Dosing for treatment with Anti-tigit and Anti-PD-l1 antagonist antibodies

Abstract

To provide a method for treating a human patient suffering from lung cancer, e.g., non-small cell lung cancer (NSCLC).SOLUTION: In one or more dosing cycles, the subject is administered anti-TIGIT antagonist antibodies at a fixed dose of about 30mg to about 1200mg every three weeks and anti-PD L1 antagonist antibodies at a fixed dose of about 80mg to about 1600mg every three weeks.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on February 25, 2019, is entitled 50474-183WO4_Sequence_Listing_02.25.19_ST25 and is 24,206 bytes in size.

[0002] The present invention relates to the treatment of cancer (e.g., lung cancer). More specifically, the present invention relates to the treatment of cancer (e.g., lung cancer) patients by the combined administration of an anti-Ig and ITIM domain-containing T cell immunoreceptor (TIGIT) antagonist antibody and an anti-programmed death receptor ligand 1 (PD-L1) antagonist antibody. [Background technology]

[0003] Cancer is characterized by the uncontrolled proliferation of cell subpopulations. It is the leading cause of death in developed countries and the second leading cause of death in developing countries, with over 14 million new cancer cases diagnosed and over 8 million cancer-related deaths occurring each year. As a result, the societal burden of cancer treatment is significant and continues to grow.

[0004] Lung cancer, in particular, remains the leading cause of cancer deaths worldwide, accounting for approximately 13% of all new cancers in 2012. In the United States, an estimated 222,500 new cases of lung cancer and 155,870 lung cancer deaths were reported in 2017. Non-small cell lung cancer (NSCLC) is the predominant subtype, accounting for approximately 85% of all cases. The overall 5-year survival rate for advanced disease is 2% to 4%. Poor prognostic factors for patients with NSCLC include advanced stage disease at initial diagnosis, poor performance status, and a history of unintentional weight loss. More than half of patients with NSCLC are diagnosed with distant recurrence, which contributes to poor survival prospects.

[0005] Although improvements have been made in first-line treatment for patients with advanced NSCLC, resulting in longer survival and reduced disease-related symptoms, nearly all patients still experience disease progression. Cancer immunotherapy, in particular, can prolong disease control. In the second-line metastatic NSCLC setting, PD-L1 / PD-1-blocking antibodies (e.g., atezolizumab, nivolumab, and pembrolizumab) have provided clinically significant benefits to patients with either unselected or PD-L1-selected advanced NSCLC; however, a significant proportion of patients remain unresponsive or progress upon anti-PD-L1 / PD-1 therapy, and the mechanisms of escape from such treatment remain unclear.

[0006] Thus, there is an unmet need in the art for the development of effective immunotherapies and dosing methods for the treatment of cancer (e.g., lung cancer, e.g., NSCLC) that achieve a more favorable benefit-risk profile. Summary of the Invention

[0007] The present invention relates to methods of treating a subject with cancer (e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC) (e.g., stage IV NSCLC)) by administering a combination of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and an anti-PD-L1 antagonist antibody (e.g., atezolizumab).

[0008] In a first aspect, the invention features a method of treating a subject with lung cancer, comprising administering to the subject, for one or more dosing cycles, an anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 1200 mg every three weeks, and an anti-PD-L1 antagonist antibody at a fixed dose of about 80 mg to about 1600 mg every three weeks.

[0009] In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 600 mg every three weeks. In some embodiments, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 600 mg every three weeks.

[0010] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs): an HVR-H1 sequence having the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence having the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence having the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence having the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence having the amino acid sequence of WASTRES (SEQ ID NO: 5); and an HVR-L3 sequence having the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following framework regions (FR) of the light chain variable region: FR-L1 having the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); FR-L2 having the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); FR-L3 having the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and FR-L4 having the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FRs: FR-H1 having the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), where X1 is Q or E; FR-H2 having the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 having the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and FR-H4 having the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In some embodiments, X1 is Q. In some embodiments, X1 is E.

[0011] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) the VH domain of (a) and the VL domain of (b).

[0012] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody comprises a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

[0013] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antagonist antibody is a human antibody (e.g., a monoclonal human antibody).

[0014] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody is a full-length antibody. In some embodiments of the first aspect, the anti-TIGIT antagonist antibody is tiragolumab.

[0015] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody is an antibody fragment that binds to TIGIT selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragment.

[0016] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody is an IgG class antibody. In some embodiments, the IgG class antibody is an IgG1 subclass antibody.

[0017] In some embodiments of the first aspect, the method comprises administering to the subject a fixed dose of about 1200 mg of the anti-PD-L1 antibody every three weeks.

[0018] In some embodiments of the first aspect, the anti-PD-L1 antagonist antibody is atezolizumab (MPDL3280A), YW243.55.S70, MSB0010718C, MDX-1105, or MEDI4736. In some embodiments, the anti-PD-L1 antagonist antibody is atezolizumab.

[0019] In some embodiments of the first aspect, the anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence having the amino acid sequence of GFTFSDSWIH (SEQ ID NO:20); an HVR-H2 sequence having the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:21); an HVR-H3 sequence having the amino acid sequence of RHWPGGFDY (SEQ ID NO:22); an HVR-L1 sequence having the amino acid sequence of RASQDVSTAVA (SEQ ID NO:23); an HVR-L2 sequence having the amino acid sequence of SASFLYS (SEQ ID NO:24); and an HVR-L3 sequence having the amino acid sequence of QQYLYHPAT (SEQ ID NO:25). In some embodiments, the anti-PD-L1 antagonist antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; (b) a light chain variable (VL) domain comprising an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) the VH domain of (a) and the VL domain of (b).

[0020] In some embodiments of the first aspect, the anti-PD-L1 antagonist antibody comprises a VH domain having the amino acid sequence of SEQ ID NO:26 and a VL domain having the amino acid sequence of SEQ ID NO:27.

[0021] In some embodiments of the first aspect, the anti-PD-L1 antagonist antibody is a monoclonal antibody, hi some embodiments, the anti-PD-L1 antagonist antibody is a humanized antibody (e.g., a monoclonal humanized antibody).

[0022] In some embodiments of the first aspect, the anti-PD-L1 antagonist antibody is a full-length antibody.

[0023] In some embodiments of the first aspect, the anti-PD-L1 antagonist antibody is an antibody fragment that binds to PD-L1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragments.

[0024] In some embodiments of the first aspect, the anti-PD-L1 antagonist antibody is an IgG class antibody, hi some embodiments, the IgG class antibody is an IgG1 subclass antibody.

[0025] In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 600 mg every three weeks and an anti-PD-L1 antagonist antibody at a fixed dose of about 1200 mg every three weeks.

[0026] In some embodiments of the first aspect, each of the one or more dosing cycles is 21 days in length.

[0027] In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody on about day 1 of each of one or more dosing cycles.

[0028] In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody before the anti-PD-L1 antagonist antibody. In some embodiments, the method comprises a first observation period after administration of the anti-TIGIT antagonist antibody and a second observation period after administration of the anti-PD-L1 antagonist antibody. In some embodiments, the first observation period and the second observation period are each about 30 minutes to about 60 minutes in length.

[0029] In some embodiments of the first aspect, the method comprises administering to the subject an anti-PD-L1 antagonist antibody before the anti-TIGIT antagonist antibody. In some embodiments, the method comprises a first observation period after administration of the anti-PD-L1 antagonist antibody and a second observation period after administration of the anti-TIGIT antagonist antibody. In some embodiments, the first observation period and the second observation period are each about 30 minutes to about 60 minutes long.

[0030] In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody simultaneously.

[0031] In some embodiments of the first aspect, the method comprises intravenously administering an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody to a subject. In some embodiments, the method comprises administering the anti-TIGIT antagonist antibody to the subject by intravenous infusion over 60±10 minutes. In some embodiments, the method comprises administering the anti-PD-L1 antagonist antibody to the subject by intravenous infusion over 60±15 minutes.

[0032] In some embodiments of the first aspect, the tumor sample taken from the subject has been determined to have a detectable level of PD-L1 expression.

[0033] In some embodiments of the first aspect, the detectable PD-L1 expression level is a detectable PD-L1 protein expression level. In some embodiments, the detectable PD-L1 protein expression level is measured by an immunohistochemistry (IHC) assay. In some embodiments, the IHC assay uses the anti-PD-L1 antibody 22C3, SP142, SP263, or 28-8.

[0034] In some embodiments of the first aspect, the anti-PD-L1 antibody 22C3 is used in an IHC assay. In some embodiments, the tumor sample has been determined to have a tumor positive score (TPS) of 1% or greater. In some embodiments, the TPS is 1% or greater and less than 50%. In some embodiments, the TPS is 50% or greater.

[0035] In some embodiments of the first aspect, the anti-PD-L1 antibody SP142 is used in the IHC assay. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in 1% or more of the tumor cells in the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in 1% or more but less than 5% of the tumor cells in the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in 5% or more but less than 50% of the tumor cells in the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in 50% or more of the tumor cells in the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells that comprise 1% or more but less than 5% of the tumor sample. In some embodiments, the tumor sample is determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise more than 5% but less than 10% of the tumor sample, hi some embodiments, the tumor sample is determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise more than 10% of the tumor sample.

[0036] In some embodiments of the first aspect, the detectable PD-L1 expression level is a detectable PD-L1 nucleic acid expression level. In some embodiments, the detectable PD-L1 nucleic acid expression level is measured by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

[0037] In some embodiments of the first aspect, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the NSCLC is locally advanced unresectable NSCLC. In some embodiments, the NSCLC is stage IIIB NSCLC. In some embodiments, the NSCLC is recurrent or metastatic NSCLC. In some embodiments, the NSCLC is stage IV NSCLC. In some embodiments, the subject has not previously been treated with stage IV NSCLC.

[0038] In some embodiments of the first aspect, the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

[0039] In some embodiments of the first aspect, the subject does not have the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

[0040] In some embodiments of the first aspect, the subject does not have an active Epstein-Barr virus (EBV) infection or a known or suspected chronic active EBV infection. In some embodiments, the subject is negative for EBV IgM or negative for EBV PCR. In some embodiments, the subject is negative for EBV IgM and negative for EBV PCR. In some embodiments, the subject is positive for EBV IgG or positive for Epstein-Barr nuclear antigen (EBNA). In some embodiments, the subject is positive for EBV IgG and positive for EBNA.

[0041] In some embodiments of the first aspect, the subject is EBV IgG negative or EBNA negative, hi some embodiments, the subject is EBV IgG negative and EBNA negative.

[0042] In some embodiments of the first aspect, the treatment results in a clinical response. In some embodiments, the clinical response is an increase in the subject's objective response rate (ORR) compared to a reference ORR. In some embodiments, the reference ORR is the median ORR of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody. In some embodiments, the clinical response is an increase in the subject's progression-free survival (PFS) duration compared to a reference PFS. In some embodiments, the reference PFS duration is the median PFS of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody.

[0043] In a second aspect, the invention features a method of treating a subject with NSCLC, comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks for one or more dosing cycles, wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

[0044] In a third aspect, the invention features a method of treating a subject afflicted with NSCLC, comprising: (a) obtaining a tumor sample from the subject; (b) detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, and determining a TPS therefrom; (c) identifying the subject, based on the TPS determined to be greater than or equal to 1% and less than 50%, as one who is likely to benefit from a treatment comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19; and (d) administering the therapy to the identified subject.

[0045] In a fourth aspect, the invention features a method of treating a subject afflicted with NSCLC, comprising: (a) obtaining a tumor sample from the subject; (b) detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, and determining a TPS therefrom; (c) identifying the subject, based on the TPS determined to be 50% or greater, as one who is likely to benefit from a treatment comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19; and (d) administering the treatment to the identified subject.

[0046] In a fifth aspect, the invention features a method of selecting a therapy for a subject with NSCLC, comprising: (a) determining a TPS from a tumor sample from the subject by an IHC assay using the anti-PD-L1 antibody 22C3; and (b) based on the TPS determined to be greater than or equal to 1% and less than 50%, selecting for the subject a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

[0047] In a sixth aspect, the invention features a method of selecting a therapy for a subject with NSCLC, comprising: (a) determining a TPS from a tumor sample from the subject by an IHC assay using the anti-PD-L1 antibody 22C3; and (b) based on the TPS determined to be 50% or greater, selecting for the subject a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

[0048] In a seventh aspect, the invention features a method of treating a subject with NSCLC, including administering to the subject tiragolumab at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks for one or more dosing cycles.

[0049] In an eighth aspect, the invention features a method of treating a subject afflicted with NSCLC, including: (a) obtaining a tumor sample from the subject; (b) detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using the anti-PD-L1 antibody 22C3, and determining a TPS therefrom; (c) identifying the subject, based on the TPS determined to be greater than or equal to 1% and less than 50%, as one who is likely to benefit from a treatment comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks; and (d) administering the therapy to the identified subject.

[0050] In a ninth aspect, the invention features a method of treating a subject afflicted with NSCLC, including: (a) obtaining a tumor sample from the subject; (b) detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, and determining a TPS therefrom; (c) identifying the subject, based on the TPS determined to be 50% or greater, as one who is likely to benefit from a treatment comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks; and (d) administering the therapy to the identified subject.

[0051] In a tenth aspect, the invention features a method for selecting a therapy for a subject with NSCLC, comprising: (a) determining a TPS from a tumor sample from the subject by an IHC assay using the anti-PD-L1 antibody 22C3; and (b) selecting for the subject a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, based on the TPS determined to be greater than or equal to 1% and less than 50%.

[0052] In an eleventh aspect, the invention features a method of selecting a therapy for a subject with NSCLC, the method including: (a) determining a TPS from a tumor sample from the subject by an IHC assay using the anti-PD-L1 antibody 22C3; and (b) selecting for the subject a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the TPS determined to be 50% or greater.

[0053] In a twelfth aspect, the invention features a method for selecting a therapy for a subject suffering from NSCLC, the method comprising: (a) detecting the mutation status of the epidermal growth factor receptor (EGFR) gene and the anaplastic lymphoma kinase (ALK) gene in a sample from the subject, and detecting the absence of a sensitizing EGFR gene mutation or an ALK gene rearrangement; and (b) selecting a therapy for the subject based on the subject not having a sensitizing EGFR gene mutation or an ALK gene rearrangement, the therapy comprising one or more dosing cycles of administering an anti-TIGIT antagonist antibody at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

[0054] In a thirteenth aspect, the invention features a method for selecting a therapy for a subject suffering from NSCLC, the method including: (a) biopsying a tumor sample from the subject to detect a subtype of NSCLC other than pulmonary lymphoepithelioma-like carcinoma; and (b) based on the subject not having the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC, selecting for the subject a therapy comprising one or more dosing cycles of administering an anti-TIGIT antagonist antibody at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

[0055] In a fourteenth aspect, the invention features a method for selecting a therapy for a subject with NSCLC, the method including: (a) detecting the presence of one or more of Epstein-Barr virus (EBV) IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr virus particles in a sample from the subject; and, based on the subject being either (i) negative for EBV IgG and / or EBNA, or (ii) positive for EBV IgG and / or EBNA and negative for both EBV IgM and Epstein-Barr virus particles, (b) selecting for the subject a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and a VL domain having the amino acid sequence of SEQ ID NO: 19.

[0056] In a fifteenth aspect, the invention features a method for selecting a therapy for a subject suffering from NSCLC, the method including: (a) detecting the mutation status of the epidermal growth factor receptor (EGFR) gene and the anaplastic lymphoma kinase (ALK) gene in a sample from the subject, and detecting the absence of a sensitizing EGFR gene mutation or an ALK gene rearrangement; and (b) selecting for the subject, based on the subject not having a sensitizing EGFR gene mutation or an ALK gene rearrangement, a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks.

[0057] In a sixteenth aspect, the invention features a method for selecting a therapy for a subject with NSCLC, the method including: (a) biopsying a tumor sample from the subject to detect a subtype of NSCLC other than pulmonary lymphoepithelioma-like carcinoma; and (b) based on the subject not having the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC, selecting for the subject a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks.

[0058] In a seventeenth aspect, the invention features a method for selecting a therapy for a subject with NSCLC, the method including: (a) detecting the presence of one or more of Epstein-Barr virus (EBV) IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr virus particles in a sample from the subject; and, based on the subject (i) being negative for EBV IgG and / or EBNA, or (ii) being positive for EBV IgG and / or EBNA and negative for both EBV IgM and Epstein-Barr virus particles, (b) selecting for the subject a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks.

[0059] In some embodiments of any of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, thirteenth, fourteenth, sixteenth, and seventeenth aspects, the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

[0060] In some embodiments of any of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, fourteenth, fifteenth, and seventeenth aspects, the subject does not have a pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

[0061] In some embodiments of any of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fifteenth, and sixteenth aspects, the subject does not have an active EBV infection or a known or suspected chronic active EBV infection. In some embodiments, the subject is negative for EBV IgM or negative for EBV PCR. In some embodiments, the subject is negative for EBV IgM and negative for EBV PCR. In some embodiments, the subject is positive for EBV IgG or positive for EBNA. In some embodiments, the subject is positive for EBV IgG and positive for EBNA.

[0062] In some embodiments of any of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fifteenth, and sixteenth aspects, the subject is EBV IgG negative or EBNA negative. In some embodiments, the subject is EBV IgG negative and EBNA negative.

[0063] In an eighteenth aspect, the invention features an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody for use in a method of treating a subject with lung cancer, the method comprising administering to the subject a fixed dose of about 30 mg to about 1200 mg of the anti-TIGIT antagonist antibody every three weeks, and a fixed dose of about 80 mg to about 1600 mg of the anti-PD-L1 antagonist antibody every three weeks for one or more dosing cycles.

[0064] In some embodiments of the eighteenth aspect, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 30 mg to about 600 mg every three weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks.

[0065] In some embodiments of the 18th aspect, the anti-TIGIT antagonist antibody comprises the following HVRs: an HVR-H1 sequence having the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence having the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence having the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence having the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence having the amino acid sequence of WASTRES (SEQ ID NO: 5); and an HVR-L3 sequence having the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following light chain variable region FRs: FR-L1 having the amino acid sequence DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); FR-L2 having the amino acid sequence WYQQKPGQPPNLLIY (SEQ ID NO: 8); FR-L3 having the amino acid sequence GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and FR-L4 having the amino acid sequence FGPGTKVEIK (SEQ ID NO: 10). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FRs: FR-H1 having the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), where X1 is Q or E; FR-H2 having the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 having the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and FR-H4 having the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In some embodiments, X1 is Q. In some embodiments, X1 is E.

[0066] In some embodiments of the 18th aspect, the anti-TIGIT antagonist antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) the VH domain of (a) and the VL domain of (b).

[0067] In some embodiments of the eighteenth aspect, the anti-TIGIT antagonist antibody comprises a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

[0068] In some embodiments of the eighteenth aspect, the anti-TIGIT antagonist antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antagonist antibody is a human antibody (e.g., a monoclonal human antibody).

[0069] In some embodiments of the eighteenth aspect, the anti-TIGIT antagonist antibody is a full-length antibody. In some embodiments of the eighteenth aspect, the anti-TIGIT antagonist antibody is tiragolumab.

[0070] In some embodiments of the 18th aspect, the anti-TIGIT antagonist antibody is an antibody fragment that binds to TIGIT selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragment.

[0071] In some embodiments of the eighteenth aspect, the anti-TIGIT antagonist antibody is an IgG class antibody. In some embodiments, the IgG class antibody is an IgG1 subclass antibody.

[0072] In some embodiments of the eighteenth aspect, the anti-PD-L1 antagonist antibody is administered to the subject at a fixed dose of about 1200 mg every three weeks.

[0073] In some embodiments of the eighteenth aspect, the anti-PD-L1 antagonist antibody is atezolizumab (MPDL3280A), YW243.55.S70, MSB0010718C, MDX-1105, or MEDI4736. In some embodiments, the anti-PD-L1 antagonist antibody is atezolizumab.

[0074] In some embodiments of the eighteenth aspect, the anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence having the amino acid sequence of GFTFSDSWIH (SEQ ID NO:20); an HVR-H2 sequence having the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:21); an HVR-H3 sequence having the amino acid sequence of RHWPGGFDY (SEQ ID NO:22); an HVR-L1 sequence having the amino acid sequence of RASQDVSTAVA (SEQ ID NO:23); an HVR-L2 sequence having the amino acid sequence of SASFLYS (SEQ ID NO:24); and an HVR-L3 sequence having the amino acid sequence of QQYLYHPAT (SEQ ID NO:25). In some embodiments, the anti-PD-L1 antagonist antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; (b) a light chain variable (VL) domain comprising an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) the VH domain of (a) and the VL domain of (b).

[0075] In some embodiments of the eighteenth aspect, the anti-PD-L1 antagonist antibody comprises a VH domain having the amino acid sequence of SEQ ID NO:26 and a VL domain having the amino acid sequence of SEQ ID NO:27.

[0076] In some embodiments of the eighteenth aspect, the anti-PD-L1 antagonist antibody is a monoclonal antibody. In some embodiments, the anti-PD-L1 antagonist antibody is a humanized antibody (e.g., a monoclonal humanized antibody).

[0077] In some embodiments of the eighteenth aspect, the anti-PD-L1 antagonist antibody is a full-length antibody.

[0078] In some embodiments of the eighteenth aspect, the anti-PD-L1 antagonist antibody is an antibody fragment that binds to PD-L1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragment.

[0079] In some embodiments of the eighteenth aspect, the anti-PD-L1 antagonist antibody is an IgG class antibody. In some embodiments, the IgG class antibody is an IgG1 subclass antibody.

[0080] In some embodiments of the eighteenth aspect, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks, and the anti-PD-L1 antagonist antibody is administered to the subject at a fixed dose of about 1200 mg every three weeks.

[0081] In some embodiments of the eighteenth aspect, each of the one or more dosing cycles is 21 days in length.

[0082] In some embodiments of the eighteenth aspect, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are administered to the subject on about day 1 of each of one or more dosing cycles.

[0083] In some embodiments of the eighteenth aspect, the anti-TIGIT antagonist antibody is administered to the subject before the anti-PD-L1 antagonist antibody. In some embodiments, a first observation period occurs after administration of the anti-TIGIT antagonist antibody, and a second observation period occurs after administration of the anti-PD-L1 antagonist antibody. In some embodiments, the length of the first observation period and the second observation period is each about 30 minutes to about 60 minutes.

[0084] In some embodiments of the eighteenth aspect, the anti-PD-L1 antagonist antibody is administered to the subject before the anti-TIGIT antagonist antibody. In some embodiments, a first observation period occurs after administration of the anti-PD-L1 antagonist antibody, and a second observation period occurs after administration of the anti-TIGIT antagonist antibody. In some embodiments, the length of the first observation period and the second observation period is each about 30 minutes to about 60 minutes.

[0085] In some embodiments of the eighteenth aspect, the anti-TIGIT antagonist antibody is administered to the subject simultaneously with the anti-PD-L1 antagonist antibody.

[0086] In some embodiments of the eighteenth aspect, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are administered intravenously to the subject. In some embodiments, the anti-TIGIT antagonist antibody is administered to the subject by intravenous infusion over a period of 60±10 minutes. In some embodiments, the anti-PD-L1 antagonist antibody is administered to the subject by intravenous infusion over a period of 60±15 minutes.

[0087] In some embodiments of the eighteenth aspect, the tumor sample obtained from the subject has been determined to have a detectable level of PD-L1 expression.

[0088] In some embodiments of the eighteenth aspect, the detectable PD-L1 expression level is a detectable PD-L1 protein expression level. In some embodiments, the detectable PD-L1 protein expression level is measured by an immunohistochemistry (IHC) assay. In some embodiments, the IHC assay uses the anti-PD-L1 antibody 22C3, SP142, SP263, or 28-8.

[0089] In some embodiments of the eighteenth aspect, the anti-PD-L1 antibody 22C3 is used in an IHC assay. In some embodiments, the tumor sample has been determined to have a tumor positive site (TPS) of 1% or greater. In some embodiments, the TPS is 1% or greater and less than 50%. In some embodiments, the TPS is 50% or greater.

[0090] In some embodiments of the eighteenth aspect, the anti-PD-L1 antibody SP142 is used in the IHC assay. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in 1% or more of the tumor cells in the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in 1% or more but less than 5% of the tumor cells in the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in 5% or more but less than 50% of the tumor cells in the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in 50% or more of the tumor cells in the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells that comprise 1% or more but less than 5% of the tumor sample. In some embodiments, the tumor sample is determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise more than 5% but less than 10% of the tumor sample, hi some embodiments, the tumor sample is determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise more than 10% of the tumor sample.

[0091] In some embodiments of the eighteenth aspect, the detectable PD-L1 expression level is a detectable PD-L1 nucleic acid expression level. In some embodiments, the detectable PD-L1 nucleic acid expression level is measured by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

[0092] In some embodiments of the eighteenth aspect, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the NSCLC is locally advanced unresectable NSCLC. In some embodiments, the NSCLC is stage IIIB NSCLC. In some embodiments, the NSCLC is recurrent or metastatic NSCLC. In some embodiments, the NSCLC is stage IV NSCLC. In some embodiments, the subject has not previously been treated with stage IV NSCLC.

[0093] In some embodiments of the eighteenth aspect, the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

[0094] In some embodiments of the seventh aspect, the subject does not have the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

[0095] In some embodiments of the eighteenth aspect, the subject does not have an active EBV infection or a known or suspected chronic active EBV infection. In some embodiments, the subject is negative for EBV IgM or negative for EBV PCR. In some embodiments, the subject is negative for EBV IgM and negative for EBV PCR. In some embodiments, the subject is positive for EBV IgG or positive for EBNA. In some embodiments, the subject is positive for EBV IgG and positive for EBNA.

[0096] In some embodiments of the eighteenth aspect, the subject is EBV IgG negative or EBNA negative, hi some embodiments, the subject is EBV IgG negative and EBNA negative.

[0097] In some embodiments of the eighteenth aspect, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are administered to produce a clinical response. In some embodiments, the clinical response is an increase in the subject's objective response rate (ORR) compared to a reference ORR. In some embodiments, the reference ORR is the median ORR of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody. In some embodiments, the clinical response is an increase in the subject's progression-free survival (PFS) compared to a reference PFS. In some embodiments, the reference PFS is the median PFS of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody.

[0098] In a nineteenth aspect, the invention features an anti-TIGIT antagonist antibody and atezolizumab for use in a method for treating a subject suffering from NSCLC, the method comprising administering to the subject the anti-TIGIT antagonist antibody at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks for one or more dosing cycles, wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

[0099] In a twentieth aspect, the invention features tiragolumab and atezolizumab for use in a method of treating a subject with NSCLC, the method including administering tiragolumab at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks to the subject for one or more dosing cycles.

[0100] In a twenty-first aspect, the invention features the use of an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in the manufacture of a medicament for use in a method of treating a subject suffering from lung cancer, the method comprising administering the medicaments to the subject in one or more dosing cycles, wherein the medicaments are formulated to administer the anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 1200 mg every three weeks, and the anti-PD-L1 antagonist antibody at a fixed dose of about 80 mg to about 1600 mg every three weeks.

[0101] In a twenty-second aspect, the invention features use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject suffering from lung cancer, the method comprising administering to the subject a medicament and an anti-PD-L1 antagonist antibody in one or more dosing cycles, wherein the medicament is formulated for administration at a fixed dose of about 30 mg to about 1200 mg every three weeks, and the anti-PD-L1 antagonist antibody is administered at a fixed dose of about 80 mg to about 1600 mg every three weeks.

[0102] In a twenty-third aspect, the invention features use of an anti-PD-L1 antagonist antibody in the manufacture of a medicament for use in a method of treating a subject with lung cancer, the method comprising administering to the subject a medicament and an anti-TIGIT antagonist antibody in one or more dosing cycles, wherein the medicament is formulated for administration at a fixed dose of about 80 mg to about 1600 mg every three weeks, and the anti-TIGIT antagonist antibody is administered at a fixed dose of about 30 mg to about 1200 mg every three weeks.

[0103] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 30 mg to about 600 mg every three weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks.

[0104] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs): an HVR-H1 sequence having the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence having the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence having the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence having the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence having the amino acid sequence of WASTRES (SEQ ID NO: 5); and an HVR-L3 sequence having the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following framework regions (FR) of the light chain variable region: FR-L1 having the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); FR-L2 having the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); FR-L3 having the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and FR-L4 having the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FRs: FR-H1 having the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), where X1 is Q or E; FR-H2 having the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 having the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and FR-H4 having the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In some embodiments, X1 is Q. In some embodiments, X1 is E.

[0105] In some embodiments of any of the 21st, 22nd, and 23rd aspects, the anti-TIGIT antagonist antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) the VH domain of (a) and the VL domain of (b).

[0106] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-TIGIT antagonist antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antagonist antibody is a human antibody (e.g., a monoclonal human antibody).

[0107] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-TIGIT antagonist antibody is a full-length antibody. In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-TIGIT antagonist antibody is tiragolumab.

[0108] In some embodiments of any of the 21st, 22nd, and 23rd aspects, the anti-TIGIT antagonist antibody is an antibody fragment that binds to TIGIT selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragment.

[0109] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-TIGIT antagonist antibody is an IgG class antibody. In some embodiments, the IgG class antibody is an IgG1 subclass antibody.

[0110] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-PD-L1 antagonist antibody is administered to the subject at a fixed dose of about 1200 mg every three weeks.

[0111] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-PD-L1 antagonist antibody is atezolizumab (MPDL3280A), YW243.55.S70, MSB0010718C, MDX-1105, or MEDI4736. In some embodiments, the anti-PD-L1 antagonist antibody is atezolizumab.

[0112] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence having the amino acid sequence of GFTFSDSWIH (SEQ ID NO:20); an HVR-H2 sequence having the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:21); an HVR-H3 sequence having the amino acid sequence of RHWPGGFDY (SEQ ID NO:22); an HVR-L1 sequence having the amino acid sequence of RASQDVSTAVA (SEQ ID NO:23); an HVR-L2 sequence having the amino acid sequence of SASFLYS (SEQ ID NO:24); and an HVR-L3 sequence having the amino acid sequence of QQYLYHPAT (SEQ ID NO:25). In some embodiments, the anti-PD-L1 antagonist antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) the VH domain of (a) and the VL domain of (b). In some embodiments, the anti-PD-L1 antagonist antibody comprises a VH domain having the amino acid sequence of SEQ ID NO: 26 and a VL domain having the amino acid sequence of SEQ ID NO: 27.

[0113] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-PD-L1 antagonist antibody is a monoclonal antibody. In some embodiments, the anti-PD-L1 antagonist antibody is a humanized antibody (e.g. a monoclonal humanized antibody).

[0114] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-PD-L1 antagonist antibody is a full-length antibody.

[0115] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-PD-L1 antagonist antibody is an antibody fragment that binds to PD-L1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragment.

[0116] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-PD-L1 antagonist antibody is an IgG class antibody. In some embodiments, the IgG class antibody is an IgG1 subclass antibody.

[0117] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks, and the anti-PD-L1 antagonist antibody is administered to the subject at a fixed dose of about 1200 mg every three weeks.

[0118] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the length of each of the one or more dosing cycles is 21 days.

[0119] In some embodiments of the eighteenth aspect, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are administered to the subject on about day 1 of each of one or more dosing cycles.

[0120] In some embodiments of any of the 21st, 22nd, and 23rd aspects, the anti-TIGIT antagonist antibody is administered to the subject before the anti-PD-L1 antagonist antibody. In some embodiments, a first observation period occurs after administration of the anti-TIGIT antagonist antibody, and a second observation period occurs after administration of the anti-PD-L1 antagonist antibody. In some embodiments, the length of the first observation period and the second observation period is each about 30 minutes to about 60 minutes.

[0121] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-PD-L1 antagonist antibody is administered to the subject before the anti-TIGIT antagonist antibody. In some embodiments, a first observation period occurs after administration of the anti-PD-L1 antagonist antibody, and a second observation period occurs after administration of the anti-TIGIT antagonist antibody. In some embodiments, the length of the first observation period and the second observation period is each about 30 minutes to about 60 minutes.

[0122] In some embodiments of the twenty-first aspect, the anti-TIGIT antagonist antibody is administered to the subject simultaneously with the anti-PD-L1 antagonist antibody.

[0123] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are administered intravenously to the subject. In some embodiments, the anti-TIGIT antagonist antibody is administered to the subject by intravenous infusion over a period of 60±10 minutes. In some embodiments, the anti-PD-L1 antagonist antibody is administered to the subject by intravenous infusion over a period of 60±15 minutes.

[0124] In some embodiments of the twenty-first, twenty-second, and twenty-third aspects, the tumor sample obtained from the subject has been determined to have a detectable level of PD-L1 expression.

[0125] In some embodiments of the twenty-first, twenty-second, and twenty-third aspects, the detectable level of PD-L1 expression is a detectable level of PD-L1 protein expression. In some embodiments, the detectable level of PD-L1 protein expression is measured by an immunohistochemistry (IHC) assay. In some embodiments, the IHC assay uses the anti-PD-L1 antibody 22C3, SP142, SP263, or 28-8.

[0126] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-PD-L1 antibody 22C3 is used in the IHC assay. In some embodiments, the tumor sample has been determined to have a tumor positive site (TPS) of 1% or greater. In some embodiments, the TPS is 1% or greater and less than 50%. In some embodiments, the TPS is 50% or greater.

[0127] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-PD-L1 antibody SP142 is used in the IHC assay. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in 1% or more of the tumor cells in the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in 1% or more but less than 5% of the tumor cells in the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in 5% or more but less than 50% of the tumor cells in the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in 50% or more of the tumor cells in the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells that comprise 1% or more of the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells that comprise 1% or more but less than 5% of the tumor sample. In some embodiments, the tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise greater than or equal to 5% but less than 10% of the tumor sample, hi some embodiments, the tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise greater than or equal to 10% of the tumor sample.

[0128] In some embodiments of the twenty-first, twenty-second, and twenty-third aspects, the detectable PD-L1 expression level is a detectable PD-L1 nucleic acid expression level. In some embodiments, the detectable PD-L1 nucleic acid expression level is measured by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

[0129] In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the lung cancer is non-small cell lung cancer (NSCLC).

[0130] In some embodiments of any of the nineteenth, twentieth, twenty-first, twenty-second, and twenty-third aspects, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the NSCLC is locally advanced unresectable NSCLC. In some embodiments, the NSCLC is stage IIIB NSCLC. In some embodiments, the NSCLC is recurrent or metastatic NSCLC. In some embodiments, the NSCLC is stage IV NSCLC. In some embodiments, the subject has not previously been treated for stage IV NSCLC.

[0131] In some embodiments of any of the nineteenth, twentieth, twenty-first, twenty-second, and twenty-third aspects, the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

[0132] In some embodiments of any of the nineteenth, twentieth, twenty-first, twenty-second, and twenty-third aspects, the subject does not have the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

[0133] In some embodiments of any of the nineteenth, twentieth, twenty-first, twenty-second, and twenty-third aspects, the subject does not have an active EBV infection or a known or suspected chronic active EBV infection. In some embodiments, the subject is negative for EBV IgM or negative for EBV PCR. In some embodiments, the subject is negative for EBV IgM and negative for EBV PCR. In some embodiments, the subject is positive for EBV IgG or positive for EBNA. In some embodiments, the subject is positive for EBV IgG and positive for EBNA.

[0134] In some embodiments of any of the nineteenth, twentieth, twenty-first, twenty-second, and twenty-third aspects, the subject is EBV IgG negative or EBNA negative. In some embodiments, the subject is EBV IgG negative and EBNA negative.

[0135] In some embodiments of any of the nineteenth, twentieth, twenty-first, twenty-second, and twenty-third aspects, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are administered to produce a clinical response. In some embodiments, the clinical response is an increase in the subject's objective response rate (ORR) compared to a reference ORR. In some embodiments, the reference ORR is the median ORR of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody. In some embodiments, the clinical response is an increase in the subject's progression-free survival (PFS) compared to a reference PFS. In some embodiments, the reference PFS is the median PFS of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody.

[0136] In a twenty-fourth aspect, the invention features the use of an anti-TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for use in a method of treating a subject suffering from NSCLC, the method comprising administering the medicament to the subject in one or more dosing cycles, wherein the medicament is formulated to administer the anti-TIGIT antagonist antibody at a fixed dose of 600 mg every three weeks and the atezolizumab at a fixed dose of 1200 mg every three weeks, and the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

[0137] In a twenty-fifth aspect, the invention features use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject suffering from NSCLC, the method comprising administering to the subject a medicament and atezolizumab for one or more dosing cycles, wherein the medicament is formulated for administration at a fixed dose of 600 mg every three weeks, and the atezolizumab is administered at a fixed dose of 1200 mg every three weeks, and the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

[0138] In a twenty-sixth aspect, the invention features the use of atezolizumab in the manufacture of a medicament for use in a method of treating a subject with NSCLC, the method comprising administering to the subject a medicament and an anti-TIGIT antagonist antibody in one or more dosing cycles, wherein the medicament is formulated for administration at a fixed dose of 1200 mg every three weeks, and the anti-TIGIT antagonist antibody is administered at a fixed dose of 600 mg every three weeks, and the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

[0139] In a twenty-seventh aspect, the invention features the use of tiragolumab and atezolizumab in the manufacture of a medicament for use in a method of treating a subject with NSCLC, the method including administering the medicament to the subject for one or more dosing cycles, wherein the medicament is formulated to administer tiragolumab at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks.

[0140] In a twenty-eighth aspect, the invention features the use of tiragolumab in the manufacture of a medicament for use in a method of treating a subject with NSCLC, the method including administering the medicament and atezolizumab to the subject for one or more dosing cycles, wherein the medicament is formulated for administration at a fixed dose of 600 mg every three weeks and the atezolizumab is administered at a fixed dose of 1200 mg every three weeks.

[0141] In a twenty-ninth aspect, the invention features the use of atezolizumab in the manufacture of a medicament for use in a method of treating a subject with NSCLC, the method including administering the medicament and tiragolumab to the subject for one or more dosing cycles, wherein the medicament is formulated for administration at a fixed dose of 1200 mg every three weeks and the tiragolumab is administered at a fixed dose of 600 mg every three weeks.

[0142] In some embodiments of any of the twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, and twenty-eighth, and twenty-ninth aspects, the subject does not have the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

[0143] In some embodiments of any of the 24th, 25th, 26th, 27th, 28th, and 29th aspects, the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

[0144] In some embodiments of any of the 24th, 25th, 26th, 27th, 28th, and 29th aspects, the subject does not have an active EBV infection or a known or suspected chronic active EBV infection. In some embodiments, the subject is negative for EBV IgM or negative for EBV PCR. In some embodiments, the subject is negative for EBV IgM and negative for EBV PCR. In some embodiments, the subject is positive for EBV IgG or positive for EBNA. In some embodiments, the subject is positive for EBV IgG and positive for EBNA.

[0145] In some embodiments of any of the 24th, 25th, 26th, 27th, 28th, and 29th aspects, the subject is EBV IgG negative or EBNA negative. In some embodiments, the subject is EBV IgG negative and EBNA negative.

[0146] In a thirtieth aspect, the invention features a kit comprising an anti-TIGIT antagonist antibody, an anti-PD-L1 antagonist antibody, and a package insert containing instructions for administering the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody to a subject suffering from lung cancer according to the method of any one of the embodiments of any of the first, second, third, fourth, seventh, eighth, and ninth aspects.

[0147] I. General techniques The techniques and procedures described or referenced herein are generally well understood by those skilled in the art and may be implemented using conventional methodology, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (F.M.A.usubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook(JECellis,ed.,1998)Academic Press;Animal Cell Culture(RIFreshney),ed.,1987);Introduction to Cell and Tissue Culture(JPMather and PERoberts,1998)Plenum Press;Cell and Tissue Culture:Laboratory Procedures(A.Doyle,JBGriffiths,and DGNewell,eds.,1993-8)J.Wiley and Sons; Handbook of Experimental Immunology (DM Weir and CC Blackwell, eds.);Gene Transfer Vectors for Mammalian Cells(JMMiller and MPCalos,eds.,1987);PCR:The Polymerase Chain Reaction,(Mullis et al.,eds.,1994);Current Protocols in Immunology(JEColigan et al.,eds.,1991);Short Protocols in Molecular Biology(Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press,2000);Using Antibodies:A Laboratory Manual(E.Harlow and D.Lane(Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993), are commonly used, using widely accepted methodologies.

[0148] II. Definition It should be understood that aspects and embodiments of the invention described herein include aspects and embodiments "comprising," "consisting of," and "consisting essentially of." As used herein, the singular forms "a," "an," and "the" include plural referents unless specifically stated otherwise.

[0149] As used herein, the term "about" refers to a normal error range for each value, which is readily understood by those skilled in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments directed to the value or parameter itself. For example, a statement referring to "about X" includes a statement of "X."

[0150] As used herein, the "amount," "level," or "expression level" of a biomarker refers to a detectable level in a biological sample. "Expression" generally refers to the process by which information (e.g., genetic coding information and / or epigenetic information) is converted into structures present and operating in a cell. Thus, as used herein, "expression" can refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and / or polypeptide modification (e.g., post-translational modification of a polypeptide). Fragments of a transcribed polynucleotide, a translated polypeptide, or a polynucleotide and / or polypeptide modification (e.g., post-translational modification of a polypeptide) should also be considered expressed, regardless of whether they are derived from a transcript or a degraded transcript generated by alternative splicing, or from post-translational processing of a polypeptide, for example, by proteolysis. "Expressed genes" also include genes that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and genes that are transcribed into RNA but not translated into a polypeptide (e.g., transcription and ribosomal RNA). The expression level can be measured by methods known to those skilled in the art and also by the methods disclosed herein. The expression level or amount of a biomarker (e.g., PD-L1) can be used to identify / characterize subjects who are afflicted with cancer (e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) and who are likely to respond to or benefit from a particular therapy (e.g., a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody).

[0151] The presence and / or expression level / amount of the various biomarkers described herein in a sample can be analyzed by several methodologies, including immunohistochemistry ("IHC"), Western blot analysis, immunoprecipitation, molecular binding assays, ELISA, ELIFA, fluorescence activated cell sorting ("FACS"), MassARRAY, proteomics, quantitative blood-based assays (e.g., serum ELISA), biochemical enzyme activity assays, in situ hybridization, fluorescence in situ hybridization, and the like. Many of these methodologies are known in the art and understood by those skilled in the art, including, but not limited to, polymerase chain reaction (PCR), including whole genome sequencing, massively parallel DNA sequencing (e.g., next-generation sequencing), NANOSTRING®, quantitative real-time PCR (qRT-PCR), and other amplification-based detection methods such as branched DNA, SISBA, TMA, RNA-Seq, microarray analysis, gene expression profiling, and / or serial analysis of gene expression ("SAGE"), as well as any one of a wide variety of assays that can be performed by protein, gene, and / or tissue array analysis. General protocols for assessing the status of genes and gene products can be found, for example, in Ausubel et al., eds., 1995, Current Protocols in Molecular Biology, Units 2 (Northern Blotting), 4 (Southern Blotting), 15 (Immunoblotting), and 18 (PCR Analysis). Multiplexed immunoassays, such as those available from Rules Based Medicine or Meso Scale Discovery ("MSD"), may also be used.

[0152] As used herein, "TIGIT" or "T-cell immunoreceptor with Ig and ITIM domains" refers to any naturally occurring TIGIT from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. TIGIT is also known in the art as DKFZp667A205, FLJ39873, V-set and immunoglobulin domain-containing protein 9, V-set and transmembrane domain-containing protein 3, VSIG9, VSTM3, and WUCAM. The term encompasses "full-length," unprocessed TIGIT (e.g., full-length human TIGIT having the amino acid sequence of SEQ ID NO: 30) and any form of TIGIT resulting from processing within cells (e.g., unprocessed human TIGIT without a signal sequence having the amino acid sequence of SEQ ID NO: 31). The term also encompasses natural variants of TIGIT, such as splice variants or allelic variants. An exemplary amino acid sequence of human TIGIT can be found, for example, in UniProt Accession No. Q495A1.

[0153] As used herein, the term "PD-L1" or "programmed death-ligand 1" refers to any native PD-L1 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. PD-L1 is also known in the art as the CD274 molecule, CD274 antigen, B7 homolog 1, PDCD1 ligand 1, PDCD1LG1, PDCD1L1, B7H1, PDL1, programmed death-ligand 1, B7-H1, and B7-H. The term also encompasses naturally occurring variants of PD-L1, such as splice variants or allelic variants. The amino acid sequence of an exemplary human PD-L1 can be found in UniProt Accession No. Q9NZQ7 (SEQ ID NO: 32).

[0154] The term "antagonist" is used in the broadest sense and includes any molecule that partially or completely blocks, inhibits, or neutralizes the biological activity of the native polypeptide disclosed herein. Suitable antagonist molecules specifically include antagonist antibodies or antagonist antibody fragments (e.g., antigen-binding fragments), fragments or amino acid sequence variants of native polypeptides, peptides, antisense oligonucleotides, and organic small molecules. A method for identifying a polypeptide antagonist can include contacting the polypeptide with a candidate antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the polypeptide.

[0155] The term "anti-TIGIT antagonist antibody" refers to an antibody or its antigen-binding fragment or variant that can bind to TIGIT with sufficient affinity, thereby substantially or completely inhibiting the biological activity of TIGIT. For example, an anti-TIGIT antagonist antibody can block signal transduction by PVR, PVRL2, and / or PVRL3, restoring functional responses (e.g., proliferation, cytokine production, target cell killing) by T cells from a defective state to antigen stimulation. Those skilled in the art will understand that in some examples, an anti-TIGIT antagonist antibody can antagonize one TIGIT activity without affecting another TIGIT activity. For example, an anti-TIGIT antagonist antibody for use in certain methods or uses described herein is an anti-TIGIT antagonist antibody that antagonizes TIGIT activity in response to one of PVR interaction, PVRL3 interaction, or PVRL2 interaction, for example, while not affecting or only minimally affecting any other TIGIT interactions. In one embodiment, the extent of binding of the anti-TIGIT antagonist antibody to an unrelated non-TIGIT protein is less than about 10% of the antibody binding to TIGIT, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the anti-TIGIT antagonist antibody that binds to TIGIT has an affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., ≦10-8 M or less, e.g., 10 -8 M~10 -13 M, e.g., 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the anti-TIGIT antagonist antibody binds to an epitope on TIGIT that is conserved among TIGITs from different species, or an epitope on TIGIT that allows cross-species reactivity. In one embodiment, the anti-TIGIT antagonist antibody is tiragolumab.

[0156] The term "anti-PD-L1 antagonist antibody" refers to an antibody or antigen-binding fragment or variant thereof that can bind to PD-L1 with sufficient affinity, thereby substantially or completely inhibiting the biological activity of PD-L1 (e.g., eliminating or preventing signaling resulting from the interaction of PD-L1 with one or more of its binding partners, e.g., PD-1, B7-1). For example, an anti-PD-L1 antagonist antibody may reduce negative costimulatory signals through or by cell surface proteins expressed on T lymphocytes that mediate signaling through PD-L1, rendering dysfunctional T cells less dysfunctional (e.g., enhancing the effector response to antigen recognition). In some embodiments, an anti-PD-L1 antagonist antibody is a molecule that inhibits the binding of PD-L1 to its binding partners. In certain aspects, an anti-PD-L1 antagonist antibody inhibits the binding of PD-L1 to PD-1 and / or B7-1. In one embodiment, the extent of binding of the anti-PD-L1 antagonist antibody to an unrelated, non-PD-L1 protein is less than about 10% of the antibody binding to PD-L1, e.g., as measured by a radioimmunoassay (RIA). In certain embodiments, the anti-PD-L1 antagonist antibody that binds to PD-L1 has a binding affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., ≦10 -8 M or less, e.g., 10 -8 M~10 -13 M, e.g., 10 -9 M~10 -13 Dissociation constant (KD ). In certain embodiments, the anti-PD-L1 antagonist antibody binds to an epitope of PD-L1 that is conserved among PD-L1 from different species. In some embodiments, the anti-PD-L1 antagonist antibody is MPDL3280A (atezolizumab), MDX-1105, MEDI4736 (durvalumab), YW243.55.S70, or MSB0010718C (avelumab). In certain aspects, the anti-PD-L1 antagonist antibody is atezolizumab.

[0157] As used herein, "administering" refers to a method of providing a dose of a compound (e.g., an anti-TIGIT antagonist antibody or an anti-PD-L1 antagonist antibody) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising an anti-TIGIT antibody and / or an anti-PD-L1 antibody) to a subject. The compounds and / or compositions utilized in the methods described herein can be administered, for example, intravenously (e.g., by intravenous infusion), subcutaneously, intramuscularly, intradermally, transcutaneously, intra-arterially, intraperitoneally, intralesionally, intracranially, intra-articularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, subconjunctivally, intravesicularly, transmucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, injection, infusion, continuous infusion, local perfusion directly to target cells, by catheter, lavage, cream, or in a lipid composition. Methods of administration can vary depending on various factors (eg, the compound or composition being administered and the severity of the condition, disease, or disorder being treated).

[0158] A "fixed" or "constant" dose of a therapeutic agent (e.g., an anti-TIGIT antagonist antibody or an anti-PD-L1 antagonist antibody) herein refers to a dose administered to a human patient, regardless of the patient's weight or body surface area (BSA). Thus, the fixed or constant dose may be expressed as a mg / kg dose or mg / m dose of the therapeutic agent. 2 It is not provided as a dose, but rather as an absolute amount (eg, mg).

[0159] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural history of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include delaying or slowing the rate of disease progression, ameliorating or alleviating the disease state, and achieving remission or improving prognosis. For example, an individual is successfully "treated" if one or more symptoms associated with cancer are reduced or eliminated, including, but not limited to, reducing the proliferation (or destruction) of cancer cells, alleviating symptoms resulting from the disease, improving the quality of life of individuals suffering from the disease, reducing the dose of other medications required to treat the disease, delaying the progression of the disease, and / or extending the individual's survival.

[0160] As used herein, "in combination" refers to the administration of one therapy in addition to another. Thus, "in combination" refers to the administration of one therapy to an individual before, during, or after the administration of another therapy.

[0161] A "disorder" or "disease" is any condition that would benefit from treatment, including, but not limited to, disorders associated with some degree of abnormal cell proliferation, e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC).

[0162] The term "dysfunction" in reference to immune dysfunction refers to a state of decreased immune responsiveness to antigenic stimulation.

[0163] As used herein, the term "dysfunction" also includes refractoriness or unresponsiveness to antigen recognition, particularly an impaired ability to translate antigen recognition into downstream T cell effector functions, such as proliferation, cytokine production (e.g., gamma interferon), and / or target cell killing.

[0164] The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies. More specific examples of such cancers include lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC), adenocarcinoma of the lung, or squamous cell carcinoma (e.g., epithelial squamous cell carcinoma); esophageal cancer; peritoneal cancer; hepatocellular carcinoma; gastric cancer, including gastrointestinal cancer and gastrointestinal stromal cancer; pancreatic cancer; glioblastoma; cervical cancer; ovarian cancer; liver cancer; bladder cancer (e.g., , urothelial bladder cancer (UBC), muscle-invasive bladder cancer (MIBC), and BCG-refractory non-muscle-invasive bladder cancer (NMIBC); urinary tract cancer; liver cancer; breast cancer (e.g., HER2+ breast cancer and estrogen receptor (ER-) negative, progesterone receptor (PR-) negative, and HER2 (HER2-) negative triple-negative breast cancer (TNBC)); colon cancer; rectal cancer; colorectal cancer; endometrial or uterine cancer; salivary gland cancer; kidney or renal cancer (e.g., renal cell carcinoma (RCC)); prostate cancer; vulvar cancer; thyroid cancer Adenocarcinoma; hepatocellular carcinoma; anal cancer; penile cancer; melanoma, including superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma, and nodular melanoma; multiple myeloma and B-cell lymphoma (including low-grade / follicular non-Hodgkin's lymphoma (NHL)); small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-cleaved cell NHL, bulky mass disease NHL, mantle cell lymphoma, and AIDS-related These include, but are not limited to, lymphoma, and Waldenstrom's macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); hairy cell leukemia; chronic myeloblastic leukemia (CML); post-transplant lymphoproliferative disorder (PTLD); myelodysplastic syndromes (MDS), as well as abnormal blood vessel proliferation associated with phacomatosis, edema (e.g., edema associated with brain tumors), Meigs' syndrome, brain cancer, head and neck cancer, and associated metastases.

[0165] The term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive when referred to herein.

[0166] "Tumor immunity" refers to the process by which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is "treated" when such evasion is attenuated and tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor regression, and tumor clearance.

[0167] As used herein, "metastasis" refers to the spread of cancer from its primary site to other locations within the body. Cancer cells can break away from the primary tumor, infiltrate lymphatic and blood vessels, circulate through the bloodstream, and grow (metastasize) at distant foci within normal tissues elsewhere in the body. Metastasis can be local or distant. It is a sequential process in which tumor cells break away from the primary tumor, travel through the bloodstream, and arrest at a distant site. At the new site, the cells establish a blood supply and can proliferate to form life-threatening cell masses. Both stimulatory and inhibitory molecular pathways within tumor cells regulate this behavior, and interactions between tumor cells and host cells at distant sites are also important.

[0168] The term "anti-cancer therapy" refers to a therapy useful in the treatment of cancer (e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)). Examples of anti-cancer therapeutics include, for example, immunomodulatory agents (e.g., agents that reduce or inhibit one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®)), an anti-TIGIT antagonist antibody, or an anti-PD-L1 antagonist antibody, or Examples of immune co-stimulatory agents include, but are not limited to, agents that increase or activate one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., OX-40 agonists, e.g., OX-40 agonist antibodies), chemotherapeutic agents, growth inhibitory agents, cytotoxic agents, agents used in radiation therapy, anti-angiogenic agents, apoptotic agents, anti-tubulin agents, and other agents for treating cancer. Combinations of these agents are also encompassed by the present invention.

[0169] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cell function and / or causes cell death or destruction. Cytotoxic agents include radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212, and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, such as nucleases; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin (including fragments and / or variants thereof); and various antitumor or anticancer drugs described below.

[0170] "Chemotherapeutic agent" includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer / Sugen), letrozole (FEMARA®, Novartis), mesylatex, and fluconazole. Imatinib (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including topotecan and irinotecan); bryostatin; kallistatin; CC-1065 (including its azozelesin, carzelesin, and bizelesin synthetic analogs);Cryptophycins (especially cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase inhibitors including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatins; aldesleukin, talc duocarmycins (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride hydrochloride), melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γ1I and calicheamicin ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin;and neocarzinostatin chromophore and related chromoproteins (enediyne antibiotic chromophores), aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, antimetabolites such as sorbicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, and 5-fluorouracil (5-FU); Folic acid analogues such as teropterin and trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid replacement solutions such as furoic acid; aseg Laton; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilones; etoglucide; gallium nitrate; hydroxyurea; lentinan; maytansinoids such as lonidynin, maytansine, and ansamitocin; mitoguazone, mitoxantrone, mopidamnol, nitraerin, pentostatin;Fenameth; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.), razoxane; rhizoxin; schizofiran; spirogermanium; tenuazonic acid; triazicone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veraculin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (chromophore-free), an albumin-modified nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (docetaxel; Sanofi-Aventis); chlorambucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; Mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; the topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0171] Chemotherapeutic agents also include (i) antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, idoxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and FARESTON® (toremifene citrate); (ii) anti-estrogen agents that inhibit the action of estrogen in the adrenal glands; aromatase inhibitors, which inhibit the aromatase enzyme that regulates aromatase production, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestane, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nivolumab, and benzodiazepines; (iv) protein kinase inhibitors (e.g., anaplastic lymphoma kinase (Alk) inhibitors such as AF-802 (also known as CH-5424802 or alectinib)); (v) lipid kinase inhibitors; (vi) Antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, such as PKC-α, Ralf, and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, such as ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN®, rIL-2;Topoisomerase 1 inhibitors, such as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0172] Chemotherapeutic agents also include antibodies, such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody-drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, nat ... Talizumab, nimotuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resivizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tuxituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and interleukin-12 and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), an exclusively human sequence recombinant full-length IgG1λ antibody genetically engineered to recognize the p40 protein.

[0173] Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise directly interact with EGFR and block or reduce its signaling activity, and are also called "EGFR antagonists." Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb579 (ATCC CRL HB8506), MAb455 (ATCC CRL HB8507), MAb225 (ATCC CRL 8508), MAb528 (ATCC CRL 8509) (see U.S. Pat. No. 4,943,533, Mendelsohn et al.), as well as variants thereof, such as chimeric 225 (C225 or cetuximab; ERBUTIX®) and reshaped human 225 (H225) (WO 96 / 40210, Imclone Systems, Inc.). Inc.); IMC-11F8, a fully human EGFR-targeting antibody (Imclone); antibodies that bind to type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind to EGFR as described in U.S. Pat. No. 5,891,996; and human antibodies that bind to EGFR, such as ABX-EGF or panitumumab (see WO 98 / 50433, Abgenix / Amgen); EMD55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996); EMD7200 (matuzumab) (EMD / Merck), a humanized EGFR antibody against EGFR that competes with both EGF and TGF-α for EGFR binding; the human EGFR antibody, HuMax-EGFR (GenMab); the fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3 and described in U.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb806 or humanized mAb806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)).Anti-EGFR antibodies may be conjugated to cytotoxic agents to form immunoconjugates (see, e.g., EP 659,439 A2, Merck Patent GmbH). EGFR antagonists include those disclosed in U.S. Patent Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602 ...6,140,332, 6,866,572, 6,399,602, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 6,140,332, 6,866,572, 6,399,602, 6,455,534, 6,455,534, 6,521,620, 6,4 and 5,747,498, and the following PCT publications: WO98 / 14451, WO98 / 50038, WO99 / 09016, and WO99 / 24037.Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech / OSI Pharmaceuticals); PD183805 (CI1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer); Inc.); ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca; ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim; PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine; CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7- ethoxy-6-quinazolinyl]-4-(dimethylamino)-2-butynamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU5271, Pfizer); and dual EGFR / HER2 tyrosine kinase inhibitors, such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

[0174] Chemotherapeutic agents also include "tyrosine kinase inhibitors," e.g., the EGFR-targeted drugs described in the preceding paragraph; inhibitors of insulin receptor tyrosine kinase, including anaplastic lymphoma kinase (Alk) inhibitors such as AF-802 (also known as CH-5424802 or alectinib), ASP3026, X396, LDK378, AP26113, crizotinib (XALKORI®), and ceritinib (ZYKADIA®); small molecule HER2 tyrosine kinase inhibitors, e.g., TAK165 available from Takeda; oral selectivity inhibitors of ErbB2 receptor tyrosine kinase, e.g., HER2 tyrosine kinase inhibitors, e.g., TAK165 available from Takeda; dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but inhibits both HER2 and EGFR overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors, such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors, such as ISIS, which inhibits Raf-1 signaling. antisense drug ISIS-5132 available from GlaxoSmithKline Pharmaceuticals; non-HER-targeted tyrosine kinase inhibitors, such as imatinib mesylate (GLEEVEC®, available from GlaxoSmithKline); multi-targeted tyrosine kinase inhibitors, such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors, such as vatalanib (PTK787 / ZK222584, Novartis / Schering) available from AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, e.g., PD153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, e.g., CGP59326, CGP60261, and CGP62706; pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide);Tyrphostins containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (e.g., antisense molecules that bind to HER-encoding nucleic acids); quinoxalines (U.S. Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); pan-HER inhibitors such as ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); CI-1033 (Pfizer); Affinitac (ISIS3521, Isis / Lilly); imatinib mesylate (GLEEVEC®); PKI166 (Novartis); GW2016 (GlaxoSmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or inhibitors described in any of the following patent publications: U.S. Pat. No. 5,804,396; WO1999 / 09016 (American Cyanamid); WO1998 / 43960 (American Cyanamid); WO1997 / 38983 (Warner Lambert); WO1999 / 06378 (Warner Lambert); WO1999 / 06396 (Warner Lambert); WO1996 / 30347 (Pfizer, Inc); WO1996 / 33978 (Zeneca); WO1996 / 3397 (Zeneca) and WO1996 / 33980 (Zeneca).

[0175] Chemotherapeutic agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, live BCG bacteria, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, These include lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

[0176] Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17 -butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate; phenylalanine-glutamine-glycine (FEG) and its D-isomer (feG) (IMULAN) Immunoselective anti-inflammatory peptides (ImSAIDs) such as BioTherapeutics, LLC; antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, and sulfasalazine; tumor necrosis factor alpha (TNFα) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi); interleukin-1 (IL-1) blockers such as anakinra (Kineret), and abatacept (Orencia). interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as rontalizumab; β7 integrin blockers such as rhuMAb β7; IgE pathway blockers such as anti-M1 prime; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / β2 blockers such as anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212, and radioactive isotopes of Lu);Various investigational drugs such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavins, flavanols, procyanidins, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; δ9-tetrahydrocannabinol (dronabinol, MARINOL®); β-lapachone; lapachol; col camptothecin; betulinic acid; acetylcamptothecin; scopolectin, and 9-aminocamptothecin; podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), bisphosphonates such as tiludronate (SKELID®), or risedronate (ACTONEL®); as well as epidermal growth factor receptor (EGF-R); vaccines such as the THERATOPE® vaccine; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; oblimersen sodium (GENASENSE®), and the like. pixantrone; farnesyltransferase inhibitors such as lonafarnib (SCH6636, SARASAR™); and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above, such as CHOP (an abbreviation for the combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone); and FOLFOX (an abbreviation for the treatment regimen of oxaliplatin (ELOXATIN™) in combination with 5-FU and leucovorin);

[0177] Chemotherapeutic agents also include nonsteroidal anti-inflammatory drugs with sedative, antipyretic, and anti-inflammatory effects.NSAIDs include nonselective inhibitors of the enzyme cyclooxygenase.Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, and diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, and tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, and valdecoxib. NSAIDs may be required for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathy, ankylosing spondylosis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, post-operative pain, mild to moderate pain due to inflammation and tissue injury, fever, intestinal obstruction, and renal colic.

[0178] An "effective amount" of a compound, e.g., an anti-TIGIT antagonist antibody or an anti-PD-L1 antagonist antibody, or a composition (e.g., a pharmaceutical composition) thereof, is the minimum amount required to achieve at least a desired therapeutic outcome, e.g., a measurable increase in overall survival or progression-free survival of a particular disease or disorder (e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)). An effective amount herein may vary depending on factors such as the patient's disease state, age, sex, and weight, as well as the ability of the antibody to elicit a desired response in the subject. An effective amount is also one in which the therapeutically beneficial effects outweigh any toxic or adverse effects of the treatment. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk of disease, reducing the severity of disease, or delaying the onset of disease, including biochemical, histological, and / or behavioral symptoms of disease, its complications, and intermediate pathological phenotypes manifest during the development of disease.For therapeutic use, beneficial or desired results include relief of one or more symptoms attributable to the disease (e.g., reduction or delay of cancer-related pain, symptomatic skeletal-related events (SSEs), and improvement in the health-related quality of life of the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire). QLQ-C30, e.g., fatigue, nausea, vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea, or general level of physical-emotional, cognitive, or social functioning); reduction in pain as measured by, e.g., a 10-point numeric rating scale (NRS) of pain severity (measured at worst), and / or reduction in symptoms related to lung cancer as assessed by the Symptoms in Lung Cancer (SILC) scale (e.g., time to worsening (TTD) of cough, dyspnea, and chest pain); improvement in the quality of life of patients with the disease; reduction in the dose of other drugs required to treat the disease; enhancement of the effect of another drug by targeting, etc.; delay in disease progression (e.g., progression-free survival or radiographic progression-free survival (rPFS)); delay in definite clinical progression (e.g., progression of cancer-related pain, symptomatic skeletal-related events, worsening of Eastern Cooperative Oncology Group (ECOG) performance status (PS) (e.g., the disease is progressing slowly in patients) Clinical outcomes include: a reduction in the number of cancer cells; a reduction in tumor size; an inhibition of (i.e., delaying to some extent or preferably stopping) cancer cell invasion into peripheral organs; an inhibition of (i.e., delaying to some extent or preferably stopping) tumor metastasis; an inhibition of (i.e., delaying to some extent or preferably stopping) tumor growth; and an alleviation to some extent of one or more symptoms associated with the disorder. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment. As understood in the clinical field, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition.Thus, an "effective amount" may be considered in terms of administration of one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if a desired result can be or is achieved when it is combined with one or more other agents.

[0179] "Immunogenicity" refers to the ability of a particular substance to induce an immune response. Tumors are immunogenic, and enhancing tumor immunogenicity aids in the clearance of tumor cells by the immune response. Examples of enhancing tumor immunogenicity include, but are not limited to, treatment with TIGIT and / or PD-L1 antagonists (e.g., anti-TIGIT antagonist antibodies and / or anti-PDL-1 antagonist antibodies).

[0180] An "individual response" or "response" can mean (1) some inhibition of disease progression (e.g., progression of cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)); (2) a reduction in tumor size; (3) inhibition (i.e., reduction, slowing, or complete cessation) of cancer cell invasion into adjacent peripheral organs and / or tissues; (4) inhibition (i.e., reduction, slowing, or complete cessation) of metastasis; (5) a reduction in the progression of a disease or disorder. Harm (e.g., some alleviation of one or more symptoms associated with cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)); (6) an increase or prolongation in length of survival, including overall survival and progression-free survival; and / or (9) a reduction in mortality at a given time point after treatment can be assessed using any endpoint that indicates benefit to the subject, including, but not limited to: (1) a reduction in the incidence of cancer-related adverse events (e.g., a decrease ...

[0181] As used herein, "complete response" or "CR" refers to the disappearance of all target lesions.

[0182] As used herein, "partial response" or "PR" refers to at least a 30% reduction in the sum of the longest diameters (SLD) of target lesions, referenced to the baseline SLD.

[0183] As used herein, "objective response rate" (ORR) refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0184] As used herein, "duration of response" (DOR) is defined as the time from the first occurrence of a documented response to disease progression or death from any cause within 30 days of the last dose of treatment, whichever occurs first.

[0185] "Sustained response" refers to a sustained effect of reducing tumor growth after treatment has ceased. For example, the tumor size may remain the same or become smaller compared to the size at the beginning of the administration period. In some embodiments, the sustained response has a duration at least equal to the treatment period, or at least 1.5, 2.0, 2.5, or 3.0 times the treatment period.

[0186] As used herein, the term "survival" refers to the patient being alive, and includes overall survival and progression-free survival.

[0187] As used herein, "overall survival" (OS) refers to the proportion of subjects in a group who are alive for a particular period of time, e.g., 1 year or 5 years from the time of diagnosis or treatment.

[0188] As used herein, "progression-free survival" (PFS) refers to the period during and after treatment during which the disease being treated (e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) does not worsen. Progression-free survival can include the amount of time a patient experiences a complete or partial response, as well as the amount of time a patient remains unchanged.

[0189] As used herein, "stable" or "SD" refers to neither sufficient shrinkage of the target lesion to qualify as PR nor sufficient increase to qualify as PD, based on the smallest SLD since the start of treatment.

[0190] As used herein, "progressive disease" or "PD" refers to at least a 20% increase in the SLD of a target lesion, referenced to the smallest SLD recorded since the start of treatment, or the presence of one or more new lesions.

[0191] As used herein, "delaying the progression" of a disorder or disease means delaying, hindering, delaying, slowing, stabilizing, and / or postponing the onset of the disease or disorder (e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)). The delay may be of different durations depending on the disease history and / or the individual being treated. As will be apparent to one of skill in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, in terminal cancer, the development of central nervous system (CNS) metastases may be delayed.

[0192] As used herein, the term "reducing or inhibiting cancer recurrence" means reducing or inhibiting the recurrence of a tumor or cancer, or the progression of a tumor or cancer.

[0193] "Reducing or inhibiting" refers to the ability to cause an overall decrease of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or more. Reducing or inhibiting can refer to the symptoms of the disorder being treated (e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the presence or size of metastases, or the size of the primary tumor.

[0194] "Extending survival" means an increase in overall survival or progression-free survival in a treated patient compared to untreated patients (e.g., compared to patients not treated with a pharmaceutical agent), or compared to patients who do not express a biomarker at a specified level, and / or compared to patients treated with an approved anti-tumor agent. Response refers to a measurable response, including complete response (CR) or partial response (PR).

[0195] The terms "detecting" and "detection" are used herein in the broadest sense and include both qualitative and quantitative measurements of a target molecule. Detection includes determining whether a target molecule is present in a sample at detectable levels, not just identifying the presence of the target molecule in a sample. Detection can be direct or indirect.

[0196] As used herein, "tumor cell positivity rate" (TPS) refers to the percentage of viable tumor cells that exhibit partial or complete membrane staining (excluding cytoplasmic staining) at any intensity relative to all viable tumor cells present in a sample following staining of the sample in an immunohistochemistry (IHC) assay, e.g., IHC assay staining for PD-L1 using antibody 22C3. Thus, using the PD-L1 IHC 22C3 pharmDx assay (Dako), TPS may be calculated, for example, by the formula: TPS = (number of PD-L1-positive tumor cells) / (total number of PD-L1-positive and PD-L1-negative tumor cells), where PD-L1 cytoplasmic staining of tumor cells and all non-tumor cells (e.g., tumor-infiltrating immune cells, normal cells, necrotic cells, and necrotic debris) is excluded from evaluation and scoring.

[0197] As used herein, "tumor-infiltrating immune cells" refers to any immune cells present in a tumor or a sample thereof. Tumor-infiltrating immune cells include, but are not limited to, intratumoral immune cells, peritumoral immune cells, other tumor stromal cells (e.g., fibroblasts), or any combination thereof. Such tumor-infiltrating immune cells may be, for example, T lymphocytes (e.g., CD8+ T lymphocytes and / or CD4+ T lymphocytes), B lymphocytes, or other myeloid cells, including granulocytes (e.g., neutrophils, eosinophils, and basophils), monocytes, macrophages, dendritic cells (e.g., interdigitating dendritic cells), histiocytes, and natural killer cells.

[0198] As used herein, the term "biomarker" refers to an indicator, e.g., a predictive, diagnostic, and / or prognostic indicator, that can be detected in a sample. A biomarker can serve as an indicator of a particular subtype of a disease or disorder (e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) characterized by specific molecular, pathological, histological, and / or clinical characteristics. In some embodiments, the biomarker is a gene. Biomarkers include, but are not limited to, polypeptide, polynucleotide (e.g., DNA and / or RNA), alterations in polynucleotide copy number (e.g., DNA copy number), polypeptide and polynucleotide modifications (e.g., post-translational modifications), carbohydrate, and / or glycolipid-based molecular markers. In some embodiments, the biomarker is PD-L1.

[0199] The term "antibody" includes monoclonal antibodies (including full-length antibodies having an immunoglobulin Fc region), antibody compositions with polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies, diabodies, and single-chain molecules), and antibody fragments (e.g., Fab, F(ab'), and Fv). The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein.

[0200] The basic four-chain antibody unit is a heterotetrameric glycoprotein consisting of two identical light (L) chains and two identical heavy (H) chains. IgM antibodies consist of five basic heterotetrameric units plus an additional polypeptide called a J chain, which contains 10 antigen-binding sites, while IgA antibodies consist of two to five basic four-chain units, which can polymerize to form multivalent aggregates with the J chain. In the case of IgG, the four-chain unit is generally approximately 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. The H and L chains also each have regularly spaced interchain disulfide bridges. Each H chain contains a variable domain (V) at its N-terminus. H ), followed by three constant domains for each of the α and γ chains (C H ), and four C for μ and ε isotypes H Each L chain has a variable domain (V L ) followed by a constant domain at the opposite end. L is V H is consistent with C L is the first constant domain of the heavy chain (C H 1) Specific amino acid residues are thought to form an interface between the light-chain variable domain and the heavy-chain variable domain. H and V Lpair together to form a single antigen-binding site. For the structure and properties of different classes of antibodies, see, for example, Basic and Clinical Immunology, 8th Edition, Daniel P. Sties, Abba I. Terr and Tristram G. Parsolw (eds), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6. The light chains of any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequence of their constant domains. Depending on the amino acid sequence of the constant domain (CH) of their heavy chains, immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, with heavy chains designated α, δ, ε, γ, and μ, respectively. The gamma and alpha classes are further divided into subclasses based on relatively minor differences in CH sequence and function; for example, humans express the following subclasses: IgG1, IgG2A, IgG2B, IgG3, IgG4, IgA1, and IgA2.

[0201] The term "hypervariable region" or "HVR" refers to the region of an antibody variable domain that is hypervariable in sequence and / or forms structurally defined loops. Antibodies typically contain six HVRs; three in the VH (H1, H2, and H3) and three in the VL (L1, L2, and L3). In natural antibodies, H3 and L3 exhibit the highest diversity of these six HVRs, and H3 in particular is thought to play a unique role in conferring superior specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu, in Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, NJ, 2003). In fact, natural camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993); Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0202] Several HVR delineations are used and encompassed herein. Kabat complementarity-determining regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)), while Chothia refers to the location of structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). AbM HVRs represent a compromise between Kabat HVRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. "Contact" HVRs are based on available complex crystal structures. Residues from each of these HVRs are listed below. Loop Kabat AbM Chothia Contact L1 L24-L34 L24-L34 L26-L32 L30-L36 L2 L50-L56 L50-L56 L50-L52 L46-L55 L3 L89-L97 L89-L97 L91-L96 L89-L96 H1 H31-H35B H26-H35B H26-H32 H30-H35B (Kabat numbering) H1 H31-H35 H26-H35 H26-H32 H30-H35 (Chothia numbering) H2 H50-H65 H50-H58 H53-H55 H47-H58 H3 H95-H102 H95-H102 H96-H101 H93-H101

[0203] HVRs may include "extended HVRs" as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in VL, and 26-35 (H1), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3) in VH. The variable domain residues are numbered according to Kabat et al., supra, for each of these definitions.

[0204] The designation "Kabat-like variable domain residue numbering" or "Kabat-like amino acid position numbering" and variations thereof refer to the numbering system used for the heavy or light chain variable domains of the antibody sequences in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, the FRs or HVRs of the variable domain. For example, a heavy chain variable domain may contain a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat). The Kabat numbering of residues may be determined for a given antibody by alignment of the antibody's sequence with the "standard" Kabat-numbered sequence at the regions of homology.

[0205] The term "variable" refers to the fact that certain segments of the variable domains differ extensively in sequence among antibodies. The V domains mediate antigen binding and define the specificity of a particular antibody for its particular antigen. However, variability is not evenly distributed throughout the variable domains. Rather, it is concentrated in three segments called hypervariable regions (HVRs) in both the light- and heavy-chain variable domains. The more highly conserved portions of the variable domains are called framework regions (FRs). Naturally occurring heavy- and light-chain variable domains each contain four FR regions, which primarily adopt a β-sheet configuration connected by three HVRs, which form loops that connect, and in some cases form part of, the β-sheet structure. The HVRs within each chain are held in close proximity by the FR regions and, together with the HVRs of the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institutes of Health, Bethesda, MD (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participating in antibody-dependent cellular cytotoxicity.

[0206] The "variable region" or "variable domain" of an antibody refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domains of the heavy and light chains are sometimes referred to as "VH" and "VL," respectively. These domains are generally the most variable parts of an antibody (relative to other antibodies of the same class) and contain the antigen-binding site.

[0207] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences generally appear in VH (or VL) as the following arrangement: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0208] The terms "full length antibody," "intact antibody," or "whole antibody" are used interchangeably and refer to an antibody in substantially intact form, as opposed to an antibody fragment. Specifically, whole antibodies include antibodies having heavy and light chains, including an Fc region. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some cases, an intact antibody may have one or more effector functions.

[0209] An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen-binding and / or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab'), and Fv fragments; diabodies; linear antibodies (see U.S. Pat. No. 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10):1057-1062

[1995] ); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies yields two identical antigen-binding fragments, called "Fab" fragments, and a remaining "Fc" fragment, a designation reflecting its ability to readily crystallize. Fab fragments contain the entire light chain plus the variable region domain of the heavy chain (V). H ), and the first constant domain of one heavy chain (C H 1). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment, which roughly corresponds to two disulfide-linked Fab fragments with different antigen-binding activities and is still capable of cross-linking antigen. Fab' fragments contain one or more cysteines from the antibody hinge region, and the C HF(ab')2 antibody fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of one domain. Fab'-SH is the designation used herein for Fab' in which the cysteine ​​residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0210] The Fc fragment contains the carboxy-terminal portions of both heavy chains held together by disulfides. The effector functions of the antibody are determined by sequences within the Fc region, which is also recognized by Fc receptors (FcRs) found on certain cell types.

[0211] "Functional fragments" of antibodies of the present invention include portions of intact antibodies, generally including the antigen-binding or variable region of the intact antibody, or the Fc region of an antibody that retains or has altered FcR binding ability. Examples of antibody fragments include linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0212] An "Fv" is the minimum antibody fragment containing a complete antigen-recognition and antigen-binding site. This fragment consists of a dimer of one heavy-chain and one light-chain variable domain in tight, non-covalent association. The folding of these two domains generates six hypervariable loops (three loops each from the H and L chains) that provide the amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three antigen-specific HVRs) has the ability to recognize and bind to antigen, albeit with lower affinity than the entire binding site.

[0213] "Single-chain Fv," also abbreviated as "sFv" or "scFv," is a VFv fragment that is linked to a single polypeptide chain. H and V LPreferably, the sFv polypeptide is an antibody fragment containing the V H Domains and V L The sFv further comprises a polypeptide linker between the domains that enables the sFv to form the desired structure for antigen binding. For a review of sFvs, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0214] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, and includes native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is usually defined to stretch from the amino acid residue at position Cys226, or from Pro230, to the carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) may be removed, for example, during antibody production or purification, or by recombinantly modifying the nucleic acid encoding the antibody heavy chain. Thus, intact antibody compositions can include antibody populations from which all K447 residues have been removed, antibody populations from which K447 residues have not been removed, and antibody populations containing a mixture of antibodies with and without the K447 residue. Native-sequence Fc regions suitable for use in the antibodies of the present invention include human IgG1, IgG2 (IgG2A, IgG2B), IgG3, and IgG4. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0215] The term "diabody" refers to a diabody that is a short linker (approximately 5-10 residues) connected to a V H Domains and V L Bispecific diabodies refer to small antibody fragments prepared by combining the V domains of two antibodies to construct an sFv fragment (see previous paragraph) to achieve inter-chain rather than intra-chain V domain pairing, thereby generating a bivalent fragment, i.e., a fragment with two antigen-binding sites. H and V L Diabodies are heterodimers of two "crossover" sFv fragments, in which the domains are present on different polypeptide chains. Diabodies are further described in, e.g., EP 404,097; WO 93 / 11161; Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993).

[0216] The monoclonal antibodies herein specifically include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). Chimeric antibodies of interest herein include PRIMATIZED® antibodies, the antigen-binding region of which is derived from, for example, an antibody produced by immunizing macaque monkeys with an antigen of interest. As used herein, "humanized antibodies" are used as a subset of "chimeric antibodies."

[0217] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0218] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen, e.g., TIGIT or PD-L1). Unless otherwise specified, as used herein, "binding affinity" refers to the intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K D ) Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0219] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. A preferred FcR is a native-sequence human FcR. Furthermore, a preferred FcR is one that binds IgG antibodies (gamma receptors), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses (including allelic variants and alternatively spliced ​​forms of these receptors); FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which have similar amino acid sequences and differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) within its cytoplasmic domain (see M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those identified in the future, are encompassed herein by the term "FcR."

[0220] A "human antibody" is an antibody having an amino acid sequence corresponding to that of an antibody produced by a human and / or an antibody produced using any of the techniques for producing human antibodies disclosed herein. This definition of human antibody specifically excludes humanized antibodies having non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). The methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991) can also be used to prepare human monoclonal antibodies. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5:368-74 (2001). Human antibodies can be prepared by administering antigen to transgenic animals, e.g., immunized xenogeneic mice, that have been engineered to produce such antibodies in response to antigen challenge but whose endogenous gene loci have been disabled (see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See also, e.g., Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006), regarding human antibodies generated by human B cell hybridoma technology.

[0221] "Humanized" forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one embodiment, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from an HVR (defined below) of the recipient are replaced by residues from an HVR of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and / or capacity. In some instances, framework ("FR") residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or the donor antibody. These modifications may be made to further refine antibody performance, such as binding affinity. Generally, a humanized antibody will comprise substantially all of at least one, and usually two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence and all or substantially all of the FR regions correspond to those of a human immunoglobulin sequence, but the FR regions may include one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FRs will typically be no more than six in the H chain and no more than three in the L chain. The humanized antibody also optionally will comprise at least a portion of an immunoglobulin constant region (Fc), typically a human immunoglobulin constant region. For further details, see, e.g., Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also, e.g., Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Patent Nos. 6,982,321 and 7,087,409.

[0222] The term "isolated antibody," as used to describe various antibodies disclosed herein, refers to an antibody that has been identified, separated, and / or recovered from a cell or cell culture in which it is expressed. Contaminant components of its natural environment are substances that would normally interfere with diagnostic or therapeutic uses of the polypeptide, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, antibodies are purified to greater than 95% or 99% purity, as measured, for example, by electrophoretic methods (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic methods (e.g., ion exchange or reverse-phase HPLC). For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. B848:79-87 (2007). In a preferred embodiment, the antibody is purified (1) sufficiently to obtain at least 15 residues of N-terminal or internal amino acid sequence using a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes antibody in situ within recombinant cells, since at least one component of the polypeptide's natural environment will not be present. However, isolated polypeptides are usually prepared by at least one purification step.

[0223] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population, i.e., the individual antibodies within the population are identical except for possible minor naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation). Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they are synthesized by a hybridoma culture, uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be produced by, for example, hybridoma techniques (e.g., Kohler and Milstein, Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14(3):253-260 (1995); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2002) nded. 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567), phage display methods (see, e.g., Clackson et al., Nature, 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al., J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004)), as well as techniques for producing human or human-like antibodies in animals that have some or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (see, e.g., WO 1998 / 24893; WO 1996 / 34096; WO 1996 / 33735; WO 1991 / 10741; Jakobovits et al., Proc. Natl. Acad. Sci. USA 90:2551 (1993); Jakobovits et al., Nature 362:255-258 (1993); Bruggemann et al., Year in Immunol. 7:33 (1993); U.S. Patent No. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 10:779-783(1992);Lonberg et al.,Nature 368:856-859(1994);Morrison,Nature 368:812-813(1994);Fishwild et al.,Nature Biotechnol.14:845-851 (1996); Neuberger, Nature Biotechnol. 14:826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol. 13:65-93 (1995)).

[0224] As used herein, the terms "bind," "specifically bind to," or "specific for" refer to a measurable and reproducible interaction, such as binding between a target and an antibody, that is determinative of the presence of the target in the presence of a heterogeneous population of molecules, including biomolecules. For example, an antibody that specifically binds to a target (which may be an epitope) is one that binds to this target with higher affinity, avidity, more readily, and / or with a longer duration than its binding to other targets. In one embodiment, the extent to which an antibody binds to an unrelated target is less than about 10% of the binding of the antibody to the target, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds to a target has a dissociation constant (K) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. D In certain embodiments, the antibody specifically binds to an epitope on a protein that is conserved among proteins from different species. In another embodiment, specific binding can include, but does not necessarily require, exclusive binding. As used herein, the term "specific binding" refers to binding that is conserved between proteins from different species, e.g., between 10 and 100% of a target. -4 M or less, alternatively 10 -5 M or less, alternatively 10 -6M Below, 10 as an alternative -7 M or less, alternatively 10 -8 M or less, alternatively 10 -9 M or less, alternatively 10 -10 M or less, alternatively 10 -11 M or less, alternatively 10 -12 K below M D , or 10 -4 M~10 -6 M or 10 -6 M~10 -10 M or 10 -7M~10 -9 K of M D As will be appreciated by those skilled in the art, affinity and K D The values ​​of K are inversely correlated. High affinity for antigen corresponds to low K D In one embodiment, the term "specific binding" refers to the binding of a molecule to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptides or polypeptide epitopes.

[0225] As used herein, the phrases "substantially reduced" or "substantially different" refer to a difference between two values ​​that would be apparent to one of ordinary skill in the art. D A difference between two numerical values ​​(typically one associated with a molecule and the other associated with a reference / comparator molecule) that is sufficiently high to be considered statistically significant with respect to the biological characteristic measured by the difference (value) between the two values ​​may be, for example, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, and / or greater than about 50% as a function of the value of the reference / comparator molecule.

[0226] As used herein, the terms "substantially similar" or "substantially the same" mean that one of ordinary skill in the art would recognize the difference between two values ​​(e.g., K D represents a sufficiently high degree of similarity between two numerical values ​​(e.g., one associated with an antibody of the invention and the other associated with a reference / comparator antibody) that there is considered to be little or no biological and / or statistical significance with respect to the biological characteristic measured by the two values ​​(e.g., the difference between the two values ​​is, for example, less than about 50%, less than about 40%, less than about 30%, less than about 20%, and / or less than about 10% as a function of the reference / comparator value).

[0227] "Percentage (%) of amino acid sequence identity" to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence after aligning the sequences and optionally introducing gaps to achieve the maximum percentage of sequence identity, and without considering conservative substitutions as part of the sequence identity. Alignment for the purpose of determining percent amino acid sequence identity can be achieved by various methods within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms required to achieve maximum alignment across the entire length of the sequences being compared. However, for purposes herein, percent amino acid sequence identity values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and the source code, along with user documentation, has been filed with the U.S. Copyright Office, Washington, DC, 20559, and is registered under U.S. Copyright No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and are not modified.

[0228] When using ALIGN-2 for amino acid sequence comparison, the percent amino acid sequence identity of a given amino acid sequence A to, with, or compared to a given amino acid sequence B (alternatively, this can be expressed as a given amino acid sequence A having or containing a certain percent amino acid sequence identity to, with, or compared to a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y where X is the number of amino acid residues scored as perfect matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the percent amino acid sequence identity of A to B will not be equal to the percent amino acid sequence identity of B to A. Unless otherwise specified, all percent amino acid sequence identity values ​​used herein are obtained using the ALIGN-2 computer program as described in the immediately preceding paragraph.

[0229] As used herein, "subject" or "individual" means a mammal, including, but not limited to, a human or non-human mammal, such as a cow, horse, dog, sheep, or cat. In some embodiments, the subject is a human. A patient is also a subject herein.

[0230] As used herein, the term "sample" refers to a composition obtained or derived from a subject and / or individual of interest that contains cellular and / or other molecular entities that one wishes to characterize and / or identify, e.g., based on physical, biochemical, chemical, and / or physiological properties. For example, the phrases "tumor sample," "disease sample," and variations thereof refer to any sample obtained from a subject of interest that is suspected or known to contain the cellular and / or molecular entities that one wishes to characterize. In some embodiments, the sample is a tumor tissue sample (e.g., a lung cancer tumor tissue sample, e.g., an NSCLC tumor tissue sample, e.g., a squamous or non-squamous NSCLC tumor tissue sample, e.g., a locally advanced unresectable NSCLC tumor tissue sample (e.g., a stage IIIB NSCLC tumor tissue sample), or a recurrent or metastatic NSCLC tumor tissue sample (e.g., a stage IV NSCLC tumor tissue sample). Other samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymphatic fluid, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, feces, tumor lysates, and tissue culture media, tissue extracts, e.g., homogenized tissues, cell extracts, and combinations thereof.

[0231] As used herein, a "reference sample," "reference cell," "reference tissue," "control sample," "control cell," or "control tissue" refers to a sample, cell, tissue, standard, or level used for comparison purposes. In one embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or unaffected part (e.g., tissue or cell) of the body of the same subject or individual. For example, a healthy and / or unaffected cell or tissue adjacent to a diseased cell or tissue (e.g., a cell or tissue adjacent to a tumor). In another embodiment, the reference sample is obtained from an untreated tissue and / or cell of the body of the same subject. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or unaffected part (e.g., tissue or cell) of the body of a subject who is not the subject. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from an untreated tissue and / or cell of the body of an individual who is not the subject.

[0232] As used herein, the term "protein," unless otherwise specified, refers to any naturally occurring protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed proteins and any form of a protein that results from processing within a cell. The term also encompasses naturally occurring variants of the protein, such as splice variants or allelic variants.

[0233] As used interchangeably herein, "polynucleotide" or "nucleic acid" refers to a polymer of nucleotides of any length, including DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. Thus, for example, a polynucleotide as defined herein includes, but is not limited to, single- and double-stranded DNA, DNA containing single- and double-stranded regions, single- and double-stranded RNA, and RNA containing single- and double-stranded regions, and hybrid molecules containing DNA and RNA that may be single-stranded or, more commonly, double-stranded, or may contain single- and double-stranded regions. Furthermore, as used herein, the term "polynucleotide" refers to triple-stranded regions containing RNA or DNA, or both RNA and DNA. The strands within such regions may be from the same molecule or different molecules. These regions can include all of one or more of these molecules, but more commonly, they include only some of these molecules. One of the molecules in a triple-helical region is often an oligonucleotide. The terms "polynucleotide" and "nucleic acid" specifically include mRNA and cDNA.

[0234] A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after synthesis, such as by conjugation with a label. Other types of modifications include, for example, "caps" that replace one or more of the naturally occurring nucleotides with analogs; internucleotide modifications, such as uncharged linkages (e.g., methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.); pendant moieties, such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.); intercalators (e.g., acridine, psoralens, etc.); chelators (e.g., metals, radioactive metals, boron, metal oxides, etc.); alkylators; modified linkages (e.g., α-anomeric nucleic acids, etc.); and unmodified forms of polynucleotide(s). Additionally, any of the hydroxyl groups normally present in the sugar may be replaced, for example, with phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to provide for additional linkage to additional nucleotides, or complexed to a solid or semi-solid support. The 5'- and 3'-terminal OH groups can be phosphorylated or substituted with amines or organic capping group moieties of 1 to 20 carbon atoms. Other hydroxyls can also be derivatized with standard protecting groups. Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars commonly known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro-, or 2'-azido-ribose, carbocyclic sugar analogs, α-anomeric sugars, epimeric sugars such as arabinose, xylose, or lyxose, pyranose sugars, furanose sugars, sedoheptulose, acrylic acid analogs, and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages can be replaced with alternative linking groups.These alternative linking groups include, but are not limited to, embodiments in which phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), "(O)NR2 ("amidate"), P(O)R, P(O)OR', CO, or CH2 ("formacetal"), where each R or R' is independently H or a substituted or unsubstituted alkyl (1-20C), aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl, optionally containing an ether (-O-) linkage. Not all linkages within a polynucleotide need be identical. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.

[0235] As used herein, the term "carrier" includes pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to cells or mammals exposed thereto at the dosages and concentrations employed. Often, physiologically acceptable carriers are pH-buffered aqueous solutions. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and / or nonionic surfactants, such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

[0236] The phrase "pharmaceutically acceptable" indicates that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients in the formulation and / or the mammal being treated therewith.

[0237] The term "pharmaceutical formulation" refers to a preparation that is in a form such that the biological activity of the active ingredients contained therein is effective and that does not contain additional ingredients that are unacceptably toxic to the subject to whom the formulation will be administered.

[0238] A "product" is any article of manufacture (e.g., package or container) or kit that includes at least one reagent, e.g., a pharmaceutical agent for treating a disease or disorder (e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), and a package insert. In certain embodiments, the product or kit is promoted, distributed, or sold as a unit for performing the methods described herein.

[0239] "Package insert" means the instructions customarily included in a commercial package of a drug product that contain information regarding directions, usage, dosage, administration, contraindications, other drugs to be used in conjunction with the packaged product, and / or warnings regarding the use of such drugs.

[0240] III. Treatment Methods and Uses Provided herein are methods and uses for treating cancer (e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) in a subject, comprising administering to the subject one or more dosing cycles of effective amounts of an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody.

[0241] Dosage regimen and administration The therapeutic methods and uses of the invention described herein, in one aspect, comprise administering to a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and an effective amount of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) in one or more dosing cycles, thereby treating the subject.

[0242] In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is about 30 mg to about 1200 mg (e.g., about 30 mg to about 1100 mg, e.g., about 60 mg to about 1000 mg, e.g., about 100 mg to about 900 mg, e.g., about 200 mg to about 800 mg, e.g., about 300 mg to about 800 mg) every three weeks. , for example, about 400 mg to about 800 mg, for example, about 400 mg to about 750 mg, for example, about 450 mg to about 750 mg, for example, about 500 mg to about 700 mg, for example, about 550 mg to about 650 mg, for example, 600 mg ± 10 mg, for example, 600 ± 6 mg, for example, 600 ± 5 mg, for example, 600 ± 3 mg, for example, 600 ± 1 mg, for example, 600 ± 0.5 mg, for example, 600 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 30 mg to about 600 mg (e.g., about 50 mg to about 600 mg, e.g., about 60 mg to about 600 mg, e.g., about 100 mg to about 600 mg, e.g., about 200 mg to about 600 mg, e.g., about 200 mg to about 550 mg, e.g., about 250 mg to about 500 mg, e.g., about 300 mg to about 450 mg, e.g., about 350 mg to about 400 mg, e.g., about 375 mg) every three weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 600 mg every three weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of 600 mg every 3 weeks. In some examples, the fixed dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) administered in combination therapy (e.g., combination therapy with an anti-PD-L1 antagonist antibody, e.g., atezolizumab) may be reduced compared to the standard dose of the anti-TIGIT antagonist antibody administered as monotherapy.

[0243] In some examples, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is about 80 mg to about 1600 mg (e.g., about 100 mg to about 1600 mg, for example, about 200 mg to about 1600 mg, for example, about 300 mg to about 1600 mg, for example, about 400 mg to about 1600 mg, for example, about 500 mg to about 1600 mg, for example, about 600 mg to about 1600 mg, for example, about 700 mg to about 1600 mg, for example, about 800 mg to about 1600 mg, For example, a fixed dose of about 900 mg to about 1500 mg, for example, about 1000 mg to about 1400 mg, for example, about 1050 mg to about 1350 mg, for example, about 1100 mg to about 1300 mg, for example, about 1150 mg to about 1250 mg, for example, about 1175 mg to about 1225 mg, for example, about 1190 mg to about 1210 mg, for example, 1200 mg ± 5 mg, for example, 1200 ± 2.5 mg, for example, 1200 ± 1.0 mg, for example, 1200 ± 0.5 mg, for example, 1200. In some examples, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a fixed dose of about 1200 mg every 3 weeks. In some examples, the effective amount of the anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a fixed dose of 1200 mg every three weeks. In some examples, the fixed dose of the anti-PD-L1 antagonist antibody (e.g., atezolizumab) administered in combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced compared to the standard dose of the anti-PD-L1 antagonist antibody administered as monotherapy.

[0244] In some examples, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a dose of about 0.01 mg / kg to about 50 mg / kg of the subject's body weight (e.g., about 0.01 mg / kg to about 45 mg / kg, e.g., about 0.1 mg / kg to about 40 mg / kg, e.g., about 1 mg / kg to about 35 mg / kg, e.g., about 2.5 mg / kg to about 30 mg / kg, e.g., about 5 mg / kg to about 25 mg / kg, e.g., about 10 mg / kg to about 20 mg / kg, e.g., about 12.5 mg / kg to about 15 mg / kg, e.g., about 15±2 mg / kg, about 15±1 mg / kg, about 15±0.5 mg / kg, about 15±0.2 mg / kg, or about 15±0.1 mg / kg, e.g., about 15 mg / kg) every 3 weeks. In some examples, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is about 0.01 mg / kg to about 15 mg / kg (e.g., about 0.1 mg / kg to about 15 mg / kg, e.g., about 0.5 mg / kg to about 15 mg / kg, e.g., about 1 mg / kg to about 15 mg / kg, e.g., about 2.5 mg / kg to about 15 mg / kg, e.g., about 5 mg / kg to about 15 mg / kg) of the subject's body weight every three weeks. In some examples, an effective dose of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is about 15 mg / kg administered every 3 weeks, e.g., about 7.5 mg / kg to about 15 mg / kg, e.g., about 10 mg / kg to about 15 mg / kg, e.g., about 12.5 mg / kg to about 15 mg / kg, e.g., about 14 mg / kg to about 15 mg / kg, e.g., about 15±1 mg / kg, e.g., about 15±0.5 mg / kg, e.g., about 15±0.2 mg / kg, e.g., about 15±0.1 mg / kg, e.g., about 15 mg / kg). In some examples, the dose of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) administered in combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced compared to the standard dose of the anti-PD-L1 antagonist antibody administered as monotherapy.

[0245] In any of the methods and uses of the invention, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the anti-PD-L1 antagonist antibody (e.g., atezolizumab) may be administered in one or more dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles). In some examples, dosing cycles of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the anti-PD-L1 antagonist antibody (e.g., atezolizumab) are continued until clinical benefit is lost (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity). In some examples, the length of each dosing cycle is about 18 to 24 days (e.g., 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, or 24 days). In some examples, the length of each dosing cycle is about 21 days. In some examples, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 1 of each dosing cycle (e.g., day 1 ± 3 days). For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 600 mg on day 1 of each 21-day cycle (i.e., at a fixed dose of about 600 mg every 3 weeks). Similarly, in some examples, an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered intravenously at about day 1 of each dosing cycle (e.g., day 1 ± 3 days). For example, an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered intravenously at a fixed dose of about 1200 mg on day 1 of each 21-day cycle (i.e., at a fixed dose of about 1200 mg every 3 weeks).In some examples, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the anti-PD-L1 antagonist antibody (e.g., atezolizumab) are administered on about day 1 of each dosing cycle (e.g., day 1 ± 3 days). For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 600 mg on day 1 of each 21-day cycle (i.e., at a fixed dose of about 600 mg every 3 weeks), and the anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered intravenously at a fixed dose of about 1200 mg on day 1 of each 21-day cycle (i.e., at a fixed dose of about 1200 mg every 3 weeks).

[0246] In some examples, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered to a subject by intravenous infusion over about 60±10 minutes (e.g., about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes). In some examples, the anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered to a subject by intravenous infusion over about 60±15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes).

[0247] In some examples, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered to the subject before the anti-PD-L1 antagonist antibody (e.g., atezolizumab). In some examples, the method includes, for example, a first observation period intervening after administration of the anti-TIGIT antagonist antibody and before administration of the anti-PD-L1 antagonist antibody. In some examples, the method further includes a second observation period after administration of the anti-PD-L1 antagonist antibody. In some examples, the method includes a first observation period after administration of the anti-TIGIT antagonist antibody and a second observation period after administration of the anti-PD-L1 antagonist antibody. In some examples, the length of the first observation period and the second observation period are each about 30 minutes to about 60 minutes. If the first and second observation periods are each about 60 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 30±10 minutes after administration of the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody during the first and second observation periods, respectively.If the first and second observation periods are each about 30 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 15±10 minutes after administration of the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody during the first and second observation periods, respectively.

[0248] In some examples, the anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered before the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab). In some examples, the method includes a first observation period, for example, intervening after administration of the anti-PD-L1 antagonist antibody and before administration of the anti-TIGIT antagonist antibody. In some examples, the method includes a second observation period after administration of the anti-TIGIT antagonist antibody. In some examples, the method includes a first observation period after administration of the anti-PD-L1 antagonist antibody and a second observation period after administration of the anti-TIGIT antagonist antibody. In some examples, the length of the first observation period and the second observation period are each about 30 minutes to about 60 minutes. If the first and second observation periods are each about 60 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 30±10 minutes after administration of the anti-PD-L1 antagonist antibody and the anti-TIGIT antagonist antibody during the first and second observation periods, respectively.If the first and second observation periods are each about 30 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 15±10 minutes after administration of the anti-PD-L1 antagonist antibody and the anti-TIGIT antagonist antibody during the first and second observation periods, respectively.

[0249] In other examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and an anti-PD-L1 antagonist antibody (e.g., atezolizumab) are administered simultaneously to the subject. In some examples, the method includes an observation period, for example, after administration of the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody. In some examples, the length of the observation periods is about 30 minutes to about 60 minutes, respectively. When the length of the observation periods is about 60 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 30±10 minutes after administration of the anti-PD-L1 antagonist antibody and the anti-TIGIT antagonist antibody, respectively, during the observation period. Where the observation periods are each about 30 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 15±10 minutes after administration of the anti-PD-L1 antagonist antibody and the anti-TIGIT antagonist antibody, respectively, during the observation period.

[0250] In another aspect, the present invention provides a method of treating a subject suffering from NSCLC (e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) by administering to the subject a fixed dose of 600 mg every three weeks of an anti-TIGIT antagonist antibody and a fixed dose of 1200 mg every three weeks of atezolizumab, for one or more dosing cycles, wherein the anti-TIGIT antagonist antibody comprises a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19, as described in more detail below.

[0251] In another aspect, the invention provides a method of treating a subject with NSCLC (e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) by administering to the subject a fixed dose of 600 mg tiragolumab every three weeks and a fixed dose of 1200 mg atezolizumab every three weeks for one or more dosing cycles.

[0252] In another aspect, the present invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and an anti-PD-L1 antagonist antibody (e.g., atezolizumab) for use in a method of treating a subject with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering to the subject an effective amount of the anti-TIGIT antagonist antibody and an effective amount of the anti-PD-L1 antagonist antibody for one or more dosing cycles.

[0253] In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is about 30 mg to about 1200 mg (e.g., about 30 mg to about 1100 mg, e.g., about 60 mg to about 1000 mg, e.g., about 100 mg to about 900 mg, e.g., about 200 mg to about 800 mg, e.g., about 300 mg to about 800 mg) every three weeks. , for example, about 400 mg to about 800 mg, for example, about 400 mg to about 750 mg, for example, about 450 mg to about 750 mg, for example, about 500 mg to about 700 mg, for example, about 550 mg to about 650 mg, for example, 600 mg ± 10 mg, for example, 600 ± 6 mg, for example, 600 ± 5 mg, for example, 600 ± 3 mg, for example, 600 ± 1 mg, for example, 600 ± 0.5 mg, for example, 600 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 30 mg to about 600 mg (e.g., about 50 mg to about 600 mg, e.g., about 60 mg to about 600 mg, e.g., about 100 mg to about 600 mg, e.g., about 200 mg to about 600 mg, e.g., about 200 mg to about 550 mg, e.g., about 250 mg to about 500 mg, e.g., about 300 mg to about 450 mg, e.g., about 350 mg to about 400 mg, e.g., about 375 mg) every three weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 600 mg every three weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of 600 mg every 3 weeks. In some examples, the fixed dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) to be administered in combination therapy (e.g., combination therapy with an anti-PD-L1 antagonist antibody, e.g., atezolizumab) may be reduced compared to the standard dose of the anti-TIGIT antagonist antibody to be administered as monotherapy.

[0254] In some examples, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is about 80 mg to about 1600 mg (e.g., about 100 mg to about 1600 mg, for example, about 200 mg to about 1600 mg, for example, about 300 mg to about 1600 mg, for example, about 400 mg to about 1600 mg, for example, about 500 mg to about 1600 mg, for example, about 600 mg to about 1600 mg, for example, about 700 mg to about 1600 mg, for example, about 800 mg to about 1600 mg, For example, a fixed dose of about 900 mg to about 1500 mg, for example, about 1000 mg to about 1400 mg, for example, about 1050 mg to about 1350 mg, for example, about 1100 mg to about 1300 mg, for example, about 1150 mg to about 1250 mg, for example, about 1175 mg to about 1225 mg, for example, about 1190 mg to about 1210 mg, for example, 1200 mg ± 5 mg, for example, 1200 ± 2.5 mg, for example, 1200 ± 1.0 mg, for example, 1200 ± 0.5 mg, for example, 1200. In some examples, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a fixed dose of about 1200 mg every 3 weeks. In some examples, the effective amount of the anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a fixed dose of 1200 mg every three weeks. In some examples, the fixed dose of the anti-PD-L1 antagonist antibody (e.g., atezolizumab) to be administered in combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced compared to the standard dose of the anti-PD-L1 antagonist antibody to be administered as monotherapy.

[0255] In some examples, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a dose of about 0.01 mg / kg to about 50 mg / kg of the subject's body weight (e.g., about 0.01 mg / kg to about 45 mg / kg, e.g., about 0.1 mg / kg to about 40 mg / kg, e.g., about 1 mg / kg to about 35 mg / kg, e.g., about 2.5 mg / kg to about 30 mg / kg, e.g., about 5 mg / kg to about 25 mg / kg, e.g., about 10 mg / kg to about 20 mg / kg, e.g., about 12.5 mg / kg to about 15 mg / kg, e.g., about 15±2 mg / kg, about 15±1 mg / kg, about 15±0.5 mg / kg, about 15±0.2 mg / kg, or about 15±0.1 mg / kg, e.g., about 15 mg / kg) every 3 weeks. In some examples, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is about 0.01 mg / kg to about 15 mg / kg (e.g., about 0.1 mg / kg to about 15 mg / kg, e.g., about 0.5 mg / kg to about 15 mg / kg, e.g., about 1 mg / kg to about 15 mg / kg, e.g., about 2.5 mg / kg to about 15 mg / kg, e.g., about 5 mg / kg to about 15 mg / kg) of the subject's body weight every three weeks. In some examples, an effective dose of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is about 15 mg / kg administered every 3 weeks, e.g., about 7.5 mg / kg to about 15 mg / kg, e.g., about 10 mg / kg to about 15 mg / kg, e.g., about 12.5 mg / kg to about 15 mg / kg, e.g., about 14 mg / kg to about 15 mg / kg, e.g., about 15±1 mg / kg, e.g., about 15±0.5 mg / kg, e.g., about 15±0.2 mg / kg, e.g., about 15±0.1 mg / kg, e.g., about 15 mg / kg). In some examples, the dose of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) administered in combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced compared to the standard dose of the anti-PD-L1 antagonist antibody administered as monotherapy.

[0256] The anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the anti-PD-L1 antagonist antibody (e.g., atezolizumab) may be administered in one or more dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles). In some examples, dosing cycles of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the anti-PD-L1 antagonist antibody (e.g., atezolizumab) are continued until clinical benefit is lost (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity). In some examples, the length of each dosing cycle is about 18 to 24 days (e.g., 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, or 24 days). In some examples, the length of each dosing cycle is about 21 days. In some examples, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 1 of each dosing cycle (e.g., day 1 ± 3 days). For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 600 mg on day 1 of each 21-day cycle (i.e., at a fixed dose of about 600 mg every 3 weeks). Similarly, in some examples, an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered intravenously at about day 1 of each dosing cycle (e.g., day 1 ± 3 days). For example, an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered intravenously at a fixed dose of about 1200 mg on day 1 of each 21-day cycle (i.e., at a fixed dose of about 1200 mg every 3 weeks).In some examples, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the anti-PD-L1 antagonist antibody (e.g., atezolizumab) are administered on about day 1 of each dosing cycle (e.g., day 1 ± 3 days). For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 600 mg on day 1 of each 21-day cycle (i.e., at a fixed dose of about 600 mg every 3 weeks), and the anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered intravenously at a fixed dose of about 1200 mg on day 1 of each 21-day cycle (i.e., at a fixed dose of about 1200 mg every 3 weeks).

[0257] In some examples, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered to a subject by intravenous infusion over about 60±10 minutes (e.g., about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes). In some examples, the anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered to a subject by intravenous infusion over about 60±15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes).

[0258] In some examples, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered to the subject before the anti-PD-L1 antagonist antibody (e.g., atezolizumab). In some examples, the method includes, for example, a first observation period intervening after administration of the anti-TIGIT antagonist antibody and before administration of the anti-PD-L1 antagonist antibody. In some examples, the method further includes a second observation period after administration of the anti-PD-L1 antagonist antibody. In some examples, the method includes a first observation period after administration of the anti-TIGIT antagonist antibody and a second observation period after administration of the anti-PD-L1 antagonist antibody. In some examples, the length of the first observation period and the second observation period are each about 30 minutes to about 60 minutes. If the first and second observation periods are each about 60 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 30±10 minutes after administration of the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody during the first and second observation periods, respectively.If the first and second observation periods are each about 30 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 15±10 minutes after administration of the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody during the first and second observation periods, respectively.

[0259] In some examples, the anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered before the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab). In some examples, the method includes a first observation period, for example, intervening after administration of the anti-PD-L1 antagonist antibody and before administration of the anti-TIGIT antagonist antibody. In some examples, the method includes a second observation period after administration of the anti-TIGIT antagonist antibody. In some examples, the method includes a first observation period after administration of the anti-PD-L1 antagonist antibody and a second observation period after administration of the anti-TIGIT antagonist antibody. In some examples, the length of the first observation period and the second observation period are each about 30 minutes to about 60 minutes. If the first and second observation periods are each about 60 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 30±10 minutes after administration of the anti-PD-L1 antagonist antibody and the anti-TIGIT antagonist antibody during the first and second observation periods, respectively.If the first and second observation periods are each about 30 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 15±10 minutes after administration of the anti-PD-L1 antagonist antibody and the anti-TIGIT antagonist antibody during the first and second observation periods, respectively.

[0260] In other examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and an anti-PD-L1 antagonist antibody (e.g., atezolizumab) are administered simultaneously to the subject. In some examples, the method includes an observation period, for example, after administration of the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody. In some examples, the length of the observation periods is about 30 minutes to about 60 minutes, respectively. When the length of the observation periods is about 60 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 30±10 minutes after administration of the anti-PD-L1 antagonist antibody and the anti-TIGIT antagonist antibody, respectively, during the observation period. Where the observation periods are each about 30 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 15±10 minutes after administration of the anti-PD-L1 antagonist antibody and the anti-TIGIT antagonist antibody, respectively, during the observation period.

[0261] In another aspect, the present invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and an anti-PD-L antibody for use in a method of treating a subject afflicted with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)). and a VL domain having the amino acid sequence of SEQ ID NO: 19, as described in more detail below.

[0262] In another aspect, the present invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and an anti-PD-L1 antagonist antibody (e.g., atezolizumab) for use in a method of treating a subject with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering to the subject an effective amount of the anti-TIGIT antagonist antibody and an effective amount of the anti-PD-L1 antagonist antibody for one or more dosing cycles.

[0263] In another aspect, the present invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and an anti-PD-L1 antagonist antibody (e.g., atezolizumab) in the manufacture or preparation of a medicament for use in a method of treating a subject afflicted with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering the medicament to the subject for one or more dosing cycles, wherein the medicament is formulated for administering an effective amount of the anti-TIGIT antagonist antibody and an effective amount of the anti-PD-L1 antagonist.

[0264] In another aspect, the invention provides use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering to the subject a medicament and an anti-PD-L1 antagonist antibody in one or more dosing cycles, wherein the medicament is formulated for administering an effective amount of the anti-TIGIT antagonist antibody and an effective amount of the anti-PD-L1 antagonist antibody.

[0265] In another aspect, the invention provides use of an anti-PD-L1 antagonist antibody in the manufacture of a medicament for use in a method of treating a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering to the subject a medicament and an anti-TIGIT antagonist antibody for one or more dosing cycles, wherein the medicament is formulated for administering an effective amount of the anti-PD-L1 antagonist antibody and an effective amount of the anti-TIGIT antagonist antibody.

[0266] In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is about 30 mg to about 1200 mg (e.g., about 30 mg to about 1100 mg, e.g., about 60 mg to about 1000 mg, e.g., about 100 mg to about 900 mg, e.g., about 200 mg to about 800 mg, e.g., about 300 mg to about 800 mg) every three weeks. , for example, about 400 mg to about 800 mg, for example, about 400 mg to about 750 mg, for example, about 450 mg to about 750 mg, for example, about 500 mg to about 700 mg, for example, about 550 mg to about 650 mg, for example, 600 mg ± 10 mg, for example, 600 ± 6 mg, for example, 600 ± 5 mg, for example, 600 ± 3 mg, for example, 600 ± 1 mg, for example, 600 ± 0.5 mg, for example, 600 mg). In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 30 mg to about 600 mg (e.g., about 50 mg to about 600 mg, e.g., about 60 mg to about 600 mg, e.g., about 100 mg to about 600 mg, e.g., about 200 mg to about 600 mg, e.g., about 200 mg to about 550 mg, e.g., about 250 mg to about 500 mg, e.g., about 300 mg to about 450 mg, e.g., about 350 mg to about 400 mg, e.g., about 375 mg) every three weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 600 mg every three weeks. In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of 600 mg every 3 weeks. In some examples, the fixed dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) to be administered in combination therapy (e.g., combination therapy with an anti-PD-L1 antagonist antibody, e.g., atezolizumab) may be reduced compared to the standard dose of the anti-TIGIT antagonist antibody to be administered as monotherapy.

[0267] In some examples, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is about 80 mg to about 1600 mg (e.g., about 100 mg to about 1600 mg, for example, about 200 mg to about 1600 mg, for example, about 300 mg to about 1600 mg, for example, about 400 mg to about 1600 mg, for example, about 500 mg to about 1600 mg, for example, about 600 mg to about 1600 mg, for example, about 700 mg to about 1600 mg, for example, about 800 mg to about 1600 mg, For example, a fixed dose of about 900 mg to about 1500 mg, for example, about 1000 mg to about 1400 mg, for example, about 1050 mg to about 1350 mg, for example, about 1100 mg to about 1300 mg, for example, about 1150 mg to about 1250 mg, for example, about 1175 mg to about 1225 mg, for example, about 1190 mg to about 1210 mg, for example, 1200 mg ± 5 mg, for example, 1200 ± 2.5 mg, for example, 1200 ± 1.0 mg, for example, 1200 ± 0.5 mg, for example, 1200. In some examples, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a fixed dose of about 1200 mg every 3 weeks. In some examples, the effective amount of the anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a fixed dose of 1200 mg every three weeks. In some examples, the fixed dose of the anti-PD-L1 antagonist antibody (e.g., atezolizumab) to be administered in combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced compared to the standard dose of the anti-PD-L1 antagonist antibody to be administered as monotherapy.

[0268] In some examples, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a dose of about 0.01 mg / kg to about 50 mg / kg of the subject's body weight (e.g., about 0.01 mg / kg to about 45 mg / kg, e.g., about 0.1 mg / kg to about 40 mg / kg, e.g., about 1 mg / kg to about 35 mg / kg, e.g., about 2.5 mg / kg to about 30 mg / kg, e.g., about 5 mg / kg to about 25 mg / kg, e.g., about 10 mg / kg to about 20 mg / kg, e.g., about 12.5 mg / kg to about 15 mg / kg, e.g., about 15±2 mg / kg, about 15±1 mg / kg, about 15±0.5 mg / kg, about 15±0.2 mg / kg, or about 15±0.1 mg / kg, e.g., about 15 mg / kg) every 3 weeks. In some examples, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is about 0.01 mg / kg to about 15 mg / kg (e.g., about 0.1 mg / kg to about 15 mg / kg, e.g., about 0.5 mg / kg to about 15 mg / kg, e.g., about 1 mg / kg to about 15 mg / kg, e.g., about 2.5 mg / kg to about 15 mg / kg, e.g., about 5 mg / kg to about 15 mg / kg) of the subject's body weight every three weeks. In some examples, an effective dose of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is about 15 mg / kg administered every 3 weeks, e.g., about 7.5 mg / kg to about 15 mg / kg, e.g., about 10 mg / kg to about 15 mg / kg, e.g., about 12.5 mg / kg to about 15 mg / kg, e.g., about 14 mg / kg to about 15 mg / kg, e.g., about 15±1 mg / kg, e.g., about 15±0.5 mg / kg, e.g., about 15±0.2 mg / kg, e.g., about 15±0.1 mg / kg, e.g., about 15 mg / kg). In some examples, the dose of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) administered in combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced compared to the standard dose of the anti-PD-L1 antagonist antibody administered as monotherapy.

[0269] In any of the uses of the invention, the pharmaceutical preparation comprising the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the anti-PD-L1 antagonist antibody (e.g., atezolizumab) may be administered in one or more dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles). In some examples, the dosing cycle of a pharmaceutical agent comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is continued until clinical benefit is lost (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity). In some examples, the length of each dosing cycle is about 18 to 24 days (e.g., 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, or 24 days). In some examples, the length of each dosing cycle is about 21 days. In some examples, the pharmaceutical agent comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 1 of each dosing cycle (e.g., day 1 ± 3 days). For example, a pharmaceutical agent comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 600 mg on day 1 of each 21-day cycle (i.e., at a fixed dose of about 600 mg every 3 weeks). Similarly, in some examples, a pharmaceutical agent comprising an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered intravenously at about day 1 of each dosing cycle (e.g., day 1 ± 3 days). For example, a pharmaceutical agent comprising an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered intravenously at a fixed dose of about 1200 mg on day 1 of each 21-day cycle (i.e., at a fixed dose of about 1200 mg every 3 weeks).In some examples, a pharmaceutical agent comprising both an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered on about day 1 of each dosing cycle (e.g., day 1 ± 3 days). For example, a pharmaceutical agent comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 600 mg on day 1 of each 21-day cycle (i.e., at a fixed dose of about 600 mg every 3 weeks), and a pharmaceutical agent comprising an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered intravenously at a fixed dose of about 1200 mg on day 1 of each 21-day cycle (i.e., at a fixed dose of about 1200 mg every 3 weeks).

[0270] In some examples, a pharmaceutical agent comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered to a subject by intravenous infusion over about 60±10 minutes (e.g., about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes). In some examples, the medicament comprising the anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered to the subject by intravenous infusion over about 60±15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes).

[0271] In some examples, a pharmaceutical agent comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered to a subject before a pharmaceutical agent comprising an anti-PD-L1 antagonist antibody (e.g., atezolizumab). In some examples, the method includes, for example, a first observation period intervening after administration of the pharmaceutical agent comprising the anti-TIGIT antagonist antibody and before administration of the pharmaceutical agent comprising the anti-PD-L1 antagonist antibody. In some examples, the method further includes a second observation period after administration of the anti-PD-L1 antagonist antibody. In some examples, the method includes a first observation period after administration of the pharmaceutical agent comprising the anti-TIGIT antagonist antibody and a second observation period after administration of the pharmaceutical agent comprising the anti-PD-L1 antagonist antibody. In some examples, the lengths of the first observation period and the second observation period are each about 30 minutes to about 60 minutes. If the first and second observation periods are each about 60 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 30±10 minutes after administration of the pharmaceutical agent comprising the anti-TIGIT antagonist antibody and the pharmaceutical agent comprising the anti-PD-L1 antagonist antibody during the first and second observation periods, respectively.If the first and second observation periods are each about 30 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 15±10 minutes after administration of the anti-PD-L1 antagonist antibody and the anti-TIGIT antagonist antibody during the first and second observation periods, respectively.

[0272] In some examples, a pharmaceutical agent comprising an anti-PD-L1 antagonist antibody (e.g., atezolizumab) is administered before an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab). In some examples, the method includes, for example, a first observation period that intervenes after administration of the pharmaceutical agent comprising an anti-PD-L1 antagonist antibody and before administration of the pharmaceutical agent comprising an anti-TIGIT antagonist antibody. In some examples, the method includes a second observation period after administration of the pharmaceutical agent comprising an anti-TIGIT antagonist antibody. In some examples, the method includes a first observation period after administration of the pharmaceutical agent comprising an anti-PD-L1 antagonist antibody and a second observation period after administration of the pharmaceutical agent comprising an anti-TIGIT antagonist antibody. In some examples, the length of the first observation period and the second observation period are each about 30 minutes to about 60 minutes. If the first and second observation periods are each about 60 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 30±10 minutes after administration of the pharmaceutical agent comprising an anti-PD-L1 antagonist antibody and the pharmaceutical agent comprising an anti-TIGIT antagonist antibody during the first and second observation periods, respectively.If the first and second observation periods are each about 30 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 15±10 minutes after administration of the pharmaceutical agent comprising an anti-PD-L1 antagonist antibody and the pharmaceutical agent comprising an anti-TIGIT antagonist antibody during the first and second observation periods, respectively.

[0273] In other examples, a pharmaceutical agent comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a pharmaceutical agent comprising an anti-PD-L1 antagonist antibody (e.g., atezolizumab) are simultaneously administered to the subject. In some examples, the method includes an observation period, for example, after administration of the pharmaceutical agent comprising an anti-TIGIT antagonist antibody and the pharmaceutical agent comprising an anti-PD-L1 antagonist antibody. In some examples, the length of the observation periods is about 30 minutes to about 60 minutes, respectively. When the length of the observation periods is about 60 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for about 30±10 minutes after administration of the pharmaceutical agent comprising an anti-PD-L1 antagonist antibody and the pharmaceutical agent comprising an anti-TIGIT antagonist antibody, respectively, during the observation period. Where the length of each observation period is approximately 30 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) for approximately 15±10 minutes after administration of the pharmaceutical agent comprising the anti-PD-L1 antagonist antibody and the pharmaceutical agent comprising the anti-TIGIT antagonist antibody during the observation period.

[0274] In another aspect, the present invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and an anti-PD-L1 antagonist antibody (e.g., atezolizumab) in the manufacture or preparation of a medicament for use in a method of treating a subject afflicted with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering the medicament to the subject in one or more dosing cycles, wherein the medicament is formulated for administration of the anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 1200 mg every three weeks, and the anti-PD-L1 antagonist antibody at a fixed dose of about 80 mg to about 1600 mg every three weeks.

[0275] In another aspect, the invention provides use of an anti-PD-L1 antagonist antibody in the manufacture of a medicament for use in a method of treating a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering to the subject a medicament and an anti-TIGIT antagonist antibody for one or more dosing cycles, wherein the medicament is formulated for administration of the anti-PD-L1 antagonist antibody at a fixed dose of about 80 mg to about 1600 mg every three weeks, and the anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 1200 mg every three weeks.

[0276] In another aspect, the invention provides use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering to the subject a medicament and an anti-PD-L1 antagonist antibody in one or more dosing cycles, wherein the medicament is formulated for administration of the anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 1200 mg every three weeks, and the anti-PD-L1 antagonist antibody at a fixed dose of about 80 mg to about 1600 mg every three weeks.

[0277] In another aspect, the invention provides use of an anti-TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for use in a method of treating a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering the medicament to the subject for one or more dosing cycles, wherein the medicament is formulated for administration of the anti-TIGIT antagonist antibody at a fixed dose of 600 mg every three weeks and the atezolizumab at a fixed dose of 1200 mg every three weeks, and the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and a VL domain having the amino acid sequence of SEQ ID NO: 19, as described in further detail below.

[0278] In another aspect, the invention provides use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering a medicament and atezolizumab to the subject for one or more dosing cycles, wherein the medicament is formulated for administration of the anti-TIGIT antagonist antibody at a fixed dose of 600 mg every three weeks, and the atezolizumab is administered at a fixed dose of 1200 mg every three weeks, and the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and a VL domain having the amino acid sequence of SEQ ID NO: 19, as described in further detail below.

[0279] In another aspect, the invention provides use of atezolizumab in the manufacture of a medicament for use in a method of treating a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering to the subject a medicament and an anti-TIGIT antagonist antibody in one or more dosing cycles, wherein the medicament is formulated for administration of atezolizumab at a fixed dose of 1200 mg every three weeks, and the anti-TIGIT antagonist antibody is administered at a fixed dose of 600 mg every three weeks, and the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and a VL domain having the amino acid sequence of SEQ ID NO: 19, as described in further detail below.

[0280] In another aspect, the invention provides the use of tiragolumab and atezolizumab in the manufacture of a medicament for use in a method of treating a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering the medicament to the subject for one or more dosing cycles, wherein the medicament is formulated for administration of tiragolumab at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks.

[0281] In another aspect, the invention provides the use of tiragolumab in the manufacture of a medicament for use in a method of treating a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering a medicament and atezolizumab to the subject for one or more dosing cycles, wherein the medicament is formulated for administration at a fixed dose of 600 mg every three weeks, and the atezolizumab is administered at a fixed dose of 1200 mg every three weeks.

[0282] In another aspect, the invention provides use of atezolizumab in the manufacture of a medicament for use in a method of treating a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the method comprising administering a medicament and tiragolumab to the subject for one or more dosing cycles, wherein the medicament is formulated for administration of atezolizumab at a fixed dose of 1200 mg every three weeks, and the tiragolumab is administered at a fixed dose of 600 mg every three weeks.

[0283] In any of the methods, uses, or compositions for use described herein, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the anti-PD-L1 antibody (e.g., atezolizumab), or pharmaceutical preparation thereof, may be administered in combination (separately or together) with one or more additional anti-cancer therapeutic(s) (e.g., chemotherapeutic agents, cytotoxic agents, growth inhibitory agents, radiotherapy / radiotherapy, and / or anti-hormonal agents, as detailed herein above).

[0284] In any of the methods, uses, or compositions for use described herein, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and anti-PD-L1 antibody (e.g., atezolizumab), or a medicament thereof, is for treating a subject with lung cancer. In some examples, the lung cancer is NSCLC. The cancer can be early or late stage. In some examples, the NSCLC is squamous NSCLC. In some examples, the NSCLC is non-squamous NSCLC. In some examples, the NSCLC is locally advanced unresectable NSCLC. In some examples, the NSCLC is stage IIIB NSCLC. In some examples, the NSCLC is recurrent or metastatic NSCLC. In some examples, the NSCLC is stage IV NSCLC. In some examples, the subject has not previously been treated with stage IV NSCLC.

[0285] In some examples, in any of the methods, uses, or compositions for use described herein, the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement. In some examples, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

[0286] In some examples, in any of the methods, uses, or compositions for use described herein, the subject does not have the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

[0287] In some examples, in any of the methods, uses, or compositions for use described herein, the subject does not have an active Epstein-Barr virus (EBV) infection or a known or suspected chronic active EBV infection. In some examples, the subject is negative for EBV IgM and / or negative for EBV PCR. In some examples, the subject is negative for EBV IgM and / or negative for EBV PCR, and positive for EBV IgG and / or positive for Epstein-Barr nuclear antigen (EBNA). In other examples, the subject is negative for EBV IgG and / or negative for EBNA.

[0288] In some examples, in any of the methods, uses, or compositions for use described herein, the subject has a PD-L1-selected tumor (e.g., tumor PD-L1 expression with a minimum TPS of ≧1% as determined by IHC using the 22C3 antibody). In some examples, a PD-L1-selected tumor is a tumor determined by an immunohistochemistry (IHC) assay to have a detectable level of PD-L1 protein expression. In some examples, the IHC assay uses the anti-PD-L1 antibody 22C3, SP142, SP263, or 28-8. In some examples, the IHC assay uses the anti-PD-L1 antibody 22C3. In some examples, the tumor sample is determined to have a tumor positive score (TPS) of ≧1%. In some examples, the TPS is ≧1% and less than 50%. In some examples, the TPS is ≧50%.

[0289] In some examples, any of the methods, uses, or compositions for use described herein utilizes the anti-PD-L1 antibody SP142 in an IHC assay. In some examples, the tumor sample has been determined to have a detectable PD-L1 expression level in 1% or more of the tumor cells in the tumor sample. In some examples, the tumor sample has been determined to have a detectable PD-L1 expression level in 1% or more but less than 5% of the tumor cells in the tumor sample. In some examples, the tumor sample has been determined to have a detectable PD-L1 expression level in 5% or more but less than 50% of the tumor cells in the tumor sample. In some examples, the tumor sample has been determined to have a detectable PD-L1 expression level in 50% or more of the tumor cells in the tumor sample. In some examples, the tumor sample has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells comprising 1% or more of the tumor sample. In some examples, the tumor sample has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells comprising 1% or more but less than 5% of the tumor sample. In some instances, the tumor sample is determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise greater than or equal to 5% but less than 10% of the tumor sample. In some instances, the tumor sample is determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise greater than or equal to 10% of the tumor sample.

[0290] In some examples, in any of the methods, uses, or compositions for use described herein, the detectable PD-L1 expression level is a detectable PD-L1 nucleic acid expression level. In some examples, the detectable PD-L1 nucleic acid expression level is measured by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

[0291] In some examples, in any of the methods, uses, or compositions for use described herein, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are administered to produce a clinical response. In some examples, the clinical response is an increase in the subject's objective response rate (ORR) compared to a reference ORR. In some examples, the reference ORR is the median ORR of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody. In some examples, the clinical response is an increase in the subject's progression-free survival (PFS) period compared to a reference PFS period. In some examples, the reference PFS period is the median PFS of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody.

[0292] IV. Diagnostic Methods and Uses The present invention provides methods of selecting a therapy for a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), wherein the therapy is guided by a diagnostic method comprising measuring the presence and / or expression level / amount of one or more biomarkers in a sample taken from the subject.

[0293] Further provided herein is a method for identifying a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) who may benefit from a treatment comprising an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody, wherein the identification is guided by a diagnostic method comprising measuring the presence and / or expression level / amount of one or more biomarkers in a sample obtained from the subject.

[0294] Further provided herein are methods for assessing the responsiveness of a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) to therapy, wherein further therapy is guided by a diagnostic method comprising measuring the presence and / or expression level / amount of one or more biomarkers in a sample taken from the subject.

[0295] Further provided herein are methods for optimizing therapy of a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), wherein further therapy is guided by a diagnostic method comprising measuring the presence and / or expression level / amount of one or more biomarkers in a sample taken from the subject.

[0296] Biomarkers for use in the methods described herein can include, but are not limited to, PD-L1 and TIGIT expression in tumor tissue, germline and somatic mutations (including, but not limited to, mutational load, MSI, and MMR deficiency) from tumor tissue and / or circulating tumor DNA in the blood identified by WGS and / or NGS, and plasma-derived cytokines. In some examples, the biomarker is PD-L1.

[0297] In some examples, the method includes determining the presence and / or expression level / amount of a biomarker (e.g., PD-L1) in a sample from the subject, and administering to the subject an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) at a fixed dose of about 30 mg to about 1200 mg every three weeks for one or more dosing cycles, and an anti-PD-L1 antagonist antibody (e.g., atezolizumab) at a fixed dose of about 80 mg to about 1600 mg every three weeks for one or more dosing cycles. In some examples, the method includes determining the presence and / or expression level / amount of a biomarker (e.g., PD-L1) in a sample from the subject, and administering to the subject an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) at a fixed dose of about 600 mg every three weeks for one or more dosing cycles, and an anti-PD-L1 antagonist antibody (e.g., atezolizumab) at a fixed dose of about 1200 mg every three weeks.

[0298] The presence and / or expression level / amount of a biomarker (e.g., PD-L1) may be determined qualitatively and / or quantitatively based on any suitable criteria known in the art, including, but not limited to, protein, protein fragment, DNA, mRNA, cDNA, and / or gene copy number.

[0299] In some examples, the expression level or amount of the biomarker is the detectable expression level of PD-L1 protein in a tumor sample from a subject. In some examples, the protein expression level of PD-L1 is measured by immunohistochemistry (IHC) assay. In some examples, the IHC assay uses anti-PD-L1 antibody 22C3, SP142, SP263, or 28-8. In a particular example, the IHC assay uses anti-PD-L1 antibody 22C3. In some examples, the tumor positive fraction (TPS) of a tumor sample is measured to be about 1% or greater (e.g., about 1% or greater, about 2% or greater, about 3% or greater, about 4% or greater, about 5% or greater, about 10% or greater, about 15% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 35% or greater, about 40% or greater, about 50% or greater, about 55% or greater, about 60% or greater, about 65% or greater, about 70% or greater, about 80% or greater, about 85% or greater, about 90% or greater, about 95% or greater, or about 99% or greater).For example, in some instances, the tumor sample may have a detectable PD-L1 protein expression level and a PD-L1 expression level of between about 1% and less than about 99% (e.g., between about 1% and less than about 95%, between about 1% and less than about 90%, between about 1% and less than about 85%, between about 1% and less than about 80%, between about 1% and less than about 75%, between about 1% and less than about 70%, between about 1% and less than about 65%, between about 1% and less than about 60%, between about 1% and less than about 55%, between about 1% and less than about 60%). Less than about 50%, about 1% to less than about 40%, about 1% to less than about 35%, about 1% to less than about 30%, about 1% to less than about 25%, about 1% to less than about 20%, about 1% to less than about 15%, about 1% to less than about 10%, about 1% to less than about 5%, about 5% to less than about 95%, about 5% to less than about 90%, about 5% to less than about 85%, about 5% to less than about 80%, about 5% to less than about 75%, about 5% to less than about 70%, about 5% to less than about 65%, about 5% to less than about 60%, about 5% to less than about 55%, about 5% to less than about 50%, about 5% to less than about 40%, about 5% to less than about 35%, about 5% to less than about 30%, about 5% to less than about 25%, about 5% to less than about 20%, about 5% to less than about 15%, about 5% to less than about 10%, about 10% to less than about 95%, about 10% to less than about 90%, about 10% to less than about 85%, about 10% to less than about 80%, about 10% to less than about 75%, about 10% to less than about 70%, about 10% to less than about 65%, about 10% to less than about 60%, about 10% to less than about 55%, about 10% to less than about 50%, about 10% to less than about 40%, about 10% to less than about 35%, about 10% to less than about 30%, about 10% to less than about 25%, about 10% to less than about 20%, about 10% to less than about 15%. In some examples, the TPS is 1% or more and less than 50% (e.g., about 1% to about 49%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 5%, or about 1% to about 2.5%). In some examples, the TPS is 50% or more (e.g., about 50% to about 99%, about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 50% to about 60%, or about 50% to about 55%).

[0300] In some examples, the anti-PD-L1 antibody SP142 is used in the IHC assay. In some examples, a tumor sample from a subject is determined to have a detectable level of PD-L1 expression in 1% or more (e.g., about 1% or more, about 2% or more, about 3% or more, about 4% or more, about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 99% or more) of the tumor cells in the tumor sample. For example, in some instances, the tumor sample may comprise, e.g., about 1% to less than about 99% (e.g., about 1% to less than about 95%, about 1% to less than about 90%, about 1% to less than about 85%, about 1% to less than about 80%, about 1% to less than about 75%, about 1% to less than about 70%, about 1% to less than about 65%, about 1% to less than about 60%, about 1% to less than about 55%, about 1% to less than about 50%, about 1% to less than about 40%) of the tumor sample, e.g., by area. less than, about 1% to less than about 35%, about 1% to less than about 30%, about 1% to less than about 25%, about 1% to less than about 20%, about 1% to less than about 15%, about 1% to less than about 10%, about 1% to less than about 5%, about 5% to less than about 95%, about 5% to less than about 90%, about 5% to less than about 85%, about 5% to less than about 80%, about 5% to less than about 75%, about 5% to less than about 70%, about 5% to less than about 65%, about 5% to about 60% less than, about 5% to less than about 55%, about 5% to less than about 50%, about 5% to less than about 40%, about 5% to less than about 35%, about 5% to less than about 30%, about 5% to less than about 25%, about 5% to less than about 20%, about 5% to less than about 15%, about 5% to less than about 10%, about 10% to less than about 95%, about 10% to less than about 90%, about 10% to less than about 85%, about 10% to less than about 80%, about 10% to less than about 75%, about 1% have detectable PD-L1 expression levels in tumor cells that comprise 0% to less than about 70%, about 10% to less than about 65%, about 10% to less than about 60%, about 10% to less than about 55%, about 10% to less than about 50%, about 10% to less than about 40%, about 10% to less than about 35%, about 10% to less than about 30%, about 10% to less than about 25%, about 10% to less than about 20%, or about 10% to less than about 15% of the tumor cells.

[0301] In some examples, a tumor sample from a subject has been determined to have a detectable PD-L1 expression level in greater than or equal to 1% but less than 5% of tumor cells in the tumor sample. In some examples, a tumor sample from a subject has been determined to have a detectable PD-L1 expression level in greater than or equal to 5% but less than 50% of tumor cells in the tumor sample. In some examples, a tumor sample from a subject has been determined to have a detectable PD-L1 expression level in greater than or equal to 50% of tumor cells in the tumor sample.

[0302] In some examples, a tumor sample from a subject is determined to have detectable PD-L1 expression levels in tumor-infiltrating immune cells that comprise 1% or more of the tumor sample (e.g., about 1% or more, about 2% or more, about 3% or more, about 4% or more, about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 99% or more), e.g., by area. For example, in some instances, the tumor sample may comprise, e.g., about 1% to less than about 99% (e.g., about 1% to less than about 95%, about 1% to less than about 90%, about 1% to less than about 85%, about 1% to less than about 80%, about 1% to less than about 75%, about 1% to less than about 70%, about 1% to less than about 65%, about 1% to less than about 60%, about 1% to less than about 55%, about 1% to less than about 50%, about 1% to less than about 40%) of the tumor sample, e.g., by area. Full, about 1% to less than about 35%, about 1% to less than about 30%, about 1% to less than about 25%, about 1% to less than about 20%, about 1% to less than about 15%, about 1% to less than about 10%, about 1% to less than about 5%, about 5% to less than about 95%, about 5% to less than about 90%, about 5% to less than about 85%, about 5% to less than about 80%, about 5% to less than about 75%, about 5% to less than about 70%, about 5% to less than about 65%, about 5% to less than about 60% , about 5% to less than about 55%, about 5% to less than about 50%, about 5% to less than about 40%, about 5% to less than about 35%, about 5% to less than about 30%, about 5% to less than about 25%, about 5% to less than about 20%, about 5% to less than about 15%, about 5% to less than about 10%, about 10% to less than about 95%, about 10% to less than about 90%, about 10% to less than about 85%, about 10% to less than about 80%, about 10% to less than about 75%, about 10% have detectable PD-L1 expression levels on tumor-infiltrating immune cells that comprise less than about 70%, about 10% to less than about 65%, about 10% to less than about 60%, about 10% to less than about 55%, about 10% to less than about 50%, about 10% to less than about 40%, about 10% to less than about 35%, about 10% to less than about 30%, about 10% to less than about 25%, about 10% to less than about 20%, or about 10% to less than about 15% of the tumor-infiltrating immune cells.

[0303] In some examples, a tumor sample from a subject has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells that comprise greater than or equal to 1% but less than 5% of the tumor sample. In some examples, a tumor sample from a subject has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells that comprise greater than or equal to 5% but less than 10% of the tumor sample. In some examples, a tumor sample from a subject has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells that comprise greater than or equal to 10% of the tumor sample.

[0304] In some examples, the expression level or amount of the biomarker is the detectable nucleic acid expression level of PD-L1 in a tumor sample from a subject. In some examples, the nucleic acid expression level of PD-L1 is measured by RNA-seq, RT-qPCR, qPCR, multiplex qPCR, or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MassARRAY® technology, in situ hybridization (ISH), or a combination thereof.

[0305] In some examples, a subject is selected as eligible for treatment with an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody based on the presence and / or expression level / amount of a biomarker (e.g., PD-L1) in a sample from the subject, for example, if PD-L1 is a biomarker for selecting the individual. In some examples, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some examples, the tissue sample is a tumor sample. In some examples, the tumor sample includes tumor-infiltrating immune cells, tumor cells, stromal cells, and any combination thereof.

[0306] In one aspect, the present invention provides a method for treating a tumor comprising obtaining a tumor sample from a subject, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on a TPS determined to be 1% or greater. The present invention provides a method for selecting a treatment for a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some examples, the method further comprises administering a therapy to the identified subject. In another aspect, the invention provides a method for selecting a treatment for a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the TPS determined to be 1% or greater.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0307] In another aspect, the present invention provides a method for detecting PD-L1 protein expression levels in a tumor sample from a subject by an IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on a TPS determined to be greater than or equal to 1% and less than 50%. The present invention provides a method for selecting a treatment for a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), by administering an anti-TIGIT antagonist antibody to a subject, wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19. In another aspect, the invention provides a method for selecting a treatment for a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on a TPS determined to be greater than or equal to 1% and less than 50%. In some examples, the method further comprises administering the therapy to the identified subject.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0308] In another aspect, the present invention provides a method for identifying a subject as likely to benefit from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, based on a TPS determined to be 50% or greater, by obtaining a tumor sample from the subject and detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using the anti-PD-L1 antibody 22C3, and determining a TPS therefrom. The present invention provides a method for selecting a treatment for a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19. In another aspect, the invention provides a method for selecting a treatment for a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the TPS determined to be 50% or greater. In some examples, the method further comprises administering the therapy to the identified subject.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0309] In some examples, the present invention provides a method for detecting a tumor associated with an anti-TIGIT antagonist antibody and an anti-PD-L1 antibody by administering the anti-TIGIT antagonist antibody at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks, by collecting a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, based on a TPS determined to be 1% or greater. Provided is a method for identifying a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), who may benefit from therapy comprising a PD-L1 antagonist antibody, wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some examples, the invention provides a method for identifying a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) who may benefit from a therapy comprising an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody, by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the TPS determined to be 1% or greater. In some examples, the method further includes administering a therapy to the identified subject.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0310] In some examples, the present invention provides a method for detecting an anti-TIGIT antagonist antibody by collecting a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on a TPS determined to be greater than or equal to 1% and less than 50%. and a method for identifying a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) who may benefit from therapy comprising an anti-TIGIT antagonist antibody, wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some examples, the invention provides a method for identifying a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) who may benefit from a therapy comprising an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody, by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on a TPS determined to be greater than or equal to 1% and less than 50%. In some examples, the method further includes administering a therapy to the identified subject.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0311] In some examples, the invention provides a method for treating a tumor comprising administering an anti-TIGIT antagonist antibody and atezolizumab at a fixed dose of 1200 mg every three weeks, by collecting a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, based on a TPS determined to be 50% or greater. The present invention provides a method for identifying a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), who may benefit from therapy comprising an anti-PD-L1 antagonist antibody, wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some examples, the invention provides a method for identifying a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) who may benefit from a therapy comprising an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody, by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the TPS determined to be 50% or greater. In some examples, the method further includes administering a therapy to the identified subject.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0312] In some examples, the invention provides a method for detecting an anti-TIGIT antagonist antibody by collecting a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on a TPS determined to be 1% or greater. and an anti-PD-L1 antagonist antibody, wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some examples, the invention provides a method for assessing the responsiveness of a subject afflicted with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), to a therapy comprising an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody, by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the TPS determined to be 1% or greater. In some examples, the method further includes administering a therapy to the identified subject.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0313] In some examples, the invention provides a method for detecting an anti-TIGIT antagonist by collecting a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on a TPS determined to be greater than or equal to 1% and less than 50%. and an anti-PD-L1 antagonist antibody, wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some examples, the invention provides a method for assessing the responsiveness of a subject afflicted with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), to a therapy comprising an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody, by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, based on a TPS determined to be greater than or equal to 1% but less than 50%. In some examples, the method further includes administering a therapy to the identified subject.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0314] In some examples, the invention provides a method for detecting an anti-TIGIT antagonist antibody by collecting a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on a TPS determined to be 50% or greater. and an anti-PD-L1 antagonist antibody, wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some examples, the invention provides a method for assessing the responsiveness of a subject afflicted with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), to a therapy comprising an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody, by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the TPS determined to be 50% or greater. In some examples, the method further includes administering a therapy to the identified subject.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0315] In some examples, the present invention provides a method for detecting cancer (e.g., lung cancer, e.g., lung cancer, e.g., lung cancer) by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on a TPS determined to be 1% or greater. Provided is a method for optimizing a therapy comprising an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in a subject with non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC), wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some examples, the invention provides a method for optimizing a therapy comprising an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the TPS determined to be 1% or greater. In some examples, the method further includes administering a therapy to the identified subject.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0316] In some examples, the present invention provides a method for detecting a patient suffering from cancer (e.g., lung cancer, For example, provided is a method for optimizing a therapy comprising an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in a subject suffering from non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC), wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some examples, the invention provides a method for optimizing a therapy comprising an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on a TPS determined to be greater than or equal to 1% and less than 50%. In some examples, the method further includes administering a therapy to the identified subject.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0317] In some examples, the present invention provides a method for detecting a patient suffering from cancer (e.g., lung cancer, e.g., lung cancer, e.g., lung cancer) by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on a TPS determined to be 50% or greater. Also provided is a method for optimizing a therapy comprising an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in a subject suffering from non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC), wherein the anti-TIGIT antagonist antibody comprises: a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some examples, the invention provides a method for optimizing a therapy comprising an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), by obtaining a tumor sample from the subject, detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using the anti-PD-L1 antibody 22C3, determining a TPS therefrom, and identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the TPS determined to be 50% or greater. In some examples, the method further includes administering a therapy to the identified subject.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0318] Further provided herein is a method of selecting a therapy for a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), wherein the therapy is guided by a diagnostic method comprising detecting the mutation status of EGFR and ALK in a sample taken from the subject.

[0319] In some examples, the method includes detecting the EGFR and ALK mutation status in a sample from the subject, detecting the absence of a sensitizing EGFR gene mutation or an ALK gene rearrangement, and selecting for the subject, based on the subject not having a sensitizing EGFR gene mutation or an ALK gene rearrangement, a therapy comprising one or more dosing cycles of a fixed dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) of about 30 mg to about 1200 mg every three weeks and a fixed dose of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) of about 80 mg to about 1600 mg every three weeks. In some examples, the method includes detecting the EGFR and ALK mutation status in a sample from the subject, detecting the absence of a sensitizing EGFR gene mutation or an ALK gene rearrangement, and selecting for the subject, based on the subject not having a sensitizing EGFR gene mutation or an ALK gene rearrangement, a therapy comprising one or more dosing cycles of a fixed dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) of about 600 mg every three weeks and an anti-PD-L1 antagonist antibody (e.g., atezolizumab) of about 1200 mg every three weeks.

[0320] Methods for detecting the mutational status of EGFR and ALK are well known in the art and include, but are not limited to, next-generation sequencing, such as targeted gene pull-down, and sequencing DNA from clinical samples (e.g., tumor biopsies or blood samples (e.g., circulating tumor DNA in the blood)) using the sequencing method described in Frampton et al. (Nature Biotechnology. 31(11):1023-1033, 2013), the entire contents of which are incorporated herein by reference. Using such next-generation sequencing methods in conjunction with any of the methods disclosed herein can detect various mutations (e.g., insertions, deletions, base substitutions, gene amplifications, and / or homozygous gene deletions), while allowing the use of small samples (e.g., small-needle biopsies, fine-needle aspirations, and / or cell block techniques) or fixed samples (e.g., formalin-fixed, paraffin-embedded (FFPE) samples). Other methods for detecting the mutational status of EGFR and ALK include fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Exemplary methods for detecting the mutational status of ALK are disclosed in U.S. Patent No. 9,651,555, which is incorporated herein by reference in its entirety. In some examples, the VENTANA® anti-ALK (D5F3) IHC assay is used to determine the mutational status of the ALK gene.

[0321] In some examples, the EGFR and ALK mutation status in a sample from the subject is used to determine the therapeutic efficacy of the present invention, including one or more dosing cycles of an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) at a fixed dose of about 30 mg to about 1200 mg every three weeks, and one or more dosing cycles of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) at a fixed dose of about 80 mg to about 1600 mg every three weeks. (e.g., the absence of a sensitizing EGFR gene mutation or an ALK gene rearrangement may be used to identify or select an individual to be a candidate for a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody described herein. In some examples, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some examples, the tissue sample is a tumor sample.

[0322] In one aspect, the present invention provides a method for selecting a treatment for a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), by detecting the mutation status of the EGFR gene and the ALK gene in a sample from the subject and detecting the absence of a sensitizing EGFR gene mutation or an ALK gene rearrangement; and selecting a therapy comprising one or more dosing cycles of administering an anti-TIGIT antagonist antibody at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks based on the subject not having a sensitizing EGFR gene mutation or an ALK gene rearrangement, wherein the anti-TIGIT antagonist antibody comprises a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In another aspect, the present invention provides a method for selecting a treatment for a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), by detecting the mutation status of EGFR and ALK genes from a sample from the subject, detecting the absence of a sensitizing EGFR gene mutation or ALK gene rearrangement, and selecting a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the subject not having a sensitizing EGFR gene mutation or ALK gene rearrangement. In some examples, the method further comprises administering the therapy to the identified subject.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0323] In some examples of any of the methods described herein, the mutation is a sensitizing EGFR mutation. Sensitizing EGFR mutations are well known in the art and include those described in U.S. Publication No. US2018 / 0235968, which are incorporated herein by reference in their entireties, and Juan et al. (Therapeutic Advances in Medical Oncology. 9(3):201-216, 2017). In some examples, the sensitizing EGFR mutation is a mutation in any one of exons 18 to 21 (e.g., a mutation in exon 18, exon 19, exon 20, and / or exon 21). In some examples, the sensitizing EGFR mutation is a deletion of exon 19 (del19). In other examples, the sensitizing EGFR mutation is an L858R point mutation in exon 21. In some examples, the sensitizing EGFR mutation is a G719X point mutation in exon 18, where "X" is most commonly C, A, or S. In some examples, the sensitizing EGFR mutation is a G719S point mutation in exon 18. In some examples, the sensitizing EGFR mutation is a G719A point mutation in exon 18. In some examples, the sensitizing EGFR mutation is a S720F point mutation in exon 18. In some examples, the sensitizing EGFR mutation is a L861Q point mutation in exon 21. In some examples, the sensitizing EGFR mutation is a L861R point mutation in exon 21. In other examples, the sensitizing EGFR mutation is a T790M point mutation. In some examples, the sensitizing EGFR mutation is an E709X point mutation, where "X" is most commonly K, A, or H. In some examples, the sensitizing EGFR mutation is a S768I point mutation.

[0324] In some examples of any of the methods described herein, the mutation is an ALK gene rearrangement. ALK gene rearrangements are well known in the art and include those described in U.S. Patent No. 9,651,555 and Du et al. (Thoracic Cancer. 9:423-430, 2018), which are incorporated herein by reference in their entireties. In some examples, the ALK gene rearrangement generates an oncogenic ALK tyrosine kinase that activates downstream signaling pathways, resulting in increased cell proliferation and survival. In some examples, the ALK gene rearrangement is an ALK rearrangement with a gene selected from the group consisting of EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SQSTM1, NPM1, BCL11A, BIRC6, RANBP2, ATIC, CLTC, TMP4, and MSN, resulting in the formation of a fusion oncogene. In some examples, the ALK gene rearrangement is an EML4 rearrangement with ALK, resulting in the formation of a fusion oncogene EML4-ALK.

[0325] Further provided herein is a method for selecting a therapy for a subject suffering from non-small cell lung cancer (NSCLC) (e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), wherein the therapy is guided by a diagnostic method comprising detecting a subtype of NSCLC (e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) in a sample obtained from the subject.

[0326] In some examples, the method includes detecting a subtype of NSCLC other than the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC in a sample from the subject, and selecting for the subject, based on the subject not having the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC, a therapy comprising one or more dosing cycles of a fixed dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) of about 30 mg to about 1200 mg every three weeks and one or more dosing cycles of a fixed dose of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) of about 80 mg to about 1600 mg every three weeks. In some examples, the method includes detecting a subtype of NSCLC other than the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC, and selecting for the subject, based on the subject not having the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC, a therapy comprising one or more dosing cycles of a fixed dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) of about 600 mg every three weeks and one or more dosing cycles of a fixed dose of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) of about 1200 mg every three weeks.

[0327] Methods for detecting NSCLC subtypes are well known in the art and include, but are not limited to, histopathological criteria or molecular features (e.g., subtypes characterized by the expression of one or a combination of biomarkers (e.g., specific genes or proteins encoded by said genes)). In some examples, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some examples, the tissue sample is a tumor sample.

[0328] In some examples, a fixed dose of about 30 mg to about 1200 mg of an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., TIGIT antagonist antibody) is administered every three weeks to a patient with NSCLC subtype (e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) determined from a sample obtained from the subject. Identify or select subjects as eligible for a therapy comprising one or more dosing cycles of an anti-PD-L1 antagonist antibody (e.g., lagolumab) and one or more dosing cycles of an anti-PD-L1 antagonist antibody (e.g., atezolizumab) at a fixed dose of about 80 mg to about 1600 mg every three weeks (e.g., absence of the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC may be used to identify and select individuals who are candidates for a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody described herein).

[0329] In one aspect, the present invention provides a method for selecting a therapy for a subject suffering from NSCLC (e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), by detecting a subtype of NSCLC other than pulmonary lymphoepithelioma-like carcinoma; and selecting, based on the subject not having the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC, a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks for the subject, wherein the anti-TIGIT antagonist antibody comprises a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In another aspect, the present invention provides a method for selecting a therapy for a subject suffering from NSCLC (e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), by biopsying a tumor sample from the subject to detect a subtype of NSCLC other than pulmonary lymphoepithelioma-like carcinoma; and based on the subject not having the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC, selecting for the subject a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.In one aspect, the invention provides a method of selecting a therapy for a subject afflicted with NSCLC (e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) by detecting a subtype of NSCLC other than pulmonary lymphoepithelioma-like carcinoma; and selecting for the subject a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the subject not having the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC. In another aspect, the invention provides a method for selecting a therapy for a subject suffering from NSCLC (e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) by biopsying a tumor sample from the subject to detect a subtype of NSCLC other than pulmonary lymphoepithelioma-like carcinoma; and selecting a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks for the subject based on the subject not having the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC. In some examples, the method further comprises administering the therapy to the identified subject.In some examples, the therapy includes one or more additional anti-cancer therapeutic(s) (e.g., an immunomodulatory agent (e.g., an immunosuppressant that inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), e.g., a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))), or one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA), e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®))). The therapeutic agent may further comprise or be administered in combination (separately or together) with an agent that increases or activates a stimulatory receptor (e.g., one or more immune costimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR, e.g., an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy / radiotherapy, and / or an antihormonal agent as detailed herein above).

[0330] Further provided herein is a method for selecting a therapy for a subject suffering from cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), wherein the therapy is guided by a diagnostic method comprising detecting the presence of one or more indicators of active or chronically active EBV infection in a sample taken from the subject.

[0331] Indicators of active or chronic active EBV infection for use in the methods described herein include, but are not limited to, EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr virus particles detected in a sample (e.g., a blood or serum sample) from a subject.

[0332] In some examples, the method detects the presence of one or more indicators of active or chronic active EBV infection, including EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr virus particles, in a sample from the subject, and determines whether the sample is (a) negative for EBV IgG and / or EBNA, (b) positive for EBV IgG and / or EBNA and negative fo...

Claims

1. 1. A method of treating a subject afflicted with lung cancer, said method comprising administering to said subject an anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 1200 mg every three weeks and an anti-PD-L1 antagonist antibody at a fixed dose of about 80 mg to about 1600 mg every three weeks for one or more dosing cycles.

2. 10. The method of claim 1, wherein the method comprises administering to the subject a fixed dose of about 30 mg to about 600 mg of an anti-TIGIT antagonist antibody every three weeks.

3. 3. The method of claim 2, wherein the method comprises administering to the subject a fixed dose of about 600 mg of an anti-TIGIT antagonist antibody every three weeks.

4. The anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs): an HVR-H1 sequence having the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence having the amino acid sequence KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence having the amino acid sequence ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence having the amino acid sequence KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence having the amino acid sequence of WASTRES (SEQ ID NO:5); and HVR-L3 sequence having the amino acid sequence QQYYSTPFT (SEQ ID NO: 6) The method according to any one of claims 1 to 3, comprising:

5. The anti-TIGIT antagonist antibody comprises the following framework region (FR) of a light chain variable region: FR-L1 having the amino acid sequence DIVMTQSPDSLAVSLGERATINC (SEQ ID NO:7); FR-L2 having the amino acid sequence WYQQKPGQPPNLLIY (SEQ ID NO: 8); FR-L3 having the amino acid sequence GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and FR-L4 having the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10) The method of claim 4 further comprising:

6. The anti-TIGIT antagonist antibody comprises the following FRs of a heavy chain variable region: X １ FR-H1 having the amino acid sequence of VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), １ is Q or E); FR-H2 having the amino acid sequence WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 having the amino acid sequence RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and FR-H4 having the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 14) The method of claim 4 further comprising:

7. In the formula, X １ The method of claim 6 , wherein is Q.

8. In the formula, X １ The method of claim 6 , wherein is E.

9. The anti-TIGIT antagonist antibody: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) the VH domain of (a) and the VL domain of (b) The method according to any one of claims 4 to 8, comprising:

10. The anti-TIGIT antagonist antibody: A VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and VL domain having the amino acid sequence of SEQ ID NO: 19 The method according to any one of claims 1 to 9, comprising:

11. The method of any one of claims 1 to 10, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

12. The method of claim 11 , wherein the anti-TIGIT antagonist antibody is a human antibody.

13. The method of any one of claims 1 to 12, wherein the anti-TIGIT antagonist antibody is a full-length antibody.

14. The method of any one of claims 1 to 6 and 8 to 13, wherein the anti-TIGIT antagonist antibody is tiragolumab.

15. The anti-TIGIT antagonist antibody may be in the form of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab'). ２ The method according to any one of claims 1 to 12, wherein the antibody fragment is an antibody fragment that binds to TIGIT, selected from the group consisting of antibody fragments.

16. The method according to any one of claims 1 to 15, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

17. The method of claim 16, wherein the IgG class antibody is an IgG1 subclass antibody.

18. 18. The method of any one of claims 1 to 17, wherein the method comprises administering to the subject a fixed dose of about 1200 mg of an anti-PD-L1 antibody every three weeks.

19. 19. The method of any one of claims 1 to 18, wherein the anti-PD-L1 antagonist antibody is atezolizumab (MPDL3280A), YW243.55.S70, MSB0010718C, MDX-1105, or MEDI4736.

20. 20. The method of claim 19, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

21. The anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence having the amino acid sequence GFTFSDSWIH (SEQ ID NO: 20); an HVR-H2 sequence having the amino acid sequence AWISPYGGSTYYADSVKG (SEQ ID NO: 21); an HVR-H3 sequence having the amino acid sequence RHWPGGFDY (SEQ ID NO: 22); an HVR-L1 sequence having the amino acid sequence RASQDVSTAVA (SEQ ID NO: 23); an HVR-L2 sequence having the amino acid sequence of SASFLYS (SEQ ID NO:24); and HVR-L3 sequence having the amino acid sequence QQYLYHPAT (SEQ ID NO: 25) The method of any one of claims 1 to 18, comprising:

22. The anti-PD-L1 antagonist antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) the VH domain of (a) and the VL domain of (b) 22. The method of claim 21, comprising:

23. The anti-PD-L1 antagonist antibody comprises: A VH domain having the amino acid sequence of SEQ ID NO: 26; and A VL domain having the amino acid sequence of SEQ ID NO: 27 The method of any one of claims 1 to 22, comprising:

24. The method of any one of claims 21 to 23, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody.

25. 25. The method of claim 24, wherein the anti-PD-L1 antagonist antibody is a humanized antibody.

26. The method of claim 24 or 25, wherein the anti-PD-L1 antagonist antibody is a full-length antibody.

27. The anti-PD-L1 antagonist antibody is in the form of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab') ２ The method according to any one of claims 21 to 25, wherein the antibody fragment is an antibody fragment that binds to PD-L1 and is selected from the group consisting of antibody fragments.

28. The method according to any one of claims 21 to 27, wherein the anti-PD-L1 antagonist antibody is an IgG class antibody.

29. The method of claim 28, wherein the IgG class antibody is an IgG1 subclass antibody.

30. 30. The method of any one of claims 1-29, wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody at a fixed dose of about 600 mg every three weeks and the anti-PD-L1 antagonist antibody at a fixed dose of about 1200 mg every three weeks.

31. 31. The method of any one of claims 1-30, wherein each of the one or more dosing cycles is 21 days in length.

32. 32. The method of any one of claims 1-31, wherein the method comprises administering the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody to the subject on about day 1 of each of the one or more dosing cycles.

33. 33. The method of any one of claims 1 to 32, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject prior to the anti-PD-L1 antagonist antibody.

34. 34. The method of claim 33, wherein the method comprises a first observation period after administration of the anti-TIGIT antagonist antibody and a second observation period after administration of the anti-PD-L1 antagonist antibody.

35. 35. The method of claim 34, wherein the first observation period and the second observation period each have a length of about 30 minutes to about 60 minutes.

36. 33. The method of any one of claims 1 to 32, wherein the method comprises administering the anti-PD-L1 antagonist antibody to the subject prior to the anti-TIGIT antagonist antibody.

37. 37. The method of claim 36, wherein the method comprises a first observation period after administration of the anti-PD-L1 antagonist antibody and a second observation period after administration of the anti-TIGIT antagonist antibody.

38. 38. The method of claim 37, wherein the first observation period and the second observation period each have a length of about 30 minutes to about 60 minutes.

39. 33. The method of any one of claims 1 to 32, wherein the method comprises administering the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody simultaneously to the subject.

40. 40. The method of any one of claims 1 to 39, wherein the method comprises intravenously administering the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody to the subject.

41. 41. The method of claim 40, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject by intravenous infusion over a period of 60±10 minutes.

42. 42. The method of claim 40 or 41, wherein the method comprises administering the anti-PD-L1 antagonist antibody to the subject by intravenous infusion over a period of 60±15 minutes.

43. The method of any one of claims 1 to 42, wherein the tumor sample taken from the subject has been determined to have a detectable PD-L1 expression level.

44. 44. The method of claim 43, wherein the detectable PD-L1 expression level is a detectable PD-L1 protein expression level.

45. 45. The method of claim 44, wherein the detectable PD-L1 protein expression level is measured by an immunohistochemistry (IHC) assay.

46. 46. ​​The method of claim 45, wherein the IHC assay uses anti-PD-L1 antibody 22C3, SP142, SP263, or 28-8.

47. 47. The method of claim 46, wherein the IHC assay uses anti-PD-L1 antibody 22C3.

48. 48. The method of claim 47, wherein the tumor sample has been determined to have a tumor positive site (TPS) of 1% or greater.

49. 49. The method of claim 48, wherein the TPS is greater than or equal to 1% and less than 50%.

50. 49. The method of claim 48, wherein the TPS is 50% or greater.

51. 47. The method of claim 46, wherein the IHC assay uses the anti-PD-L1 antibody SP142.

52. 52. The method of claim 51, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in 1% or more of the tumor cells in the tumor sample.

53. 53. The method of claim 52, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 1% and less than 5% of the tumor cells in the tumor sample.

54. 53. The method of claim 52, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 5% but less than 50% of the tumor cells in the tumor sample.

55. 53. The method of claim 52, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in 50% or more of the tumor cells in the tumor sample.

56. 56. The method of any one of claims 51-55, wherein the tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells comprising 1% or more of the tumor sample.

57. 57. The method of claim 56, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells comprising greater than or equal to 1% and less than 5% of the tumor sample.

58. 57. The method of claim 56, wherein the tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells comprising greater than or equal to 5% and less than 10% of the tumor sample.

59. 57. The method of claim 56, wherein the tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells comprising 10% or more of the tumor sample.

60. 44. The method of claim 43, wherein the detectable PD-L1 expression level is a detectable PD-L1 nucleic acid expression level.

61. 61. The method of claim 60, wherein the detectable PD-L1 nucleic acid expression level is measured by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

62. 62. The method of any one of claims 1 to 61, wherein the lung cancer is non-small cell lung cancer (NSCLC).

63. 63. The method of claim 62, wherein the NSCLC is squamous NSCLC.

64. 63. The method of claim 62, wherein the NSCLC is a non-squamous NSCLC.

65. The method of any one of claims 62 to 64, wherein the NSCLC is locally advanced unresectable NSCLC.

66. 66. The method of claim 65, wherein the NSCLC is stage IIIB NSCLC.

67. The method of any one of embodiments 62-64, wherein said NSCLC is recurrent or metastatic NSCLC.

68. 68. The method of claim 67, wherein the NSCLC is stage IV NSCLC.

69. 69. The method of claim 67 or 68, wherein the subject has not been previously treated for stage IV NSCLC.

70. 70. The method of any one of claims 1 to 69, wherein the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

71. 71. The method of any one of claims 1 to 70, wherein the subject does not have the lung lymphoepithelioma-like carcinoma subtype of NSCLC.

72. 72. The method of any one of claims 1 to 71, wherein the subject does not have an active Epstein-Barr virus (EBV) infection or a known or suspected chronic active EBV infection.

73. 73. The method of any one of claims 1 to 72, wherein the subject is EBV IgM negative or EBV PCR negative.

74. 74. The method of claim 73, wherein the subject is negative for EBV IgM and negative by EBV PCR.

75. 75. The method of claim 73 or 74, wherein the subject is positive for EBV IgG or positive for Epstein-Barr Nuclear Antigen (EBNA).

76. 76. The method of claim 75, wherein the subject is positive for EBV IgG and positive for EBNA.

77. 75. The method of any one of claims 1 to 74, wherein the subject is negative for EBV IgG or negative for EBNA.

78. 78. The method of claim 77, wherein the subject is negative for EBV IgG and negative for EBNA.

79. 79. The method of any one of claims 1 to 78, wherein the treatment results in a clinical response.

80. 80. The method of claim 79, wherein the clinical response is an increase in the subject's objective response rate (ORR) compared to a reference ORR.

81. 81. The method of claim 80, wherein the reference ORR is the median ORR of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody.

82. 82. The method of any one of claims 79-81, wherein the clinical response is an increase in the subject's progression-free survival (PFS) compared to a reference PFS period.

83. The method of any one of claims 79 to 82, wherein the reference PFS period is the median PFS period of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody.

84. 1. A method of treating a subject suffering from NSCLC, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks for one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is: A VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and VL domain having the amino acid sequence of SEQ ID NO: 19 The method of treatment comprises:

85. 1. A method of treating a subject suffering from NSCLC, said method comprising: (a) obtaining a tumor sample from said subject; (b) detecting the protein expression level of PD-L1 in said tumor sample by IHC assay using anti-PD-L1 antibody 22C3, and determining TPS therefrom; (c) based on the TPS determined to be greater than or equal to 1% and less than 50%, identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody: A VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and VL domain having the amino acid sequence of SEQ ID NO: 19 said method further comprising: (d) administering said therapy to said identified subject.

86. 1. A method of treating a subject suffering from NSCLC, said method comprising: (a) obtaining a tumor sample from said subject; (b) detecting the protein expression level of said PD-L1 in said tumor sample by an IHC assay using anti-PD-L1 antibody 22C3, and determining a TPS therefrom; (c) based on the TPS determined to be 50% or greater, identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody: A VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and VL domain having the amino acid sequence of SEQ ID NO: 19 said method further comprising: (d) administering said therapy to said identified subject.

87. 1. A method for selecting a therapy for a subject suffering from NSCLC, said method comprising: (a) determining TPS from a tumor sample from said subject by an IHC assay using anti-PD-L1 antibody 22C3; and (b) based on the TPS determined to be greater than or equal to 1% and less than 50%, selecting for the subject a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody is selected from the group consisting of: A VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and VL domain having the amino acid sequence of SEQ ID NO: 19 The selection method includes:

88. 1. A method for selecting a therapy for a subject suffering from NSCLC, said method comprising: (a) determining TPS from a tumor sample from said subject by an IHC assay using anti-PD-L1 antibody 22C3; and (b) based on the TPS determined to be 50% or greater, selecting for the subject a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody is selected from the group consisting of: A VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and VL domain having the amino acid sequence of SEQ ID NO: 19 The selection method includes:

89. 1. A method for selecting a therapy for a subject suffering from NSCLC, said method comprising: (a) detecting the mutation status of the epidermal growth factor receptor (EGFR) gene and the anaplastic lymphoma kinase (ALK) gene in a sample from the subject, and detecting the absence of a sensitizing EGFR gene mutation or an ALK gene rearrangement; and (b) selecting for the subject, based on the subject's absence of a sensitizing EGFR gene mutation or an ALK gene rearrangement, a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody is: A VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and VL domain having the amino acid sequence of SEQ ID NO: 19 The selection method includes:

90. 1. A method for selecting a therapy for a subject suffering from NSCLC, said method comprising: (a) biopsying a tumor sample from the subject to detect a subtype of NSCLC other than pulmonary lymphoepithelioma-like carcinoma; and (b) selecting for the subject a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the subject's absence of the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC, wherein the anti-TIGIT antagonist antibody is: A VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and VL domain having the amino acid sequence of SEQ ID NO: 19 The selection method includes:

91. 1. A method for selecting a therapy for a subject suffering from NSCLC, said method comprising: (a) detecting the presence of one or more of Epstein-Barr virus (EBV) IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr virus particles in a sample from the subject; and (b) the subject is: (i) negative for EBV IgG and / or EBNA; or (ii) based on the positive result for EBV IgG and / or EBNA and the negative result for both EBV IgM and Epstein-Barr virus particles, selecting for the subject a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, wherein the anti-TIGIT antagonist antibody is: A VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and VL domain having the amino acid sequence of SEQ ID NO: 19 The selection method includes:

92. 1. A method of treating a subject with NSCLC, said method comprising administering to said subject tiragolumab at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks for one or more dosing cycles.

93. 1. A method of treating a subject suffering from NSCLC, said method comprising: (a) obtaining a tumor sample from said subject; (b) detecting the protein expression level of PD-L1 in said tumor sample by IHC assay using anti-PD-L1 antibody 22C3, and determining TPS therefrom; (c) identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the TPS being determined to be greater than or equal to 1% and less than 50%; and (d) administering said therapy to said identified subject.

94. 1. A method of treating a subject suffering from NSCLC, said method comprising: (a) obtaining a tumor sample from said subject; (b) detecting the protein expression level of PD-L1 in said tumor sample by IHC assay using anti-PD-L1 antibody 22C3, and determining TPS therefrom; (c) identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the TPS being determined to be 50% or greater; and (d) administering said therapy to said identified subject.

95. 1. A method for selecting a therapy for a subject suffering from NSCLC, said method comprising: (a) determining TPS from a tumor sample from said subject by an IHC assay using anti-PD-L1 antibody 22C3; and (b) selecting for the subject a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the TPS determined to be greater than or equal to 1% and less than 50%.

96. 1. A method for selecting a therapy for a subject suffering from NSCLC, said method comprising: (a) determining TPS from a tumor sample from said subject by an IHC assay using anti-PD-L1 antibody 22C3; and (b) selecting for the subject a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the TPS determined to be 50% or greater.

97. 1. A method for selecting a therapy for a subject suffering from NSCLC, said method comprising: (a) detecting the mutation status of the epidermal growth factor receptor (EGFR) gene and the anaplastic lymphoma kinase (ALK) gene in a sample from the subject, and detecting the absence of a sensitizing EGFR gene mutation or an ALK gene rearrangement; and (b) selecting for the subject a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, based on the subject's absence of a sensitizing EGFR gene mutation or an ALK gene rearrangement.

98. 1. A method for selecting a therapy for a subject suffering from NSCLC, said method comprising: (a) biopsying a tumor sample from the subject to detect a subtype of NSCLC other than pulmonary lymphoepithelioma-like carcinoma; and (b) selecting for the subject a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the subject's absence of the lung lymphoepithelioma-like carcinoma subtype of NSCLC.

99. 1. A method for selecting a therapy for a subject suffering from NSCLC, said method comprising: (a) detecting the presence of one or more of Epstein-Barr virus (EBV) IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr virus particles in a sample from the subject; and (b) the subject is: (i) negative for EBV IgG and / or EBNA; or (ii) selecting for the subject a therapy comprising one or more dosing cycles of tiragolumab administered at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks based on the subject's positive result for EBV IgG and / or EBNA and negative result for both EBV IgM and Epstein-Barr virus particles.

100. An anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody for use in a method of treating a subject suffering from lung cancer, the method comprising administering to the subject the anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 1200 mg every three weeks and the anti-PD-L1 antagonist antibody at a fixed dose of about 80 mg to about 1600 mg every three weeks for one or more dosing cycles.

101. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 100, wherein the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 30 mg to about 600 mg every three weeks.

102. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 101, wherein the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks.

103. the anti-TIGIT antagonist antibody comprises the following HVRs: an HVR-H1 sequence having the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence having the amino acid sequence KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence having the amino acid sequence ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence having the amino acid sequence KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence having the amino acid sequence of WASTRES (SEQ ID NO:5); and HVR-L3 sequence having the amino acid sequence QQYYSTPFT (SEQ ID NO: 6) The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 102, comprising:

104. The anti-TIGIT antagonist antibody comprises the following FR of a light chain variable region: FR-L1 having the amino acid sequence DIVMTQSPDSLAVSLGERATINC (SEQ ID NO:7); FR-L2 having the amino acid sequence WYQQKPGQPPNLLIY (SEQ ID NO: 8); FR-L3 having the amino acid sequence GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and FR-L4 having the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10) The anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody for use according to claim 103, comprising:

105. The anti-TIGIT antagonist antibody comprises the following FRs of a heavy chain variable region: X １ FR-H1 having the amino acid sequence of VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), １ is Q or E); FR-H2 having the amino acid sequence WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 having the amino acid sequence RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and FR-H4 having the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 14) The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 103, further comprising:

106. X １ The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 105, wherein

107. X １ The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 105, wherein

108. The anti-TIGIT antagonist antibody: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) the VH domain of (a) and the VL domain of (b) The anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody for use according to any one of claims 103 to 107, comprising:

109. The anti-TIGIT antagonist antibody: A VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and VL domain having the amino acid sequence of SEQ ID NO: 19 The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 108, comprising:

110. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 109, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

111. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 110, wherein the anti-TIGIT antagonist antibody is a human antibody.

112. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 111, wherein the anti-TIGIT antagonist antibody is a full-length antibody.

113. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 105 and 107 to 112, wherein the anti-TIGIT antagonist antibody is tiragolumab.

114. The anti-TIGIT antagonist antibody may be in the form of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab'). ２ The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 111, which are antibody fragments that bind to TIGIT, selected from the group consisting of TIGIT-binding fragments.

115. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 114, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

116. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 115, wherein the IgG class antibody is an IgG1 subclass antibody.

117. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 116, wherein the anti-PD-L1 antagonist antibody is administered to the subject at a fixed dose of about 1200 mg every three weeks.

118. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 117, wherein the anti-PD-L1 antagonist antibody is atezolizumab (MPDL3280A), YW243.55.S70, MSB0010718C, MDX-1105, or MEDI4736.

119. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 118, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

120. The anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence having the amino acid sequence GFTFSDSWIH (SEQ ID NO: 20); an HVR-H2 sequence having the amino acid sequence AWISPYGGSTYYADSVKG (SEQ ID NO: 21); an HVR-H3 sequence having the amino acid sequence RHWPGGFDY (SEQ ID NO: 22); an HVR-L1 sequence having the amino acid sequence RASQDVSTAVA (SEQ ID NO: 23); an HVR-L2 sequence having the amino acid sequence of SASFLYS (SEQ ID NO:24); and HVR-L3 sequence having the amino acid sequence QQYLYHPAT (SEQ ID NO: 25) The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 117, comprising:

121. The anti-PD-L1 antagonist antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) the VH domain of (a) and the VL domain of (b) The anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody for use according to claim 120, comprising:

122. The anti-PD-L1 antagonist antibody comprises: A VH domain having the amino acid sequence of SEQ ID NO: 26; and A VL domain having the amino acid sequence of SEQ ID NO: 27 The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 121, comprising:

123. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 120 to 122, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody.

124. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 123, wherein the anti-PD-L1 antagonist antibody is a humanized antibody.

125. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 123 or 124, wherein the anti-PD-L1 antagonist antibody is a full-length antibody.

126. The anti-PD-L1 antagonist antibody is in the form of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab') ２ The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 120 to 124, which is an antibody fragment that binds to PD-L1, selected from the group consisting of fragments.

127. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 120 to 126, wherein the anti-PD-L1 antagonist antibody is an IgG class antibody.

128. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 127, wherein the IgG class antibody is an IgG1 subclass antibody.

129. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 128, wherein the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks, and the anti-PD-L1 antagonist antibody is administered to the subject at a fixed dose of about 1200 mg every three weeks.

130. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 129, wherein each of the one or more dosing cycles has a length of 21 days.

131. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 130, wherein the anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody are administered to the subject on about day 1 of each of the one or more dosing cycles.

132. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 131, wherein the anti-TIGIT antagonist antibody is administered to the subject before the anti-PD-L1 antagonist antibody.

133. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 132, wherein a first observation period is after administration of the anti-TIGIT antagonist antibody and a second observation period is after administration of the anti-PD-L1 antagonist antibody.

134. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 133, wherein the length of the first observation period and the second observation period is from about 30 minutes to about 60 minutes, respectively.

135. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 131, wherein the anti-PD-L1 antagonist antibody is administered to the subject before the anti-TIGIT antagonist antibody.

136. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 135, wherein a first observation period is after administration of the anti-PD-L1 antagonist antibody and a second observation period is after administration of the anti-TIGIT antagonist antibody.

137. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 136, wherein the length of the first observation period and the second observation period is from about 30 minutes to about 60 minutes, respectively.

138. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 131, wherein the anti-TIGIT antagonist antibody is administered to the subject simultaneously with the anti-PD-L1 antagonist antibody.

139. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 138, wherein the anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody are administered intravenously to the subject.

140. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 139, wherein the anti-TIGIT antagonist antibody is administered to the subject by intravenous infusion over a period of 60±10 minutes.

141. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 139 or 140, wherein the anti-PD-L1 antagonist antibody is administered to the subject by intravenous infusion over 60±15 minutes.

142. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 141, wherein a tumor sample taken from the subject has been determined to have a detectable PD-L1 expression level.

143. The anti-TIGIT antagonist antibody and anti-PD-L1 antibody for use according to claim 142, wherein the detectable PD-L1 expression level is a detectable PD-L1 protein expression level.

144. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 143, wherein the detectable PD-L1 protein expression level is measured by an immunohistochemistry (IHC) assay.

145. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 144, wherein the IHC assay uses anti-PD-L1 antibody 22C3, SP142, SP263, or 28-8.

146. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 145, wherein the anti-PD-L1 antibody 22C3 is used in the IHC assay.

147. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 146, wherein the tumor sample has been determined to have a tumor positive site (TPS) of 1% or more.

148. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 147, wherein the TPS is 1% or more and less than 50%.

149. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 147, wherein the TPS is 50% or more.

150. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 145, wherein the anti-PD-L1 antibody SP142 is used in the IHC assay.

151. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 150, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in 1% or more of the tumor cells in the tumor sample.

152. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 151, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 1% and less than 5% of the tumor cells in the tumor sample.

153. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 151, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 5% and less than 50% of the tumor cells in the tumor sample.

154. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 151, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in 50% or more of the tumor cells in the tumor sample.

155. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 150 to 154, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells that comprise 1% or more of the tumor sample.

156. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 155, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells comprising greater than or equal to 1% and less than 5% of the tumor sample.

157. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 155, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells comprising greater than or equal to 5% and less than 10% of the tumor sample.

158. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 155, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells comprising 10% or more of the tumor sample.

159. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 142, wherein the detectable PD-L1 expression level is a detectable PD-L1 nucleic acid expression level.

160. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 159, wherein the detectable PD-L1 nucleic acid expression level is measured by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

161. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 160, wherein the lung cancer is non-small cell lung cancer (NSCLC).

162. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 161, wherein the NSCLC is squamous NSCLC.

163. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 161, wherein the NSCLC is non-squamous NSCLC.

164. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 161 to 163, wherein the NSCLC is locally advanced unresectable NSCLC.

165. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 164, wherein the NSCLC is stage IIIB NSCLC.

166. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 161 to 163, wherein the NSCLC is recurrent or metastatic NSCLC.

167. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 166, wherein the NSCLC is stage IV NSCLC.

168. 168. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 166 or 167, wherein the subject has not been previously treated for stage IV NSCLC.

169. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 168, wherein the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

170. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 169, wherein the subject is not affected by the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

171. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 170, wherein the subject does not have an active EBV infection or a known or suspected chronic active EBV infection.

172. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 171, wherein the subject is negative for EBV IgM or negative by EBV PCR.

173. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 172, wherein the subject is negative for EBV IgM and negative by EBV PCR.

174. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 172 or 173, wherein the subject is positive for EBV IgG or positive for EBNA.

175. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 174, wherein the subject is positive for EBV IgG and positive for EBNA.

176. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 173, wherein the subject is negative for EBV IgG or negative for EBNA.

177. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 176, wherein the subject is negative for EBV IgG and negative for EBNA.

178. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 100 to 177, wherein administration of the anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody results in a clinical response.

179. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 178, wherein the clinical response is an increase in the objective response rate (ORR) in the subject compared to a reference ORR.

180. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 179, wherein the reference ORR is the median ORR of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody.

181. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 178 to 180, wherein the clinical response is an increase in the progression-free survival (PFS) period of the subject compared to a reference PFS period.

182. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to any one of claims 178 to 181, wherein the reference PFS period is the median PFS period of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody.

183. 1. An anti-TIGIT antagonist antibody and atezolizumab for use in a method of treating a subject suffering from NSCLC, said method comprising administering to said subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks, wherein said anti-TIGIT antagonist antibody is: A VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and VL domain having the amino acid sequence of SEQ ID NO: 19 The anti-TIGIT antagonist antibody and atezolizumab.

184. 1. Tiragolumab and atezolizumab for use in a method of treatment of a subject suffering from NSCLC, said method comprising administering to said subject tiragolumab at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks for one or more dosing cycles.

185. 1. Use of an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in the manufacture of a medicament for use in a method of treating a subject suffering from lung cancer, said method comprising administering said medicaments to said subject in one or more dosing cycles, wherein said medicaments are formulated for administration of said anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 1200 mg every three weeks, and said anti-PD-L1 antagonist antibody at a fixed dose of about 80 mg to about 1600 mg every three weeks.

186. 1. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject suffering from lung cancer, said method comprising administering to said subject said medicament and an anti-PD-L1 antagonist antibody in one or more dosing cycles, wherein said medicament is formulated for administration at a fixed dose of about 30 mg to about 1200 mg every three weeks, and said anti-PD-L1 antagonist antibody is administered at a fixed dose of about 80 mg to about 1600 mg every three weeks.

187. 1. Use of an anti-PD-L1 antagonist antibody in the manufacture of a medicament for use in a method of treating a subject suffering from lung cancer, said method comprising administering to said subject said medicament and an anti-TIGIT antagonist antibody in one or more dosing cycles, wherein said medicament is formulated for administration at a fixed dose of about 80 mg to about 1600 mg every three weeks, and said anti-TIGIT antagonist antibody is administered at a fixed dose of about 30 mg to about 1200 mg every three weeks.

188. The use of any one of claims 185 to 187, wherein the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 30 mg to about 600 mg every three weeks.

189. The use of claim 188, wherein the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks.

190. The anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs): an HVR-H1 sequence having the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence having the amino acid sequence KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence having the amino acid sequence ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence having the amino acid sequence KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence having the amino acid sequence of WASTRES (SEQ ID NO:5); and HVR-L3 sequence having the amino acid sequence QQYYSTPFT (SEQ ID NO: 6) 190. The use according to any one of claims 185 to 189, comprising:

191. The anti-TIGIT antagonist antibody comprises the following framework region (FR) of a light chain variable region: FR-L1 having the amino acid sequence DIVMTQSPDSLAVSLGERATINC (SEQ ID NO:7); FR-L2 having the amino acid sequence WYQQKPGQPPNLLIY (SEQ ID NO: 8); FR-L3 having the amino acid sequence GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and FR-L4 having the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10) 191. The use of claim 190, further comprising:

192. The anti-TIGIT antagonist antibody comprises the following FRs of a heavy chain variable region: X １ FR-H1 having the amino acid sequence of VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), １ is Q or E); FR-H2 having the amino acid sequence WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 having the amino acid sequence RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and FR-H4 having the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 14) 191. The use of claim 190, further comprising:

193. X １ The use of claim 192, wherein is Q.

194. X １ The use of claim 192, wherein is E.

195. The anti-TIGIT antagonist antibody: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) the VH domain of (a) and the VL domain of (b) 195. The use according to any one of claims 190 to 194, comprising:

196. The anti-TIGIT antagonist antibody: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) the VH domain of (a) and the VL domain of (b) 196. The use according to any one of claims 185 to 195, comprising:

197. The use of any one of claims 185 to 196, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

198. The use of claim 197, wherein the anti-TIGIT antagonist antibody is a human antibody.

199. The use of any one of claims 185 to 198, wherein the anti-TIGIT antagonist antibody is a full-length antibody.

200. 200. The use of any one of claims 185 to 192 and 194 to 199, wherein the anti-TIGIT antagonist antibody is tiragolumab.

201. The anti-TIGIT antagonist antibody may be in the form of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab'). ２ The use according to any one of claims 185 to 198, which is an antibody fragment that binds to TIGIT, selected from the group consisting of antibody fragments.

202. The use according to any one of claims 185 to 201, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

203. The use described in claim 202, wherein the IgG class antibody is an IgG1 subclass antibody.

204. The use of any one of claims 185 to 203, wherein the anti-PD-L1 antagonist antibody is administered to the subject at a fixed dose of about 1200 mg every three weeks.

205. The use of any one of claims 185 to 204, wherein the anti-PD-L1 antagonist antibody is atezolizumab (MPDL3280A), YW243.55.S70, MSB0010718C, MDX-1105, or MEDI4736.

206. The use of claim 205, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

207. The anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence having the amino acid sequence GFTFSDSWIH (SEQ ID NO: 20); an HVR-H2 sequence having the amino acid sequence AWISPYGGSTYYADSVKG (SEQ ID NO: 21); an HVR-H3 sequence having the amino acid sequence RHWPGGFDY (SEQ ID NO: 22); an HVR-L1 sequence having the amino acid sequence RASQDVSTAVA (SEQ ID NO: 23); an HVR-L2 sequence having the amino acid sequence of SASFLYS (SEQ ID NO:24); and HVR-L3 sequence having the amino acid sequence QQYLYHPAT (SEQ ID NO: 25) The use according to any one of claims 185 to 204, comprising:

208. The anti-PD-L1 antagonist antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) the VH domain of (a) and the VL domain of (b) The use of claim 207, comprising:

209. The anti-PD-L1 antagonist antibody comprises: A VH domain having the amino acid sequence of SEQ ID NO: 26; and A VL domain having the amino acid sequence of SEQ ID NO: 27 The use according to any one of claims 185 to 208, comprising:

210. The use according to any one of claims 207 to 209, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody.

211. The use of claim 210, wherein the anti-PD-L1 antagonist antibody is a humanized antibody.

212. The use of claim 210 or 211, wherein the anti-PD-L1 antagonist antibody is a full-length antibody.

213. The anti-PD-L1 antagonist antibody is in the form of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab') ２ The use according to any one of claims 207 to 211, wherein the antibody fragment is an antibody fragment that binds to PD-L1, selected from the group consisting of antibody fragments.

214. The use according to any one of claims 207 to 213, wherein the anti-PD-L1 antagonist antibody is an IgG class antibody.

215. The use described in claim 214, wherein the IgG class antibody is an IgG1 subclass antibody.

216. The use of any one of claims 185 to 215, wherein the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks, and the anti-PD-L1 antagonist antibody is administered to the subject at a fixed dose of about 1200 mg every three weeks.

217. 217. The use of any one of claims 185 to 216, wherein each of the one or more dosing cycles is 21 days in length.

218. The use of any one of claims 185 to 217, wherein the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are administered to the subject on about day 1 of each of the one or more dosing cycles.

219. The use of any one of claims 185 to 218, comprising administering the anti-TIGIT antagonist antibody to the subject prior to the anti-PD-L1 antagonist antibody.

220. 220. The use of claim 219, wherein a first observation period is after administration of the anti-TIGIT antagonist antibody and a second observation period is after administration of the anti-PD-L1 antagonist antibody.

221. 221. The use of claim 220, wherein the first observation period and the second observation period each have a length of about 30 minutes to about 60 minutes.

222. The use of any one of claims 185 to 218, comprising administering the anti-PD-L1 antagonist antibody to the subject prior to the anti-TIGIT antagonist antibody.

223. The use of claim 222, wherein a first observation period is after administration of the anti-PD-L1 antagonist antibody and a second observation period is after administration of the anti-TIGIT antagonist antibody.

224. 224. The use of claim 223, wherein the first observation period and the second observation period each have a length of about 30 minutes to about 60 minutes.

225. The use of any one of claims 185 to 218, wherein the anti-TIGIT antagonist antibody is administered to the subject simultaneously with the anti-PD-L1 antagonist antibody.

226. The use of any one of claims 185 to 225, wherein the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are administered intravenously to the subject.

227. 227. The use of claim 226, wherein the anti-TIGIT antagonist antibody is administered to the subject by intravenous infusion over 60±10 minutes.

228. 228. The use of claim 226 or 227, wherein the anti-PD-L1 antagonist antibody is administered to the subject by intravenous infusion over 60±15 minutes.

229. The use of any one of claims 185 to 228, wherein the tumor sample taken from the subject has been determined to have a detectable level of PD-L1 expression.

230. The use of claim 229, wherein the detectable PD-L1 expression level is a detectable PD-L1 protein expression level.

231. The use of claim 230, wherein the detectable PD-L1 protein expression level is measured by an immunohistochemistry (IHC) assay.

232. The use of claim 231, wherein the IHC assay uses anti-PD-L1 antibody 22C3, SP142, SP263, or 28-8.

233. The use of claim 232, wherein the IHC assay uses anti-PD-L1 antibody 22C3.

234. The use of claim 233, wherein the tumor sample has been determined to have a tumor positive site (TPS) of 1% or greater.

235. The use of claim 234, wherein the TPS is greater than or equal to 1% and less than 50%.

236. The use described in claim 234, wherein the TPS is 50% or more.

237. The use of claim 232, wherein the IHC assay uses the anti-PD-L1 antibody SP142.

238. The use of claim 237, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in 1% or more of the tumor cells in the tumor sample.

239. The use of claim 238, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 1% and less than 5% of the tumor cells in the tumor sample.

240. The use of claim 238, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 5% but less than 50% of the tumor cells in the tumor sample.

241. The use of claim 238, wherein the tumor sample has been determined to have a detectable PD-L1 expression level in 50% or more of the tumor cells in the tumor sample.

242. 242. The use of any one of claims 237 to 241, wherein the tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells comprising 1% or more of the tumor sample.

243. The use of claim 242, wherein the tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells comprising greater than or equal to 1% and less than 5% of the tumor sample.

244. The use of claim 242, wherein the tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells comprising greater than or equal to 5% and less than 10% of the tumor sample.

245. The use of claim 242, wherein the tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells comprising 10% or more of the tumor sample.

246. The use of claim 229, wherein the detectable PD-L1 expression level is a detectable PD-L1 nucleic acid expression level.

247. The use of claim 246, wherein the detectable PD-L1 nucleic acid expression level is measured by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

248. The use of any one of claims 185 to 247, wherein the lung cancer is non-small cell lung cancer (NSCLC).

249. The use of claim 248, wherein the NSCLC is squamous NSCLC.

250. The use of claim 248, wherein the NSCLC is non-squamous NSCLC.

251. The use of any one of claims 248 to 250, wherein the NSCLC is locally advanced unresectable NSCLC.

252. 252. The use of claim 251, wherein the NSCLC is stage IIIB NSCLC.

253. The use of any one of claims 248 to 251, wherein the NSCLC is recurrent or metastatic NSCLC.

254. The use of claim 253, wherein the NSCLC is stage IV NSCLC.

255. 255. The use of claim 253 or 254, wherein the subject has not been previously treated for stage IV NSCLC.

256. 256. The use of any one of claims 185 to 255, wherein the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

257. The use of any one of claims 185 to 256, wherein the subject does not have the lung lymphoepithelioma-like carcinoma subtype of NSCLC.

258. The use of any one of claims 185 to 257, wherein the subject does not have an active EBV infection or a known or suspected chronic active EBV infection.

259. The use of any one of claims 185 to 258, wherein the subject is EBV IgM negative or EBV PCR negative.

260. 260. The use of claim 259, wherein the subject is negative for EBV IgM and negative by EBV PCR.

261. The use of claim 259 or 260, wherein the subject is positive for EBV IgG or positive for EBNA.

262. The use of claim 261, wherein the subject is positive for EBV IgG and positive for EBNA.

263. The use of any one of claims 185 to 262, wherein the subject is negative for EBV IgG or negative for EBNA.

264. The use of claim 263, wherein the subject is negative for EBV IgG and negative for EBNA.

265. The use of any one of claims 185 to 264, wherein administration of the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody results in a clinical response.

266. The use of claim 265, wherein the clinical response is an increase in the subject's objective response rate (ORR) compared to a reference ORR.

267. The use of claim 266, wherein the reference ORR is the median ORR of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody.

268. The use of any one of claims 265 to 267, wherein said clinical response is an increase in the progression free survival (PFS) period of said subject compared to a reference PFS period.

269. The use of any one of claims 265 to 268, wherein the reference PFS period is the median PFS period of a population of subjects treated with an anti-PD-L1 antagonist antibody but not an anti-TIGIT antagonist antibody.

270. 1. Use of an anti-TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for use in a method of treating a subject with NSCLC, the method comprising administering the medicament to the subject in one or more dosing cycles, wherein the medicament is formulated to administer the anti-TIGIT antagonist antibody at a fixed dose of 600 mg every three weeks and the atezolizumab at a fixed dose of 1200 mg every three weeks, and wherein the anti-TIGIT antagonist antibody is: A VH domain having the amino acid sequence of SEQ ID NO: 17 or 18; and VL domain having the amino acid sequence of SEQ ID NO: 19 The use.

271. 1. Use of tiragolumab and atezolizumab in the manufacture of a medicament for use in a method of treating a subject with NSCLC, said method comprising administering said medicament to said subject for one or more dosing cycles, wherein said medicament is formulated for administration of tiragolumab at a fixed dose of 600 mg every three weeks and atezolizumab at a fixed dose of 1200 mg every three weeks.

272. A kit comprising an anti-TIGIT antagonist antibody, an anti-PD-L1 antagonist antibody, and a package insert containing instructions for administering the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody to a subject suffering from lung cancer according to the method of any one of claims 1 to 86 and 192 to 194.

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