regression, increased survival, partial response, and complete response.

91. The method of claim 90, wherein cancer growth is delayed by at least 10 days compared to an untreated subject.

92. The method of claim 90, wherein the cancer growth is inhibited by at least 50% compared to an untreated subject.

93. The method of claim 90, wherein the cancer growth is inhibited by at least 20% compared to a subject who is given any antibody as a monotherapy.

94. The method of any one of claims 49 to 93, wherein the subject experienced improvements in pathological complete response (pCR) obtained by blinded independent pathological review (BIPR) in tumor samples resected after treatment, event-free survival (as assessed by the investigator), major pathological response (MPR) obtained by BIPR, MPR (by local pathological review), tumor response to neoadjuvant therapy obtained by investigator assessment, safety and tolerability, pharmacokinetics, immunogenicity, incidence of surgery-related perioperative complications (within 90 days of surgery), and patient-reported outcomes.

95. The method of any one of claims 44 to 94, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (HCDR1, HCDR2, and HCDR3) of the heavy chain variable region (HCVR) and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the light chain variable region (LCVR), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO:

8.

96. The method of claim 95, wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 1, and the LCVR comprises the amino acid sequence of SEQ ID NO:

2.

97. The method of any one of claims 44 to 96, wherein the anti-PD-1 antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

98. The method of any one of claims 44 to 97, wherein the anti-LAG-3 antibody or its antigen-binding fragment comprises a heavy chain CDR (HCDR1, HCDR2, and HCDR3) of HCVR and three light chain CDRs (LCDR1, LCDR2, and LCDR3) of LCVR, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; HCDR3 comprises the amino acid sequence of SEQ ID NO: 15; LCDR1 comprises the amino acid sequence of SEQ ID NO: 16; LCDR2 comprises the amino acid sequence of SEQ ID NO: 17; and LCDR3 comprises the amino acid sequence of SEQ ID NO:

18.

99. The method of claim 98, wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 11, and the LCVR comprises the amino acid sequence of SEQ ID NO:

12.

100. The method of any one of claims 44 to 99, wherein the anti-LAG-3 antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 19 and a light chain containing the amino acid sequence of SEQ ID NO:

20.

101. The method of any one of claims 44 to 100, wherein the inhibition is more effective than administering any antibody as a monotherapy.

102. The method of claim 44 or claim 49, the method comprising administering to the subject (a) 350 mg of an anti-PD-1 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2 or an antigen-binding fragment thereof, and (b) 400 mg or 1600 mg of an anti-LAG-3 antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 11 / 12 or an antigen-binding fragment thereof.

103. The method of claim 102, wherein the application is performed every 3 weeks.

104. The method of claim 102, wherein the application is performed every 6 weeks.

105. The method of any one of claims 1 to 104, wherein the anti-PD-1 antibody is cimipril.

106. The method of any one of claims 1 to 105, wherein the anti-LAG-3 antibody is fumaramide.

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