KR20240047393A - A therapeutic combination comprising a TIGIT antagonist, a PD-1 antagonist and a chemotherapy agent(s) - Google Patents

Abstract

Human patients in need of treatment of cancer may be administered a combination of (a) a TIGIT antagonist; (b) PD-1 antagonist; and (c) administering one or more chemotherapy agents. Also provided are kits containing such agents and the use of therapeutic combinations of such agents for the treatment of cancer.

Description

A therapeutic combination comprising a TIGIT antagonist, a PD-1 antagonist and a chemotherapy agent(s)

Field

Treatment of cancer using a combination of (a) a T cell immunoreceptor with Ig and ITIM domains (TIGIT) antagonist, (b) a programmed death 1 protein (PD-1) antagonist, and (c) one or more chemotherapeutic agents. , methods of treating infectious diseases or infections are provided herein.

Cross-reference to related applications

This application claims priority from U.S. Provisional Patent Application No. 63/231,525, filed August 10, 2021, and U.S. Provisional Patent Application No. 63/327,070, filed April 4, 2022, each of which is incorporated herein by reference in its entirety. It is included as

Reference to electronically submitted sequence listing

This application contains a sequence listing that has been submitted electronically in XML format, which is incorporated herein by reference in its entirety. The XML file created on August 1, 2022 has the file name 25305-WO-PCT_SL.XML and is 352 KB in size.

TIGIT is an immunomodulatory receptor expressed primarily on activated T cells and NK cells. TIGIT is also known as VSIG9, VSTM3 and WUCAM. Its structure displays one extracellular immunoglobulin domain, a type 1 transmembrane region and two ITIM motifs. TIGIT forms part of a co-stimulatory network consisting of positive (CD226) and negative (TIGIT) immunomodulatory receptors on T cells and ligands (CD155 and CD112) expressed on APCs.

An important feature in the structure of TIGIT is the presence of an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail domain. Like PD-1, the ITIM domain within the cytoplasmic region of TIGIT recruits tyrosine phosphatases, such as SHP-1 and SHP-2, and subsequently activates the immunoreceptor tyrosine-base activation motif (ITAM) on the T cell receptor (TCR) subunit. It is predicted to dephosphorylate tyrosine residues in Therefore, ligation of TIGIT by the receptor-ligands CD155 and CD112 expressed by tumor cells or TAMS may contribute to the inhibition of TCR-signaling and T cell activation, which are essential for initiating effective antitumor immunity. Therefore, TIGIT-specific antagonist antibodies can suppress CD155- and CD112-induced T cell response suppression and enhance antitumor immunity.

PD-1 is recognized as an important player in immune regulation and maintenance of peripheral tolerance. Immune checkpoint therapies targeting PD-1 or its ligands (e.g., PD-L1) have led to dramatic improvements in clinical response in multiple human cancer types (Brahmer et al., N Engl J Med, 366: 2455-2465 (2012); Garon et al., N Engl J Med, 372:2018-2028 (2015); Hamid et al., N Engl J Med, 369:134-144 (2013); Robert et al., Lancet, 384:1109-1117 (2014); Robert et al., N Engl J Med, 372: 2521-2532 (2015); Robert et al., N Engl J Med, 372:320-330 (2015); Topalian et al., N Engl J Med, 366:2443-2454 (2012); Topalian et al., J Clin Oncol, 32:1020-1030 (2014); Wolchok et al., N Engl J Med, 369:122- 133 (2013)). Immunotherapies targeting the PD-1 axis include monoclonal antibodies directed against the PD-1 receptor (e.g., KEYTRUDA® (pembrolizumab), Merck and Co., Inc.). , Inc.), Kenilworth, NJ; OPDIVO® (nivolumab), Bristol-Myers Squibb Company, Princeton, NJ) and antibodies that bind to the PD-L1 ligand (e.g. For example, TECENTRIQ® (atezolizumab), Genentech, San Francisco, CA).

Chemotherapeutic agents typically provide non-specific administration of intracellular poisons to inhibit mitosis or induce DNA damage. For example, chemotherapy agents are cytotoxic by interfering with cell division (mitosis), but cancer cells vary widely in their sensitivity to these agents. Chemotherapy can be thought of as a way to damage or stress cells, which can then lead to cell death when apoptosis is initiated.

The present disclosure provides methods, pharmaceutical compositions, uses, and kits for treating cancer, infectious diseases, or infections using combinations of therapeutic agents, e.g., combinations of antibodies or antigen-binding fragments thereof.

The present disclosure relates to a TIGIT antagonist (e.g., an antibody (e.g., a monoclonal antibody) or antigen-binding fragment thereof), a PD-1 antagonist (e.g., an antibody (e.g., a monoclonal antibody) or Provided are methods of treating cancer, infectious diseases, or infections using a combination of an antigen-binding fragment thereof) and one or more chemotherapeutic agents (e.g., alkylating agents, antimetabolites, anti-microtubule agents, etc.).

In particular, the present disclosure relates to one or more chemotherapeutic agents (e.g., alkylating agents (e.g., cisplatin), antimetabolites (e.g., 5-fluorouracil, gemcitabine, capecy) as provided herein. Certain combinations of immune checkpoint inhibitors (e.g., TIGIT antagonists and PD-1 antagonists) in combination with anti-microtubule agents (e.g., paclitaxel), anti-tabine, etc.) cause significant additional toxicity compared to conventional treatment. It encompasses the insight that efficacy can be improved without It has been suggested that the efficacy of anti-TIGIT antagonist antibodies and anti-PD-1 antagonist antibodies may be enhanced when administered in combination with other approved or experimental cancer therapies; There are no clear guidelines as to which agents in combination with -1 antagonistic antibodies may be effective or in which patients the combination may enhance therapeutic efficacy.

The present disclosure discloses the use of a combination of a TIGIT antagonist, a PD-1 antagonist, 5-fluorouracil represented by Formula (I), and cisplatin represented by Formula (II) to treat cancer (e.g., esophageal cancer, triple Provides a method of treating negative breast cancer (TNBC), biliary tract cancer, stomach cancer, etc.).

The present disclosure relates to the treatment of cancer (e.g., esophageal cancer, TNBC, biliary tract cancer, stomach cancer, etc.) using a combination of a TIGIT antagonist, a PD-1 antagonist, and paclitaxel or a pharmaceutically acceptable salt thereof represented by Formula (III). Provides treatment methods.

The present disclosure relates to the treatment of cancer (e.g., , esophageal cancer, TNBC, biliary tract cancer, etc.).

The present disclosure relates to cancer (e.g., For example, esophageal cancer, TNBC, biliary tract cancer, etc.) are provided.

The present disclosure further provides kits comprising a TIGIT antagonist, a PD-1 antagonist, 5-fluorouracil, and cisplatin.

The present disclosure further provides a kit comprising a TIGIT antagonist, a PD-1 antagonist, and paclitaxel or a pharmaceutically acceptable salt thereof.

The present disclosure further provides a kit comprising a TIGIT antagonist, a PD-1 antagonist, gemcitabine or a pharmaceutically acceptable salt thereof, and cisplatin.

The present disclosure further provides a kit comprising a TIGIT antagonist, a PD-1 antagonist, capecitabine or a pharmaceutically acceptable salt thereof, and oxaliplatin.

Also provided herein is the use of a therapeutic combination for treating cancer (e.g., esophageal cancer), wherein the therapeutic combination comprises a TIGIT antagonist, a PD-1 antagonist, 5-fluorouracil and cisplatin. do.

Also disclosed herein is the use of a therapeutic combination for treating cancer (e.g., TNBC), wherein the therapeutic combination comprises a TIGIT antagonist, a PD-1 antagonist, and paclitaxel or a pharmaceutically acceptable salt thereof. provided.

Also, the use of a therapeutic combination for treating cancer (e.g., biliary tract cancer), wherein the therapeutic combination comprises a TIGIT antagonist, a PD-1 antagonist, gemcitabine or a pharmaceutically acceptable salt thereof, and cisplatin. Uses are provided herein.

Also, the use of a therapeutic combination for treating cancer (e.g., gastric cancer), wherein the therapeutic combination comprises a TIGIT antagonist, a PD-1 antagonist, capecitabine or a pharmaceutically acceptable salt thereof, and oxaliplatin. Uses are provided herein.

In one aspect, provided herein is a method of treating cancer comprising administering to a human patient in need thereof:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) 5-fluorouracil; and

(d) Cisplatin.

In one aspect, provided herein is a therapeutic combination for use in treating cancer, comprising administering to a human patient in need thereof:

(a) TIGIT antagonist;

(b) PD-1 antagonist; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein is a method of treating cancer comprising administering to a human patient in need thereof:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) gemcitabine or a pharmaceutically acceptable salt thereof; and

(d) Cisplatin.

In one aspect, provided herein is a method of treating cancer comprising administering to a human patient in need thereof:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) capecitabine or a pharmaceutically acceptable salt thereof; and

(d) Oxaliplatin.

In some embodiments, the cancer is osteosarcoma, rhabdomyosarcoma, neuroblastoma, kidney cancer, leukemia, renal transitional cell cancer, bladder cancer, Wilms cancer, ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, bone cancer, lung cancer (e.g., non-small cell cancer) lung cancer), stomach cancer, colorectal cancer, cervical cancer, synovial sarcoma, head and neck cancer, squamous cell carcinoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL) or non-Hodgkin lymphoma (NHL)), multiple myeloma, Renal cell carcinoma, retinoblastoma, hepatoblastoma, hepatocellular carcinoma, melanoma, rhabdoid tumor of the kidney, Ewing sarcoma, chondrosarcoma, brain cancer, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, primitive neuroectodermal tumor, medulloblastoma. , astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, choroid plexus papilloma, polycythemia vera, thrombocytemia, idiopathic myelofibrosis, soft tissue sarcoma, thyroid cancer, endometrial cancer and carcinoid cancer. In some embodiments, the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, triple negative breast cancer (TNBC), and gastric cancer. In some embodiments, the cancer is esophageal cancer, TNBC, biliary tract cancer, or stomach cancer.

In certain embodiments, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In another embodiment, the cancer is relapsed and refractory. In certain embodiments, the cancer is resectable.

In another aspect, provided herein is a kit comprising:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) 5-fluorouracil; and

(d) Cisplatin.

In certain embodiments, the kit further includes instructions for administering the TIGIT antagonist, PD-1 antagonist, 5-fluorouracil, and cisplatin to the human patient.

In another aspect, provided herein is a kit comprising:

(a) TIGIT antagonist;

(b) PD-1 antagonist; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In certain embodiments, the kit further includes instructions for administering the TIGIT antagonist, PD-1 antagonist, and paclitaxel or a pharmaceutically acceptable salt thereof to the human patient.

In another aspect, provided herein is a kit comprising:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) gemcitabine or a pharmaceutically acceptable salt thereof; and

(d) Cisplatin.

In certain embodiments, the kit further includes instructions for administering the TIGIT antagonist, PD-1 antagonist, gemcitabine or a pharmaceutically acceptable salt thereof, and cisplatin to the human patient.

In another aspect, provided herein is a kit comprising:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) capecitabine or a pharmaceutically acceptable salt thereof; and

(d) Oxaliplatin.

In certain embodiments, the kit further includes instructions for administering the TIGIT antagonist, PD-1 antagonist, capecitabine or a pharmaceutically acceptable salt thereof, and oxaliplatin to the human patient.

In another aspect, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) 5-fluorouracil; and

(d) Cisplatin.

In another aspect, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) TIGIT antagonist;

(b) PD-1 antagonist; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) gemcitabine or a pharmaceutically acceptable salt thereof; and

(d) Cisplatin.

In another aspect, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) capecitabine or a pharmaceutically acceptable salt thereof; and

(d) Oxaliplatin.

In certain embodiments of the methods, pharmaceutical compositions, kits, uses or combinations for use provided herein, the subject is a human patient.

In certain embodiments, the methods, pharmaceutical compositions, kits, uses, or combinations for use provided herein are for treating cancer.

In certain embodiments of the methods, pharmaceutical compositions, kits, uses or combinations for use provided herein, the cancer is esophageal cancer, TNBC, biliary tract cancer, or gastric cancer.

In certain embodiments of the methods, pharmaceutical compositions, kits or uses provided herein, the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen binding fragment thereof.

In other embodiments of the methods, pharmaceutical compositions, kits or uses provided herein, the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or antigen binding fragment thereof.

In some embodiments of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is a humanized antibody.

In other embodiments of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is a human antibody.

In some embodiments of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-L1 monoclonal antibody is a humanized antibody.

In other embodiments of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-L1 monoclonal antibody is a human antibody.

In certain embodiments of the methods, pharmaceutical compositions, kits or uses provided herein, the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen binding fragment thereof.

In some embodiments of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human TIGIT monoclonal antibody is a humanized antibody.

In other embodiments of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human TIGIT monoclonal antibody is a human antibody.

In another embodiment of the methods, pharmaceutical compositions, kits, and uses provided herein, the anti-PD-1 antibody is independently selected from pembrolizumab, nivolumab, cemiplimab, sintilimab, tislelizumab, camrelizumab, and It is selected from toripalimab.

In one embodiment of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is pembrolizumab.

In another embodiment of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is nivolumab.

In another embodiment of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is cemiplimab.

In another embodiment of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is pidilizumab (U.S. Pat. No. 7,332,582).

In another embodiment of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is AMP-514 (MedImmune LLC, Gay, MD). Dersburg).

In another embodiment of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is PDR001 (U.S. Patent No. 9,683,048).

In another embodiment of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is BGB-A317 (U.S. Pat. No. 8,735,553).

In another embodiment of the methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is MGA012 (MacroGenics, Rockville, MD).

In certain embodiments of the methods, kits or uses provided herein, the anti-human TIGIT monoclonal antibody has three light chain CDRs: CDRL1, comprising the amino acid sequence as set forth in SEQ ID NO: 111, sequence CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: comprising the amino acid sequence as set forth in SEQ ID NO: 108 CDRH1, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110.

In some embodiments of the methods, kits or uses provided herein, the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof has a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 148 and SEQ ID NO: and a light chain variable region comprising the amino acid sequence as set forth in 152.

In other embodiments of the methods, kits or uses provided herein, the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 294 and a light chain and SEQ ID NO: : Comprising a heavy chain comprising or consisting of an amino acid sequence as set forth in 295.

In one specific embodiment of the methods, kits or uses provided herein, the PD-1 antagonist is pembrolizumab; The TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113. CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110 It is a monoclonal antibody or antigen-binding fragment thereof containing CDRH3 containing the amino acid sequence as described above.

In one specific embodiment of the methods, kits or uses provided herein, the PD-1 antagonist is nivolumab; The TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113. CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. It is a monoclonal antibody or antigen-binding fragment thereof containing CDRH3 containing the amino acid sequence as described above.

In one specific embodiment of the methods, kits or uses provided herein, the PD-1 antagonist is cemiplimab; The TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113. CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. It is a monoclonal antibody or antigen-binding fragment thereof containing CDRH3 containing the amino acid sequence as described above.

In another aspect, provided herein is a method of enhancing T cell activity comprising contacting the T cell with:

(a) anti-human TIGIT antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(b) anti-human PD-1 antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(c) 5-fluorouracil; and

(d) Cisplatin.

In another aspect, provided herein is a method of enhancing T cell activity comprising contacting the T cell with:

(a) anti-human TIGIT antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(b) anti-human PD-1 antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of enhancing T cell activity comprising contacting the T cell with:

(a) anti-human TIGIT antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(b) anti-human PD-1 antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(c) gemcitabine or a pharmaceutically acceptable salt thereof; and

(d) Cisplatin.

In another aspect, provided herein is a method of enhancing T cell activity comprising contacting the T cell with:

(a) anti-human TIGIT antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(b) anti-human PD-1 antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(c) capecitabine or a pharmaceutically acceptable salt thereof; and

(d) Oxaliplatin.

In some embodiments, enhancement of T cell activity occurs in vitro. In other embodiments, enhancement of T cell activity occurs in vivo. For example, enhancement occurs in a subject, including but not limited to a human subject or human patient.

In certain embodiments, enhancement of T cell activity is measured by increased cytokine production. In other embodiments, enhancement of T cell activity is measured by increased cell proliferation.

In some embodiments, provided herein is a method of increasing cytokine production of a T cell comprising contacting the T cell with:

(a) anti-human TIGIT antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(b) anti-human PD-1 antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(c) 5-fluorouracil; and

(d) Cisplatin.

In some embodiments, provided herein is a method of increasing cytokine production of a T cell comprising contacting the T cell with:

(a) anti-human TIGIT antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(b) anti-human PD-1 antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a method of increasing cytokine production of a T cell comprising contacting the T cell with:

(a) anti-human TIGIT antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(b) anti-human PD-1 antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(c) gemcitabine or a pharmaceutically acceptable salt thereof; and

(d) Cisplatin.

In some embodiments, provided herein is a method of increasing cytokine production of a T cell comprising contacting the T cell with:

(a) anti-human TIGIT antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(b) anti-human PD-1 antibody (e.g., monoclonal antibody) or antigen-binding fragment thereof;

(c) capecitabine or a pharmaceutically acceptable salt thereof; and

(d) Oxaliplatin.

In some embodiments, increased cytokine production by T cells occurs in vitro. In other embodiments, increased cytokine production by T cells occurs in vivo.

In some embodiments of the methods, kits, or uses described herein, the human patient is administered about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab, and pembrolizumab is administered once every three weeks. In one embodiment, the human patient is administered about 200 mg pembrolizumab once every 3 weeks. In one embodiment, the human patient is administered about 240 mg pembrolizumab once every 3 weeks. In one embodiment, human patients are administered about 2 mg/kg pembrolizumab once every 3 weeks.

In certain embodiments of the methods, kits, or uses described herein, the human patient is administered about 400 mg pembrolizumab, and pembrolizumab is administered once every six weeks.

In other embodiments of the methods, kits or uses described herein, the human patient is administered about 240 mg or about 3 mg/kg nivolumab once every two weeks or about 480 mg nivolumab once every four weeks. In one specific embodiment, human patients are administered about 240 mg nivolumab once every two weeks. In one specific embodiment, human patients are administered about 3 mg/kg nivolumab once every two weeks. In one specific embodiment, human patients are administered about 480 mg nivolumab once every four weeks.

In another embodiment of the methods, kits or uses described herein, the human patient is administered about 350 mg of cemiplimab, and cemiplimab is administered once every three weeks.

In some embodiments of the methods, kits or uses described herein, a human patient is administered about 200 mg, about 240 mg or about 2 mg/kg of a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 294. And administering an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 295, and administering an anti-human TIGIT monoclonal antibody or antigen thereof. The combined fragment is administered once every three weeks. In one embodiment, a human patient is administered about 200 mg of an anti-human TIGIT monoclonal antibody, or antigen-binding fragment thereof, once every three weeks. In one embodiment, a human patient is administered about 240 mg of an anti-human TIGIT monoclonal antibody, or antigen-binding fragment thereof, once every three weeks. In one embodiment, a human patient is administered about 2 mg/kg of an anti-human TIGIT monoclonal antibody, or antigen-binding fragment thereof, once every three weeks.

In certain embodiments of the methods, kits or uses described herein, a human patient is administered about 400 mg of a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 294 and a light chain as set forth in SEQ ID NO: 295. An anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain comprising or consisting of an amino acid sequence is administered, and the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof is administered once every 6 weeks. .

In another embodiment of the methods, kits or uses described herein, the human patient is administered about 3000 mg/m ² to about 4000 mg/m ² 5-fluorouracil, wherein the 5-fluorouracil is administered every 3 weeks. Administer 5 times. In some embodiments, the human patient is administered about 600 or about 800 mg/m ² 5-fluorouracil per day.

In some embodiments, the human patient is administered between about 40 mg/m ² and about 100 mg/m ² cisplatin, wherein the cisplatin is administered once every 3 weeks. In some embodiments, the human patient is administered about 60 or about 80 mg/m ² cisplatin, wherein the cisplatin is administered once every 3 weeks.

In some embodiments, the human patient is administered:

(a) about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab once every 3 weeks;

(b) about 200 mg, about 240 mg or about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, the amino acid sequence as set forth in SEQ ID NO: 112 CDRL2 comprising and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, as set forth in SEQ ID NO: 154 An anti-human TIGIT antibody or antigen-binding fragment thereof, comprising CDRH2 comprising the same amino acid sequence and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110 once every 3 weeks or once every 6 weeks;

(c) a total of about 3000 mg/m ² or 4000 mg/m ² 5-fluorouracil per cycle (e.g., about 600 mg/m ² or 800 mg/m ² 5 times every 3 weeks); and

(d) Approximately 60 mg/m ² or 80 mg/m ² cisplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab once every 3 weeks;

(b) about 200 mg, about 240 mg or about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, the amino acid sequence as set forth in SEQ ID NO: 112 CDRL2 comprising and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, as set forth in SEQ ID NO: 154 An anti-human TIGIT antibody or antigen-binding fragment thereof, comprising CDRH2 comprising the same amino acid sequence and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110 once every three weeks;

(c) a total of about 3000 mg/m ² or 4000 mg/m ² 5-fluorouracil per cycle (e.g., about 600 mg/m ² or 800 mg/m ² 5 times every 3 weeks); and

(d) Approximately 60 mg/m ² or 80 mg/m ² cisplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) approximately 200 mg pembrolizumab once every 3 weeks;

(b) about 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every three weeks;

(c) a total of about 3000 mg/m ² or 4000 mg/m ² 5-fluorouracil per cycle (e.g., about 600 mg/m ² or 800 mg/m ² 5 times every 3 weeks); and

(d) Approximately 60 mg/m ² or 80 mg/m ² cisplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) approximately 240 mg pembrolizumab once every 3 weeks;

(b) about 240 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every three weeks;

(c) a total of about 3000 mg/m ² or 4000 mg/m ² 5-fluorouracil per cycle (e.g., about 600 mg/m ² or 800 mg/m ² 5 times every 3 weeks); and

(d) Approximately 60 mg/m ² or 80 mg/m ² cisplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) approximately 2 mg/kg pembrolizumab once every 3 weeks;

(b) about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: : CDRL3 and three heavy chain CDRs comprising the amino acid sequence as set forth in SEQ ID NO: 113: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and An anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 once every three weeks;

(c) a total of about 3000 mg/m ² or 4000 mg/m ² 5-fluorouracil per cycle (e.g., about 600 mg/m ² or 800 mg/m ² 5 times every 3 weeks); and

(d) Approximately 60 mg/m ² or 80 mg/m ² cisplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) approximately 400 mg pembrolizumab once every 6 weeks;

(b) about 400 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every 6 weeks;

(c) a total of about 3000 mg/m ² or 4000 mg/m ² 5-fluorouracil per cycle (e.g., about 600 mg/m ² or 800 mg/m ² 5 times every 3 weeks); and

(d) Approximately 60 mg/m ² or 80 mg/m ² cisplatin once every 3 weeks.

In a specific embodiment, provided herein is a method of treating esophageal cancer, comprising administering to a human patient in need of treatment esophageal cancer:

(a) approximately 200 mg pembrolizumab once every 3 weeks;

(b) about 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every three weeks;

(c) a total of about 3000 mg/m ² or 4000 mg/m ² 5-fluorouracil per cycle (e.g., about 600 mg/m ² or 800 mg/m ² 5 times every 3 weeks); and

(d) Approximately 60 mg/m ² or 80 mg/m ² cisplatin once every 3 weeks.

In some embodiments, the human patient is administered between about 70 mg/m ² and about 100 mg/m ² paclitaxel, wherein the paclitaxel is administered once weekly. In some embodiments, the human patient is administered about 80 mg/m ² or about 90 mg/m ² paclitaxel, wherein paclitaxel is administered once weekly.

In some embodiments, the human patient is administered:

(a) about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab once every 3 weeks;

(b) about 200 mg, about 240 mg or about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, the amino acid sequence as set forth in SEQ ID NO: 112 CDRL2 comprising and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, as set forth in SEQ ID NO: 154 An anti-human TIGIT antibody or antigen-binding fragment thereof, comprising CDRH2 comprising the same amino acid sequence and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110 once every 3 weeks or once every 6 weeks; and

(c) About 80 mg/m ² or about 90 mg/m ² paclitaxel once weekly.

In certain embodiments, the human patient is administered:

(a) about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab once every 3 weeks;

(b) about 200 mg, about 240 mg or about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, the amino acid sequence as set forth in SEQ ID NO: 112 CDRL2 comprising and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, as set forth in SEQ ID NO: 154 An anti-human TIGIT antibody or antigen-binding fragment thereof, comprising CDRH2 comprising the same amino acid sequence and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110 once every three weeks; and

(c) About 80 mg/m ² or about 90 mg/m ² paclitaxel once weekly.

In certain embodiments, the human patient is administered:

(a) approximately 200 mg pembrolizumab once every 3 weeks;

(b) about 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every three weeks; and

(c) About 80 mg/m ² or about 90 mg/m ² paclitaxel once weekly.

In certain embodiments, the human patient is administered:

(a) approximately 240 mg pembrolizumab once every 3 weeks;

(b) about 240 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every three weeks; and

(c) About 80 mg/m ² or about 90 mg/m ² paclitaxel once weekly.

In certain embodiments, the human patient is administered:

(a) approximately 2 mg/kg pembrolizumab once every 3 weeks;

(b) about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: : CDRL3 and three heavy chain CDRs comprising the amino acid sequence as set forth in SEQ ID NO: 113: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and An anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 once every three weeks; and

(c) About 80 mg/m ² or about 90 mg/m ² paclitaxel once weekly.

In certain embodiments, the human patient is administered:

(a) approximately 400 mg pembrolizumab once every 6 weeks;

(b) about 400 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every 6 weeks; and

(c) About 80 mg/m ² or about 90 mg/m ² paclitaxel once weekly.

In specific embodiments, provided herein is a method of treating TNBC comprising administering to a human patient in need of treatment for TNBC:

(a) approximately 200 mg pembrolizumab once every 3 weeks;

(b) about 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every three weeks; and

(c) About 80 mg/m ² or about 90 mg/m ² paclitaxel once weekly.

In another embodiment of the method, kit or use described herein, a human patient is administered about 500 mg/m ² to about 1500 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof, wherein gemcitabine or a pharmaceutical thereof Administer permissible salts every 3 weeks. In some embodiments, the human patient is administered about 800 mg/m ² to about 1000 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof, wherein gemcitabine or a pharmaceutically acceptable salt thereof is administered every 3 weeks. . In some embodiments, the human patient is administered about 800 mg/m ² or about 1000 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof, wherein gemcitabine or a pharmaceutically acceptable salt thereof is administered every 3 weeks. .

In some embodiments, the human patient is administered about 10 mg/m ² to about 50 mg/m ² cisplatin, wherein cisplatin is administered once every 3 weeks. In some embodiments, the human patient is administered about 20 mg/m ² to about 25 mg/m ² cisplatin, wherein cisplatin is administered once every 3 weeks. In some embodiments, the human patient is administered about 20 or about 25 mg/m ² cisplatin, wherein the cisplatin is administered once every 3 weeks.

In some embodiments, the human patient is administered:

(a) about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab once every 3 weeks;

(b) about 200 mg, about 240 mg or about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, the amino acid sequence as set forth in SEQ ID NO: 112 CDRL2 comprising and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, as set forth in SEQ ID NO: 154 An anti-human TIGIT antibody or antigen-binding fragment thereof, comprising CDRH2 comprising the same amino acid sequence and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110 once every 3 weeks or once every 6 weeks;

(c) about 800 mg/m ² or 1000 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof once every 3 weeks; and

(d) Approximately 20 mg/m ² or 25 mg/m ² cisplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab once every 3 weeks;

(b) about 200 mg, about 240 mg or about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, the amino acid sequence as set forth in SEQ ID NO: 112 CDRL2 comprising and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, as set forth in SEQ ID NO: 154 An anti-human TIGIT antibody or antigen-binding fragment thereof, comprising CDRH2 comprising the same amino acid sequence and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110 once every three weeks;

(c) about 800 mg/m ² or 1000 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof once every 3 weeks; and

(d) Approximately 20 mg/m ² or 25 mg/m ² cisplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) approximately 200 mg pembrolizumab once every 3 weeks;

(b) about 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every three weeks;

(c) about 800 mg/m ² or 1000 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof once every 3 weeks; and

(d) Approximately 20 mg/m ² or 25 mg/m ² cisplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) approximately 240 mg pembrolizumab once every 3 weeks;

(b) about 240 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every three weeks;

(c) about 800 mg/m ² or 1000 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof once every 3 weeks; and

(d) Approximately 20 mg/m ² or 25 mg/m ² cisplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) approximately 2 mg/kg pembrolizumab once every 3 weeks;

(b) about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: : CDRL3 and three heavy chain CDRs comprising the amino acid sequence as set forth in SEQ ID NO: 113: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and An anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 once every three weeks;

(c) about 800 mg/m ² or 1000 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof once every 3 weeks; and

(d) Approximately 20 mg/m ² or 25 mg/m ² cisplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) approximately 400 mg pembrolizumab once every 6 weeks;

(b) about 400 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every 6 weeks;

(c) about 800 mg/m ² or 1000 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof once every 3 weeks; and

(d) Approximately 20 mg/m ² or 25 mg/m ² cisplatin once every 3 weeks.

In a specific embodiment, provided herein is a method of treating biliary tract cancer, comprising administering to a human patient in need of treatment for biliary tract cancer:

(a) approximately 200 mg pembrolizumab once every 3 weeks;

(b) about 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every three weeks;

(c) about 800 mg/m ² or 1000 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof once every 3 weeks; and

(d) Approximately 20 mg/m ² or 25 mg/m ² cisplatin once every 3 weeks.

In some embodiments of the methods, kits or uses described herein, a human patient is administered about 500 mg/m ² to about 1500 mg/m ² capecitabine or a pharmaceutically acceptable salt thereof, wherein capecitabine or a pharmaceutically acceptable salt thereof is administered. Pharmaceutically acceptable salts are administered twice daily. In some embodiments, the human patient is administered about 750 mg/m ² to about 1000 mg/m ² capecitabine or a pharmaceutically acceptable salt thereof, wherein the capecitabine or pharmaceutically acceptable salt thereof is administered 2 times per day. Administer once. In some embodiments, the human patient is administered about 750 mg/m ² or about 1000 mg/m ² capecitabine or a pharmaceutically acceptable salt thereof, wherein the capecitabine or pharmaceutically acceptable salt thereof is administered 2 times per day. Administer once.

In some embodiments, the human patient is administered about 80 mg/m ² to about 150 mg/m ² oxaliplatin, wherein the oxaliplatin is administered once every 3 weeks. In some embodiments, the human patient is administered about 100 mg/m ² to about 130 mg/m ² oxaliplatin, wherein the oxaliplatin is administered once every 3 weeks. In some embodiments, the human patient is administered about 100 or about 130 mg/m ² oxaliplatin, wherein the oxaliplatin is administered once every 3 weeks.

In some embodiments, the human patient is administered:

(a) about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab once every 3 weeks;

(b) about 200 mg, about 240 mg or about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, the amino acid sequence as set forth in SEQ ID NO: 112 CDRL2 comprising and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, as set forth in SEQ ID NO: 154 An anti-human TIGIT antibody or antigen-binding fragment thereof, comprising CDRH2 comprising the same amino acid sequence and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110 once every 3 weeks or once every 6 weeks;

(c) about 750 mg/m ² or 1000 mg/m ² capecitabine or a pharmaceutically acceptable salt thereof twice daily; and

(d) Approximately 100 mg/m ² or 130 mg/m ² oxaliplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab once every 3 weeks;

(b) about 200 mg, about 240 mg or about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, the amino acid sequence as set forth in SEQ ID NO: 112 CDRL2 comprising and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, as set forth in SEQ ID NO: 154 An anti-human TIGIT antibody or antigen-binding fragment thereof, comprising CDRH2 comprising the same amino acid sequence and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110 once every three weeks;

(c) about 750 mg/m ² or 1000 mg/m ² capecitabine or a pharmaceutically acceptable salt thereof twice daily; and

(d) Approximately 100 mg/m ² or 130 mg/m ² oxaliplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) approximately 200 mg pembrolizumab once every 3 weeks;

(b) about 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every three weeks;

(c) about 750 mg/m ² or 1000 mg/m ² capecitabine or a pharmaceutically acceptable salt thereof twice daily; and

(d) Approximately 100 mg/m ² or 130 mg/m ² oxaliplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) approximately 240 mg pembrolizumab once every 3 weeks;

(b) about 240 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every three weeks;

(c) about 750 mg/m ² or 1000 mg/m ² capecitabine or a pharmaceutically acceptable salt thereof twice daily; and

(d) Approximately 100 mg/m ² or 130 mg/m ² oxaliplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) approximately 2 mg/kg pembrolizumab once every 3 weeks;

(b) about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: : CDRL3 and three heavy chain CDRs comprising the amino acid sequence as set forth in SEQ ID NO: 113: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and An anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 once every three weeks;

(c) about 750 mg/m ² or 1000 mg/m ² capecitabine or a pharmaceutically acceptable salt thereof twice daily; and

(d) Approximately 100 mg/m ² or 130 mg/m ² oxaliplatin once every 3 weeks.

In certain embodiments, the human patient is administered:

(a) approximately 400 mg pembrolizumab once every 6 weeks;

(b) about 400 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every 6 weeks;

(c) about 750 mg/m ² or 1000 mg/m ² capecitabine or a pharmaceutically acceptable salt thereof twice daily; and

(d) Approximately 100 mg/m ² or 130 mg/m ² oxaliplatin once every 3 weeks.

In a specific embodiment, provided herein is a method of treating gastric cancer, comprising administering to a human patient in need of treatment for gastric cancer:

(a) approximately 200 mg pembrolizumab once every 3 weeks;

(b) about 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: Anti-human TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110 once every three weeks;

(c) about 750 mg/m ² or 1000 mg/m ² capecitabine or a pharmaceutically acceptable salt thereof twice daily; and

(d) Approximately 100 mg/m ² or 130 mg/m ² oxaliplatin once every 3 weeks.

In certain embodiments of the methods, kits, and uses provided herein, the anti-human TIGIT monoclonal antibody and anti-human PD-1 monoclonal antibody are administered on the same day. In some embodiments, the anti-human TIGIT monoclonal antibody and anti-human PD-1 monoclonal antibody are administered sequentially. In another embodiment, the anti-human TIGIT monoclonal antibody and anti-human PD-1 monoclonal antibody are co-administered. In some embodiments, the anti-human TIGIT monoclonal antibody and the anti-human PD-1 monoclonal antibody are co-formulated.

Figure 1 shows tumor volume size as a function of time for one or more cancer treatments, including combination treatment with a PD-1 antagonist, a TIGIT antagonist, 5-fluorouracil (5-FU), and cisplatin.
Figure 2 shows the change in tumor volume at day 17 for treatment of one or more cancers including combination treatment of PD-1 antagonist, TIGIT antagonist, 5-FU and cisplatin.
Figure 3 depicts tumor volume size as a function of time for one or more cancer treatments, including combination treatment of PD-1 antagonist, TIGIT antagonist, gemcitabine, and cisplatin.
Figure 4 depicts best overall response presented as percent change in tumor volume at end of study for one or more cancer treatments including combination treatment of PD-1 antagonist, TIGIT antagonist, gemcitabine, and cisplatin.

Justice

Certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere in the specification, all other technical and scientific terms used herein have meanings commonly understood by a person of ordinary skill in the art to which this disclosure pertains.

Numerically defined parameters (e.g., anti-TIGIT antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof, 5-fluorouracil, cisplatin, paclitaxel or a pharmaceutically acceptable salt thereof, When used to modify gemcitabine or a pharmaceutically acceptable salt thereof, a twice-daily dose of capecitabine or a pharmaceutically acceptable salt thereof and/or oxaliplatin, or the length of treatment period using the combination therapy described herein) “About” means that a parameter is within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5% of the numerical value or range stated for that parameter. means within 4%, within 3%, within 2%, within 1% or less; Where appropriate, mentioned parameters may be rounded to the nearest integer. For example, a dose of about 5 mg/kg may vary from 4.5 mg/kg to 5.5 mg/kg.

As used herein, including in the appended claims, the singular forms "a," "an," and "the" include their plural referents unless the context clearly dictates otherwise.

The term “administration” or “administering” refers to a substance present outside the body (e.g., an anti-TIGIT antibody, an anti-PD-1 antibody, 5-fluorouracil, cisplatin, paclitaxel, or pharmaceuticals thereof as described herein). acceptable salt, gemcitabine or a pharmaceutically acceptable salt thereof, capecitabine or a pharmaceutically acceptable salt thereof and/or oxaliplatin) is administered by injection into the patient or otherwise physically, such as orally, mucosally, intradermally, intravenously, refers to delivery by subcutaneous, intramuscular delivery and/or any other physical delivery method described herein or known in the art.

As used herein, the term “antibody” refers to any form of immunoglobulin molecule that exhibits the desired biological or binding activity. Therefore, it is used in the broadest sense and specifically refers to monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, and Including, but not limited to, chimeric antibodies. A “parent antibody” is an antibody obtained by exposure of the immune system to an antigen prior to modification of the antibody for its intended use, such as humanization of the antibody for use as a human therapeutic. As used herein, the term “antibody” refers to intact polyclonal or monoclonal antibodies, as well as, unless otherwise specified, fusion proteins comprising an antigen-binding portion and an antigen thereof that competes with the intact antibody for specific binding. It encompasses any other modified configuration of the immunoglobulin molecule, including binding fragments.

Generally, the basic antibody structural units include tetramers. Each tetramer contains two identical pairs of polypeptide chains, each pair having one “light” chain (about 25 kDa) and one “heavy” chain (about 50-70 kDa). The amino-terminal portion of each chain contains a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The variable region of each light/heavy chain pair forms the antibody binding site. Therefore, generally, an intact antibody has two binding sites. The carboxy-terminal portion of the heavy chain may define the constant region, which is primarily responsible for effector functions. Typically, human light chains are classified into kappa and lambda light chains. Additionally, human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within the light and heavy chains, the variable and constant regions are joined by a “J” region of at least about 12 amino acids, and the heavy chain also includes a “D” region of at least about 10 amino acids. In general, see Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)).

As used herein, “variable region” or “V region” or “V chain” refers to a segment of an IgG chain that is variable in sequence between different antibodies. The “variable region” of an antibody refers to the variable region of the light chain of an antibody or the variable region of the heavy chain of an antibody, alone or in combination. The variable region of the heavy chain may be referred to as “V _H ”. The variable region of the light chain may be referred to as “V _L ”.

Typically, the variable regions of both heavy and light chains contain three hypervariable regions, also called complementarity determining regions (CDRs), located within relatively conserved framework regions (FRs). CDRs are typically aligned by framework regions, allowing binding to specific epitopes. Generally, both light and heavy chain variable domains include, from N-terminus to C-terminus, FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. As mentioned herein, the light chain CDRs are CDRL1, CDRL2, and CDRL3, respectively, and the heavy chain CDRs are CDRH1, CDRH2, and CDRH3, respectively. The assignment of amino acids to each domain is generally described in Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901-917 or Chothia, et al., (1989) Nature 342:878-883.

“CDR” refers to one of the three hypervariable regions (H1, H2 or H3) within the non-framework region of the antibody V _H β-sheet framework or one of the three hypervariable regions (H1, H2 or H3) within the non-framework region of the antibody V _L β-sheet framework Refers to one of the hypervariable regions (L1, L2, or L3). Accordingly, CDRs are variable region sequences interspersed within framework region sequences. CDR regions are well known to those skilled in the art and have been defined by Kabat, for example, as the most hypervariable regions within an antibody variable domain. The CDR region sequence was also structurally defined as residues that are not part of the b-sheet framework conserved by Chothia and can therefore be adapted to different conformations. Both terms are widely recognized in the art. CDR region sequences were also defined by AbM, contact and IMGT. The positions of CDRs within canonical antibody variable regions were determined by comparison of numerous structures (Al-Lazikani et al., 1997, J. Mol. Biol. 273:927-48; Morea et al., 2000, Methods 20:267 -79). Because the number of residues within the hypervariable region varies in different antibodies, additional residues compared to the canonical positions are typically numbered as a, b, c, etc. next to the residue number in the canonical variable region numbering scheme (Al-Lazikani et al. , supra). This nomenclature is similarly well known to those skilled in the art. Correspondences between numbering systems, including for example the Kabat numbering and the IMGT unique numbering system, are well known to those skilled in the art and are presented in Table 1 below. In some embodiments, CDRs are as defined by the Kabat numbering system. In other embodiments, CDRs are as defined by the IMGT numbering system. In another embodiment, the CDRs are as defined by the AbM numbering system. In another embodiment, the CDRs are as defined by the Chothia numbering system. In another embodiment, the CDRs are as defined by the contact numbering system.

Table 1. Correspondence between CDR numbering systems

A “chimeric antibody” is one in which one portion of the heavy and/or light chain is derived from a particular species (e.g., human) or contains sequences belonging to a particular antibody class or subclass, and the remainder of the chain(s) is from another species (e.g., human). refers to antibodies derived from (e.g., mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies so long as they exhibit the desired biological activity.

“Human antibody” refers to an antibody comprising human immunoglobulin protein sequences or derivatives thereof. Human antibodies may contain murine carbohydrate chains when produced in mice, mouse cells, or hybridomas derived from mouse cells. Similarly, “mouse antibody” or “rat antibody” refers to an antibody comprising only mouse or rat immunoglobulin sequences or derivatives thereof, respectively.

“Humanized antibody” refers to a form of antibody that contains sequences from human antibodies as well as non-human (e.g., murine) antibodies. These antibodies contain minimal sequence derived from non-human immunoglobulins. Generally, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, wherein all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin, and all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin. The FR region is from a human immunoglobulin sequence. The humanized antibody will also optionally comprise at least a portion of the immunoglobulin constant region (Fc), typically that of a human immunoglobulin. The prefix “hum”, “hu” or “h” may be added to the antibody clone name when necessary to distinguish the humanized antibody from the parental rodent antibody. Humanized forms of rodent antibodies will generally contain the same CDR sequences of the parent rodent antibody, but may also include specific amino acid substitutions to increase affinity, increase stability of the humanized antibody, or for other reasons.

As used herein, “monoclonal antibody” or “mAb” or “Mab” refers to a population of antibodies that are substantially homogeneous, i.e., the antibody molecules comprising the population are free from possible naturally occurring mutations that may be present in trace amounts. The amino acid sequence is identical. In contrast, conventional (polyclonal) antibody preparations typically include multiple different antibodies with different amino acid sequences in their variable domains, especially their CDRs, often specific for different epitopes. The modifier “monoclonal” refers to the characteristics of the antibody as obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with the present disclosure may be described in Kohler et al. (1975) Nature 256:495, or by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). “Monoclonal antibodies” also refer to, for example, Clackson et al. (1991) Nature 352:624-628 and Marks et al. (1991) J. Mol. Biol. 222:581-597. Additionally, Presta (2005) J. Allergy Clin. Immunol. 116:731].

Unless otherwise indicated, as used herein, “antibody fragment” or “antigen binding fragment” refers to a fragment of an antibody that retains the ability to specifically bind to an antigen, e.g., one or more CDR regions and an antigen. It refers to a fragment that possesses the ability to do something. An antibody that “binds specifically to” TIGIT or PD-1 is one that exhibits preferential binding to TIGIT or PD-1 (as appropriate) compared to other proteins, but this specificity does not require absolute binding specificity. An antibody is considered “specific” for its intended target if its binding, for example, determines the presence of the target protein in a sample without producing undesirable results, such as false positives. The antibody or binding fragment thereof has an affinity that is at least 2-fold greater, preferably at least 10-fold greater, more preferably at least 20-fold greater, and most preferably at least 100-fold greater than the affinity for the non-target protein. It will then bind to the target protein.

Antigen binding moieties include, for example, fragments containing Fab, Fab', F(ab')2, Fd, Fv, CDR and single chain variable fragment antibodies (scFv), and antigens (e.g., TIGIT or PD- 1) A polypeptide containing at least one portion of an immunoglobulin sufficient to confer specific antigen binding to. Antibodies include antibodies of any class, such as IgG, IgA or IgM (or subclasses thereof), and the antibodies need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of the heavy chain, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, several of which are further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. It can be divided into: The heavy chain constant regions corresponding to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional shapes of different classes of immunoglobulins are well known.

As used herein, the terms “at least one” item or “one or more” items each include a single item selected from the list as well as mixtures of two or more items selected from the list.

As used herein, the term “immune response” refers to any one or more of the following: specific immune response, non-specific immune response, both specific and non-specific response, innate response, primary immune response. , adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell-proliferation, immune cell differentiation and cytokine expression.

As used herein, the term “subject” (alternatively “patient”) refers to a mammal that is the subject of treatment, observation, or experimentation. Mammals can be male or female. Mammals include humans, bovines (e.g. cattle), porcines (e.g. pigs), ovines (e.g. sheep), caprines (e.g. goats), equines (e.g. horses) , canines (e.g., domestic dogs), felines (e.g., domestic cats), lagomorphs (e.g., rabbits), rodents (e.g., rats or mice), Procyon rotors (e.g., raccoons) ) may be one or more types selected from the group consisting of In certain embodiments, the subject is a human.

As used herein, the term “subject in need” refers to a subject diagnosed with or suspected of having cancer or an infectious disease as defined herein.

The therapeutic agents and compositions provided by the present disclosure may be administered via any suitable enteral or parenteral route of administration. The term “enteral route of administration” refers to administration through any part of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, buccal and rectal routes or intragastric routes. “Parental route” of administration refers to a route of administration other than the enteral route. Examples of parenteral routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumoral, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, and subarachnoid. , including intrathecal, epidural and intrasternal, subcutaneous or topical administration. The therapeutic agents and compositions of the present disclosure can be administered using any suitable method, such as by oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump. Suitable routes and methods of administration may vary depending on a number of factors, such as the specific therapeutic agent used, the desired rate of absorption, the specific formulation or dosage form used, the type or severity of the disorder being treated, the specific site of action, and the condition of the patient; It can be easily selected by a person skilled in the art.

The term “variant” when used in reference to an antibody (e.g., an anti-TIGIT antibody or an anti-PD-1 antibody) or an amino acid region within an antibody, refers to one or more variants (e.g., A peptide or polypeptide comprising amino acid sequence substitutions, deletions and/or additions (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5). can refer to. For example, a variant of an anti-PD-1 antibody may have one or more amino acid sequences relative to the native or previously unmodified anti-PD-1 antibody (e.g., from about 1 to about 25, from about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) changes. Variants can be naturally occurring or artificially constructed. Polypeptide variants can be prepared from the corresponding nucleic acid molecule encoding the variant. In specific embodiments, the antibody variant (e.g., an anti-TIGIT antibody variant or an anti-PD-1 antibody variant) retains at least antibody functional activity. In specific embodiments, the anti-TIGIT antibody variant binds TIGIT and/or antagonizes TIGIT activity. In some embodiments, the anti-PD-1 antibody variant binds PD-1 and/or antagonizes PD-1 activity.

“Conservatively modified variants” or “conservative substitutions” are amino acids in a protein that are similar so that frequent changes can be made without altering the protein's biological activity or other desired properties, such as antigen affinity and/or specificity. refers to substitution with another amino acid having different characteristics (e.g., charge, side chain size, hydrophobicity/hydrophilicity, backbone conformation and rigidity, etc.). Those skilled in the art generally recognize that single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, for example, Watson et al. (1987) Molecular Biology of the Gene, The Benjamin/Cummings Pub. Co., p. 224 (4th Ed.)]. Additionally, substitution of structurally or functionally similar amino acids is less likely to destroy biological activity. Exemplary conservative substitutions are presented in Table 2 below.

Table 2. Exemplary Conservative Amino Acid Substitutions

“Homology” refers to the sequence similarity between two polypeptide sequences when they are optimally aligned. If the position in both compared sequences is occupied by the same amino acid monomer subunit, for example, if the position in the light chain CDRs of two different Abs is occupied by alanine, then the two Abs will be It is the same. The percent homology is the number of homologous positions shared by the two sequences divided by the total number of positions compared x 100. For example, if the sequences are optimally aligned and 8 out of 10 positions in the two sequences match, the two sequences are 80% homologous. Typically, comparisons are made when two sequences are aligned to provide maximum percent homology. For example, comparisons can be performed by the BLAST algorithm, where the parameters of the algorithm are selected to provide the maximum match between each sequence over the entire length of each reference sequence.

The following references relate to the BLAST algorithm, which is often used in sequence analysis: BLAST algorithm: Altschul, S.F., et al., (1990) J. Mol. Biol. 215:403-410; Gish, W., et al., (1993) Nature Genet. 3:266-272; Madden, T.L., et al., (1996) Meth. Enzymol. 266:131-141; Altschul, S.F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J.C., et al., (1993) Comput. Chem. 17:149-163; Hancock, J.M. et al., (1994) Comput. Appl. Biosci. 10:67-70]; Alignment scoring system: Dayhoff, M.O., et al., “A model of evolutionary change in proteins.” in Atlas of Protein Sequence and Structure, (1978) vol. 5, sup. 3.M.O. Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, D.C.; Schwartz, R.M., et al., “Matrices for detecting distant relationships.” in Atlas of Protein Sequence and Structure, (1978) vol. 5, sup. 3." M. O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, S. F., (1991) J. Mol. Biol. 219:555-565; States, D. J., et al., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919; Altschul, S. F., et al. , (1993) J. Mol. Evol. 36:290-300];Alignment statistics: Karlin, S., et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin , S., et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul. , S.F. "Evaluating the statistical significance of multiple distinct local alignments." in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1-14, Plenum, New York].

As used herein, “RECIST 1.1 response criteria” refer to target lesions or non-target lesions based on the context in which response is measured, as appropriate, as described in Eisenhauer, E.A. et al., Eur. J. Cancer 45:228-247 (2009)].

“Sustained response” means a sustained therapeutic effect after discontinuation of treatment as described herein. In some embodiments, the sustained response has a duration at least equal to the duration of treatment or at least 1.5, 2.0, 2.5 or 3 times longer than the duration of treatment.

As used herein, the term “treat” or “treating” refers to a PD-1 antagonist, a TIGIT antagonist, and one or more chemotherapy agents (e.g., an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, Anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof and one or more chemotherapy agents (e.g., 5-fluorouracil, cisplatin, paclitaxel or a pharmaceutically acceptable salt thereof, gemcitabine or a pharmaceutically acceptable salt thereof) Means administering a therapeutic combination of salt, capecitabine or a pharmaceutically acceptable salt thereof and/or oxaliplatin) or a pharmaceutically acceptable salt thereof) to a subject or patient having one or more disease symptoms as provided herein. do. Typically, the agents of the therapeutic combination are intended to inhibit the progression of one or more disease symptom(s), either by inducing regression or inhibiting the progression of such symptoms to any clinically measurable degree in the treated subject or population. It is administered in an amount effective for relief. The amount of agent in a therapeutic combination effective to alleviate any particular disease symptom may vary depending on factors such as the disease state, age and weight of the patient, and the ability of the therapeutic combination to elicit the desired response in the subject. Whether disease symptoms are alleviated can be assessed by any clinical measure typically used by a physician or other skilled health care provider to assess the severity or progression of the symptoms.

As used herein, “treat” or “treating” cancer means administering to a subject having cancer or diagnosed with cancer a PD-1 antagonist, a TIGIT antagonist, and one or more chemotherapeutic agents or pharmaceutically acceptable salts thereof (e.g. For example, an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof and one or more chemotherapy agents (e.g., 5-fluorouracil, Administering a therapeutic combination of cisplatin, paclitaxel or a pharmaceutically acceptable salt thereof, gemcitabine or a pharmaceutically acceptable salt thereof, capecitabine or a pharmaceutically acceptable salt thereof and/or oxaliplatin) (orally, mucosally, intradermally) , intravenous, subcutaneous, intramuscular delivery and/or administration by any other physical delivery method described herein or known in the art) to produce at least one positive therapeutic effect, such as, for example, It is meant to achieve reduced cancer cell number, reduced tumor size, reduced cancer cell invasion rate into peripheral organs or reduced tumor metastasis or tumor growth rate. In specific embodiments, the therapeutic combination is a therapeutic combination of an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, 5-fluorouracil, and cisplatin. ; a therapeutic combination of an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, and paclitaxel or a pharmaceutically acceptable salt thereof; A therapeutic combination of anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, gemcitabine or a pharmaceutically acceptable salt thereof and cisplatin; or a therapeutic combination of an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, capecitabine or a pharmaceutically acceptable salt thereof, and oxaliplatin. “Treatment” may include one or more of the following: inducing/increasing an anti-tumor immune response, reducing the number of one or more tumor markers, treating the growth or disease of a tumor or hematologic malignancy, such as cancer. Stopping or delaying progression, stabilizing disease, inhibiting the growth or survival of tumor cells, eliminating or reducing the size of one or more cancerous lesions or tumors, reducing the level of one or more tumor markers , improving or eliminating clinical signs of a disease, reducing the severity or duration of clinical symptoms, prolonging the patient's survival compared to expected survival in a similar untreated patient, and complete or partial relief of the cancerous condition. Inducing (wherein the disease is cancer, and in certain embodiments the cancer is endometrial cancer, cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, bladder cancer, breast cancer, triple negative breast cancer (TNBC), non-small cell lung cancer ( NSCLC), colorectal cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and melanoma). The amount of therapeutic agent effective to alleviate any particular disease symptom may vary depending on factors such as the patient's disease state, age and weight, and the drug's ability to elicit the desired response in the subject. Whether disease symptoms are alleviated can be assessed by any clinical measure typically used by a physician or other skilled health care provider to assess the severity or progression of the symptoms.

Positive therapeutic effects in cancer can be measured in a number of ways (see WA Weber, J. Nucl. Med. 50:1S-10S (2009)). For example, with respect to tumor growth inhibition, according to NCI standards, T/C ≤ 42% is the minimum level of antitumor activity. T/C <10% is considered a high level of anti-tumor activity, T/C (%) = median tumor volume of treatment group/median tumor volume of control group x 100. In some embodiments, the treatment achieved by the combination therapy of the present disclosure is any of PR, CR, OR, PFS, DFS, and OS. PFS, also referred to as “time to tumor progression,” refers to the length of time the cancer is not growing during and after treatment, and is the amount of time a patient experiences a CR or PR, as well as the amount of time a patient experiences SD. Includes sheep. DFS refers to the length of time during and after treatment during which a patient remains disease-free. OS refers to the extension of life expectancy compared to naïve or untreated individuals or patients. In some embodiments, the response to the combination therapy of the present disclosure is any of PR, CR, PFS, DFS, or OR assessed using RECIST 1.1 response criteria. The treatment regimen for a combination therapy of the present disclosure that is effective in treating a cancer patient may vary depending on factors such as the patient's disease state, age and weight, and the ability of the therapy to elicit an anti-cancer response in the subject. An embodiment of any aspect of the disclosure may not be effective in achieving a positive therapeutic effect in all subjects, but may be performed using any statistical test known in the art, such as Student's t-test, Chi ² -test, It should be effective in a statistically significant number of subjects as determined by the U-test according to Mann-Whitney, Kruskal-Wallis test (H-test), Jonkeer-Tupstra-test and Wilcoxon-test.

As used herein, “treat” or “treating” an infectious disease or infection (e.g., caused by many pathogens, including bacteria, viruses, and fungi) refers to treating a subject with PD-1. Antagonists, TIGIT antagonists and one or more chemotherapeutic agents or pharmaceutically acceptable salts thereof (e.g., anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, anti-human TIGIT monoclonal antibody or antigen thereof Binding fragment and one or more chemotherapy agents (e.g., 5-fluorouracil, cisplatin, paclitaxel or a pharmaceutically acceptable salt thereof, gemcitabine or a pharmaceutically acceptable salt thereof, capecitabine or a pharmaceutically acceptable salt thereof It means achieving at least one positive therapeutic effect by administering a therapeutic combination of salt and/or oxaliplatin) or a pharmaceutically acceptable salt thereof.

The term “co-formulation” refers to a preparation containing two or more therapeutic agents. In some embodiments, the co-agent includes a TIGIT antagonist and a PD-1 antagonist.

The term “pharmaceutically acceptable carrier” refers to any inert material suitable for use in a formulation for the delivery of a therapeutic agent. The carrier may be an anti-adhesion agent, binder, coating agent, disintegrant, filler or diluent, preservative (such as antioxidant, antibacterial or antifungal agent), sweetener, absorption delaying agent, wetting agent, emulsifier, buffering agent, etc. Examples of suitable pharmaceutically acceptable carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), dextrose, vegetable oils (such as olive oil), saline, buffers, buffered saline and isotonic agents such as sugars, Contains polyalcohols, sorbitol and sodium chloride.

As used herein, the terms “combination,” “combination therapy,” and “therapeutic combination” refer to at least one PD-1 antagonist, at least one TIGIT antagonist, and one or more chemotherapeutic agents or pharmaceutically acceptable salts thereof, and Optionally refers to treatment in which each of the additional therapeutic agents is administered to the patient in a coordinated manner, sequentially, simultaneously or separately over an overlapping period of time. In specific embodiments, treatment comprises at least one anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, at least one anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, 5-fluorotherapy Combination of louracil and cisplatin; A combination of at least one anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, at least one anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof and paclitaxel or a pharmaceutically acceptable salt thereof ; At least one anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, at least one anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, gemcitabine or a pharmaceutically acceptable salt thereof, and Combination of cisplatin; or at least one anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, at least one anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, capecitabine or a pharmaceutically acceptable antibody thereof. It is a combination of salt and oxaliplatin; Each optionally has additional therapeutic agents. The period of treatment with at least one TIGIT antagonist (“anti-TIGIT treatment”) is the period during which the patient is receiving treatment with a TIGIT antagonist, e.g., an anti-human TIGIT monoclonal antibody (or antigen-binding fragment thereof); That is, the period from the initial administration with the TIGIT antagonist to the final day of the treatment cycle. Similarly, a period of treatment with at least one PD-1 antagonist (“anti-PD-1 treatment”) may be defined as a period of treatment in which the patient is receiving a PD-1 antagonist, e.g., an anti-human PD-1 monoclonal antibody (or antigen thereof). -period of treatment with combined fragments); That is, the period from the initial administration with the PD-1 antagonist to the final day of the treatment cycle.

Duration of treatment with 5-fluorouracil and/or cisplatin (“5-FU/cisplatin treatment”) refers to the period during which the patient receives treatment with 5-fluorouracil and/or cisplatin; That is, the period from the initial administration with 5-fluorouracil and/or cisplatin to the final day of the treatment cycle. In the methods, uses and treatment combinations described herein, the anti-TIGIT treatment overlaps with the anti-PD-1 treatment by at least 1 day and overlaps with the 5-FU/cisplatin treatment by at least 1 day. In certain embodiments, the anti-TIGIT treatment, anti-PD-1 treatment and 5-FU/cisplatin treatment are of the same duration. In some embodiments, anti-TIGIT treatment is initiated prior to anti-PD-1 and/or 5-FU/cisplatin treatment. In other embodiments, anti-TIGIT treatment begins after anti-PD-1 and/or 5-FU/cisplatin treatment. In another embodiment, anti-PD-1 treatment is initiated prior to anti-TIGIT and/or 5-FU/cisplatin treatment. In another embodiment, anti-PD-1 treatment begins after anti-TIGIT and/or 5-FU/cisplatin treatment. In some embodiments, 5-FU/cisplatin treatment is initiated prior to anti-PD-1 and/or anti-TIGIT treatment. In other embodiments, 5-FU/cisplatin treatment begins after anti-PD-1 and/or anti-TIGIT treatment. In certain embodiments, anti-TIGIT treatment is terminated prior to termination of anti-PD-1 and/or 5-FU/cisplatin treatment. In other embodiments, anti-TIGIT treatment is terminated after termination of anti-PD-1 and/or 5-FU/cisplatin treatment. In another embodiment, anti-PD-1 treatment is terminated prior to termination of anti-TIGIT and/or 5-FU/cisplatin treatment. In another embodiment, anti-PD-1 treatment is terminated after termination of anti-TIGIT and/or 5-FU/cisplatin treatment. In certain embodiments, 5-FU/cisplatin treatment is terminated prior to termination of anti-PD-1 and/or anti-TIGIT treatment. In other embodiments, 5-FU/cisplatin treatment is terminated after termination of anti-PD-1 and/or anti-TIGIT treatment.

The period of treatment with paclitaxel or a pharmaceutically acceptable salt thereof (“paclitaxel treatment”) refers to the period during which the patient receives treatment with paclitaxel or a pharmaceutically acceptable salt thereof; That is, the period from the initial administration with paclitaxel or a pharmaceutically acceptable salt thereof to the final day of the treatment cycle. In the methods, uses and treatment combinations described herein, the anti-TIGIT treatment overlaps the anti-PD-1 treatment by at least 1 day and overlaps the paclitaxel treatment by at least 1 day. In certain embodiments, the anti-TIGIT treatment, anti-PD-1 treatment, and paclitaxel treatment are of the same duration. In some embodiments, anti-TIGIT treatment is initiated prior to anti-PD-1 and/or paclitaxel treatment. In other embodiments, anti-TIGIT treatment is initiated following anti-PD-1 and/or paclitaxel treatment. In another embodiment, anti-PD-1 treatment is initiated prior to anti-TIGIT and/or paclitaxel treatment. In another embodiment, anti-PD-1 treatment begins after anti-TIGIT and/or paclitaxel treatment. In some embodiments, paclitaxel treatment is initiated prior to anti-PD-1 and/or anti-TIGIT treatment. In other embodiments, paclitaxel treatment begins after anti-PD-1 and/or anti-TIGIT treatment. In certain embodiments, anti-TIGIT treatment is terminated prior to termination of anti-PD-1 and/or paclitaxel treatment. In other embodiments, anti-TIGIT treatment is terminated after termination of anti-PD-1 and/or paclitaxel treatment. In another embodiment, anti-PD-1 treatment is terminated prior to termination of anti-TIGIT and/or paclitaxel treatment. In another embodiment, anti-PD-1 treatment is terminated after termination of anti-TIGIT and/or paclitaxel treatment. In certain embodiments, paclitaxel treatment is terminated prior to termination of anti-PD-1 and/or anti-TIGIT treatment. In other embodiments, paclitaxel treatment is terminated after termination of anti-PD-1 and/or anti-TIGIT treatment.

The period of treatment using gemcitabine or a pharmaceutically acceptable salt thereof and/or cisplatin (“gemcitabine/cisplatin treatment”) is the period during which the patient receives treatment using gemcitabine or a pharmaceutically acceptable salt thereof and/or cisplatin; That is, it is the period from the initial administration using gemcitabine or a pharmaceutically acceptable salt thereof and/or cisplatin to the final day of the treatment cycle. In the methods, uses and treatment combinations described herein, the anti-TIGIT treatment overlaps the anti-PD-1 treatment by at least 1 day and overlaps the gemcitabine/cisplatin treatment by at least 1 day. In certain embodiments, the anti-TIGIT treatment, anti-PD-1 treatment and gemcitabine/cisplatin treatment are of the same duration. In some embodiments, anti-TIGIT treatment is initiated prior to anti-PD-1 and/or gemcitabine/cisplatin treatment. In other embodiments, anti-TIGIT treatment is initiated after anti-PD-1 and/or gemcitabine/cisplatin treatment. In another embodiment, anti-PD-1 treatment is initiated prior to anti-TIGIT and/or gemcitabine/cisplatin treatment. In another embodiment, anti-PD-1 treatment begins after anti-TIGIT and/or gemcitabine/cisplatin treatment. In some embodiments, gemcitabine/cisplatin treatment is initiated prior to anti-PD-1 and/or anti-TIGIT treatment. In another embodiment, gemcitabine/cisplatin treatment begins after anti-PD-1 and/or anti-TIGIT treatment. In certain embodiments, anti-TIGIT treatment is terminated prior to termination of anti-PD-1 and/or gemcitabine/cisplatin treatment. In other embodiments, anti-TIGIT treatment is terminated after termination of anti-PD-1 and/or gemcitabine/cisplatin treatment. In another embodiment, anti-PD-1 treatment is terminated prior to termination of anti-TIGIT and/or gemcitabine/cisplatin treatment. In another embodiment, anti-PD-1 treatment is terminated after termination of anti-TIGIT and/or gemcitabine/cisplatin treatment. In certain embodiments, gemcitabine/cisplatin treatment is terminated prior to termination of anti-PD-1 and/or anti-TIGIT treatment. In other embodiments, gemcitabine/cisplatin treatment is terminated after termination of anti-PD-1 and/or anti-TIGIT treatment.

The period of treatment with capecitabine or its pharmaceutically acceptable salt and/or oxaliplatin (“capecitabine/oxaliplatin treatment”) refers to the period during which the patient receives treatment with capecitabine or its pharmaceutically acceptable salt and/or oxaliplatin. period; That is, the period from the initial administration with capecitabine or a pharmaceutically acceptable salt thereof and/or oxaliplatin to the final day of the treatment cycle. In the methods, uses and treatment combinations described herein, the anti-TIGIT treatment overlaps with the anti-PD-1 treatment by at least 1 day and overlaps with the capecitabine/oxaliplatin treatment by at least 1 day. In certain embodiments, the anti-TIGIT treatment, anti-PD-1 treatment and capecitabine/oxaliplatin treatment are of the same duration. In some embodiments, anti-TIGIT treatment is initiated prior to anti-PD-1 and/or capecitabine/oxaliplatin treatment. In other embodiments, anti-TIGIT treatment begins after anti-PD-1 and/or capecitabine/oxaliplatin treatment. In another embodiment, anti-PD-1 treatment is initiated prior to anti-TIGIT and/or capecitabine/oxaliplatin treatment. In another embodiment, anti-PD-1 treatment begins after anti-TIGIT and/or capecitabine/oxaliplatin treatment. In some embodiments, capecitabine/oxaliplatin treatment is initiated prior to anti-PD-1 and/or anti-TIGIT treatment. In other embodiments, capecitabine/oxaliplatin treatment begins after anti-PD-1 and/or anti-TIGIT treatment. In certain embodiments, anti-TIGIT treatment is terminated prior to termination of anti-PD-1 and/or capecitabine/oxaliplatin treatment. In other embodiments, anti-TIGIT treatment is terminated after termination of anti-PD-1 and/or capecitabine/oxaliplatin treatment. In another embodiment, anti-PD-1 treatment is terminated prior to termination of anti-TIGIT and/or capecitabine/oxaliplatin treatment. In another embodiment, anti-PD-1 treatment is terminated after termination of anti-TIGIT and/or capecitabine/oxaliplatin treatment. In certain embodiments, capecitabine/oxaliplatin treatment is terminated prior to termination of anti-PD-1 and/or anti-TIGIT treatment. In other embodiments, capecitabine/oxaliplatin treatment is terminated after termination of anti-PD-1 and/or anti-TIGIT treatment.

The terms “treatment regimen,” “dosage protocol,” and “dosage regimen” are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in the combination therapy of the present disclosure.

The terms “cancer,” “cancerous,” or “malignant” refer to or describe a physiological condition in mammals that is typically characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, and sarcoma. More specific examples of these cancers include squamous cell carcinoma, myeloma, small cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal (ductal) cancer, and renal cancer. , ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, Including, but not limited to, stomach cancer, bladder cancer, hepatocellular carcinoma, hepatocellular carcinoma, biliary tract cancer, esophageal cancer, breast cancer, triple negative breast cancer, colon carcinoma, and head and neck cancer.

“Tumor” when applied to a subject diagnosed with cancer or suspected of having cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumors and secondary neoplasms. Non-limiting examples of tumors include solid tumors (e.g., sarcomas (e.g. chondrosarcoma), carcinomas (e.g. colon carcinoma), blastomas (e.g. hepatoblastoma), etc.) and hematological tumors (e.g., leukemias (e.g. acute myeloid leukemia) AML), lymphomas (e.g. DLBCL), multiple myeloma (MM), etc.).

“Tumor burden,” also referred to as “tumor load,” refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of the tumor(s) throughout the body, including the lymph nodes and bone marrow. Tumor burden can be determined by a variety of methods known in the art, such as upon removal from the subject, e.g. using calipers, or while still within the body using imaging techniques such as ultrasound, bone scan, computer It can be determined by measuring the dimensions of the tumor(s) using a tomography (CT) or magnetic resonance imaging (MRI) scan.

The term “tumor volume” or “tumor size” refers to the total size of a tumor, which can be measured as the length and width of the tumor. Tumor size can be determined by a variety of methods known in the art, e.g., upon removal from the subject, e.g., using calipers, or while still within the body, using imaging techniques, e.g., bone scan, ultrasound, CT, or This can be determined by measuring the dimensions of the tumor(s) using an MRI scan.

As used herein, the term “effective amount” means a measurable improvement in one or more symptoms or progression of an infection or disease, e.g., cancer, when administered to a cell, tissue, or subject, alone or in combination with an additional therapeutic agent. PD-1 antagonists, TIGIT antagonists and one or more chemotherapeutic agents effective for inducing or pharmaceutically acceptable salts thereof (e.g., anti-TIGIT antibodies or antigen-binding fragments of the present invention, anti-PD-1 antibodies or antigens) Binding fragment and one or more chemotherapy agents (e.g., 5-fluorouracil, cisplatin, paclitaxel or a pharmaceutically acceptable salt thereof, gemcitabine or a pharmaceutically acceptable salt thereof, capecitabine or a pharmaceutically acceptable salt thereof salt and/or oxaliplatin)). An effective amount further refers to an amount of antibody or fragment sufficient to cause at least partial improvement of symptoms, e.g., tumor shrinkage or elimination, lack of tumor growth, and increased survival time. When applied to an individual active ingredient administered alone, an effective amount refers to that ingredient alone. When applied to a combination, an effective amount refers to the combined amount of active ingredients that produces a therapeutic effect, whether administered in combination, sequentially, or simultaneously. An effective amount of therapeutic agent will exceed the diagnostic measure or parameter by at least 10%; Typically at least 20%; preferably at least about 30%; More preferably, it can be improved by at least 40%, and most preferably by at least 50%. Effective doses may also result in improvements in subjective measures when such measures are used to assess disease severity. The toxicity and therapeutic efficacy of an antibody or antigen-binding fragment of the invention, administered alone or in combination with another therapeutic agent, can be determined by any number of systems or means. For example, the toxicity and therapeutic efficacy of an antibody or antigen-binding fragment or compound of the invention can be determined, for example, by determining the LD50 (the dose that is lethal in 50% of the population) and the ED50 (the dose that is therapeutically effective in 50% of the population). This can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index (LD50/ED50). Data obtained from these cell culture assays and animal studies can be used to formulate dosage ranges for use in humans. The dosage of these compounds is preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. Dosages may vary within this range depending on the dosage form and route of administration used.

It is understood that wherever an embodiment is described herein with the term “comprising,” other similar embodiments described with the terms “consisting of” and/or “consisting essentially of” are also provided.

As used throughout the specification and claims, variations such as “consisting essentially of” and “consisting essentially of” or “consisting essentially of” include any stated element or group of elements and the specified administration regimen, method, or Indicates the optional inclusion of other elements of similar or different nature to the elements mentioned, which do not substantially change the basic or novel properties of the composition.

Unless explicitly stated otherwise, all ranges recited herein are inclusive; That is, the range includes the values for the upper and lower limits of the range, as well as all values in between. By way of example, temperature ranges, percentages, equivalent ranges, etc. described herein include the upper and lower limits of the range and any continuous values in between. Numerical values provided herein and use of the term “about” mean variations of ±1%, ±2%, ±3%, ±4%, ±5%, ±10%, ±15% and ±20% and equivalent values thereof. may include. All ranges are also intended to include all sub-ranges, although this is not necessarily explicitly indicated. For example, a range of 3 to 7 days is intended to include 3, 4, 5, 6, and 7 days. Additionally, as used herein, the term “or” refers to alternatives that may be combined where appropriate; That is, the term “or” includes each individually listed alternative as well as combinations thereof.

Where aspects or embodiments of the disclosure are described in terms of Markush groups or other alternative groups, the disclosure refers to the entire group listed as a whole, as well as each member of the individual group and every possible member of the major group. It encompasses major groups in which one or more members of the group are absent, as well as subgroups. This disclosure also contemplates the express exclusion of one or more members of any group from the scope of the claims.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which this disclosure pertains. In case of conflict, the present specification, including definitions, will control. Throughout this specification and claims, the word "comprise" or variations such as "includes" or "comprising" include the stated integer or group of integers but do not exclude any other integer or group of integers. It will be understood as implying that it is not. Unless the context otherwise requires, singular terms shall include pluralities and plural terms shall include the singular. Any example(s) following the terms “such as” or “for example” are not intended to be exhaustive or limiting.

Although exemplary methods and materials are described herein, methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. The materials, methods and examples are illustrative only and are not intended to be limiting.

Abbreviations and Expanded Terms

Table 3. Abbreviations

PD-1 antagonist

Any method, composition disclosed herein, comprising any chemical compound or biological molecule that blocks the binding of PD-L1 to PD-1, and preferably also blocks the binding of PD-L2 to PD-1, Provided herein are PD-1 antagonists or anti-human PD-1 monoclonal antibodies that can be used in kits and applications.

Any monoclonal antibody that binds to a PD-1 polypeptide, PD-1 polypeptide fragment, PD-1 peptide, or PD-1 epitope and blocks the interaction between PD-1 and its ligand PD-L1 or PD-L2. can be used. In some embodiments, the anti-human PD-1 monoclonal antibody binds a PD-1 polypeptide, PD-1 polypeptide fragment, PD-1 peptide, or PD-1 epitope, and binds to a PD-1 epitope and binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, or a PD-1 epitope. Blocks the action. In other embodiments, the anti-human PD-1 monoclonal antibody binds to a PD-1 polypeptide, PD-1 polypeptide fragment, PD-1 peptide, or PD-1 epitope, and binds to a PD-1 polypeptide or PD-1 epitope and Blocks the action. In another embodiment, the anti-human PD-1 monoclonal antibody binds to a PD-1 polypeptide, PD-1 polypeptide fragment, PD-1 peptide, or PD-1 epitope and binds to a PD-1 epitope and interaction and blocks the interaction between PD-1 and PD-L2.

Any monoclonal antibody that binds to a PD-L1 polypeptide, PD-L1 polypeptide fragment, PD-L1 peptide, or PD-L1 epitope and blocks the interaction between PD-L1 and PD-1 can also be used.

In certain embodiments, the anti-human PD-1 monoclonal antibody is pembrolizumab, nivolumab, cemiplimab, pidilizumab (U.S. Patent No. 7,332,582), AMP-514 (MedImmune LLC, Gaithers, MD) Berg), PDR001 (U.S. Patent No. 9,683,048), BGB-A317 (U.S. Patent No. 8,735,553), and MGA012 (Macrogenics, Rockville, MD). In one embodiment, the anti-human PD-1 monoclonal antibody is pembrolizumab. In one embodiment, the anti-human PD-1 monoclonal antibody is pembrolizumab. In another embodiment, the anti-human PD-1 monoclonal antibody is nivolumab. In another embodiment, the anti-human PD-1 monoclonal antibody is cemiplimab. In another embodiment, the anti-human PD-1 monoclonal antibody is pidilizumab. In one embodiment, the anti-human PD-1 monoclonal antibody is AMP-514. In another embodiment, the anti-human PD-1 monoclonal antibody is PDR001. In another embodiment, the anti-human PD-1 monoclonal antibody is BGB-A317. In another embodiment, the anti-human PD-1 monoclonal antibody is MGA012.

In some embodiments, the anti-human PD-1 antibody or antigen-binding fragment thereof for use in the methods, kits, uses and co-formulations of the invention comprises the three light chain CDRs of CDRL1, CDRL2 and CDRL3 and/or CDRH1, CDRH2 and the three heavy chain CDRs of CDRH3.

In one embodiment of the invention, CDRL1 comprises an amino acid sequence as set forth in SEQ ID NO: 1 or a variant of the amino acid sequence as set forth in SEQ ID NO: 1, and CDRL2 comprises an amino acid sequence as set forth in SEQ ID NO: 2. CDRL3 comprises an amino acid sequence or a variant of the amino acid sequence as set forth in SEQ ID NO: 2, and CDRL3 comprises an amino acid sequence as set forth in SEQ ID NO: 3 or a variant of the amino acid sequence as set forth in SEQ ID NO: 3. .

In one embodiment, CDRH1 comprises an amino acid sequence as set forth in SEQ ID NO:6 or a variant of the amino acid sequence as set forth in SEQ ID NO:6, and CDRH2 comprises an amino acid sequence as set forth in SEQ ID NO:7 or and a variant of the amino acid sequence as set forth in SEQ ID NO: 7, wherein CDRH3 comprises an amino acid sequence as set forth in SEQ ID NO: 8 or a variant of the amino acid sequence as set forth in SEQ ID NO: 8.

In one embodiment, the three light chain CDRs have amino acid sequences as set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, and the three heavy chain CDRs have amino acid sequences as set forth in SEQ ID NO: 6, SEQ ID NO: 3. : 7 and SEQ ID NO: 8.

In an alternative embodiment of the invention, CDRL1 comprises an amino acid sequence as set forth in SEQ ID NO: 11 or a variant of the amino acid sequence as set forth in SEQ ID NO: 11, and CDRL2 comprises an amino acid sequence as set forth in SEQ ID NO: 12. CDRL3 comprises the same amino acid sequence or a variant of the amino acid sequence as set forth in SEQ ID NO: 12, and CDRL3 comprises an amino acid sequence as set forth in SEQ ID NO: 13 or a variant of the amino acid sequence as set forth in SEQ ID NO: 13. do.

In one embodiment, CDRH1 comprises an amino acid sequence as set forth in SEQ ID NO: 16 or a variant of the amino acid sequence as set forth in SEQ ID NO: 16, and CDRH2 comprises an amino acid sequence as set forth in SEQ ID NO: 17 or and a variant of the amino acid sequence as set forth in SEQ ID NO: 17, and CDRH3 comprises an amino acid sequence as set forth in SEQ ID NO: 18 or a variant of the amino acid sequence as set forth in SEQ ID NO: 18.

In one embodiment, the three light chain CDRs have amino acid sequences as set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, and the three heavy chain CDRs have amino acid sequences as set forth in SEQ ID NO: 6, SEQ ID NO: 3. : 7 and SEQ ID NO: 8.

In an alternative embodiment, the three light chain CDRs have amino acid sequences as set forth in SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, and the three heavy chain CDRs have amino acid sequences as set forth in SEQ ID NO: 16, SEQ ID NO: 13. It has an amino acid sequence as shown in SEQ ID NO: 17 and SEQ ID NO: 18.

In a further embodiment of the invention, CDRL1 comprises an amino acid sequence as set forth in SEQ ID NO: 21 or a variant of the amino acid sequence as set forth in SEQ ID NO: 21, and CDRL2 comprises an amino acid sequence as set forth in SEQ ID NO: 22. CDRL3 comprises an amino acid sequence or a variant of the amino acid sequence as set forth in SEQ ID NO: 22, and CDRL3 comprises an amino acid sequence as set forth in SEQ ID NO: 23 or a variant of the amino acid sequence as set forth in SEQ ID NO: 23. .

In another embodiment, CDRH1 comprises an amino acid sequence as set forth in SEQ ID NO: 24 or a variant of the amino acid sequence as set forth in SEQ ID NO: 24, and CDRH2 comprises an amino acid sequence as set forth in SEQ ID NO: 25. or a variant of the amino acid sequence as set forth in SEQ ID NO: 25, and CDRH3 comprises an amino acid sequence as set forth in SEQ ID NO: 26 or a variant of the amino acid sequence as set forth in SEQ ID NO: 26.

In another embodiment, the three light chain CDRs have amino acid sequences as set forth in SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23, and the three heavy chain CDRs have amino acid sequences as set forth in SEQ ID NO: 24, SEQ ID NO: 23. It has an amino acid sequence as shown in SEQ ID NO: 25 and SEQ ID NO: 26.

Some anti-human PD-1 antibodies and antigen binding fragments of the invention comprise a light chain variable region and a heavy chain variable region. In some embodiments, the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:4 or a variant of the amino acid sequence as set forth in SEQ ID NO:4, and the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:4. It includes the same amino acid sequence or a variant of the amino acid sequence as set forth in SEQ ID NO: 9. In a further embodiment, the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 14 or a variant of the amino acid sequence as set forth in SEQ ID NO: 14, and the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 19. It includes the same amino acid sequence or a variant of the amino acid sequence as set forth in SEQ ID NO: 19. In a further embodiment, the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 27 or a variant of the amino acid sequence as set forth in SEQ ID NO: 27, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 28. The same amino acid sequence or a variant of an amino acid sequence as set forth in SEQ ID NO: 28, SEQ ID NO: 29 or a variant of an amino acid sequence as set forth in SEQ ID NO: 29, or SEQ ID NO: 30 or SEQ ID NO: 30 Includes variants of the amino acid sequence as set forth in. In this embodiment, the light chain variable region or heavy chain variable region sequence is identical to the reference sequence except with 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the substitution is in a framework region (i.e., outside of the CDRs). In some embodiments, 1, 2, 3, 4, or 5 of the amino acid substitutions are conservative substitutions.

In one embodiment of the co-formulation, method, kit or use of the invention, the anti-human PD-1 antibody or antigen binding fragment has a light chain variable region comprising or consisting of an amino acid sequence as set forth in SEQ ID NO:4. and a heavy chain variable region comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 9. In a further embodiment, the anti-human PD-1 antibody or antigen binding fragment has a light chain variable region comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 14 and an amino acid sequence as set forth in SEQ ID NO: 19. A heavy chain variable region comprising or consisting of. In one embodiment of the formulation of the invention, the anti-human PD-1 antibody or antigen binding fragment comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 28 and a light chain variable region set forth in SEQ ID NO: 27. and a heavy chain variable region comprising or consisting of an amino acid sequence as defined. In a further embodiment, the anti-human PD-1 antibody or antigen binding fragment has a light chain variable region comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 29 and an amino acid sequence as set forth in SEQ ID NO: 27. A heavy chain variable region comprising or consisting of. In another embodiment, the antibody or antigen-binding fragment has a light chain variable region comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 30 and a light chain variable region comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 27. Contains a heavy chain variable region.

In another embodiment, the co-agent, method, kit or use of the invention comprises at least 95%, 90%, 85%, 80%, 75% or 50% of the V _L domain or V _H domain described above. and anti-human PD-1 antibodies or antigen binding proteins that have a V _L domain and/or V _H domain with sequence homology and that exhibit specific binding to PD-1. In another embodiment, the anti-human PD-1 antibody or antigen binding protein of the co-formulation of the invention comprises the V _L and V _H domains with up to 1, 2, 3, 4 or 5 or more amino acid substitutions. It includes and shows specific binding to PD-1.

In any of the above embodiments, the PD-1 antagonist may be a full-length anti-PD-1 antibody or antigen-binding fragment thereof that specifically binds human PD-1. In certain embodiments, the PD-1 antagonist is a full-length anti-PD-1 antibody selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE. Preferably, the antibody is an IgG antibody. Any isotype of IgG can be used, including IgG ₁ , IgG ₂ , IgG ₃ , and IgG ₄ . Different constant domains can be added to the V _L and V _H regions provided herein. For example, if the particular intended use of the antibody (or fragment) of the invention requires altered effector functions, heavy chain constant domains other than IgG1 may be used. Although IgG1 antibodies provide a long half-life and effector functions such as complement activation and antibody-dependent cellular cytotoxicity, these activities may not be desirable for all uses of the antibody. In this case, for example an IgG4 constant domain may be used.

In an embodiment of the invention, the PD-1 antagonist comprises or consists of a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 5 and a sequence of amino acid residues as set forth in SEQ ID NO: 10 or It is an anti-PD-1 antibody comprising a heavy chain consisting of the same. In an alternative embodiment, the PD-1 antagonist comprises a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 15 and a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 20. It is an anti-PD-1 antibody comprising a heavy chain consisting of In a further embodiment, the PD-1 antagonist comprises a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 32 and a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 31. It is an anti-PD-1 antibody containing heavy chains. In a further embodiment, the PD-1 antagonist comprises or consists of a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 33 and a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 31. It is an anti-PD-1 antibody comprising a heavy chain consisting of In a further embodiment, the PD-1 antagonist comprises a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 34 and a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 31. It is an anti-PD-1 antibody comprising a heavy chain consisting of In some co-formulations, methods, kits or uses of the invention, the PD-1 antagonist is pembrolizumab or a pembrolizumab biosimilar. In some co-formulations, methods, kits or uses of the invention, the PD-1 antagonist is nivolumab or a nivolumab biosimilar.

Typically, amino acid sequence variants of the anti-PD-1 antibodies and antigen-binding fragments and anti-TIGIT antibodies and antigen-binding fragments of the invention include the amino acid sequence of the reference antibody or antigen-binding fragment (e.g., heavy chain, light chain, V _H , V _L or humanized sequence), more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95, 98 or 99%. It will have an amino acid sequence with amino acid sequence identity. Identity or homology to a sequence is defined by aligning the sequences and introducing gaps where necessary to achieve maximum percent sequence identity and then comparing the residues of the reference antibody or antigen-binding fragment with any conservative substitutions, without being considered part of the sequence identity. It is defined herein as the percentage of amino acid residues within the same candidate sequence. None of the N-terminal, C-terminal or internal extensions, deletions or insertions into the antibody sequence should be construed as affecting sequence identity or homology.

Sequence identity refers to the degree to which the amino acids of two polypeptides are identical at equivalent positions when the two sequences are optimally aligned. Sequence identity can be determined using the BLAST algorithm, where the parameters of the algorithm are chosen to provide the maximum match between each sequence over the entire length of each reference sequence. The following references relate to the BLAST algorithm, which is often used in sequence analysis: BLAST algorithm: Altschul, S.F., et al., (1990) J. Mol. Biol. 215:403-410; Gish, W., et al., (1993) Nature Genet. 3:266-272; Madden, T.L., et al., (1996) Meth. Enzymol. 266:131-141; Altschul, S.F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J.C., et al., (1993) Comput. Chem. 17:149-163; Hancock, J.M. et al., (1994) Comput. Appl. Biosci. 10:67-70]; Alignment scoring system: Dayhoff, M.O., et al., “A model of evolutionary change in proteins.” in Atlas of Protein Sequence and Structure, (1978) vol. 5, sup. 3.M.O. Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, D.C.; Schwartz, R.M., et al., “Matrices for detecting distant relationships.” in Atlas of Protein Sequence and Structure, (1978) vol. 5, sup. 3." M. O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, S. F., (1991) J. Mol. Biol. 219:555-565; States, D. J., et al., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919; Altschul, S. F., et al. , (1993) J. Mol. Evol. 36:290-300];Alignment statistics: Karlin, S., et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin , S., et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul. , S.F. "Evaluating the statistical significance of multiple distinct local alignments." in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1-14, Plenum, New York].

Likewise, either class of light chain can be used in the compositions and methods herein. Specifically, kappa, lambda, or variants thereof are useful in the compositions and methods of the present invention.

Table 4. Exemplary PD-1 antibody sequences

Table 5. Additional PD-1 antibodies and antigen binding fragments useful in the co-formulations, compositions, methods, kits and uses of the invention.

TIGIT Antagonist

Provided herein are anti-human TIGIT monoclonal antibodies or antigen-binding fragments thereof that can be used in the methods, pharmaceutical compositions, kits, and uses disclosed herein. Any monoclonal antibody that binds a TIGIT polypeptide, TIGIT polypeptide fragment, TIGIT peptide or TIGIT epitope and blocks the interaction between TIGIT and its ligands CD155 and/or CD112 can be used. In some embodiments, the anti-human TIGIT monoclonal antibody binds a TIGIT polypeptide, TIGIT polypeptide fragment, TIGIT peptide, or TIGIT epitope and blocks the interaction between TIGIT and CD155. In other embodiments, the anti-human TIGIT monoclonal antibody binds to a TIGIT polypeptide, TIGIT polypeptide fragment, TIGIT peptide, or TIGIT epitope and blocks the interaction between TIGIT and CD112. In another embodiment, the anti-human TIGIT monoclonal antibody binds to a TIGIT polypeptide, TIGIT polypeptide fragment, TIGIT peptide, or TIGIT epitope and blocks the interaction between TIGIT and CD155 and the interaction between TIGIT and CD112. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region.

Exemplary anti-TIGIT antibody sequences are presented in Tables 6 and 7 below.

Table 6. Exemplary anti-TIGIT antibodies

In some embodiments, the anti-TIGIT antibody or antigen binding fragment thereof comprises three light chain CDRs of CDRL1, CDRL2, and CDRL3 and/or three heavy chain CDRs of CDRH1, CDRH2, and CDRH3.

In one embodiment, the anti-TIGIT antibody or antigen binding fragment thereof comprises CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 35, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 36, SEQ ID NO: : CDRH3 comprising any of the amino acid sequences as set forth in 37, 103, 104, 105, 106, 107 or 160, CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 38, SEQ ID NO: 39, 89 CDRL2 comprising any of the amino acid sequences as set forth in , 90, 91, 92, 93, 94, 95, 96, 97 or 161 and SEQ ID NO: 40, 98, 99, 100, 101, 102 or 162 CDRL3 comprising any of the amino acid sequences described above.

In another embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 81, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 82, SEQ ID NO: CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 83, CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 84, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 85 and SEQ ID NO: Includes CDRL3 containing the amino acid sequence as shown in 86.

In another embodiment, the anti-TIGIT antibody or antigen binding fragment thereof comprises CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 109, 116, 117, 118, 119, 120, 121, CDRH2 comprising any of the amino acid sequences set forth in 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 154, 155 or 167, SEQ ID NO: 110, 173, 174, 175, CDRH3 comprising any of the amino acid sequences set forth in 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186 or 187, comprising the amino acid sequence set forth in SEQ ID NO: 111 CDRL1, CDRL2 comprising any of the amino acid sequences set forth in SEQ ID NO: 112, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142 or 168 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as shown.

In one embodiment, the anti-TIGIT antibody or antigen binding fragment thereof comprises CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 35, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 36, SEQ ID NO: : CDRH3 comprising the amino acid sequence as set forth in 37, CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 38, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 39 and SEQ ID NO: 40 CDRL3 containing the amino acid sequence as shown.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 108, any of the amino acid sequences set forth in SEQ ID NO: 109, 154, or 145. CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 110, CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 112 CDRL2 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113.

In another embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154, SEQ ID NO: CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110, CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: CDRL3 comprising the amino acid sequence as set forth in 113.

In some embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof has a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 294 and an amino acid sequence comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 295. It includes a heavy chain consisting of

In one embodiment, the anti-TIGIT antibody or antigen binding fragment thereof comprises a variable heavy chain region and a variable light chain variable region. In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 41 and a variable light chain region comprising an amino acid sequence as set forth in SEQ ID NO: 42. Includes.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 87 and a variable light chain region comprising an amino acid sequence as set forth in SEQ ID NO: 88. Includes.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 114 and a variable light chain region comprising an amino acid sequence as set forth in SEQ ID NO: 115. Includes.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof has a variable heavy chain region comprising any of the amino acid sequences set forth in SEQ ID NOs: 43-58, 65-75, and 87 and SEQ ID NO: 59-64. , and a variable light chain region comprising any of the amino acid sequences as set forth in 76-80 and 88.

In one embodiment, the anti-TIGIT antibody, or antigen-binding fragment thereof, comprises a variable heavy chain region comprising any of the amino acid sequences set forth in SEQ ID NOs: 144-149 and an amino acid sequence as set forth in SEQ ID NOs: 150-153. A variable light chain region comprising any of the above.

In one embodiment, the anti-TIGIT antibody, or antigen-binding fragment thereof, comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. It includes a variable light chain region comprising.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 147 and a variable light chain region comprising an amino acid sequence as set forth in SEQ ID NO: 150. Includes.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a variable light chain region comprising an amino acid sequence as set forth in SEQ ID NO: 153. Includes.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 163 and a variable light chain region comprising an amino acid sequence as set forth in SEQ ID NO: 165. Includes.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 169 and a variable light chain region comprising an amino acid sequence as set forth in SEQ ID NO: 171. Includes.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 164 and a variable light chain region comprising an amino acid sequence as set forth in SEQ ID NO: 166. Includes.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 170 and a variable light chain region comprising an amino acid sequence as set forth in SEQ ID NO: 172. Includes.

Table 7. Exemplary sequences of anti-TIGIT antibodies

In one embodiment, the anti-TIGIT antibody or antigen binding fragment comprises CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 188, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 189, SEQ ID NO: CDRH3 comprising any of the amino acid sequences as set forth in 190, 220, 221 or 222, CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 191, CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 192 CDRL2 and CDRL3 comprising any of the amino acid sequences set forth in SEQ ID NO: 193, 232, 233, 234, 235, 236 or 237.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 204, SEQ ID NO: 205, 256, 257, 258, 259, 260, 261, 262. or CDRH2 comprising any of the amino acid sequences as set forth in 263, CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 206, CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 207, SEQ ID NO: : CDRL2 comprising the amino acid sequence as set forth in 208 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 209.

In one embodiment, the anti-TIGIT antibody or antigen binding fragment thereof comprises a variable heavy chain region and a variable light chain variable region. In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 194 and a variable light chain region comprising an amino acid sequence as set forth in SEQ ID NO: 195. Includes.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 196 and a variable light chain region comprising an amino acid sequence as set forth in SEQ ID NO: 200. Includes.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 210 and a variable light chain region comprising an amino acid sequence as set forth in SEQ ID NO: 211. Includes.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence as set forth in SEQ ID NO: 212 and a variable light chain region comprising an amino acid sequence as set forth in SEQ ID NO: 216. Includes.

In one embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof has any of the amino acid sequences set forth in SEQ ID NOs: 197, 198, 199, 223, 224, 225, 226, 227, 228, 229, 230, and 231. Variable heavy chain region comprising and SEQ ID NOs: 201, 202, 203, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254 and a variable light chain region comprising any of the amino acid sequences set forth in 255.

In one embodiment, the anti-TIGIT antibody or antigen binding fragment thereof has SEQ ID NO: 213, 214, 215, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276. , 277, 278, 279, 280, 281, 282, 283, 284, 285 and 286, and a variable heavy chain region comprising any of the amino acid sequences as set forth in SEQ ID NOs: 217, 218 and 219. A variable light chain region comprising any of the above.

Additional anti-TIGIT antibodies that can be used in the formulations described herein include, for example, PCT International Application No. WO 2016/106302; WO 2016/011264; and those disclosed in WO 2009/126688.

Table 8. Exemplary heavy chain sequences

In any of the above-mentioned embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof is an antibody comprising any of the variable heavy chains and any of the human heavy chain constant domains described above. In one embodiment, the antibody or antigen-binding fragment thereof of the invention is of the IgG isotype and comprises a human IgG1, IgG2, IgG3 or IgG4 human heavy chain constant domain. In one embodiment, the antibody or antigen-binding fragment thereof of the invention comprises a human heavy chain IgG1 constant domain (SEQ ID NO: 291) or a variant thereof, wherein the variant comprises up to 20 modified amino acid substitutions. In one embodiment, the antibody or antigen-binding fragment thereof of the invention is an antibody comprising a human heavy chain IgG1 constant domain comprising the amino acid sequence set forth in SEQ ID NO:291. In one embodiment, the antibody or antigen-binding fragment thereof of the invention comprises a human heavy chain IgG1 constant domain, wherein the IgG1 constant domain is non-fucosylated. In one embodiment, the antibody or antigen-binding fragment thereof of the invention comprises a human heavy chain IgG4 constant domain or a variant thereof, wherein the variant comprises up to 20 modified amino acid substitutions. In another embodiment, the antibody or antigen-binding fragment thereof of the invention comprises a human heavy chain IgG4 constant domain wherein the amino acid at position 228 (using the EU numbering scheme) is substituted for Ser to Pro. In one embodiment, the antibody or antigen-binding fragment thereof of the invention comprises a human heavy chain IgG4 constant domain comprising the amino acid sequence set forth in SEQ ID NO:292.

In any of the above-mentioned embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof may comprise any of the variable light chains and human light chain constant domains described above. In one embodiment, the antibody or antigen-binding fragment thereof of the invention comprises a human kappa light chain constant domain or a variant thereof, wherein the variant comprises up to 20 modified amino acid substitutions. In another embodiment, the antibody or antigen-binding fragment thereof of the invention comprises a human lambda light chain constant domain or a variant thereof, wherein the variant comprises up to 20 modified amino acid substitutions. In one embodiment, the antibody or antigen-binding fragment thereof of the invention comprises a human kappa light chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 293.

Methods for treating cancer using a combination of PD-1 antagonist, TIGIT antagonist, 5-fluorouracil and cisplatin

In another aspect, provided herein is a method of treating cancer (e.g., esophageal cancer) using a combination of a TIGIT antagonist, a PD-1 antagonist, 5-fluorouracil, and cisplatin.

In certain embodiments, the TIGIT antagonist is an anti-TIGIT antibody or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody or antigen binding fragment thereof.

In certain embodiments, a method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In some embodiments, the cancer is selected from the group consisting of: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Lung: Bronchiogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroid hamartoma, mesothelioma; Gastrointestinal: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine. (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal (adenocarcinoma, tubular adenoma, trophoblastic adenoma, hamartoma, leiomyoma); Genitourinary Tract: Kidney (adenocarcinoma, Wilms tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma) , embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma) ), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous System: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deforming), meninges (meningioma, meningosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pinealoma], pleomorphism) glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecology: Uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-neoplastic cervical dysplasia), ovary (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulo-follicular cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphylococcal sarcoma (embryonic sarcoma) rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Hematology: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome); hematopoiesis of the lymphatic system Tumors such as leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, Myeloma and Burkitt's lymphoma; hematopoietic tumors of the myeloid system, such as acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, such as fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, such as astrocytomas , neuroblastoma, glioma and schwannoma; and other tumors such as melanoma, skin (non-melanoma) cancer, mesothelioma (cell), seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid Follicular carcinoma and Kaposi's sarcoma.

In some embodiments, the cancer is anal cancer, biliary tract cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer (CRC), esophageal cancer, gastrointestinal cancer, glioblastoma, glioma, head and neck cancer (HNSCC), and hepatocellular carcinoma (HCC). ), lung cancer, liver cancer, lymphoma, melanoma, mesothelioma, multiple myeloma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), renal cell carcinoma (RCC), salivary gland selected from the group consisting of cancer, thyroid cancer and other neoplastic malignancies.

In some embodiments, the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, and triple negative breast cancer (TNBC).

In some embodiments, the cancer is esophageal cancer. In some embodiments, the esophageal cancer is locally advanced and unresectable. In some embodiments, the esophageal cancer is metastatic adenocarcinoma. In some embodiments, the esophageal cancer is squamous cell carcinoma of the esophagus (ESCC). In some embodiments, the esophageal cancer is advanced Siewert type 1 adenocarcinoma of the gastroesophageal junction (GEJ). In some embodiments, the esophageal cancer is metastatic Siewert type 1 adenocarcinoma of the gastroesophageal junction (GEJ).

In some embodiments, a combination of a TIGIT antagonist, PD-1 antagonist, 5-fluorouracil, and cisplatin may provide enhanced efficacy compared to existing treatments. For example, TIGIT and PD-L1 are densely co-expressed in adenocarcinoma and ESCC. Combinations of TIGIT antagonists and PD-1 antagonists may provide additional benefits compared to single-agent checkpoint blockade. Without wishing to be bound by any particular theory, chemotherapy agents (i) induce immunogenic cell death, (ii) enhance dendritic cell maturation and activation, and (iii) promote T-cell infiltration and function in tumors. (iv) improving the presentation of tumor antigens, and (v) eliminating immunosuppressive cells. In certain embodiments, the tolerability of vivostolimab (anti-TIGIT antibody) is a potential additional benefit over combination with one or more chemotherapy agents and a PD-1 antagonist.

In certain embodiments, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In another embodiment, the cancer is relapsed and refractory.

In certain embodiments, a human patient in need of treatment for esophageal cancer (e.g., locally advanced unresectable, metastatic adenocarcinoma, ESCC, advanced Siewert type 1 adenocarcinoma of the GEJ, or metastatic Siewert type 1 adenocarcinoma of the GEJ) is administered the following: Provided herein is a method of treating esophageal cancer, comprising administering:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In certain embodiments, a method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) a TIGIT antagonist as disclosed in the section entitled TIGIT Antagonist;

(b) a PD-1 antagonist as disclosed in the section entitled PD-1 Antagonist;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In certain embodiments, the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human PD-1 monoclonal antibody is a human antibody. In other embodiments, the anti-human PD-1 monoclonal antibody is a humanized antibody.

In certain embodiments, the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human PD-L1 monoclonal antibody is a human antibody. In other embodiments, the anti-human PD-L1 monoclonal antibody is a humanized antibody.

In certain embodiments, the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human TIGIT monoclonal antibody is a human antibody. In other embodiments, the anti-human TIGIT monoclonal antibody is a humanized antibody.

Accordingly, in certain embodiments, provided herein is a method of treating cancer comprising administering to a human patient in need thereof:

(a) human or humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a human or humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In some embodiments, provided herein is a method of treating cancer comprising administering to a human patient in need of treatment of cancer:

(a) human anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) human anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In another embodiment, provided herein is a method of treating cancer comprising administering to a human patient in need thereof:

(a) humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In one embodiment of the methods, compositions, kits and uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab.

In another embodiment of the methods, compositions, kits and uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab.

In another embodiment of the methods, compositions, kits and uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is cemiplimab.

In certain embodiments of the methods, compositions, kits and uses provided herein, the anti-TIGIT antibody or antigen-binding fragment thereof has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: : CDRL2 comprising the amino acid sequence as set forth in 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110.

In some embodiments of the methods, compositions, kits and uses provided herein, the anti-TIGIT antibody or antigen-binding fragment thereof has a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. and a light chain variable region comprising the amino acid sequence as shown.

In certain embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof has a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 294 and an amino acid sequence comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 295. It includes a heavy chain consisting of

In one specific embodiment of the methods provided herein, the method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In one specific embodiment of the methods provided herein, the method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In one specific embodiment of the methods provided herein, the method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In one specific embodiment of the methods provided herein, the method of treating esophageal cancer comprises administering to a human patient in need of treatment of esophageal cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In one specific embodiment of the methods provided herein, the method of treating esophageal cancer comprises administering to a human patient in need of treatment of esophageal cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In one specific embodiment of the methods provided herein, the method of treating esophageal cancer comprises administering to a human patient in need of treatment of esophageal cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

Methods of treating cancer using a combination of a PD-1 antagonist, a TIGIT antagonist, and paclitaxel or a pharmaceutically acceptable salt thereof

In another aspect, the disclosure provides a method for treating cancer (e.g., TNBC) using a combination of a TIGIT antagonist represented by Formula (III), a PD-1 antagonist, and (c) paclitaxel or a pharmaceutically acceptable salt thereof. Provides a method.

In certain embodiments, the TIGIT antagonist is an anti-TIGIT antibody or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody or antigen binding fragment thereof.

In certain embodiments, a method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) TIGIT antagonist;

(b) PD-1 antagonist; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof represented by formula (III).

In some embodiments, the cancer is selected from the group consisting of: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Lung: Bronchiogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroid hamartoma, mesothelioma; Gastrointestinal: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine. (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal (adenocarcinoma, tubular adenoma, trophoblastic adenoma, hamartoma, leiomyoma); Genitourinary Tract: Kidney (adenocarcinoma, Wilms tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma) , embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma) ), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous System: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deforming), meninges (meningioma, meningosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pinealoma], pleomorphism) glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecology: Uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-neoplastic cervical dysplasia), ovary (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulo-follicular cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphylococcal sarcoma (embryonic sarcoma) rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Hematology: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome); hematopoiesis of the lymphatic system Tumors such as leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, Myeloma and Burkitt's lymphoma; hematopoietic tumors of the myeloid system, such as acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, such as fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, such as astrocytomas , neuroblastoma, glioma and schwannoma; and other tumors such as melanoma, skin (non-melanoma) cancer, mesothelioma (cell), seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid Follicular carcinoma and Kaposi's sarcoma.

In some embodiments, the cancer is anal cancer, biliary tract cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer (CRC), esophageal cancer, gastrointestinal cancer, glioblastoma, glioma, head and neck cancer (HNSCC), and hepatocellular carcinoma (HCC). ), lung cancer, liver cancer, lymphoma, melanoma, mesothelioma, multiple myeloma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), renal cell carcinoma (RCC), salivary gland selected from the group consisting of cancer, thyroid cancer and other neoplastic malignancies.

In some embodiments, the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, and triple negative breast cancer (TNBC).

In some embodiments, the cancer is TNBC. In some embodiments, the TNBC is recurrent and unresectable. In some embodiments, TNBC is metastatic.

In some embodiments, a combination of a TIGIT antagonist, a PD-1 antagonist, and paclitaxel or a pharmaceutically acceptable salt thereof may provide enhanced efficacy compared to existing treatments. For example, TNBC may be an immune-reactive disease that is susceptible to immune modulation of the tumor microenvironment and highly expresses TIGIT and PD-L1. Without wishing to be bound by any particular theory, chemotherapy agents (i) induce immunogenic cell death, (ii) enhance dendritic cell maturation and activation, and (iii) promote T-cell infiltration and function in tumors. (iv) improving the presentation of tumor antigens, and (v) eliminating immunosuppressive cells. In certain embodiments, the tolerability of vivostolimab is a potential additional benefit over combination with chemotherapy and a PD-1 antagonist.

In certain embodiments, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In another embodiment, the cancer is relapsed and refractory.

In certain embodiments, provided herein is a method of treating TNBC, comprising administering to a human patient in need of treatment for TNBC:

(a) TIGIT antagonist;

(b) PD-1 antagonist; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof represented by formula (III).

In some embodiments, provided herein is a method of treating hepatocellular carcinoma, comprising administering to a human patient in need of treatment of hepatocellular carcinoma:

(a) TIGIT antagonist;

(b) PD-1 antagonist; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof represented by formula (III).

In certain embodiments, a method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) a TIGIT antagonist as disclosed in the section entitled TIGIT Antagonist;

(b) a PD-1 antagonist as disclosed in the section entitled PD-1 Antagonist; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In certain embodiments, the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human PD-1 monoclonal antibody is a human antibody. In other embodiments, the anti-human PD-1 monoclonal antibody is a humanized antibody.

In certain embodiments, the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human PD-L1 monoclonal antibody is a human antibody. In other embodiments, the anti-human PD-L1 monoclonal antibody is a humanized antibody.

In certain embodiments, the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human TIGIT monoclonal antibody is a human antibody. In other embodiments, the anti-human TIGIT monoclonal antibody is a humanized antibody.

Accordingly, in certain embodiments, provided herein is a method of treating cancer comprising administering to a human patient in need thereof:

(a) human or humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a human or humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a method of treating cancer comprising administering to a human patient in need of treatment of cancer:

(a) human anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) human anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating cancer comprising administering to a human patient in need thereof:

(a) humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In one embodiment of the methods, compositions, kits and uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab.

In another embodiment of the methods, compositions, kits and uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab.

In another embodiment of the methods, compositions, kits and uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is cemiplimab.

In certain embodiments of the methods, compositions, kits and uses provided herein, the anti-TIGIT antibody or antigen-binding fragment thereof has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: : CDRL2 comprising the amino acid sequence as set forth in 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110.

In some embodiments of the methods, compositions, kits and uses provided herein, the anti-TIGIT antibody or antigen-binding fragment thereof has a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. and a light chain variable region comprising the amino acid sequence as shown.

In certain embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof has a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 294 and an amino acid sequence comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 295. It includes a heavy chain consisting of

In one specific embodiment of the methods provided herein, the method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In one specific embodiment of the methods provided herein, the method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In one specific embodiment of the methods provided herein, the method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110 an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In one specific embodiment of the methods provided herein, the method of treating TNBC comprises administering to a human patient in need of treatment of TNBC:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In one specific embodiment of the methods provided herein, the method of treating TNBC comprises administering to a human patient in need of treatment of TNBC:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In one specific embodiment of the methods provided herein, the method of treating TNBC comprises administering to a human patient in need of treatment of TNBC:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

Methods for treating cancer using a combination of PD-1 antagonist, TIGIT antagonist, gemcitabine and cisplatin

In another aspect, provided herein is a method of treating cancer (e.g., biliary tract cancer) using a combination of a TIGIT antagonist, a PD-1 antagonist, gemcitabine, and cisplatin.

In certain embodiments, the TIGIT antagonist is an anti-TIGIT antibody or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody or antigen binding fragment thereof.

In certain embodiments, a method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In some embodiments, the cancer is selected from the group consisting of: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Lung: Bronchiogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroid hamartoma, mesothelioma; Gastrointestinal: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine. (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal (adenocarcinoma, tubular adenoma, trophoblastic adenoma, hamartoma, leiomyoma); Genitourinary Tract: Kidney (adenocarcinoma, Wilms tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma) , embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma) ), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous System: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deforming), meninges (meningioma, meningosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pinealoma], pleomorphism) glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecology: Uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-neoplastic cervical dysplasia), ovary (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulo-follicular cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphylococcal sarcoma (embryonic sarcoma) rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Hematology: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome); hematopoiesis of the lymphatic system Tumors such as leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, Myeloma and Burkitt's lymphoma; hematopoietic tumors of the myeloid system, such as acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, such as fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, such as astrocytomas , neuroblastoma, glioma and schwannoma; and other tumors such as melanoma, skin (non-melanoma) cancer, mesothelioma (cell), seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid Follicular carcinoma and Kaposi's sarcoma.

In some embodiments, the cancer is anal cancer, biliary tract cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer (CRC), esophageal cancer, gastrointestinal cancer, glioblastoma, glioma, head and neck cancer (HNSCC), and hepatocellular carcinoma (HCC). ), lung cancer, liver cancer, lymphoma, melanoma, mesothelioma, multiple myeloma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), renal cell carcinoma (RCC), salivary gland selected from the group consisting of cancer, thyroid cancer and other neoplastic malignancies.

In some embodiments, the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, and triple negative breast cancer (TNBC).

In some embodiments, the cancer is biliary tract cancer. In some embodiments, the biliary tract cancer is locally recurrent and unresectable. In some embodiments, the biliary tract cancer is metastatic.

In some embodiments, a combination of a TIGIT antagonist, a PD-1 antagonist, gemcitabine, and cisplatin may provide enhanced efficacy compared to existing treatments. For example, TIGIT and PD-L1 are densely co-expressed in adenocarcinoma and ESCC. Combinations of TIGIT antagonists and PD-1 antagonists may provide additional benefits compared to single-agent checkpoint blockade. Without wishing to be bound by any particular theory, chemotherapy agents (i) induce immunogenic cell death, (ii) enhance dendritic cell maturation and activation, and (iii) promote T-cell infiltration and function in tumors. (iv) improving the presentation of tumor antigens, and (v) eliminating immunosuppressive cells. In certain embodiments, the tolerability of vivostolimab is a potential additional benefit over combination with one or more chemotherapy agents and a PD-1 antagonist.

In certain embodiments, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In another embodiment, the cancer is relapsed and refractory.

In certain embodiments, provided herein are methods of treating biliary tract cancer (e.g., locally recurrent unresectable or metastatic) comprising administering to a human patient in need thereof:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In certain embodiments, a method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) a TIGIT antagonist as disclosed in the section entitled TIGIT Antagonist;

(b) a PD-1 antagonist as disclosed in the section entitled PD-1 Antagonist;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In certain embodiments, the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human PD-1 monoclonal antibody is a human antibody. In other embodiments, the anti-human PD-1 monoclonal antibody is a humanized antibody.

In certain embodiments, the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human PD-L1 monoclonal antibody is a human antibody. In other embodiments, the anti-human PD-L1 monoclonal antibody is a humanized antibody.

In certain embodiments, the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human TIGIT monoclonal antibody is a human antibody. In other embodiments, the anti-human TIGIT monoclonal antibody is a humanized antibody.

Accordingly, in certain embodiments, provided herein is a method of treating cancer comprising administering to a human patient in need thereof:

(a) human or humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a human or humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In some embodiments, provided herein is a method of treating cancer comprising administering to a human patient in need of treatment of cancer:

(a) human anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) human anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In another embodiment, provided herein is a method of treating cancer comprising administering to a human patient in need thereof:

(a) humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In one embodiment of the methods, compositions, kits and uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab.

In another embodiment of the methods, compositions, kits and uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab.

In another embodiment of the methods, compositions, kits and uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is cemiplimab.

In certain embodiments of the methods, compositions, kits and uses provided herein, the anti-TIGIT antibody or antigen-binding fragment thereof has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: : CDRL2 comprising the amino acid sequence as set forth in 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110.

In some embodiments of the methods, compositions, kits and uses provided herein, the anti-TIGIT antibody or antigen-binding fragment thereof has a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. and a light chain variable region comprising the amino acid sequence as shown.

In certain embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof has a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 294 and an amino acid sequence comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 295. It includes a heavy chain consisting of

In one specific embodiment of the methods provided herein, the method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In one specific embodiment of the methods provided herein, the method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In one specific embodiment of the methods provided herein, the method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In one specific embodiment of the methods provided herein, the method of treating biliary tract cancer comprises administering to a human patient in need of treatment biliary tract cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In one specific embodiment of the methods provided herein, the method of treating biliary tract cancer comprises administering to a human patient in need of treatment biliary tract cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In one specific embodiment of the methods provided herein, the method of treating biliary tract cancer comprises administering to a human patient in need of treatment biliary tract cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

Methods for treating cancer using a combination of PD-1 antagonist, TIGIT antagonist, capecitabine, and oxaliplatin

In another aspect, provided herein is a method of treating cancer (e.g., gastric cancer) using a combination of a TIGIT antagonist, a PD-1 antagonist, capecitabine or a pharmaceutically acceptable salt thereof, and oxaliplatin.

In certain embodiments, the TIGIT antagonist is an anti-TIGIT antibody or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody or antigen binding fragment thereof.

In certain embodiments, a method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In some embodiments, the cancer is selected from the group consisting of: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Lung: Bronchiogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroid hamartoma, mesothelioma; Gastrointestinal: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine. (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal (adenocarcinoma, tubular adenoma, trophoblastic adenoma, hamartoma, leiomyoma); Genitourinary Tract: Kidney (adenocarcinoma, Wilms tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma) , embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma) ), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous System: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deforming), meninges (meningioma, meningosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pinealoma], pleomorphism) glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecology: Uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-neoplastic cervical dysplasia), ovary (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulo-follicular cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphylococcal sarcoma (embryonic sarcoma) rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Hematology: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome); hematopoiesis of the lymphatic system Tumors such as leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, Myeloma and Burkitt's lymphoma; hematopoietic tumors of the myeloid system, such as acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, such as fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, such as astrocytomas , neuroblastoma, glioma and schwannoma; and other tumors such as melanoma, skin (non-melanoma) cancer, mesothelioma (cell), seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid Follicular carcinoma and Kaposi's sarcoma.

In some embodiments, the cancer is anal cancer, biliary tract cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer (CRC), esophageal cancer, gastrointestinal cancer, glioblastoma, glioma, head and neck cancer (HNSCC), and hepatocellular carcinoma (HCC). ), lung cancer, liver cancer, lymphoma, melanoma, mesothelioma, multiple myeloma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), renal cell carcinoma (RCC), salivary gland selected from the group consisting of cancer, thyroid cancer and other neoplastic malignancies.

In some embodiments, the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, triple negative breast cancer (TNBC), and gastric cancer.

In some embodiments, the cancer is stomach cancer. In some embodiments, the gastric cancer is advanced or GEJ adenocarcinoma. In some embodiments, the stomach cancer is HER2 negative. In some embodiments, the stomach cancer has not been previously treated.

In some embodiments, a combination of a TIGIT antagonist, a PD-1 antagonist, gemcitabine, and cisplatin may provide enhanced efficacy compared to existing treatments. For example, TIGIT and PD-L1 are densely co-expressed in adenocarcinoma and ESCC. Combinations of TIGIT antagonists and PD-1 antagonists may provide additional benefits compared to single-agent checkpoint blockade. Without wishing to be bound by any particular theory, chemotherapy agents (i) induce immunogenic cell death, (ii) enhance dendritic cell maturation and activation, and (iii) promote T-cell infiltration and function in tumors. (iv) improving the presentation of tumor antigens, and (v) eliminating immunosuppressive cells. In certain embodiments, the tolerability of vivostolimab is a potential additional benefit over combination with one or more chemotherapy agents and a PD-1 antagonist.

In certain embodiments, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In another embodiment, the cancer is relapsed and refractory.

In certain embodiments, provided herein is a method of treating gastric cancer, comprising administering to a human patient in need of treatment for gastric cancer:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In certain embodiments, a method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) a TIGIT antagonist as disclosed in the section entitled TIGIT Antagonist;

(b) a PD-1 antagonist as disclosed in the section entitled PD-1 Antagonist;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In certain embodiments, the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human PD-1 monoclonal antibody is a human antibody. In other embodiments, the anti-human PD-1 monoclonal antibody is a humanized antibody.

In certain embodiments, the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human PD-L1 monoclonal antibody is a human antibody. In other embodiments, the anti-human PD-L1 monoclonal antibody is a humanized antibody.

In certain embodiments, the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human TIGIT monoclonal antibody is a human antibody. In other embodiments, the anti-human TIGIT monoclonal antibody is a humanized antibody.

Accordingly, in certain embodiments, provided herein is a method of treating cancer comprising administering to a human patient in need thereof:

(a) human or humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a human or humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In some embodiments, provided herein is a method of treating cancer comprising administering to a human patient in need of treatment of cancer:

(a) human anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) human anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In another embodiment, provided herein is a method of treating cancer comprising administering to a human patient in need thereof:

(a) humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In one embodiment of the methods, compositions, kits and uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab.

In another embodiment of the methods, compositions, kits and uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab.

In another embodiment of the methods, compositions, kits and uses provided herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is cemiplimab.

In certain embodiments of the methods, compositions, kits and uses provided herein, the anti-TIGIT antibody or antigen-binding fragment thereof has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: : CDRL2 comprising the amino acid sequence as set forth in 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110.

In some embodiments of the methods, compositions, kits and uses provided herein, the anti-TIGIT antibody or antigen-binding fragment thereof has a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. and a light chain variable region comprising the amino acid sequence as shown.

In certain embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof has a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 294 and an amino acid sequence comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 295. It includes a heavy chain consisting of

In one specific embodiment of the methods provided herein, the method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In one specific embodiment of the methods provided herein, the method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In one specific embodiment of the methods provided herein, the method of treating cancer comprises administering to a human patient in need of treatment of cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In one specific embodiment of the methods provided herein, the method of treating gastric cancer comprises administering to a human patient in need of treatment of gastric cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In one specific embodiment of the methods provided herein, the method of treating gastric cancer comprises administering to a human patient in need of treatment of gastric cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In one specific embodiment of the methods provided herein, the method of treating gastric cancer comprises administering to a human patient in need of treatment of gastric cancer:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

Dosing and Administration

TIGIT antagonist (e.g., anti-TIGIT monoclonal antibody or antigen-binding fragment thereof), PD-1 antagonist (e.g., anti-PD-1 monoclonal antibody or antigen-binding fragment thereof) and one or more chemicals Therapeutic agents (e.g., 5-fluorouracil, cisplatin, paclitaxel or a pharmaceutically acceptable salt thereof, gemcitabine or a pharmaceutically acceptable salt thereof, capecitabine or a pharmaceutically acceptable salt thereof, and/or oxaliplatin) Further provided herein are dosing regimens and routes of administration for treating cancer (e.g., esophageal cancer, TNBC, biliary tract cancer, gastric cancer) using the combination.

A TIGIT antagonist disclosed herein (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen binding fragment thereof), a PD-1 antagonist (e.g., an anti-PD-1 antibody (e.g., For example, anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof) or one or more chemotherapy agents (for example, 5-fluorouracil, cisplatin, paclitaxel or a pharmaceutically acceptable salt thereof, gemci Tabine or a pharmaceutically acceptable salt thereof, capecitabine or a pharmaceutically acceptable salt thereof and/or oxaliplatin), for example, daily, 1-7 times a week, weekly, every other week, every 3 weeks, every 4 weeks. , can be administered by doses administered every 5 weeks, every 6 weeks, monthly, every other month, quarterly, semi-annually, annually, etc. The dose may be administered, for example, intravenously, subcutaneously, topically, orally, intranasally, rectally, intramuscularly, intracerebrally, intrathecally or by inhalation. In certain embodiments, the dose is administered intravenously. In certain embodiments, the dose is administered subcutaneously. In certain embodiments, the dose is administered orally.

In some embodiments, the TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen-binding fragment thereof) has about 10, about 20, about 50, about 80, or about 100. , about 200, about 300, about 400, about 500, about 1000 or about 2500 mg/subject weekly, every other week, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 8 weeks, every 9 weeks, It is administered subcutaneously or intravenously on a 10-week, 12-week, monthly, bimonthly, or quarterly basis.

In some specific methods, the dose of the TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen-binding fragment thereof) is from about 0.01 mg/kg to about 50 mg/kg, About 0.05 mg/kg to about 25 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.2 mg/kg to about 9 mg/kg, about 0.3 mg/kg to about 8 mg/kg, about 0.4 mg/kg to about 7 mg/kg, about 0.5 mg/kg to about 6 mg/kg, about 0.6 mg/kg to about 5 mg/kg, about 0.7 mg/kg to about 4 mg/kg, about 0.8 mg/kg. kg to about 3 mg/kg, about 0.9 mg/kg to about 2 mg/kg, about 1.0 mg/kg to about 1.5 mg/kg, about 1.0 mg/kg to about 2.0 mg/kg, about 1.0 mg/kg to About 3.0 mg/kg or about 2.0 mg/kg to about 4.0 mg/kg. In some specific methods, the dose of PD-1 antagonist (e.g., an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof) is from about 10 mg to about 500 mg. mg, about 25 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 150 mg to about 250 mg, about 175 mg to about 250 mg, about 200 mg to about 250 mg, about 150 mg to about 240 mg, about 175 mg to about 240 mg, or about 200 mg to about 240 mg. In some embodiments, the dose of PD-1 antagonist (e.g., an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof) is about 50 mg, about 75 mg. mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 240 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg.

In some embodiments, the PD-1 antagonist (e.g., an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof) has about 10, about 20, about 50 , about 80, about 100, about 200, about 300, about 400, about 500, about 1000 or about 2500 mg/subject weekly, every other week, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, 8 weeks. It is administered subcutaneously or intravenously on a monthly, bimonthly, or quarterly basis.

In some specific methods, the dose of PD-1 antagonist (e.g., an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof) is from about 0.01 mg/kg to About 50 mg/kg, about 0.05 mg/kg to about 25 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.2 mg/kg to about 9 mg/kg, about 0.3 mg/kg to about 8 mg/kg, about 0.4 mg/kg to about 7 mg/kg, about 0.5 mg/kg to about 6 mg/kg, about 0.6 mg/kg to about 5 mg/kg, about 0.7 mg/kg to about 4 mg/kg kg, about 0.8 mg/kg to about 3 mg/kg, about 0.9 mg/kg to about 2 mg/kg, about 1.0 mg/kg to about 1.5 mg/kg, about 1.0 mg/kg to about 2.0 mg/kg, about 1.0 mg/kg to about 3.0 mg/kg or about 2.0 mg/kg to about 4.0 mg/kg. In some specific methods, the dose of PD-1 antagonist (e.g., an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof) is from about 10 mg to about 500 mg. mg, about 25 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 150 mg to about 250 mg, about 175 mg to about 250 mg, about 200 mg to about 250 mg, about 150 mg to about 240 mg, about 175 mg to about 240 mg, or about 200 mg to about 240 mg. In some embodiments, the dose of PD-1 antagonist (e.g., an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof) is about 50 mg, about 75 mg. mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 240 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg.

In some embodiments of the methods described herein, the TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) has three light chain CDRs: SEQ ID NO: CDRL1 comprising the amino acid sequence as set forth in 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: sequence CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110, Human patients are administered about 100 mg, about 150 mg, about 200 mg, about 240 mg, about 400 mg, about 480 mg or about 720 mg or about 2 mg/kg of the TIGIT antagonist, wherein the TIGIT antagonist is administered every three weeks. Alternatively, administer once every 6 weeks. In one embodiment, the human patient is administered about 200 mg of a TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) once every three weeks. In one embodiment, the human patient is administered 240 mg of a TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) once every three weeks. In one embodiment, the human patient is administered 2 mg/kg TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) once every 3 weeks. . In one embodiment, the human patient is administered 400 mg of a TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) once every three weeks.

In certain embodiments of the methods described herein, the TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) has the three light chain CDRs: SEQ ID NO: CDRL1 comprising the amino acid sequence as set forth in 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: sequence CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110, Human patients are administered 400 mg anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody), and anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody) is administered once every 6 weeks. do.

In some embodiments of the methods described herein, the TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) has three light chain CDRs: SEQ ID NO: CDRL1 comprising the amino acid sequence as set forth in 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: sequence CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110, A human patient is administered 200 mg, 240 mg, 400 mg, 480 mg, 720 mg or 2 mg/kg of a TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or an antigen thereof. binding fragment), wherein the TIGIT antagonist is administered once every 6 weeks. In one embodiment, the human patient is administered 200 mg of a TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) once every 6 weeks. In one embodiment, the human patient is administered 240 mg of a TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) once every 6 weeks. In one embodiment, the human patient is administered 400 mg of a TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) once every 6 weeks. In one embodiment, the human patient is administered about 480 mg of a TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) once every 6 weeks. In one embodiment, the human patient is administered 720 mg of a TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen binding fragment thereof) once every 6 weeks. In one embodiment, the human patient is administered 2 mg/kg TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen-binding fragment thereof) once every 6 weeks. .

In some embodiments of the methods described herein, the PD-1 antagonist, anti-PD-1 antibody, or anti-PD-1 monoclonal antibody is pembrolizumab and is administered to the human patient in doses of about 200 mg, about 240 mg, or about 400 mg. mg, about 480 mg, about 720 mg, or about 2 mg/kg pembrolizumab is administered, and pembrolizumab is administered once every 3 weeks or once every 6 weeks. In one embodiment, the human patient is administered about 200 mg pembrolizumab once every 3 weeks. In one embodiment, the human patient is administered about 240 mg pembrolizumab once every 3 weeks. In one embodiment, human patients are administered 2 mg/kg pembrolizumab once every 3 weeks. In one embodiment, human patients are administered 400 mg pembrolizumab once every 3 weeks.

In certain embodiments of the methods described herein, the PD-1 antagonist, anti-PD-1 antibody, or anti-PD-1 monoclonal antibody is pembrolizumab, and the human patient is administered 400 mg pembrolizumab, and the pembrolizumab Rolizumab is administered once every 6 weeks.

In some embodiments of the methods described herein, the PD-1 antagonist, anti-PD-1 antibody, or anti-PD-1 monoclonal antibody is pembrolizumab and is administered to the human patient in doses of about 200 mg, about 240 mg, or about 400 mg. mg, about 480 mg, about 720 mg, or about 2 mg/kg pembrolizumab is administered, and pembrolizumab is administered once every 6 weeks. In one embodiment, human patients are administered about 200 mg pembrolizumab once every 6 weeks. In one embodiment, the human patient is administered about 240 mg pembrolizumab once every 6 weeks. In one embodiment, the human patient is administered about 400 mg pembrolizumab once every 6 weeks. In one embodiment, human patients are administered 480 mg pembrolizumab once every 6 weeks. In one embodiment, human patients are administered 720 mg pembrolizumab once every 6 weeks. In one embodiment, human patients are administered 2 mg/kg pembrolizumab once every 6 weeks.

In some embodiments of the invention, a TIGIT antagonist (e.g., an anti-TIGIT antibody or antigen-binding fragment thereof) and a PD-1 antagonist (e.g., an anti-PD-1 antibody or antigen-binding fragment thereof) are administered to the patient. It is administered approximately once every 6 weeks for at least 12 weeks. In other embodiments, the TIGIT antagonist (e.g., an anti-TIGIT antibody or antigen binding fragment thereof) and the PD-1 antagonist (e.g., an anti-PD-1 antibody or antigen binding fragment thereof) are administered to the patient for at least 18 weeks, 6 weeks for at least 24 weeks, at least 30 weeks, at least 36 weeks, at least 42 weeks, at least 48 weeks, at least 54 weeks, at least 60 weeks, at least 66 weeks, at least 72 weeks, at least 78 weeks, at least 84 weeks, or at least 90 weeks It is administered once each time. In one embodiment, administration occurs on the same day.

In a sub-embodiment, the TIGIT antagonist (e.g., an anti-TIGIT antibody or antigen-binding fragment thereof) and the PD-1 antagonist (e.g., an anti-PD-1 antibody or antigen-binding fragment thereof) are administered sequentially on the same day. , simultaneously or separately (e.g., as a single agent, as a co-formulation, or jointly as separate agents). In an alternative embodiment, the anti-TIGIT antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered sequentially (e.g., as separate agents) in either order on the same day. In one embodiment of sequential administration on the same day, the anti-TIGIT antibody or antigen-binding fragment thereof is administered first. In another embodiment of sequential administration on the same day, the anti-PD-1 antibody or antigen binding fragment thereof is administered first.

In certain embodiments of the methods, compositions, kits and uses described herein, the TIGIT antagonist (e.g., an anti-human TIGIT antibody or antigen-binding fragment thereof) comprises three light chain CDRs: amino acids as set forth in SEQ ID NO: 111 CDRL1 comprising the sequence, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: set forth in SEQ ID NO: 108. CDRH1 comprising the amino acid sequence as set forth, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and administered to a human patient at 200 mg. A TIGIT antagonist is administered, and the TIGIT antagonist is administered once every three weeks. In certain embodiments of the methods, compositions, kits and uses described herein, the TIGIT antagonist (e.g., an anti-human TIGIT antibody or antigen-binding fragment thereof) comprises three light chain CDRs: amino acids as set forth in SEQ ID NO: 111 CDRL1 comprising the sequence, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: set forth in SEQ ID NO: 108. CDRH1 comprising the amino acid sequence as set forth, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110, and administered to a human patient at about 400 mg. A TIGIT antagonist is administered, and the TIGIT antagonist is administered once every 6 weeks.

In certain embodiments of the method compositions, kits, and uses described herein, the PD-1 antagonist or anti-human PD-1 monoclonal antibody is pembrolizumab, and about 200 mg pembrolizumab is administered to the human patient, and the pembrolizumab Rolizumab is administered once every 3 weeks. In certain embodiments of the method compositions, kits, and uses described herein, the PD-1 antagonist or anti-human PD-1 monoclonal antibody is pembrolizumab, and about 400 mg pembrolizumab is administered to the human patient, and the pembrolizumab Rolizumab is administered once every 6 weeks.

In other embodiments of the method compositions, kits and uses described herein, the PD-antagonist or anti-human PD-1 monoclonal antibody is nivolumab, and the human patient is administered about 240 mg or about 3 mg/kg nivolumab. And, nivolumab is administered once every two weeks. In one specific embodiment, human patients are administered about 240 mg nivolumab once every two weeks. In one specific embodiment, human patients are administered about 3 mg/kg nivolumab once every two weeks. In other embodiments of the methods described herein, the PD-1 antagonist or anti-human PD-1 monoclonal antibody is nivolumab, and the human patient is administered about 480 mg nivolumab, and nivolumab is administered once every 4 weeks. Administer.

In another embodiment of the method compositions, kits and uses described herein, the PD-1 antagonist (e.g., an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof) is cemiplimab and is administered to a human patient. Approximately 350 mg of cemiplimab is administered, and cemiplimab is administered once every 3 weeks.

In some embodiments, a TIGIT antagonist (e.g., an anti-TIGIT antibody) and a PD-1 antagonist (e.g., an anti-PD-1 antibody) are co-formulated. In one embodiment, about 200 mg of pembrolizumab or a pembrolizumab variant and 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, as set forth in SEQ ID NO: 112 CDRL2 comprising the same amino acid sequence and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 154 A co-formulated product with an antibody comprising CDRH2 comprising the amino acid sequence as set forth in and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110 is used for intravenous infusion. In one embodiment, 200 mg pembrolizumab or a pembrolizumab variant and 300 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, as set forth in SEQ ID NO: 112 CDRL2 comprising the amino acid sequence and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 154 A co-formulated product with an antibody comprising CDRH2 comprising the amino acid sequence as set forth and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 is used for intravenous infusion. In one embodiment, about 200 mg of pembrolizumab or a pembrolizumab variant and about 400 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: 112 CDRL2 comprising the amino acid sequence as set forth in and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: A co-formulated product with an antibody comprising CDRH2 comprising the amino acid sequence as set forth in 154 and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110 is used for intravenous infusion. In another embodiment, about 200 mg of pembrolizumab or a pembrolizumab variant and about 500 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: 112 CDRL2 comprising the amino acid sequence as set forth and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: A co-formulated product with an antibody comprising CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 is used for intravenous infusion. In another embodiment, about 200 mg of pembrolizumab or a pembrolizumab variant and about 600 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: 112 CDRL2 comprising the amino acid sequence as set forth and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: A co-formulated product with an antibody comprising CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 is used for intravenous infusion. In another embodiment, about 200 mg of pembrolizumab or a pembrolizumab variant and about 700 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: 112 CDRL2 comprising the amino acid sequence as set forth and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: A co-formulated product with an antibody comprising CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 is used for intravenous infusion.

In certain embodiments, 5-fluorouracil is administered intravenously (e.g., as a continuous IV infusion). In certain embodiments, 5-fluorouracil is administered 5 times every 3 weeks. In some embodiments, the human patient is administered a total of about 3000 mg/m ² or about 4000 mg/m ² 5-fluorouracil per cycle. In some embodiments, a human patient is administered about 500 mg/m ² , about 600 mg/m ² , about 650 mg/m ² , about 700 mg/m ² , about 750 mg/m ² , or about 800 mg/day. m ² or about 900 mg/m ² 5-fluorouracil is administered, where 5-fluorouracil is administered 5 times every 3 weeks. In some embodiments, 5-fluorouracil is administered on the first 5 days of a 3-week cycle.

In certain embodiments, cisplatin is administered intravenously (e.g., as a 60- to 120-minute IV infusion). In certain embodiments, cisplatin is administered once every three weeks. In some embodiments, the human patient is administered about 40 mg/m ² to about 100 mg/m ² cisplatin once every 3 weeks. In some embodiments, the human patient is administered about 60 mg/m ² to about 80 mg/m ² cisplatin once every 3 weeks.

Accordingly, in some embodiments of the method compositions, kits and uses provided herein, to human patients.

(a) about 100 mg, about 150 mg, about 200 mg, about 250 mg or about 400 mg or about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111 , CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: amino acid sequence as set forth in SEQ ID NO: 108 An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH1 comprising CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110;

(b) about 100 mg, about 150 mg, about 200 mg, about 250 mg or about 400 mg or about 2 mg/kg pembrolizumab;

(c) a total of about 3000 mg/m ² or 4000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 60 mg/m ² or 80 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b) and (d) is administered once every 3 weeks or every 6 weeks, and where (c) is administered 5 times every 3 weeks or every 6 weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg, about 240 mg, about 2 mg/kg or about 22 mg/mL of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: 112 CDRL2 comprising the amino acid sequence as set forth in and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: An anti-TIGIT antibody or antigen-binding fragment thereof, comprising CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110;

(b) about 200 mg, about 240 mg, about 2 mg/kg, or about 22 mg/mL pembrolizumab;

(c) a total of about 3000 mg/m ² or 4000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 60 mg/m ² or 80 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b) and (d) is administered once every three weeks, and where (c) is administered five times every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 200 mg pembrolizumab;

(c) a total of about 3000 mg/m ² or 4000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 60 mg/m ² or 80 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b) and (d) is administered once every three weeks, and where (c) is administered five times every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 200 mg pembrolizumab;

(c) a total of about 4000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 80 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b) and (d) is administered once every three weeks, and where (c) is administered five times every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 200 mg pembrolizumab;

(c) a total of about 3000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 60 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b) and (d) is administered once every three weeks, and where (c) is administered five times every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of an anti-TIGIT antibody comprising a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 152 or an antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab;

(c) a total of about 4000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 80 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b) and (d) is administered once every three weeks, and where (c) is administered five times every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of an anti-TIGIT antibody comprising a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 152 or an antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab;

(c) a total of about 3000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 60 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b) and (d) is administered once every three weeks, and where (c) is administered five times every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of anti- TIGIT antibody or antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab;

(c) a total of about 4000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 80 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b) and (d) is administered once every three weeks, and where (c) is administered five times every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of anti- TIGIT antibody or antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab;

(c) a total of about 3000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 60 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b) and (d) is administered once every three weeks, and where (c) is administered five times every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 240 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 240 mg pembrolizumab;

(c) a total of about 4000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 80 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b) and (d) is administered once every three weeks, and where (c) is administered five times every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: : CDRL3 and three heavy chain CDRs comprising the amino acid sequence as set forth in SEQ ID NO: 113: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110;

(b) about 2 mg/kg pembrolizumab;

(c) a total of about 4000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 80 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b) and (d) is administered once every three weeks, and where (c) is administered five times every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 400 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 400 mg pembrolizumab;

(c) a total of about 4000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 80 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a) and (b) is administered once every 6 weeks, where (c) is administered 5 times every 3 weeks, and where (d) is administered once every 3 weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 200 mg pembrolizumab;

(c) a total of about 4000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 80 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a) and (b) is administered once every 6 weeks, where (c) is administered 5 times every 3 weeks, and where (d) is administered once every 3 weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 400 mg pembrolizumab;

(c) a total of about 4000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 80 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a) and (d) is administered once every 3 weeks, where (b) is administered once every 6 weeks, and where (c) is administered 5 times every 3 weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 400 mg pembrolizumab;

(c) a total of about 4000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and

(d) about 80 mg/m ² of cisplatin represented by formula (II)

is administered, wherein each of (a) and (d) is administered once every three weeks, where (b) is administered once every six weeks, and where (c) is administered five times every three weeks.

In certain embodiments of the methods, compositions, kits and uses described herein, pembrolizumab and three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, as set forth in SEQ ID NO: 112 CDRL2 comprising the amino acid sequence and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 154 A co-formulation of an anti-TIGIT antibody or antigen binding fragment thereof comprising CDRH2 comprising the amino acid sequence as set forth and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 is administered by IV infusion. In some embodiments, the co-agent is administered over about 30 minutes every three weeks. In some embodiments, the co-formulation is administered for about 25 minutes to about 40 minutes every three weeks.

In certain embodiments, paclitaxel or a pharmaceutically acceptable salt thereof is administered intravenously. In certain embodiments, paclitaxel or a pharmaceutically acceptable salt thereof is administered once weekly. In some embodiments, the human patient is administered about 70 mg/m ² to about 100 mg/m ² paclitaxel, or a pharmaceutically acceptable salt thereof, once weekly. In some embodiments, the human patient is administered about 80 mg/m ² to about 90 mg/m ² paclitaxel, or a pharmaceutically acceptable salt thereof, once weekly. In some embodiments, the human patient is administered about 70 mg/m ² , about 80 mg/m ² , about 90 mg/m ² or about 100 mg/m ² paclitaxel, or a pharmaceutically acceptable salt thereof, once weekly. In some embodiments, the human patient is administered about 80 mg/m ² or about 90 mg/m ² paclitaxel, or a pharmaceutically acceptable salt thereof, once weekly.

Accordingly, in some embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 100 mg, about 150 mg, about 200 mg, about 250 mg or about 400 mg or about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111 , CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: amino acid sequence as set forth in SEQ ID NO: 108 An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH1 comprising CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110;

(b) about 100 mg, about 150 mg, about 200 mg, about 250 mg or about 400 mg or about 2 mg/kg pembrolizumab; and

(c) about 80 mg/m ² or about 90 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where each of (a) and (b) is administered once every 3 weeks or once every 6 weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg, about 240 mg, about 2 mg/kg or about 22 mg/mL of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: 112 CDRL2 comprising the amino acid sequence as set forth in and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: An anti-TIGIT antibody or antigen-binding fragment thereof, comprising CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110; and

(b) about 200 mg, about 240 mg, about 2 mg/kg, or about 22 mg/mL pembrolizumab; and

(c) about 80 mg/m ² to about 90 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where each of (a) and (b) is administered once every three weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 200 mg pembrolizumab; and

(c) about 80 mg/m ² or about 90 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where each of (a) and (b) is administered once every three weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 200 mg pembrolizumab; and

(c) about 90 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where each of (a) and (b) is administered once every three weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 200 mg pembrolizumab; and

(c) about 80 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where each of (a) and (b) is administered once every three weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of an anti-TIGIT antibody comprising a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 152 or an antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab; and

(c) about 90 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where each of (a) and (b) is administered once every three weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of an anti-TIGIT antibody comprising a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 152 or an antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab; and

(c) about 80 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where each of (a) and (b) is administered once every three weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of anti- TIGIT antibody or antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab; and

(c) about 90 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where each of (a) and (b) is administered once every three weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of anti- TIGIT antibody or antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab; and

(c) about 80 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where each of (a) and (b) is administered once every three weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 240 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 240 mg pembrolizumab; and

(c) about 90 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where each of (a) and (b) is administered once every three weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: : CDRL3 and three heavy chain CDRs comprising the amino acid sequence as set forth in SEQ ID NO: 113: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110;

(b) about 2 mg/kg pembrolizumab; and

(c) about 90 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where each of (a) and (b) is administered once every three weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 400 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 400 mg pembrolizumab; and

(c) about 90 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where each of (a) and (b) is administered once every 6 weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 200 mg pembrolizumab; and

(c) about 90 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where each of (a) and (b) is administered once every 6 weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 400 mg pembrolizumab; and

(c) about 90 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where (a) is administered once every 3 weeks, where (b) is administered once every 6 weeks, and where (c) is administered once a week.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 400 mg pembrolizumab; and

(c) about 90 mg/m ² paclitaxel or a pharmaceutically acceptable salt thereof.

is administered, where (a) is administered once every 3 weeks, where (b) is administered once every 6 weeks, and where (c) is administered once a week.

In certain embodiments, gemcitabine or a pharmaceutically acceptable salt thereof is administered intravenously (e.g., as a continuous IV infusion). In certain embodiments, gemcitabine or a pharmaceutically acceptable salt thereof is administered once every three weeks. In some embodiments, the human patient is administered about 500 mg/m ² to about 1500 mg/m ² gemcitabine, or a pharmaceutically acceptable salt thereof, once every 3 weeks. In some embodiments, the human patient is administered about 800 mg/m ² to about 1000 mg/m ² gemcitabine, or a pharmaceutically acceptable salt thereof, once every 3 weeks. In some embodiments, the human patient is administered about 500 mg/m ² , about 600 mg/m ² , about 700 mg/m ² , about 800 mg/m ² , about 900 mg/m ² , about 1000 mg/m ² , About 1100 mg/m ² , about 1200 mg/m ² , about 1300 mg/m ² , about 1400 mg/m ² or about 1500 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof is administered once every 3 weeks. do. In some embodiments, the human patient is administered about 800 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof once every 3 weeks. In some embodiments, the human patient is administered about 1000 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof once every 3 weeks.

In certain embodiments, cisplatin is administered intravenously (e.g., as a 60- to 120-minute IV infusion). In certain embodiments, cisplatin is administered once every three weeks. In some embodiments, the human patient is administered about 10 mg/m ² to about 50 mg/m ² cisplatin once every 3 weeks. In some embodiments, the human patient is administered about 20 mg/m ² to about 25 mg/m ² cisplatin once every 3 weeks. In some embodiments, the human patient is administered a dose of about 10 mg/m ² , about 15 mg/m ² , about 20 mg/m ² , about 25 mg/m ² , about 30 mg/m ² , about 35 mg/m ² , About 40 mg/m ² , about 45 mg/m ² or about 50 mg/m ² cisplatin is administered once every 3 weeks.

Accordingly, in some embodiments of the method compositions, kits and uses provided herein, in human patients

(a) about 100 mg, about 150 mg, about 200 mg, about 250 mg or about 400 mg or about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111 , CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: amino acid sequence as set forth in SEQ ID NO: 108 An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH1 comprising CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110;

(b) about 100 mg, about 150 mg, about 200 mg, about 250 mg or about 400 mg or about 2 mg/kg pembrolizumab;

(c) about 800 mg/m ² or 1000 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 20 mg/m ² or 25 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b), (c) and (d) is administered once every 3 weeks or once every 6 weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg, about 240 mg, about 2 mg/kg or about 22 mg/mL of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: 112 CDRL2 comprising the amino acid sequence as set forth in and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: An anti-TIGIT antibody or antigen-binding fragment thereof, comprising CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110;

(b) about 200 mg, about 240 mg, about 2 mg/kg, or about 22 mg/mL pembrolizumab;

(c) about 800 mg/m ² or 1000 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 20 mg/m ² or 25 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b), (c), and (d) is administered once every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 200 mg pembrolizumab;

(c) about 800 mg/m ² or 1000 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 20 mg/m ² or 25 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b), (c), and (d) is administered once every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 200 mg pembrolizumab;

(c) about 1000 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 25 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b), (c), and (d) is administered once every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 200 mg pembrolizumab;

(c) about 800 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 20 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b), (c), and (d) is administered once every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of an anti-TIGIT antibody comprising a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 152 or an antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab;

(c) about 1000 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 25 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b), (c), and (d) is administered once every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of an anti-TIGIT antibody comprising a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 152 or an antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab;

(c) about 800 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 20 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b), (c), and (d) is administered once every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of anti- TIGIT antibody or antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab;

(c) about 1000 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 25 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b), (c), and (d) is administered once every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of anti- TIGIT antibody or antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab;

(c) about 800 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 20 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b), (c), and (d) is administered once every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 240 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 240 mg pembrolizumab;

(c) about 800 mg/m ² or about 1000 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 200 mg/m ² or about 25 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b), (c), and (d) is administered once every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: : CDRL3 and three heavy chain CDRs comprising the amino acid sequence as set forth in SEQ ID NO: 113: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110;

(b) about 2 mg/kg pembrolizumab;

(c) about 800 mg/m ² or about 1000 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 200 mg/m ² or about 25 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b), (c), and (d) is administered once every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 400 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 400 mg pembrolizumab;

(c) about 800 mg/m ² or about 1000 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 200 mg/m ² or about 25 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a) and (b) is administered once every 6 weeks, and each of (c) and (d) is administered once every 3 weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 200 mg pembrolizumab;

(c) about 800 mg/m ² or about 1000 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 200 mg/m ² or about 25 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (b), (c), and (d) is administered once every three weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 400 mg pembrolizumab;

(c) about 800 mg/m ² or about 1000 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and

(d) about 200 mg/m ² or about 25 mg/m ² of cisplatin represented by formula (II)

is administered, where each of (a), (c) and (d) is administered once every 3 weeks, and (b) is administered once every 6 weeks.

In certain embodiments, capecitabine or a pharmaceutically acceptable salt thereof is administered orally. In certain embodiments, capecitabine or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, the human patient is administered between about 500 mg/m ² and about 1500 mg/m ² capecitabine, or a pharmaceutically acceptable salt thereof, twice daily. In some embodiments, a human patient is administered about 750 mg/m ² to about 1000 mg/m ² capecitabine, or a pharmaceutically acceptable salt thereof, twice daily. In some embodiments, the human patient receives about 750 mg/m ² , about 800 mg/m ² , about 850 mg/m ² , about 900 mg/m ² , about 950 mg/m ² or about 1000 mg/m ² caffe. Cytabine or its pharmaceutically acceptable salt is administered twice a day. In some embodiments, a human patient is administered about 750 mg/m ² capecitabine, or a pharmaceutically acceptable salt thereof, twice daily. In some embodiments, a human patient is administered about 1000 mg/m ² capecitabine, or a pharmaceutically acceptable salt thereof, twice daily.

In certain embodiments, oxaliplatin is administered intravenously (e.g., as a 60- to 120-minute IV infusion). In certain embodiments, oxaliplatin is administered once every three weeks. In some embodiments, the human patient is administered about 80 mg/m ² to about 150 mg/m ² oxaliplatin once every 3 weeks. In some embodiments, the human patient is administered about 100 mg/m ² to about 130 mg/m ² cisplatin once every 3 weeks. In some embodiments, the human patient is administered about 100 mg/m ² , about 120 mg/m ² or about 130 mg/m ² oxaliplatin once every 3 weeks.

Accordingly, in some embodiments of the method compositions, kits and uses provided herein, to human patients.

(a) about 100 mg, about 150 mg, about 200 mg, about 250 mg or about 400 mg or about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111 , CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: amino acid sequence as set forth in SEQ ID NO: 108 An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH1 comprising CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 110;

(b) about 100 mg, about 150 mg, about 200 mg, about 250 mg or about 400 mg or about 2 mg/kg pembrolizumab;

(c) about 750 mg/m ² or 1000 mg/m ² of capecitabine represented by formula (V) or a pharmaceutically acceptable salt thereof; and

(d) about 100 mg/m ² or 130 mg/m ² of oxaliplatin represented by formula (VI)

is administered, where each of (a) and (b) is administered once every 3 weeks or 6 weeks, (c) is administered twice a day, and (d) is administered once every 3 weeks.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg, about 240 mg, about 2 mg/kg or about 22 mg/mL of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: 112 CDRL2 comprising the amino acid sequence as set forth in and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: An anti-TIGIT antibody or antigen-binding fragment thereof, comprising CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110;

(b) about 200 mg, about 240 mg, about 2 mg/kg, or about 22 mg/mL pembrolizumab;

(c) about 750 mg/m ² or 1000 mg/m ² of capecitabine represented by formula (V) or a pharmaceutically acceptable salt thereof; and

(d) about 100 mg/m ² or 130 mg/m ² of oxaliplatin represented by formula (VI)

is administered, where each of (a), (b), and (d) is administered once every three weeks, and (c) is administered twice a day.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 200 mg pembrolizumab;

(c) about 750 mg/m ² or 1000 mg/m ² of capecitabine represented by formula (V) or a pharmaceutically acceptable salt thereof; and

(d) about 100 mg/m ² or 130 mg/m ² of oxaliplatin represented by formula (VI)

is administered, where each of (a), (b), and (d) is administered once every three weeks, and (c) is administered twice a day.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of an anti-TIGIT antibody comprising a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 152 or an antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab;

(c) about 750 mg/m ² or 1000 mg/m ² of capecitabine represented by formula (V) or a pharmaceutically acceptable salt thereof; and

(d) about 100 mg/m ² or 130 mg/m ² of oxaliplatin represented by formula (VI)

is administered, where each of (a), (b), and (d) is administered once every three weeks, and (c) is administered twice a day.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 200 mg of anti- TIGIT antibody or antigen-binding fragment thereof;

(b) about 200 mg pembrolizumab;

(c) about 750 mg/m ² or 1000 mg/m ² of capecitabine represented by formula (V) or a pharmaceutically acceptable salt thereof; and

(d) about 100 mg/m ² or 130 mg/m ² of oxaliplatin represented by formula (VI)

is administered, where each of (a), (b), and (d) is administered once every three weeks, and (c) is administered twice a day.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 240 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 240 mg pembrolizumab;

(c) about 750 mg/m ² or 1000 mg/m ² of capecitabine represented by formula (V) or a pharmaceutically acceptable salt thereof; and

(d) about 100 mg/m ² or 130 mg/m ² of oxaliplatin represented by formula (VI)

is administered, where each of (a), (b), and (d) is administered once every three weeks, and (c) is administered twice a day.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) about 2 mg/kg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: : CDRL3 and three heavy chain CDRs comprising the amino acid sequence as set forth in SEQ ID NO: 113: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110;

(b) about 2 mg/kg pembrolizumab;

(c) about 750 mg/m ² or 1000 mg/m ² of capecitabine represented by formula (V) or a pharmaceutically acceptable salt thereof; and

(d) about 100 mg/m ² or 130 mg/m ² of oxaliplatin represented by formula (VI)

is administered, where each of (a), (b), and (d) is administered once every three weeks, and (c) is administered twice a day.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 400 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 400 mg pembrolizumab;

(c) about 750 mg/m ² or 1000 mg/m ² of capecitabine represented by formula (V) or a pharmaceutically acceptable salt thereof; and

(d) about 100 mg/m ² or 130 mg/m ² of oxaliplatin represented by formula (VI)

is administered, where each of (a), (b), and (d) is administered once every three weeks, and (c) is administered twice a day.

In certain embodiments of the methods, compositions, kits and uses provided herein, in human patients

(a) About 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113. CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;

(b) about 400 mg pembrolizumab;

(c) about 750 mg/m ² or 1000 mg/m ² of capecitabine represented by formula (V) or a pharmaceutically acceptable salt thereof; and

(d) about 100 mg/m ² or 130 mg/m ² of oxaliplatin represented by formula (VI)

is administered, where (a) and (d) are administered once every 3 weeks, (b) is administered once every 6 weeks, and (c) is administered twice a day.

In certain embodiments of the methods, compositions, kits and uses described herein, pembrolizumab and three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, as set forth in SEQ ID NO: 112 CDRL2 comprising the amino acid sequence and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 154 A co-formulation of an anti-TIGIT antibody or antigen binding fragment thereof comprising CDRH2 comprising the amino acid sequence as set forth and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110 is administered by IV infusion. In some embodiments, the co-agent is administered over about 30 minutes every three weeks. In some embodiments, the co-formulation is administered for about 25 minutes to about 40 minutes every three weeks.

In some embodiments, a therapeutic agent in a combination therapy (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or binding fragment thereof, an anti-PD-1 antibody (e.g., an anti- PD-1 monoclonal antibody) or binding fragment thereof, 5-fluorouracil, cisplatin, or paclitaxel) at the same dosage as typically used when the therapeutic agent is used as monotherapy to treat the same condition. It is administered using a regimen (dose, frequency and duration of treatment). In other embodiments, the patient is receiving a therapeutic agent (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or binding fragment thereof, an anti-PD-1 monoclonal antibody or binding fragment thereof, 5 At least one of - fluorouracil, cisplatin or paclitaxel) receives a lower total amount of treatment, e.g., lower doses, less frequent doses and/or shorter treatment duration, in combination therapy than when used as monotherapy.

The combination therapy disclosed herein may be used before or after surgery to remove a tumor and may be used before, during, or after radiation therapy.

In some embodiments, the combination therapy disclosed herein is administered to patients who have not previously been treated with a biotherapeutic agent or a chemotherapy agent, i.e., are treatment-naive. In another embodiment, the combination therapy is administered to treatment-experienced patients who have failed to achieve a sustained response after prior therapy with a biotherapeutic agent or a chemotherapy agent.

The therapeutic combinations disclosed herein may be combined with one or more other active agents, including but not limited to other anti-cancer agents, used to prevent, treat, control, ameliorate or reduce the risk of a particular disease or condition (e.g., cancer). can be used These other active agents may be administered simultaneously or sequentially with one or more therapeutic agents in the combinations disclosed herein, by routes and in amounts conventionally used therefor.

One or more additional active agents may be a TIGIT antagonist (e.g., an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen-binding fragment thereof), a PD-1 antagonist (e.g., an anti-PD -1 co-administration with an antibody (e.g., anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof) or one or more chemotherapy agents (e.g., 5-fluorouracil, cisplatin, or paclitaxel) It can be. Additional active agent(s) include TIGIT antagonists (e.g., anti-TIGIT antibodies (e.g., anti-TIGIT monoclonal antibodies) or antigen-binding fragments thereof), PD-1 antagonists, e.g., anti-PD- 1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof) and one or more chemotherapy agents (e.g., 5-fluorouracil, cisplatin, or paclitaxel) It can be administered in a single dosage form along with a co-administered agent. Additional active agent(s) may also be TIGIT antagonists (e.g., anti-TIGIT antibodies (e.g., anti-TIGIT monoclonal antibodies) or antigen-binding fragments thereof), PD-1 antagonists (e.g., anti- PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof) or one or more chemotherapy agents (e.g., 5-fluorouracil, cisplatin, paclitaxel or pharmaceutical agents thereof) It can be administered in a separate dosage form(s) from the dosage form containing the acceptable salt, gemcitabine or a pharmaceutically acceptable salt thereof, capecitabine or a pharmaceutically acceptable salt thereof, and/or oxaliplatin.

Administration of the PD-1 antagonist and/or TIGIT antagonist may be by any suitable route and may be facilitated by agents such as hyaluronan degrading enzymes such as hyaluronidase, such as soluble PH20 polypeptides and variants thereof. . For systemic administration, facilitating agents can be modified to increase pharmacological properties, such as serum half-life, by modifying such agents, such as with polymers. See, for example, US Patent Nos. 7,767,429, 8,431,380, 7,871,607, International Publication No. WO 2020/022791, US Patent Publication No. US2006/0104968 and European Patent 1858926, and numerous other patents and publications. Examples of such agents are the known agents PEGPH20 or rHuPH20. Accordingly, specific embodiments include pharmaceuticals comprising a PD-1 antagonist and/or a TIGIT antagonist and any one of a hyaluronan degrading enzyme, hyaluronidase, soluble hyaluronidase, soluble PH20 polypeptide, or a variant of any of the foregoing enzymes. Contains a composition. In certain embodiments, the pharmaceutical composition comprises a PD-1 antagonist and a soluble PH20 polypeptide or variant thereof. In another specific embodiment, the pharmaceutical composition comprises a TIGIT antagonist and a soluble PH20 polypeptide or variant thereof. In some embodiments, the pharmaceutical composition comprises a PD-1 antagonist, a TIGIT antagonist, and a soluble PH20 polypeptide or variant thereof. In some embodiments, the pharmaceutical composition comprises a PD-1 antagonist, a TIGIT antagonist, 5-fluorouracil, cisplatin, and a soluble PH20 polypeptide or variant thereof. In some embodiments, the pharmaceutical composition comprises a PD-1 antagonist, a TIGIT antagonist, paclitaxel or a pharmaceutically acceptable salt thereof, and a soluble PH20 polypeptide or variant thereof. In some embodiments, the pharmaceutical composition comprises a PD-1 antagonist, a TIGIT antagonist, gemcitabine or a pharmaceutically acceptable salt thereof, cisplatin, and a soluble PH20 polypeptide or a variant thereof. In some embodiments, the pharmaceutical composition comprises a PD-1 antagonist, a TIGIT antagonist, capecitabine or a pharmaceutically acceptable salt thereof, oxaliplatin, and a soluble PH20 polypeptide or variant thereof.

pharmaceutical composition

In another aspect, a therapeutic agent disclosed herein (e.g., a TIGIT antagonist, a PD-1 antagonist and one or more chemotherapy agents (e.g., 5-fluorouracil, cisplatin, paclitaxel or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising gemcitabine or a pharmaceutically acceptable salt thereof, capecitabine or a pharmaceutically acceptable salt thereof and/or oxaliplatin) is provided herein.

In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

Anti-human TIGIT antibody (e.g., anti-TIGIT monoclonal antibody) or antigen-binding fragment thereof, anti-human PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof Fragments and one or more chemotherapy agents (e.g., 5-fluorouracil, cisplatin, paclitaxel or a pharmaceutically acceptable salt thereof, gemcitabine or a pharmaceutically acceptable salt thereof, capecitabine or a pharmaceutically acceptable salt thereof and/or oxaliplatin), wherein the antibody or compound having the desired degree of purity is optionally mixed with a physiologically acceptable carrier, excipient or stabilizer (e.g., as described in Remington, Remington's Pharmaceutical Sciences (18 ^th ed. 1980) can be prepared for storage in an aqueous solution or lyophilized form or other dried form.

Pharmaceutically acceptable carriers, excipients or stabilizers are non-toxic to cells or mammals exposed thereto at the dosages and concentrations employed. Often the pharmaceutically acceptable carrier is an aqueous pH buffered solution. Examples of pharmaceutically acceptable carriers include buffers such as phosphate, citrate, acetate and other organic acids; Antioxidants such as ascorbic acid; low molecular weight (e.g., less than about 10 amino acid residues) polypeptides; Proteins such as serum albumin, gelatin or immunoglobulin; Hydrophilic polymers such as polyvinylpyrrolidone; Amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates such as 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™. A pharmaceutically acceptable carrier may also refer to a diluent, an adjuvant (e.g., Freund's adjuvant (complete or incomplete)), an excipient, or a vehicle. Such carriers may be sterile liquids, such as water and oils, such as those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the composition (eg, pharmaceutical composition) is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, especially for injections. Suitable excipients (e.g. pharmaceutical excipients) include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol. , propylene, glycol, water, ethanol, etc. If desired, the composition may also contain traces of wetting or emulsifying agents or pH buffering agents. Compositions may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc.

kit

In another aspect, a therapeutic agent disclosed herein (e.g., a TIGIT antagonist, a PD-1 antagonist, and one or more chemotherapeutic agents (e.g., 5-fluorouracil, cisplatin, paclitaxel or thereof) packaged into a suitable packaging material. A kit comprising a pharmaceutically acceptable salt, gemcitabine or a pharmaceutically acceptable salt thereof, capecitabine or a pharmaceutically acceptable salt thereof and/or oxaliplatin)) or a pharmaceutical composition thereof is provided herein. The kit optionally includes a label or packaging insert containing a description of the ingredients therein or instructions for in vitro, in vivo or in vitro use of the ingredients.

In some embodiments, the kit includes:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In certain embodiments, the kit further includes instructions for administering the TIGIT antagonist, PD-1 antagonist, 5-fluorouracil, and cisplatin to the human patient.

In one embodiment, the kit comprises (a) one or more doses of an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen-binding fragment thereof; (b) one or more doses of an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof; (c) one or more doses of 5-fluorouracil; (d) one or more doses of cisplatin; and (e) instructions for administering anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, 5-fluorouracil and cisplatin to human patients. Includes.

In some embodiments, the TIGIT antagonist is an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-L1 monoclonal antibody or antigen-binding fragment thereof.

In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is pembrolizumab. In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is nivolumab. In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is cemiplimab.

Anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody), anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody), 5-fluoro antibody at a dosage described herein Uracil or cisplatin can be used in various kits herein. In some embodiments, the kit includes a sufficient dosage of each component for a specific treatment period (e.g., 3, 6, 12, or 24 weeks, etc.). For example, the kit may contain pembrolizumab at a dose of about 200 mg, an anti-TIGIT antibody at a dose of about 200 mg, or 5 of about 600 mg/m ² or about 800 mg/m ² , sufficient for 3 weeks of treatment. A single dose of 5-fluorouracil and a dose of about 60 or 80 mg/m ² of cisplatin may be included. Alternatively, the kit may also include a dose of about 400 mg of pembrolizumab, a single dose of about 400 mg of an anti-TIGIT antibody, about 600 mg/m ² or about 800 mg/m ² of pembrolizumab, sufficient for 6 weeks of treatment. It may comprise 10 doses of 5-fluorouracil and 2 doses of cisplatin at about 60 or 80 mg/m ² .

In some embodiments, the kit includes:

(a) TIGIT antagonist;

(b) PD-1 antagonist; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof represented by formula (III).

In certain embodiments, the kit further includes instructions for administering the TIGIT antagonist, PD-1 antagonist, and paclitaxel or a pharmaceutically acceptable salt thereof to the human patient.

In one embodiment, the kit comprises (a) one or more doses of an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen-binding fragment thereof; (b) one or more doses of an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof; (c) one or more doses of paclitaxel or a pharmaceutically acceptable salt thereof; and (d) administering to a human patient an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, and paclitaxel or a pharmaceutically acceptable salt thereof. Includes instructions.

In some embodiments, the TIGIT antagonist is an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-L1 monoclonal antibody or antigen-binding fragment thereof.

In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is pembrolizumab. In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is nivolumab. In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is cemiplimab.

Anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody), anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or paclitaxel or pharmaceuticals thereof at dosages described herein. Any acceptable salt may be used in the various kits herein. In some embodiments, the kit includes a sufficient dosage of each component for a specific treatment period (e.g., 3, 6, 12, or 24 weeks, etc.). For example, the kit may contain a dose of about 200 mg of pembrolizumab, a dose of about 200 mg of an anti-TIGIT antibody, and a dose of about 80 mg/m ² or about 90 mg/m ² sufficient for 3 weeks of treatment. It may contain an amount of paclitaxel or a pharmaceutically acceptable salt thereof. Alternatively, the kit may also contain two doses of pembrolizumab at a dose of about 400 mg, an anti-TIGIT antibody at a dose of about 400 mg, about 80 mg/m ² or about 90 mg/m ^{2 ,} sufficient for 6 weeks of treatment. It may contain a dosage of paclitaxel or a pharmaceutically acceptable salt thereof.

In some embodiments, the kit includes:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In certain embodiments, the kit further includes instructions for administering the TIGIT antagonist, PD-1 antagonist, gemcitabine or a pharmaceutically acceptable salt thereof, and cisplatin to the human patient.

In one embodiment, the kit comprises (a) one or more doses of an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen-binding fragment thereof; (b) one or more doses of an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof; (c) one or more doses of gemcitabine or a pharmaceutically acceptable salt thereof; (d) one or more doses of cisplatin; and (e) administering anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, gemcitabine or a pharmaceutically acceptable salt thereof, and cisplatin to a human patient. Includes instructions on how to do it.

In some embodiments, the TIGIT antagonist is an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-L1 monoclonal antibody or antigen-binding fragment thereof.

In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is pembrolizumab. In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is nivolumab. In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is cemiplimab.

Anti-TIGIT antibody (e.g., anti-TIGIT monoclonal antibody), anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody), gemcitabine or its dosage described herein Pharmaceutically acceptable salts or cisplatin may be used in the various kits herein. In some embodiments, the kit includes a sufficient dosage of each component for a specific treatment period (e.g., 3, 6, 12, or 24 weeks, etc.). For example, the kit may contain a dose of pembrolizumab at a dose of about 200 mg, an anti-TIGIT antibody at a dose of about 200 mg, a dose of about 800 mg/m ² or about 1000 mg/m ^{2 ,} sufficient for 3 weeks of treatment. It may include an amount of gemcitabine or a pharmaceutically acceptable salt thereof and cisplatin in a dosage of about 20 mg/m ² to about 25 mg/m ² . Alternatively, the kit may also include a dose of about 400 mg of pembrolizumab, a single dose of about 400 mg of an anti-TIGIT antibody, about 800 mg/m ² or about 1000 mg/m ² of pembrolizumab, sufficient for 6 weeks of treatment. It may include two doses of gemcitabine or a pharmaceutically acceptable salt thereof and about 20 mg/m ² to about 25 mg/m ² of cisplatin.

In some embodiments, the kit includes:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In certain embodiments, the kit further includes instructions for administering the TIGIT antagonist, PD-1 antagonist, capecitabine or a pharmaceutically acceptable salt, and oxaliplatin to the human patient.

In one embodiment, the kit comprises (a) one or more doses of an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen-binding fragment thereof; (b) one or more doses of an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof; (c) one or more doses of capecitabine or a pharmaceutically acceptable salt; (d) one or more doses of oxaliplatin; and (e) administering to the human patient an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof, an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, capecitabine or a pharmaceutically acceptable salt, and oxaliplatin. Includes instructions on how to do it.

In some embodiments, the TIGIT antagonist is an anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody) or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody) or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-L1 monoclonal antibody or antigen-binding fragment thereof.

In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is pembrolizumab. In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is nivolumab. In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is cemiplimab.

An anti-TIGIT antibody (e.g., an anti-TIGIT monoclonal antibody), an anti-PD-1 antibody (e.g., an anti-PD-1 monoclonal antibody), capecitabine, or Pharmaceutically acceptable salts or oxaliplatin may be used in the various kits herein. In some embodiments, the kit includes a sufficient dosage of each component for a specific treatment period (e.g., 3, 6, 12, or 24 weeks, etc.). For example, the kit may contain a dose of about 200 mg of pembrolizumab, a dose of about 200 mg of anti-TIGIT antibody, and 62 doses of about 750 or about 1000 mg/m ² , sufficient for 3 weeks of treatment. It may include capecitabine or a pharmaceutically acceptable salt thereof and oxaliplatin at a dosage of about 100 or about 130 mg/m ² . Alternatively, the kit may also include a dose of pembrolizumab of about 400 mg, a single dose of an anti-TIGIT antibody of about 400 mg, or 124 doses of about 750 or about 1000 mg/m ² , sufficient for 6 weeks of treatment. of capecitabine or a pharmaceutically acceptable salt thereof and two doses of oxaliplatin of about 100 or about 130 mg/m ² .

In some embodiments, the kit includes means for individually holding the components, such as containers, divided bottles, or divided foil packets. Kits of the present disclosure can be used for different dosage forms, e.g., oral and parenteral, for administration of individual compositions at different dosing intervals, or for titration of individual compositions with respect to each other.

Use of therapeutic combinations to treat cancer

In another aspect, provided herein is the use of a therapeutic combination for treating cancer (e.g., esophageal cancer) in a human patient, wherein the therapeutic combination comprises:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In some embodiments, the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, triple negative breast cancer (TNBC), and gastric cancer.

In certain embodiments, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In another embodiment, the cancer is relapsed and refractory.

In one embodiment, the cancer is esophageal cancer.

In one embodiment, provided herein is the use of a therapeutic combination for treating esophageal cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In another embodiment, provided herein is the use of a therapeutic combination for treating cancer in a patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) a TIGIT antagonist as disclosed herein;

(b) a PD-1 antagonist as disclosed herein;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In certain embodiments, the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human TIGIT monoclonal antibody is a human antibody. In other embodiments, the anti-human TIGIT monoclonal antibody is a humanized antibody.

In certain embodiments, the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human PD-1 monoclonal antibody is a human antibody. In other embodiments, the anti-human PD-1 monoclonal antibody is a humanized antibody.

In certain embodiments, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) human or humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a human or humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In some embodiments, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) human anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) human anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In another embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In some embodiments of the various uses provided herein, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is pembrolizumab. In some embodiments of the various uses provided herein, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is nivolumab. In some embodiments of the various uses provided herein, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is cemiplimab.

In certain embodiments of the various uses provided herein, the anti-TIGIT antibody or antigen binding fragment thereof has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, as set forth in SEQ ID NO: 112 CDRL2 comprising the same amino acid sequence and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 154 CDRH2 comprising the amino acid sequence as set forth in and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110.

In some embodiments of the various uses provided herein, the anti-TIGIT antibody or antigen-binding fragment thereof has a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. It includes a light chain variable region comprising.

In other embodiments of the various uses provided herein, the anti-human TIGIT monoclonal antibody, or antigen-binding fragment thereof, comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 294 and a light chain thereof and an amino acid sequence as set forth in SEQ ID NO: 295. and a heavy chain comprising or consisting of the amino acid sequence as set forth.

Accordingly, in one specific embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating esophageal cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating esophageal cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating esophageal cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab;

(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II).

In another aspect, provided herein is the use of a therapeutic combination for treating cancer (e.g., TNBC) in a human patient, wherein the therapeutic combination comprises:

(a) TIGIT antagonist;

(b) PD-1 antagonist; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In some embodiments, the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, triple negative breast cancer (TNBC), and gastric cancer.

In certain embodiments, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In another embodiment, the cancer is relapsed and refractory.

In one embodiment, the cancer is TNBC.

In one embodiment, provided herein is the use of a therapeutic combination for treating TNBC in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) TIGIT antagonist;

(b) PD-1 antagonist; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is the use of a therapeutic combination for treating cancer in a patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) a TIGIT antagonist as disclosed herein;

(b) a PD-1 antagonist as disclosed herein; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In certain embodiments, the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human TIGIT monoclonal antibody is a human antibody. In other embodiments, the anti-human TIGIT monoclonal antibody is a humanized antibody.

In certain embodiments, the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human PD-1 monoclonal antibody is a human antibody. In other embodiments, the anti-human PD-1 monoclonal antibody is a humanized antibody.

In certain embodiments, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) human or humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a human or humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) human anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) human anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In some embodiments of the various uses provided herein, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is pembrolizumab. In some embodiments of the various uses provided herein, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is nivolumab. In some embodiments of the various uses provided herein, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is cemiplimab.

In certain embodiments of the various uses provided herein, the anti-TIGIT antibody or antigen binding fragment thereof has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, as set forth in SEQ ID NO: 112 CDRL2 comprising the same amino acid sequence and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 154 CDRH2 comprising the amino acid sequence as set forth in and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110.

In some embodiments of the various uses provided herein, the anti-TIGIT antibody or antigen-binding fragment thereof has a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. It includes a light chain variable region comprising.

In other embodiments of the various uses provided herein, the anti-human TIGIT monoclonal antibody, or antigen-binding fragment thereof, comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 294 and a light chain thereof and an amino acid sequence as set forth in SEQ ID NO: 295. and a heavy chain comprising or consisting of the amino acid sequence as set forth.

Accordingly, in one specific embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In one specific embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In one specific embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In one specific embodiment, provided herein is the use of a therapeutic combination for treating TNBC in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In one specific embodiment, provided herein is the use of a therapeutic combination for treating TNBC in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In one specific embodiment, provided herein is the use of a therapeutic combination for treating TNBC in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab; and

(c) Paclitaxel or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is the use of a therapeutic combination for treating cancer (e.g., biliary tract cancer) in a human patient, wherein the therapeutic combination comprises:

(c) TIGIT antagonist;

(d) PD-1 antagonist;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In some embodiments, the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, triple negative breast cancer (TNBC), and gastric cancer.

In certain embodiments, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In another embodiment, the cancer is relapsed and refractory.

In one embodiment, the cancer is biliary tract cancer.

In one embodiment, provided herein is the use of a therapeutic combination for treating biliary tract cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In another embodiment, provided herein is the use of a therapeutic combination for treating cancer in a patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) a TIGIT antagonist as disclosed herein;

(b) a PD-1 antagonist as disclosed herein;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In certain embodiments, the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human TIGIT monoclonal antibody is a human antibody. In other embodiments, the anti-human TIGIT monoclonal antibody is a humanized antibody.

In certain embodiments, the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human PD-1 monoclonal antibody is a human antibody. In other embodiments, the anti-human PD-1 monoclonal antibody is a humanized antibody.

In certain embodiments, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) human or humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a human or humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In some embodiments, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) human anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) human anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In another embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In some embodiments of the various uses provided herein, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is pembrolizumab. In some embodiments of the various uses provided herein, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is nivolumab. In some embodiments of the various uses provided herein, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is cemiplimab.

In certain embodiments of the various uses provided herein, the anti-TIGIT antibody or antigen binding fragment thereof has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, as set forth in SEQ ID NO: 112 CDRL2 comprising the same amino acid sequence and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 154 CDRH2 comprising the amino acid sequence as set forth in and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110.

In some embodiments of the various uses provided herein, the anti-TIGIT antibody or antigen-binding fragment thereof has a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. It includes a light chain variable region comprising.

In other embodiments of the various uses provided herein, the anti-human TIGIT monoclonal antibody, or antigen-binding fragment thereof, comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 294 and a light chain thereof and an amino acid sequence as set forth in SEQ ID NO: 295. and a heavy chain comprising or consisting of the amino acid sequence as set forth.

Accordingly, in one specific embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating biliary tract cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating biliary tract cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating biliary tract cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110 an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab;

(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II).

In another aspect, provided herein is the use of a therapeutic combination for treating cancer (e.g., biliary tract cancer) in a human patient, wherein the therapeutic combination comprises:

(e) TIGIT antagonist;

(f) PD-1 antagonist;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In some embodiments, the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, triple negative breast cancer (TNBC), and gastric cancer.

In certain embodiments, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In another embodiment, the cancer is relapsed and refractory.

In one embodiment, the cancer is stomach cancer. In some embodiments, the gastric cancer is advanced or GEJ adenocarcinoma. In some embodiments, the stomach cancer is HER2 negative. In some embodiments, the stomach cancer has not been previously treated.

In one embodiment, provided herein is the use of a therapeutic combination for treating biliary tract cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) TIGIT antagonist;

(b) PD-1 antagonist;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In another embodiment, provided herein is the use of a therapeutic combination for treating cancer in a patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) a TIGIT antagonist as disclosed herein;

(b) a PD-1 antagonist as disclosed herein;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In certain embodiments, the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human TIGIT monoclonal antibody is a human antibody. In other embodiments, the anti-human TIGIT monoclonal antibody is a humanized antibody.

In certain embodiments, the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the anti-human PD-1 monoclonal antibody is a human antibody. In other embodiments, the anti-human PD-1 monoclonal antibody is a humanized antibody.

In certain embodiments, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) human or humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a human or humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In some embodiments, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) human anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) human anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (V).

In another embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) humanized anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof;

(b) a humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In some embodiments of the various uses provided herein, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is pembrolizumab. In some embodiments of the various uses provided herein, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is nivolumab. In some embodiments of the various uses provided herein, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is cemiplimab.

In certain embodiments of the various uses provided herein, the anti-TIGIT antibody or antigen binding fragment thereof has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, as set forth in SEQ ID NO: 112 CDRL2 comprising the same amino acid sequence and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 154 CDRH2 comprising the amino acid sequence as set forth in and CDRH3 comprising the amino acid sequence as set forth in SEQ ID NO: 110.

In some embodiments of the various uses provided herein, the anti-TIGIT antibody or antigen-binding fragment thereof has a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. It includes a light chain variable region comprising.

In other embodiments of the various uses provided herein, the anti-human TIGIT monoclonal antibody, or antigen-binding fragment thereof, comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 294 and a light chain thereof and an amino acid sequence as set forth in SEQ ID NO: 295. and a heavy chain comprising or consisting of the amino acid sequence as set forth.

Accordingly, in one specific embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating gastric cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) pembrolizumab;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating gastric cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) nivolumab;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

In one specific embodiment, provided herein is the use of a therapeutic combination for treating gastric cancer in a human patient in need thereof, wherein the therapeutic combination comprises an effective amount of:

(a) three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and amino acids as set forth in SEQ ID NO: 113 CDRL3 and three heavy chain CDRs comprising the sequences: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: 110. an anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as defined;

(b) cemiplimab;

(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI).

A number of embodiments of the invention have been described. It will be understood that various changes may be made without departing from the spirit and scope of the invention. It will be further understood that each embodiment may be combined with one or more other embodiments to the extent that such combinations are consistent with the description of the embodiments.

general method

Standard methods in molecular biology include Sambrook, Fritsch and Maniatis (1982 & 1989 ^2nd Edition, 2001 ^3rd Edition) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Sambrook and Russell (2001) Molecular Cloning, ^3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, CA)]. Standard methods are also described in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols.1-4, John Wiley and Sons, Inc. New York, NY], including Cloning and DNA Mutagenesis in Bacterial Cells (Vol. 1), Cloning in Mammalian Cells and Yeast (Vol. 2), Glycoconjugates and Protein Expression (Vol. 3), and Bioinformatics (Vol. 4) is described.

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

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

An alternative to humanization is the use of human antibody libraries displayed on phage or in transgenic mice (Vaughan et al. (1996) Nature Biotechnol. 14:309-314; Barbas (1995) Nature Medicine 1:837-839; Mendez et al. (1997) Nature Genetics 15:146-156; Hoogenboom and Chames (2000) Immunol. Today 21:371-377; Barbas et al. (2001) Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; Kay et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, CA; de Bruin et al. (1999) Nature Biotechnol. 17:397-399]).

Purification of the antigen is not necessary for the production of antibodies. Animals can be immunized with cells bearing the antigen of interest. Splenocytes can then be isolated from the immunized animal, and the splenocytes can be fused with a myeloma cell line to produce hybridomas (see, e.g., Meyaard et al. (1997) Immunity 7:283-290; Wright et al. (2000) Immunity 13:233-242; Preston et al., supra; Kaithamana et al. (1999) J. Immunol. 163:5157-5164).

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

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

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

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

Analysis method

Analytical methods suitable for assessing product stability include size exclusion chromatography (SEC), dynamic light scattering (DLS), differential scanning calorimetry (DSC), iso-asp quantification, potency, UV at 340 nm, and UV spectroscopy. and Fourier-transform infrared spectroscopy (FTIR). SEC (J. Pharm. Scien., 83:1645-1650, (1994); Pharm. Res., 11:485 (1994); J. Pharm. Bio. Anal., 15:1928 (1997); J . Pharm. Bio. Anal., 14:1133-1140 (1986)] determines the percent monomer in the product and provides information on the amount of soluble aggregates. DSC (Pharm. Res., 15:200 (1998); Pharm. Res., 9:109 (1982)) provides information on protein denaturation temperature and glass transition temperature. DLS (American Lab., November (1991)) measures the average diffusion coefficient and provides information on the amount of soluble and insoluble aggregates. UV at 340 nm measures the scattered light intensity at 340 nm and provides information regarding the amount of soluble and insoluble aggregates. UV spectroscopy measures absorbance at 278 nm and provides information on protein concentration. FTIR (Eur. J. Pharm. Biopharm., 45:231 (1998); Pharm. Res., 12:1250 (1995); J. Pharm. Scien., 85:1290 (1996); J. Pharm. Scien., 87:1069 (1998)]) measures the IR spectrum in the amide 1 region and provides information on the protein secondary structure.

Iso-asp content in samples is measured using the Isoquant isoaspartate detection system (Promega). The kit uses the enzyme protein isoaspartyl methyltransferase (PIMT) to specifically detect the presence of isoaspartic acid residues in target proteins. PIMT catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to the isoaspartic acid .alpha.-carboxyl position, generating S-adenosyl-L-homocysteine (SAH) in the process. This is a relatively small molecule and can be isolated and quantified by reverse phase HPLC, typically using the SAH HPLC standard provided in the kit.

The potency or bioidentity of an antibody can be measured by its ability to bind to its antigen. The specific binding of an antibody to its antigen can be quantified by any method known to those skilled in the art, for example by immunoassays such as ELISA (enzyme-linked immunosorbent assay).

All publications mentioned herein are incorporated by reference for the purpose of describing and disclosing methodologies and materials that may be used in connection with the present invention.

Although different embodiments of the invention have been described herein with reference to the accompanying drawings, the invention is not limited to these precise embodiments, without departing from the scope or spirit of the invention as defined in the appended claims. It should be understood that various changes and modifications can be made therein by those skilled in the art.

Example

The examples in this section are provided by way of example and not by way of limitation.

Example 1: Clinical trial administering a combination of anti-TIGIT antibody and anti-PD-1 antibody with one or more chemotherapy agents in patients with esophageal cancer, TNBC, or biliary tract cancer

This study is a multicenter, open-label, phase 2 study of an anti-TIGIT antagonist and an anti-PD-1 antagonist with or without one or more chemotherapy agents for the treatment of esophageal cancer or TNBC.

For esophageal cancer, approximately 40 participants with locally advanced unresectable or metastatic esophageal adenocarcinoma or esophageal squamous cell carcinoma (ESCC) or advanced/metastatic Siewert type 1 adenocarcinoma of the gastroesophageal junction (GEJ) were randomly assigned to receive the composition. A (co-formulation of pembrolizumab and vivostolimab; vivostolimab comprises a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 295 and a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 294 will be assigned to) + 5-fluorouracil (5-FU) + cisplatin. A total of 40 participants will be assigned to receive RP2D for Composition A plus 5-fluorouracil/cisplatin.

For TNBC, approximately 40 participants with locally recurrent unresectable or metastatic TNBC will be assigned by non-random assignment to Composition A + paclitaxel. A total of 40 participants will be assigned to receive RP2D for Composition A plus paclitaxel.

For biliary tract cancer, approximately 40 participants with locally recurrent unresectable or metastatic biliary tract cancer will be assigned to Composition A by non-random assignment. Approximately 10 to 14 participants with locally recurrent unresectable or metastatic biliary tract cancer will be assigned to Composition A plus gemcitabine/cisplatin by non-random assignment. A total of 10 participants will be assigned to receive RP2D for Composition A plus gemcitabine/cisplatin.

For gastric cancer, approximately 40 participants with previously untreated, HER2 negative, advanced gastric or GEJ adenocarcinoma will be assigned by non-random assignment to Composition A in combination with capecitabine/oxaliplatin.

Purpose and Endpoint

A list of objectives and endpoints for clinical trial substudies is presented in the table below.

Table 9. Objectives and endpoints for clinical trials.

administration

● Esophageal cancer

Preliminary recommendation of 5-FU/cisplatin for use in combination with Composition A for the treatment of participants with esophageal cancer, using a modified toxicity probability interval (mTPI) design with target dose-limiting toxicity (DLT) rate of 30% Phase 2 capacity (RP2D) will be confirmed. If titration is required by mTPI, the dose of 5-FU/cisplatin will be reduced, while the dose of Composition A will remain fixed. There are two predetermined dose levels of 5-FU/cisplatin that can be explored in an mTPI design. If mTPI requires additional dose reduction, registration will be closed.

Treatment with Composition A will continue for a total of 35 doses (approximately 2 years) or until any discontinuation criteria are met. Treatment with RP2D of 5-FU and cisplatin will continue until any discontinuation criteria are met.

There are two predetermined dose levels that can be explored in the mTPI design (Table 10). If mTPI requires additional dose reduction, enrollment will be held while the sponsor evaluates the observed DLT.

● TNBC

Using an mTPI design with a target DLT rate of 30%, the preliminary RP2D of paclitaxel for use in combination with Composition A for the treatment of participants with TNBC will be identified. If a dose reduction is required by mTPI, the dose of paclitaxel will be reduced, while the dose of Composition A will remain fixed. There are two predetermined dose levels of paclitaxel that can be explored in the mTPI design (Table 10). If mTPI requires additional dose reduction, enrollment in Cohort F will be closed.

Treatment with Composition A will continue for a total of 35 doses (approximately 2 years) or until any discontinuation criteria are met. Treatment with the RP2D of paclitaxel will continue until any discontinuation criteria are met.

● Biliary tract cancer

A total of 10 participants will be assigned to receive RP2D for Composition A plus gemcitabine/cisplatin (Table 10). Using an mTPI design with a target DLT rate of 30%, the preliminary RP2D of gemcitabine/cisplatin for use in combination with Composition A for the treatment of participants with biliary tract cancer will be identified. If a dose reduction is required by mTPI, the dose of gemcitabine/cisplatin will be reduced, while the dose of Composition A will remain fixed. There are two predetermined dose levels of gemcitabine/cisplatin that can be explored in an mTPI design.

● Stomach cancer

Using an mTPI design with a target DLT rate of 30%, the preliminary RP2D of capecitabine/oxaliplatin for use in combination with Composition A for the treatment of participants with gastric cancer will be identified. If a dose reduction is required by mTPI, the dose of capecitabine/oxaliplatin will be reduced, while the dose of Composition A will remain fixed. There are two predetermined dose levels of capecitabine/oxaliplatin that can be explored in the mTPI design (Table 10).

Treatment with MK-7684A will continue for a total of 35 doses (approximately 2 years) or until any discontinuation criteria are met.

Table 10. Predetermined dose levels of 5-FU, cisplatin, paclitaxel, gemcitabine, capecitabine, and oxaliplatin to determine recommended phase 2 doses of chemotherapy.

Participants are scheduled for starting doses of chemotherapy agents as listed in Table 10. However, depending on incidence, completion of the DLT assessment period, and number of DLTs observed, fewer participants may be enrolled at that starting dose. Participants will be followed closely for DLTs during the first cycle (DLT Assessment Period) after the first dose of the study intervention. Dosage will be assessed on an ongoing basis as participants complete the DLT assessment period. In Table 11, columns represent the number of participants treated at the current dose level and rows represent the number of participants who experienced a DLT. The entries in the table are dose-setting decisions: E, S, D, and DU represent dose escalation, maintenance at the same dose, dose reduction, and dose exclusion from study due to unacceptable toxicity, respectively. For example, if a DLT occurred in 2 out of 3 participants at this dose level, the dose would be reduced to the next lower dose level, but may be increased again at a later date if the lower dose is well tolerated. DLTs occurred in 3 out of 3 participants, indicating unacceptable toxicity at this dose. If permitted by protocol, the dose should be reduced and the current dose will not be explored further.

Table 11. Dose-setting rules according to mTPI design (up to 30% target toxicity rate)

If a dose reduction or ramp-up decision is made before 10 participants have completed enrollment at the starting dose, enrollment at this dose level will be stopped and a new set of participants will be enrolled and treated at the next lower dose level. . This process involves a maximum of 10 DLT-evaluable participants enrolled at each dose explored, with 10 participants enrolled at any tested dose and an “S” (at current dose) for the 10th participant evaluated. maintenance) will continue until a decision is made on administration. If the dosing decision is “E” after evaluating all enrolled patients at a given dose at any time, the dose is escalated to the higher predetermined dose, unless the higher dose was previously discontinued due to a “DU” decision. It can be.

A "D" or "DU" determination at the lowest dose level will stop evaluation of the combination under study. An “E” decision at the highest capacity level will result in maintenance at that level. During dose-setting, tapering or escalation to intermediate doses that are not predefined and not previously studied may be permitted (if assessment of toxicity at these doses is required).

The maximum dose/exposure allowed in this study is 200 mg vivostolimab / 200 mg pembrolizumab for up to 2 years (35 treatment cycles) of initial treatment/first course.

The maximum tolerated dose/exposure of 5-FU is 4000 mg/m ² /cycle (21-day cycle) for up to 2 years (35 treatment cycles) of initial treatment.

The maximum dose/exposure of cisplatin allowed is 80 mg/m ² for up to 6 cycles.

Paclitaxel will be administered according to the approved product label and applicable institutional standards.

Based on overall clinical practice patterns, 1000 mg/m ² gemcitabine will be administered on days 1 and 8 of a 21-day cycle until PD or unacceptable toxicity. Cisplatin at 25 mg/m ² will be administered on days 1 and 8 of a 21-day cycle for a maximum of 8 cycles.

The capecitabine/oxaliplatin dosage regimen consisted of oxaliplatin (130 mg/m ² IV) on Day 1 of each treatment cycle (Q3W) plus capecitabine (130 mg/m 2 IV) on Days 1 to 14 of each treatment cycle (Q3W). 1000 mg/m ² orally twice daily). The duration of oxaliplatin treatment may be capped at 6 cycles according to local national guidelines.

When appropriate, dose adjustments in response to treatment-related AEs are permitted to ensure participants remain on study medication. In general, Composition A, 5-FU, cisplatin, paclitaxel and/or gemcitabine may be discontinued together or separately at the discretion of the clinical investigator to determine which treatment component is the source for a given toxicity. Actions may be taken independently for each component of the study treatment (e.g., chemotherapy should be discontinued for chemotherapy-related contraindications, but Composition A may be continued if well tolerated). Chemotherapy may be stopped, dose reduced, or discontinued. Composition A can only be stopped or discontinued.

AEs associated with Composition A exposure may represent immune-related reactions. These immune-related AEs (irAEs) may occur immediately after the first dose or several months after the last dose of pembrolizumab monotherapy, co-agent, or immuno-oncology (IO) combination treatment, and affect more than one body system simultaneously. can affect Therefore, early recognition and initiation of treatment are important to reduce complications. Based on existing clinical study data, most irAEs were reversible and could be managed with discontinuation of pembrolizumab monotherapy, co-agent or IO combination administration of corticosteroids, and/or other supportive management. For suspected irAEs, ensure appropriate evaluation to confirm the etiology or rule out other causes. Additional procedures or tests, such as bronchoscopy, endoscopy, and skin biopsy, may be included as part of the evaluation.

Table 12. Dose adjustment and toxicity management guidelines for immune-related adverse events associated with pembrolizumab monotherapy, co-formulation, or IO combination.

Interruption of chemotherapy (5-FU, cisplatin, paclitaxel, gemcitabine, capecitabine, or oxaliplatin) for more than 6 weeks will require sponsor approval before treatment can resume.

For participants who experience an AE requiring a dose adjustment of the study intervention, this ( The treatment period following use of these) drug(s) may be delayed.

Clinicians can attribute each toxic event to 5-FU, cisplatin, or Composition A and use a stepwise approach to dose reduction of 5-FU and cisplatin (Table 10). Participants may have up to two dose reductions for each component throughout the course of the study. If the dose has been reduced, it may not be increased again. If a participant experiences multiple toxicities and there are conflicting recommendations, follow the recommended most conservative dose adjustment (i.e., appropriate dose reduction for the most severe toxicity). Participants requiring a third dose adjustment for any component will discontinue that agent.

In the clinician's opinion, when toxicity is clearly related to one of the chemotherapy agents, it is appropriate to reduce that agent rather than the other agent. If toxicity is associated with a combination of two chemotherapy agents, both drugs should be reduced according to recommended dose adjustments. If toxicity is associated with the combination of all study interventions administered, chemotherapy should be reduced, discontinued or discontinued and Composition A should be discontinued or discontinued according to recommended dose adjustments.

Participants may discontinue 5-FU or cisplatin and continue to receive the other components in combination with Composition A. Participants can discontinue both 5-FU and cisplatin and continue receiving Composition A.

Dose adjustment criteria for 5-FU and cisplatin are provided in Table 13 and Table 14, respectively.

Table 13. Dose modification guidelines for 5-FU-related adverse events.

Table 14. Dose modification guidelines for cisplatin-related adverse events.

Clinicians can attribute each toxic event to paclitaxel or Composition A and use a stepwise approach to dose reduction of paclitaxel. Participants may have up to one dose reduction of paclitaxel throughout the course of the study. If the dose has been reduced, it may not be increased again. If a participant experiences multiple toxicities and there are conflicting recommendations, follow the recommended most conservative dose adjustment (i.e., appropriate dose reduction for the most severe toxicity).

If toxicity is associated with the combination of all study interventions administered, paclitaxel should be reduced, discontinued, or discontinued, and Composition A should be discontinued or discontinued according to recommended dose adjustments.

Participants may discontinue paclitaxel and continue receiving Composition A. If paclitaxel is discontinued, participants do not need to come to the clinic on days when chemotherapy alone is administered.

Dosage adjustment criteria for paclitaxel are provided in Table 15.

Table 15. Dose adjustment guidelines for paclitaxel-related adverse events.

Gemcitabine should be administered with caution to participants with evidence of significant renal or hepatic impairment, as there is insufficient information from clinical studies to allow clear dosage recommendations for this patient population. In cases of significant renal impairment, defined as creatinine clearance (CrCl) <30 mL/min, consider dose reduction and discuss with sponsor. For serum bilirubin >1.6 mg/dL, consider a dose reduction of gemcitabine to 800 mg/m ² . Monitor carefully and discontinue gemcitabine if any drug-related exacerbations occur.

Gemcitabine may be used to treat any evidence of microangiopathic hemolytic anemia, such as a rapid fall in hemoglobin with thrombocytopenia and elevations in serum bilirubin, serum creatinine, blood urea nitrogen, or LDH (which may indicate the development of hemolytic uremic syndrome). ) should be discontinued at the first sign of Renal failure may not be reversible despite discontinuation of therapy, and dialysis may be required.

The maximum dose reduction allowed is up to 40% of the starting dose of cisplatin (10 mg/m ² ) and gemcitabine (400 mg/m ² ). Doses below this level will not be considered therapeutic and participants will be discontinued from relevant chemotherapy.

Dose adjustment criteria for gemcitabine/cisplatin are provided in Table 16.

Table 16. Dose adjustment guidelines for gemcitabine/cisplatin-related adverse events.

Dose adjustments for the capecitabine/oxaliplatin combination, oxaliplatin, and capecitabine are detailed in Tables 17, 18, and 19, respectively.

In participants with unrecognized dihydropyrimidine dehydrogenase deficiency, acute life-threatening toxicities may occur if the participant is treated with capecitabine. It is recommended that the dihydropyrimidine dehydrogenase test be performed appropriately according to local guidelines.

Table 17. Dose Modification Guidelines for CAPOX Drug-Related Adverse Events

Table 18. Dose modification guidelines for oxaliplatin drug-related adverse events.

Table 19. Dose Modification Guidelines for Capecitabine Drug-Related Adverse Events

Composition A Co-Formulation Administration

Composition A co-formulation will be administered using a 30 minute IV infusion every 3 weeks. The site should make every effort to time the injection as close to 30 minutes as possible. However, taking into account the variability of infusion pumps from site to site, a range of -5 and +10 minutes is acceptable (i.e., infusion time is 25 to 40 minutes).

5-Fluorouracil + cisplatin administration

5-FU administration is continued as long as the total dose of 4000 mg/m ² per 3-week cycle is followed (e.g., 1000 mg/m ² /day is also allowed on Q3W days 1 to 4). It will be administered as a continuous IV infusion at 800 mg/m ² /day on each of Days 1 to 5 of Q3W according to the approved prescribing information in each country/region during the period or according to local standards. 5-FU will be administered after composition A and cisplatin administration. Treatment with 5-FU may follow 1 to 2 days of Composition A (e.g., day 2 or day 3), as needed, according to local standard of care. The duration of 5-FU treatment will not exceed 35 cycles.

Cisplatin 80 mg/m ² is administered as a Q3W 60-minute or 120-minute IV infusion on Day 1 of each treatment cycle following the administration of Composition A according to the approved prescribing information or local institutional guidelines in each country/region (or at the site). will be administered (according to standard practice). The duration of cisplatin treatment will be capped at 6 doses; If cisplatin is withheld for one or more cycles during cycles 2 through 6, cisplatin administration may occur after cycle 6. Treatment with cisplatin may follow 1 to 2 days of Composition A (e.g., day 2 or day 3), as needed, according to local standard of care.

Paclitaxel administration

Paclitaxel will be administered at a dose of 90 mg/m ² Q3W on days 1, 8, and 15 of each 28-day treatment cycle according to the approved prescribing information or local institutional guidelines in each country/region. . If Composition A and paclitaxel are administered on the same day, paclitaxel will be administered after Composition A.

Gemcitabine + cisplatin administration

Cisplatin will be administered as an IV infusion on days 1 and 8 of the 3-week cycle, followed by hydration procedures, and should be administered in accordance with local guidelines/product label procedures. Cisplatin may be administered on day 2 if required by local guidelines; Day 1 is the preferred day for intervention administration. Gemcitabine will be administered as an IV infusion on days 1 and 8 of a 3-week cycle according to local guidelines and product label procedures.

Premedication with antiemetic therapy may be given prior to cisplatin and gemcitabine administration. Following the Multinational Association of Supportive Care in Cancer (MASCC) guidelines (http://www.mascc.org/antiemetic-guidelines) and 5-HT3 receptor antagonist, dexamethasone, according to the MASCC guidelines. (or equivalent) and aprepitant (or equivalent). Based on data showing the potential impact of steroid use on the efficacy of PD-1 and PD-L1 blockade, the use of systemic steroids as anti-nausea medications should be limited to what is considered safe by clinicians.

Capecitabine + oxaliplatin administration

Oxaliplatin 130 mg/m ² will be administered as a 60 to 120 minute IV infusion on Day 1 of each treatment cycle or according to standard practice in the field.

Capecitabine will be administered orally at a dose of 1000 mg/m ² twice daily on days 1 to 14 of each treatment cycle. The evening dose of capecitabine should be taken approximately 12 hours after the morning dose. Capecitabine should be taken with food or within 30 minutes of food/meal, with approximately 200 mL of water. Sites may follow local practice patterns regarding calculation of capecitabine milligram doses. See the product label for additional instructions on dosing procedures for capecitabine.

If a participant is enrolled later in the day, the first dose is permitted to be taken on Day 1, and twice daily dosing can continue on Days 2 through 14; The final dose will be taken on the morning of day 15.

Clinicians are advised to advise participants assigned to receive capecitabine about the risk of photosensitivity and to take sun protection measures accordingly. Participants receiving capecitabine should be carefully monitored for ocular complications and skin reactions.

efficacy endpoint

This study will use objective response rate as the primary efficacy endpoint. Objective response rate is defined as the proportion of participants with the best response as a CR or PR. Responses are based on blinded independent central center review (BICR) using RECIST 1.1 (modified to follow up to 10 target lesions and up to 5 target lesions per center). Objective response rate is an appropriate endpoint for evaluating the antitumor activity of a treatment arm of a clinical trial. For the randomized cohort, ORR is defined as the percentage of participants achieving a confirmed CR or PR according to RECIST 1.1 as assessed by BICR. For single-arm cohorts, ORR is defined as the percentage of participants achieving confirmed CR or PR according to RECIST 1.1 as assessed by the clinical investigator. For the randomized cohort, PFS is defined as the time from randomization to first documented disease progression according to RECIST 1.1 by BICR or death from any cause, whichever occurs first.

This study will use PFS as a secondary efficacy endpoint. Progression-free survival is defined as the time from the date of randomization/assignment to the first date of disease progression or death from any cause, whichever comes first, based on RECIST 1.1 criteria as assessed by BICR. For single-arm cohorts, PFS is defined as the time from the first dose of study intervention to first documented disease progression according to RECIST 1.1 by the investigator or death from any cause, whichever occurs first. .

Additionally, this study will use OS as an exploratory efficacy endpoint. Overall survival in this study is defined as the time from the date of randomization/assignment to death from any cause. For the randomized cohort, OS is defined as the time from randomization to death from any cause. For single-arm cohorts, OS is defined as the time from the first dose of study intervention to death from any cause.

Inclusion criteria

All participants will be provided with a participant identification card identifying them as participants in the research study. The card will contain study-site contact information (including direct phone number) to be used in case of an emergency. The clinical investigator or qualified designee will provide the participant with a participant identification card immediately after the participant provides written informed consent. At the time of intervention assignment/randomization, site staff will add the treatment/randomization number to the participant identification card.

The participant ID card also contains contact information for an emergency unblinding call center so that health care providers can obtain information regarding study intervention in emergency situations when a clinical investigator is not available.

Medical history will be obtained by the clinical investigator or his/her qualified designee. The medical history will collect all active conditions and any conditions diagnosed within the previous 10 years that are deemed clinically significant by the investigator. Details regarding the medical conditions for which participants are enrolled in the study will be recorded individually and will not be listed as medical history.

If a medical condition is diagnosed at screening due to a physical examination, laboratory tests, radiological evaluation, other evaluations, and/or a combination of these evaluations, the medical condition may be diagnosed at any protocol-specified intervention (e.g., procedure, washout, or preparatory treatment, including a placebo preparation), should be recorded as a baseline condition along with the participant's other medical history.

Comprehensive details regarding the participant's cancer history will be recorded individually and will not be listed as a medical history. These details include, but are not limited to, stage at diagnosis, histopathology, location(s) of tumor burden, investigator-determined tumor size per RECIST 1.1, and any prior treatment (including neoadjuvant radiation, neoadjuvant chemotherapy, and neoadjuvant surgery). It doesn't work.

The clinical investigator or qualified designee will review medication use, including any protocol-specified medication washout requirements, and will record any prior medications taken by the participant within 28 days prior to the first dose of the study intervention.

The clinical investigator or qualified designee, if present, will record medications taken by participants during the study.

All consenting participants will be provided with a unique screening number that will be used to identify participants for all procedures occurring prior to randomization/intervention assignment. Each participant will be assigned only one screening number. Screening numbers should not be reused for different participants.

Any participant screened multiple times will retain the original screening number assigned at the initial screening visit.

All eligible participants will be assigned by non-random assignment and will receive a treatment/randomization number. The treatment/randomization number identifies the participant for all procedures that occur after treatment assignment/randomization. Once a treatment/randomization number is assigned to a participant, it can never be reassigned to another participant.

A single participant may not be assigned more than one treatment/randomization number.

Exclusion criteria

A participant must be excluded from the study if the participant:

1. History of a second malignancy, unless potentially curative treatment has been completed for 3 years without evidence of malignancy. The time requirement does not apply to participants who have undergone successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, cervical carcinoma in situ, or other carcinoma in situ.

In the case of gastric cancer, there is an additional known malignancy that is progressing or has required active treatment within the last 5 years.

2. Human immunodeficiency virus (HIV)-infected participants with a history of Kaposi's sarcoma and/or multicentric Castleman disease.

3. Received prior systemic therapy for advanced (metastatic) or unresectable (locally advanced) biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma or gallbladder cancer), excluding permitted neoadjuvant/adjuvant therapy. Neoadjuvant/adjuvant therapy must have been completed at least 6 months prior to diagnosis of advanced and/or unresectable disease, and participants must not have received gemcitabine and/or cisplatin in a neoadjuvant/adjuvant setting. Participants who have received prior neoadjuvant/adjuvant therapy and have R2 postoperative pathology of oncologic resection are excluded.

4. Have squamous cell or undifferentiated gastric cancer.

5. Have pre-existing peripheral neuropathy >grade 1.

6. Received prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-TIGIT agents.

7. Received prior systemic anticancer therapy, including investigational agent, within 4 weeks prior to randomization/assignment.

8. Received prior radiotherapy or had radiation-related toxicity requiring corticosteroids within 2 weeks of starting study intervention. Palliative radiotherapy of up to 2 weeks followed by a 1-week washout is permitted for non-central nervous system (CNS) diseases.

9. Received a live or live-attenuated vaccine within 30 days prior to the first dose of the study intervention. Administration of killed vaccines is permitted.

10. Received prior anticancer therapy (e.g., transarterial chemoembolization (TACE), palliative surgery) for advanced unresectable biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma or gallbladder cancer), including an investigational agent, within 4 weeks prior to allocation.

11. Received neoadjuvant therapy for locally advanced, unresectable, or metastatic gastric/GEJ cancer. Participants may have received prior neoadjuvant and/or adjuvant therapy as long as it was completed at least 6 months prior to randomization.

12. Received prior therapy with an agonist directed against stimulatory or co-inhibitory T-cell receptors (e.g., CTLA-4, OX 40, CD137).

13. Received an investigational agent or used an investigational device within 4 days prior to administration of the study intervention.

14. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (>10 mg of prednisone equivalents per day) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication.

15. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases must ensure that they are radiologically stable (i.e., without evidence of progression) and clinically stable for at least 4 weeks by repeat imaging (repeat imaging must be performed during study screening). , are eligible to participate as long as they do not require steroid treatment for at least 14 days prior to the first dose of the study intervention. Participants with known untreated asymptomatic brain metastases (i.e., no neurological symptoms, no need for corticosteroids, no or minimal surrounding edema, and no lesions >1.5 cm) are eligible to participate, but may participate in Imaging will be required.

16. Known severe hypersensitivity (≥ Grade 3).

17. Have an active autoimmune disease requiring systemic treatment in the past 2 years, excluding alternative therapy (e.g., thyroxine, insulin, or physiologic corticosteroids).

18. Have a history of (non-infectious) pneumonitis/interstitial lung disease requiring steroids or currently have pneumonitis/interstitial lung disease.

19. Has an active infection requiring systemic therapy.

20. Any condition, therapy or laboratory that, in the opinion of the treatment investigator, may confound the results of the study, may prevent the participant's participation for the full duration of the study, or for which participation is not in the best interest of the participant. Has the above history or current evidence thereof.

21. Has a known mental or substance abuse disorder that would interfere with the participant's ability to cooperate with study requirements.

22. Present or progressive accumulation of pleural fluid, ascites fluid, or pericardial fluid requiring drainage or diuretic medications within 2 weeks prior to randomization/assignment.

23. Co-active hepatitis B (defined as positive hepatitis B surface antigen (HBsAg) and/or detectable hepatitis B virus (HBV) DNA) and hepatitis C virus (anti-hepatitis C virus (HCV) Ab defined as positive and detectable HCV RNA) infection. Hepatitis B and C screening tests are not required unless there is a known history of HBV and HCV infection or if ordered by the local health agency.

24. In case of stomach cancer, there is a known history of active tuberculosis (TB; Bacillus tuberculosis).

25. For gastric cancer, participants with hypokalemia (serum potassium below the lower limit of normal).

26. For gastric cancer, participants with hypomagnesemia (serum magnesium below the lower limit of normal).

27. For gastric cancer, participants with hypocalcemia (serum calcium below the lower limit of normal).

28. Participants who have not adequately recovered from major surgery or have ongoing surgical complications.

29. There is a possibility that participants, in the judgment of the clinical investigator, will not comply with study procedures, restrictions, and study requirements.

30. Received an allogeneic tissue/solid organ transplant.

31. For participants who will receive paclitaxel, have a history of class II-IV congestive heart failure or myocardial infarction within 6 months of allocation.

Dose-limiting toxicity

All toxicities will be graded using the National Cancer Institute (NCI) CTCAE version 5.0 based on clinical investigator assessment. DLT observation ranges will be made during cycle 1 for each dose level.

The occurrence of any of the following toxicities during the first cycle of each dose level, if assessed by the clinician as related to administration of the study intervention, will be considered a DLT:

a. Grade 4 non-hematological toxicity (non-laboratory).

b. Grade 4 hematological toxicities lasting ≥7 days, excluding thrombocytopenia:

● Grade 4 thrombocytopenia of any duration.

● Grade 3 thrombocytopenia associated with clinically significant bleeding.

c. Any non-hematological AE of severity ≥Grade 3 should be considered a DLT, with the following exceptions: Grade 3 fatigue lasting ≤3 days; Grade 3 diarrhea, nausea, or vomiting without antiemetics or antidiarrheals according to standard care; Grade 3 rash without corticosteroids or anti-inflammatory drugs according to standard care

d. Any Grade 3 or Grade 4 non-hematologic laboratory values for:

● Clinically significant medical intervention is required to treat the participant, or

● The abnormality leads to hospitalization, or

● Abnormalities persist for >1 week

● Abnormalities result in drug-induced liver injury (DILI)

Exceptions: Laboratory abnormalities that are not clinically significant, treatable, or reversible, such as liver function tests, uric acid, etc.

e. Grade 3 or Grade 4 febrile neutropenia:

● Grade 3 is defined as an absolute neutrophil count (ANC) <1000/mm ³ at a single temperature >38.3°C (101°F) or sustained temperature ≥38°C (100.4°F) for >1 hour.

● Grade 4 is defined as ANC <1000 units/mm ³ at a single temperature >38.3°C (101°F) or sustained temperature ≥38°C (100.4°F) for >1 hour, with life-threatening consequences and urgent intervention. do.

f. Prolonged delay in starting cycle 2 (>2 weeks) due to intervention-related toxicities.

g. Any intervention-related toxicity requiring the participant to discontinue the intervention during cycle 1.

h. Grade 5 toxicity.

Evaluation at screening and prior to RECIST 1.1

There is no separate iRECIST assessment until radiographic disease progression based on RECIST 1.1.

RECIST 1.1 Evaluation and decision during progress

For participants who demonstrate radiological disease progression by RECIST 1.1, the investigator will decide whether the participant will continue to receive study intervention until a repeat scan is obtained in 4 to 8 weeks.

Tumor flare may manifest as any factor leading to radiographic progression according to RECIST 1.1, including:

● Increase to ≥20% of the sum of the diameters of target lesion(s) identified at baseline and ≥5 mm from nadir. The Evaluation Criteria for Response of Solid Tumors to Immune-Based Therapeutics 1.1 (iRECIST) publication uses the term “sum of measurements,” but consistent with the original RECIST 1.1 terminology, “sum of diameters” will be used in this protocol.

● Apparent progression of non-target lesion(s) identified at baseline.

● Occurrence of new lesion(s)

iRECIST defines new response categories including iUPD (unconfirmed progressive disease) and iCPD (confirmed progressive disease). For the purposes of the iRECIST assessment, the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) response in iUPD, regardless of which factor caused the progression.

At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will routinely be evaluated.

New lesions will be classified as measurable or non-measurable using the same size thresholds and rules as for baseline lesion evaluation in RECIST 1.1. From the measurable new lesions, a total of up to 5 lesions (maximum 2 per organ) can be selected as new lesion-targets. The sum of the diameters of these lesions will be calculated and maintained separately from the sum of the diameters for the target lesion at baseline. All other new lesions will be tracked qualitatively as new lesions - non-targets.

Evaluation during confirmatory imaging

At the confirmatory scan, participants were assessed either as confirmed progression (overall response on iCPD) or as showing persistent unconfirmed progression (overall response on iUPD) or as showing disease stability or response (stable disease (iSD) by iRECIST/by iRECIST). will be classified as showing a partial response (iPR) / complete response (iCR) by iRECIST).

confirmation of progress

If any of the following occurs, progression is considered confirmed and the overall response will be confirmed progressive disease (iCPD) by iRECIST:

● Indicates worsening of any of the factors underlying the iUPD at the previous visit

○ For target lesions, worsening is a further increase in total diameter of ≥5 mm compared to any previous iUPD time point.

○ For non-target lesions, worsening is any significant growth of the entire lesion compared to the previous iUPD time point; It does not have to meet the “clear” standards of RECIST 1.1

○ For new lesions, worsening is which of these:

■ Increase in the total number of new lesions in diameter by ≥5 mm from the time of the previous iUPD.

■ Visible growth of new non-target lesions.

■ Appearance of additional new lesions

● A random new factor appears to have triggered disease progression by RECIST 1.1.

Persistence iUPD

In the following cases, progression is considered unconfirmed and the overall response remains iUPD:

● None of the progress-checking factors identified above occur, and

● The sum of the diameters of target lesions (initial target lesion) remains above the initial disease progression threshold (by RECIST 1.1)

Additional scans for confirmation should be scheduled 4 to 8 weeks from the scan where iUPD was observed. This may correspond to the next visit in the original visit schedule. Evaluation of follow-up confirmation scans proceeds in the same manner with available iCPD, iUPD and iSD/iPR/iCR results.

Resolving iUPD

In the following cases, progression is considered unconfirmed and overall response is iSD/iPR/iCR:

● None of the progress-checking factors identified above occur, and

● The sum of the diameters of target lesions (initial target lesion) does not exceed the disease progression threshold.

Responses are classified as iSD or iPR (based on the sum of the diameters of target lesions) or iCR if all lesions resolve.

In this case, the initial iUPD is considered pseudoprogressive and the level of suspicion for progression is “reset”. This means that the next visit showing radiographic progression, whenever it occurs, is reclassified as an iUPD by iRECIST, and the confirmation process is repeated before a response of iCPD can be assigned.

Management after confirmatory imaging

If repeat scans do not confirm disease progression and the participant remains clinically stable, study intervention should be continued. You should follow a regular scanning schedule. If disease progression is confirmed, participants may discontinue the study intervention.

If the participant has confirmed radiographic progression (iCPD) and clinically meaningful benefit, the study intervention may continue after consultation with the sponsor. If study intervention continues, tumor scans should be performed after that period.

Detection of progression at visits following resolution of pseudo-progression

After resolution of pseudoprogression (i.e., after iSD/iPR/iCR), another case of progression (another iUPD) is indicated by any of the following events:

● Target lesion

○ The sum of diameters reaches the disease progression threshold (≥20% and ≥5 mm increase from nadir) for the first time or after resolution of previous pseudoprogression. The nadir is always the minimum sum of diameters observed during the entire study before or after in case of pseudoprogression.

● Non-target lesions

○ If a non-target lesion has never shown obvious progression, it is an iUPD if this is the first time it has done so.

○ If the non-target lesion has previously shown apparent progression and this progression has not resolved, iUPD results from any significant further growth of the non-target lesion taken as a whole.

○ New lesions

○ New lesions appear for the first time

○ Additional new lesions appear

○ Previously identified new target lesions show an increase in the sum of the diameters of the new lesions of ≥5 mm from the nadir value of the sum

○ Previously identified non-target lesions show any significant growth

If any of the above events occur, the overall response for that visit is iUPD and the iUPD assessment process (see assessment at confirmatory scan above) is repeated. Progression must be confirmed before iCPD can occur.

The decision process for subsequent iUPD is the same as that for iUPD identification for initial disease progression, with the one exception that in a previous iUPD case a new lesion has developed and has not resolved and then worsened (increased in size or number) leading to a second iUPD. This may occur in some cases. iUPD cannot resolve with iSD or iPR unless new worsening lesions resolve on confirmatory scan. This will maintain iUPD until a reduction in new lesion burden allows resolution to iSD or iPR or until a new or worsening cause of progression indicates iCPD.

stop

Discontinuation of study intervention does not indicate withdrawal from the study. Because certain data on clinical events following discontinuation of the study intervention may be important to the study, such data should be collected at the participant's last scheduled follow-up, even if the participant discontinues the study intervention. Therefore, any participant who discontinues the study intervention prior to completion of the protocol-specified treatment period will still continue to be monitored in the study and participate in study visits and procedures unless the participant withdraws from the study.

Participants may discontinue the study intervention at any time for any reason or at the discretion of the clinical investigator if any unexpected effects occur. Additionally, participants may withdraw from a study intervention by the investigator or sponsor because the study intervention is inappropriate, the study protocol has been violated, or for administrative and/or other safety reasons.

Participants must discontinue study intervention but continue to be monitored in the study for any of the following reasons:

● The participant or the participant's legally authorized representative requests discontinuation of research intervention.

● Any extended suspension of study intervention beyond the permitted period, for management of irAEs or AEs or other permitted dose interruptions, requires sponsor consultation prior to restarting treatment. If treatment is not restarted, participants will continue to be monitored in the study and the reason for discontinuation of study intervention will be recorded in the medical record.

● The participant has a medical condition or personal situation that, in the opinion of the investigator and/or sponsor, places the participant at unnecessary risk from continued administration of the study intervention.

● Participants are confirmed to have a positive serum pregnancy test.

● Radiographic disease progression (after obtaining the informed consent addendum and sponsor contact, the investigator may elect to continue treatment after imaging CRO (iCRO)-verified disease progression).

● Any progression or recurrence of a malignancy, or any occurrence of another malignancy requiring aggressive treatment.

● Any study intervention-related toxicity specified as a reason for permanent discontinuation as defined in the guidelines for dose modification due to AE.

● Participants are required to take any prohibited concomitant medications listed.

● Severe or life-threatening event, presumed to be immune-related, or recurrence of any of the laboratory abnormalities listed above.

If the participant or the participant's legally authorized representative withdraws consent from the study, the participant must withdraw from the study. If a participant withdraws from the study, they will no longer receive study intervention or will be followed at scheduled protocol visits. If a participant fails to return to the clinic for a required study visit and/or if the site is unable to contact the participant, the following procedures should be performed:

● Sites should attempt to contact participants to reschedule missed visits. Once participants are contacted, they should be advised of the importance of maintaining the protocol-specified visit schedule.

● The clinician or designee must make every effort to regain contact with the participant at each missed visit (e.g., telephone call and/or certified letter to the participant's last known mailing address or local equivalent). equivalent method). These contact attempts must be documented in the participant's medical record.

● Note: Participants are not considered lost to follow-up until the last scheduled visit for an individual participant. Missing data for participants will be managed through prespecified statistical data handling and analysis guidelines.

informed consent

The clinical investigator or medically qualified designee (consistent with local requirements) must obtain written informed consent from each potential participant (or his/her legally authorized representative) prior to participation in this clinical study. If there are changes to the participant's condition (e.g., health or age of majority) during the study, the investigator or medically competent designee must ensure that appropriate written informed consent is obtained.

Tumor imaging and evaluation of disease

The term “scan” refers to any medical imaging data used to assess tumor burden and may include cross-sectional imaging (such as CT or MRI), medical imaging, or other methods as specified in this protocol.

In addition to survival, efficacy will be assessed based on assessment of scan changes in tumor burden over time until participants discontinue from the study or enter survival follow-up. The scan acquisition and transfer process to iCRO can be found in the Field Imaging Manual (SIM). Tumor scan by CT is highly desirable. For the abdomen and pelvis, contrast-enhanced MRI may be used when CT with iodinated contrast media is contraindicated or when indicated by local practice.

For the purpose of evaluating tumor scans, the term “clinical investigator” refers to a local clinical investigator at the site and/or a radiological reviewer at an on-site or off-site facility.

If brain scans are performed, MRI is preferred; In cases where MRI is medically contraindicated, CT imaging will be permitted.

A bone scan can be performed to evaluate bone metastases. Any supplemental scans performed to support a positive or negative bone scan, such as plain X-rays obtained for correlation, must also be submitted to the iCRO.

Other imaging modalities that are collected and submitted to iCRO and may be included in response assessment and other imaging modalities that should not be submitted to iCRO and will not be included in response assessment are defined in SIM.

At screening, participant eligibility will require radiographic documentation of at least one lesion that meets the requirements for selection as a target lesion prior to participant allocation.

All scheduled scans for participants will be submitted to iCRO. Additionally, scans obtained at unscheduled times for any reason (including suspected progression or other clinical reasons) may also be used if they show disease progression or to support response assessment. must be submitted to iCRO. All scans acquired within the protocol-specified time window surrounding a scheduled scan visit should be classified as pertaining to that visit.

Initial tumor imaging

Initial tumor scan at screening must be performed within 28 days prior to randomization/assignment date. Any scans obtained after day 1 of cycle 1 cannot be included in the screening evaluation. Sites must review the screening scan to confirm that the participant has a measurable disease according to RECIST 1.1.

Tumor scans performed as part of routine clinical care are acceptable for screening and can be evaluated by iCRO if they have acceptable diagnostic quality and are performed within 28 days of randomization.

If brain scans are required to document the stability of existing metastases, brain MRI should be obtained during screening.

Bone scans are required at the time of screening for participants with a history of bone metastases and/or with index clinical signs/symptoms such as bone pain or elevated alkaline phosphatase levels.

Tumor imaging during study

The first study scan must be performed 9 weeks (day 63 + 7 days) from the date of randomization/assignment. Follow-up tumor scans should be performed every 9 weeks (63 days ± 7 days) or more frequently if clinically indicated. After 54 weeks (378 days ±7 days), participants maintaining treatment will have scans performed every 12 weeks (84 days ±7 days). Scan timing should be according to the calendar day and should not be adjusted for delays in cycle start. Scans should be performed until disease progression is confirmed by the clinical investigator or notified by the sponsor, or until initiation of new anticancer treatment, withdrawal of consent, or death, whichever occurs first.

Alternatively, it should be confirmed by a repeat scan performed at least 4 weeks after the first indicator of response was observed. The participant will then return to their regular scan schedule starting at the next scheduled time point. Participants who have additional scans for confirmation do not need to have their next scheduled scan if it is less than 4 weeks later; The scan may be resumed at a subsequently scheduled time.

On-study brain or bone scans should be performed if clinically indicated or to confirm CR (if other lesions indicate CR and brain or bone lesions are present at baseline).

If radiological disease progression is confirmed by the investigator in a clinically stable participant, disease progression should be confirmed by another set of scans performed 4 to 8 weeks later.

If disease progression is not confirmed, clinically stable participants should continue the study intervention until progression is confirmed. The participant should return to his regular scanning schedule. If the next scheduled scan will occur in less than 4 weeks, this scheduled scan may be skipped.

If disease progression is confirmed, study intervention will be discontinued.

safety endpoint

Safety endpoints include AEs, SAEs, and discontinuation of study intervention due to AEs. Safety and tolerability will be assessed by clinical review of all relevant parameters, including AEs, laboratory tests, and vital signs. For the safety lead-in phase cohort, safety endpoints also include the incidence of DLT.

Adverse events (AEs)

An AE is any unexpected medical event in a clinical research participant that is temporally associated with the use of the study intervention, whether or not considered related to the study intervention.

An AE may therefore be any adverse and unintended sign (including abnormal laboratory findings), symptom, or condition (new or worsening) temporally associated with the use of the study intervention.

For the purposes of defining an AE, an investigational intervention (also referred to as Sponsor's product) is manufactured by the Sponsor for human use in the study, whether for clinical trials or marketed (including placebo, active comparator product, or preparatory intervention). Includes any pharmaceutical product, biological product, vaccine, diagnostic agent, medical device, combination product, or protocol-specified procedure that is available, licensed by, provided by, or distributed by him.

The following are included as AEs:

● Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety evaluations (e.g., ECG, radiological scan, vital signs) that, in the clinical and scientific judgment of the investigator, are considered clinically significant; measurements) (including worsening from baseline).

● Chronic or intermittent worsening of a pre-existing condition, including an increase in the frequency and/or intensity of the condition.

● A new condition detected or diagnosed after administration of the study intervention, even though it may have existed before the start of the study.

● Signs, symptoms or clinical sequelae of a suspected drug-drug interaction.

● Signs, symptoms, or clinical sequelae of suspected overdose of study intervention or concomitant medication.

● For all reports of overdose with associated AEs (whether accidental or intentional), the AE term should reflect clinical symptoms or abnormal laboratory results. Overdoses without any associated clinical symptoms or abnormal laboratory results are reported using the term “accidental or intentional overdose without adverse effects.”

● Any new cancer (not status of study). Cancer progression under study is not a reportable event.

The following events do not meet the definition of AE for the purposes of this study:

● Medical or surgical procedures (e.g., endoscopy, appendectomy): Conditions leading to these procedures are AEs.

● Situations in which no unexpected medical event has occurred (admission to hospital for social and/or convenience reasons).

● Expected day-to-day fluctuations in pre-existing disease(s) or condition(s) present or detected at the start of the study, without worsening.

● Surgical procedure(s) planned prior to informed consent to treat a pre-existing condition that has not worsened.

Serious Adverse Event (SAE)

If an event is not an AE according to the above, it cannot be a SAE even if serious conditions are met. A SAE is defined as any unexpected medical event at any dose that is:

● Causes death.

● Life-threatening. In the definition of "serious," the term "life-threatening" refers to an event in which the participant was at risk of death at the time of the event. It does not refer to events that could hypothetically lead to death in more severe cases.

● Inpatient hospitalization or extension of existing hospitalization is required. Hospitalization is defined as an inpatient hospitalization regardless of length of stay, even if the hospitalization is a precautionary measure to continue observation. Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened is not an SAE. A pre-existing condition is a clinical condition diagnosed prior to use of the combination disclosed herein and documented in the participant's medical history.

● Causes persistent or significant disability/disability. The term disability refers to a substantial disruption of a person's ability to perform normal life functions. This definition refers to experiences of relatively minor medical significance that may interfere with or prevent daily functioning but do not constitute substantial disruption, such as uncomplicated headaches, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., a sprained ankle). It is not intended to be inclusive.

● It is a congenital anomaly/birth defect. In offspring of participants taking the product, regardless of time to diagnosis.

● Other significant medical events. Medical or scientific judgment may be warranted in other circumstances, such as reporting a SAE, such as may not be immediately life-threatening or may not result in death or hospitalization but may endanger the participant or prevent one of the other outcomes listed in the definition above. This should be done in determining whether medical or surgical intervention is appropriate in serious medical cases where medical or surgical intervention may be required. These events should normally be considered serious. Examples of such events include invasive or malignant cancer, intensive care in the emergency room or at home for allergic bronchospasm, hematologic dystrophy or convulsions that do not result in hospitalization, or the development of drug dependence or drug abuse.

Study treatments are outlined in Tables 20-23 below.

Table 20. Summary of clinical trials - initial treatment of esophageal, biliary tract, and stomach cancer.

Table 21. Clinical Trial Summary - Initial Treatment of TNBC

Table 22. Clinical trial summary - second-course treatment of esophageal, biliary tract, and gastric cancer.

Table 23. Summary of clinical trials - second course treatment of TNBC

Example 2

This example describes the antitumor effect of a TIGIT antagonist and a PD-1 antagonist in combination with 5-fluorouracil (5-FU) and cisplatin chemotherapy using a mouse syngeneic model.

Seven-week-old female C57BL/6J mice weighing 18 to 21 grams were anesthetized and injected subcutaneously into the posterior lateral abdomen with 0.5 x 10 ⁶ sublogarithmic phase confluent MC38 cells. When the average tumor volume of the inoculated MC38 tumors reached approximately 340 mm ³ mice were pair-matched into treatment groups of 10 mice per group.

Antibody reagents in this example include:

● Anti-PD-1 mIgG1 antibody, which is a murine version of rat anti-mouse PD1 Ab with mouse IgG1 Fc;

● Anti-TIGIT mIgG2a antibody with a mouse Fc region of the mIgG2a subtype, which is the murine counterpart to the human isotype IgG1;

● Isotype mIgG1 antibody, a mouse IgG1 isotype-matched control monoclonal antibody specific for adenovirus hexon 25; and

● Isotype mIgG2a antibody, a mouse IgG2a isotype-matched control monoclonal antibody specific for adenovirus hexon 25.

The amino acid sequences of the antibody reagents are listed in Table 24.

Table 24. Sequences of antibodies used in Examples 2 and 3.

The treatment group consisted of:

1) isotype mouse IgG1 antibody (mIgG1) + isotype mouse IgG2a antibody (mIgG2a) + 0.9% saline;

2) anti-PD-1 mIgG1 antibody (murinated pembrolizumab) + isotype mIgG2a antibody + 0.9% saline;

3) anti-TIGIT mIgG2a antibody (murinated bivostolimab) + isotype mIgG1 antibody + 0.9% saline;

4) anti-PD-1 mIgG1 antibody + anti-TIGIT mIgG2a antibody + 0.9% saline;

5) 5-FU + cisplatin + isotype mIgG1 antibody + isotype mIgG2a antibody; and

6) Anti-PD-1 mIgG1 antibody + anti-TIGIT mIgG2a antibody + 5-FU + cisplatin.

Isotype mIgG1 control, mouse monoclonal antibody specific for adenovirus hexon of isotype IgG1, and anti-PD-1 antibody were administered intraperitoneally every 5 days at 5 mg/kg body weight. Isotype mIgG2a control, mouse monoclonal antibody specific for adenovirus hexon of isotype IgG2a, and anti-TIGIT antibody were administered intraperitoneally every 5 days at 10 mg/kg body weight. 5-FU was administered intraperitoneally once a week at 60 mg/kg body weight. Cisplatin was administered intraperitoneally once a week at 4 mg/kg body weight. The start of treatment was considered day 0, and schedule-based dosing continued as described until day 38. Caliper measurements of tumor and body weight were collected twice weekly. Statistical analysis was performed by one-way ANOVA using the Kruskal-Wallis multiple comparison test at the indicated day 17 when the isotype groups reached the endpoint.

As shown in Figures 1 and 2, combination treatment of anti-PD-1 antibody, anti-TIGIT antibody, 5-FUm, and cisplatin resulted in the greatest tumor regression (CR), with 9 out of 10 animals achieving complete tumor regression (CR). Antitumor efficacy was demonstrated, with no measurable tumors detected by the end of the study. In the anti-PD-1 antibody + anti-TIGIT antibody group, 8 out of 10 animals achieved a CR, whereas in the anti-PD-1 antibody monotherapy group, 2 out of 10 animals achieved a CR. As shown in Figure 2, no other treatment group had CR. A summary of best overall response as measured by change in tumor volume is shown in Figure 2. As shown in Table 25, the mean antitumor response of quadruple combination treatment (i.e., group 6) was observed in isotype-treated animals (p<0.001) or 5-FU + cisplatin chemotherapy group (p=0.007). was significantly greater than the antitumor response. A summary of relevant mean tumor volume comparisons at Day 17, when the isotype treatment group ended the study, is presented in Table 25. No significant weight loss or adverse events were observed in any of the animals treated with this regimen, indicating that the treatment was well tolerated.

Table 25. Summary of one-way ANOVA comparisons of mean tumor volumes used to determine significance between treatment groups. Analysis performed based on day 17, when isotype-treated animals exited the study.

Example 3

This example describes the antitumor effects of TIGIT antagonist and PD-1 antagonist in combination with gemcitabine and cisplatin chemotherapy using a mouse syngeneic model.

Seven-week-old female C57BL/6J mice weighing 18 to 21 grams were anesthetized and injected subcutaneously into the posterior lateral abdomen with 0.5 x 10 ⁶ sublogarithmic phase confluent MC38 cells. When the average tumor volume of the inoculated MC38 tumors reached approximately 335 mm ³ mice were pair-matched into treatment groups of 10 mice per group.

Antibody reagents in this example include:

● Anti-PD-1 mIgG1 antibody, which is a murine version of rat anti-mouse PD1 Ab with mouse IgG1 Fc;

● Anti-TIGIT mIgG2a antibody with a mouse Fc region of the mIgG2a subtype, which is the murine counterpart to the human isotype IgG1;

● Isotype mIgG1 antibody, a mouse IgG1 isotype-matched control monoclonal antibody specific for adenovirus hexon 25; and

● Isotype mIgG2a antibody, a mouse IgG2a isotype-matched control monoclonal antibody specific for adenovirus hexon 25.

The amino acid sequences of the antibody reagents are listed in Table 24.

The treatment group consisted of:

1) isotype mIgG1 antibody + isotype mIgG2a antibody + 0.9% saline;

2) anti-PD-1 mIgG1 antibody + isotype mIgG2a antibody + 0.9% saline;

3) anti-TIGIT mIgG2a antibody + isotype mIgG1 antibody + 0.9% saline;

4) anti-PD-1 mIgG1 antibody + anti-TIGIT mIgG2a antibody + 0.9% saline;

5) gemcitabine + cisplatin + isotype mIgG1 antibody + isotype mIgG2a antibody; and

6) Anti-PD-1 mIgG1 antibody + anti-TIGIT mIgG2a antibody + gemcitabine + cisplatin.

Isotype mIgG1 and anti-PD-1 antibody were administered intraperitoneally every 5 days at 5 mg/kg body weight. Isotype mIgG2a and anti-TIGIT antibody were administered intraperitoneally at 10 mg/kg body weight every 5 days. Gemcitabine was administered intraperitoneally once a week at 100 mg/kg body weight for a total of 4 doses. Cisplatin was administered intraperitoneally once a week at 4 mg/kg body weight for a total of 4 doses. The start of treatment was considered day 0, and schedule-based dosing continued as described until day 55. Caliper measurements of tumor and body weight were collected twice weekly. Statistical analysis was performed by one-way ANOVA with Kruskal-Wallis multiple comparison test at the indicated day 14 when the control isotype group reached the endpoint.

As shown in Figures 3 and 4, quadruple combination treatment with anti-PD-1 + anti-TIGIT + gemcitabine + cisplatin demonstrated the greatest antitumor efficacy. Ten of the ten animals achieved partial tumor regression (PR), with final tumor volumes being smaller than when treatment was initiated. The results are summarized in Table 26. In the anti-PD-1 + anti-TIGIT group, 6 of 10 animals achieved a PR, whereas in the anti-PD-1 monotherapy group, 2 of 10 animals achieved a PR. No treatment group had complete tumor regression. A summary of best overall response as measured by change in tumor volume is shown in Figure 4. As shown in Table 27, the mean antitumor response of the quadruple combination treatment (Group 6) was greater than that observed in isotype-treated animals (p<0.001) or gemcitabine + cisplatin chemotherapy group (p=0.032). It was significantly larger than the response. Although the quadruple combination group had more animals achieving PR than the anti-PD-1 + anti-TIGIT group, there was no statistically significant difference in tumor volume, mainly due to variability in the latter group. A summary of relevant mean tumor volume comparisons at Day 14, when the isotype treatment group ended the study, is presented in Table 27. No significant weight loss or adverse events were observed in any of the animals treated with this regimen, indicating that the treatment was well tolerated.

Table 26. Summary of % tumor growth inhibition (TGI) at day 14, when control animals exited the study, and total number of partial tumor regressions observed at end of study (day 55).

Table 27. Summary of one-way ANOVA comparisons of mean tumor volumes used to determine significance between treatment groups. Analysis performed on day 14, when isotype-treated animals exited the study.

Claims (258)

An effective amount for human patients in need of cancer treatment.
(a) TIGIT antagonist;
(b) PD-1 antagonist;
(c) 5-fluorouracil represented by formula (I); and

(d) Cisplatin represented by formula (II)

A method of treating cancer comprising administering a therapeutic combination comprising. The method of claim 1, wherein the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, and triple negative breast cancer (TNBC). The method of claim 2, wherein the cancer is esophageal cancer. The method of claim 3, wherein the esophageal cancer is advanced esophageal cancer. The method of claim 3, wherein the esophageal cancer is metastatic esophageal cancer. The method of claim 3, wherein the esophageal cancer is locally advanced and unresectable. The method of claim 3, wherein the esophageal cancer is metastatic adenocarcinoma. 4. The method of claim 3, wherein the esophageal cancer is squamous cell carcinoma of the esophagus (ESCC). 4. The method of claim 3, wherein the esophageal cancer is advanced Siewert type 1 adenocarcinoma of the gastroesophageal junction (GEJ). The method of claim 3, wherein the esophageal cancer is metastatic Siewert type 1 adenocarcinoma of the GEJ. effective amount
(a) TIGIT antagonist;
(b) PD-1 antagonist;
(c) 5-fluorouracil represented by formula (I); and
(d) Cisplatin represented by formula (II)
Kit containing . 12. The kit of claim 11, further comprising instructions for administering the TIGIT antagonist, PD-1 antagonist, 5-fluorouracil, and cisplatin to a human patient in need thereof. Use of a therapeutic combination for the treatment of cancer in a human patient in need thereof, wherein the therapeutic combination is administered in an effective amount.
(a) TIGIT antagonist;
(b) PD-1 antagonist;
(c) 5-fluorouracil represented by formula (I); and
(d) Cisplatin represented by formula (II)
Uses that include. 14. Use according to claim 13, wherein the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer and triple negative breast cancer (TNBC). Use according to claim 14, wherein the cancer is esophageal cancer. Use according to claim 15, wherein the esophageal cancer is advanced esophageal cancer. Use according to claim 15, wherein the esophageal cancer is metastatic esophageal cancer. Use according to claim 15, wherein the esophageal cancer is locally advanced and unresectable. Use according to claim 15, wherein the esophageal cancer is metastatic adenocarcinoma. 16. Use according to claim 15, wherein the esophageal cancer is squamous cell carcinoma of the esophagus (ESCC). 16. Use according to claim 15, wherein the esophageal cancer is advanced Siewert type 1 adenocarcinoma of the gastroesophageal junction (GEJ). Use according to claim 15, wherein the esophageal cancer is metastatic Siewert type 1 adenocarcinoma of the GEJ. 23. The method, kit or use according to any one of claims 1 to 22, wherein the PD-1 antagonist and the TIGIT antagonist are formulated separately. 23. The method, kit or use according to any one of claims 1 to 22, wherein the PD-1 antagonist and the TIGIT antagonist are in a fixed dose combination. 23. The method, kit or use according to any one of claims 1 to 22, wherein the PD-1 antagonist and the TIGIT antagonist are co-formulated. 26. The method, kit or use according to any one of claims 1 to 25, wherein the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof. 26. The method, kit or use according to any one of claims 1 to 25, wherein the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or antigen-binding fragment thereof. 27. The method, kit or use of claim 26, wherein the anti-human PD-1 monoclonal antibody is a humanized antibody. 27. The method, kit or use of claim 26, wherein the anti-human PD-1 monoclonal antibody is a human antibody. 30. The method, kit or use according to any one of claims 1 to 29, wherein the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen binding fragment thereof. 31. The method, kit or use of claim 30, wherein the anti-human TIGIT monoclonal antibody is a humanized antibody. 31. The method, kit or use of claim 30, wherein the anti-human TIGIT monoclonal antibody is a human antibody. 27. The method, kit or use of claim 26, wherein the anti-human PD-1 monoclonal antibody is pembrolizumab. 27. The method, kit or use of claim 26, wherein the anti-human PD-1 monoclonal antibody is nivolumab. 27. The method, kit or use of claim 26, wherein the anti-human PD-1 monoclonal antibody is cemiplimab. 31. The method of claim 30, wherein the anti-human TIGIT monoclonal antibody or antigen binding fragment thereof comprises three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: 112 CDRL2 comprising the amino acid sequence and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 154 A method, kit or use comprising a CDRH2 comprising an amino acid sequence as set forth and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 110. 37. The method of claim 36, wherein the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof has a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. A method, kit, or use comprising a light chain variable region comprising: 38. The method of claim 37, wherein the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof comprises or consists of a light chain as set forth in SEQ ID NO: 294 and an amino acid sequence as set forth in SEQ ID NO: 295. A method, kit or use comprising a heavy chain comprising or consisting of. According to any one of claims 1 to 25,
(a) the PD-1 antagonist is pembrolizumab;
(b) the TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and SEQ ID NO: Comprising a CDRH3 comprising the amino acid sequence as set forth in 110
Method, kit or use. According to any one of claims 1 to 25,
(a) the PD-1 antagonist is nivolumab;
(b) the TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and SEQ ID NO: Comprising a CDRH3 comprising the amino acid sequence as set forth in 110
Method, kit or use. According to any one of claims 1 to 25,
(a) the PD-1 antagonist is cemiplimab;
(b) the TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and SEQ ID NO: Comprising a CDRH3 comprising the amino acid sequence as set forth in 110
Method, kit or use. 42. The method of any one of claims 39 to 41, wherein the TIGIT antagonist comprises a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 152. A method, kit, or use comprising a variable region. 43. The method of claim 42, wherein the TIGIT antagonist comprises a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 294 and a heavy chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 295. method, kit, or use. 44. The method of any one of claims 39, 42, and 43, wherein the human patient is administered about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab once every 3 weeks. 45. The method of claim 44, wherein the human patient is administered about 200 mg pembrolizumab once every three weeks. 41. The method of claim 40, wherein the human patient is administered about 240 mg or about 3 mg/kg nivolumab once every two weeks or about 480 mg nivolumab once every four weeks. 42. The method of claim 41, wherein the human patient is administered about 350 mg cemiplimab once every three weeks. 44. The method of any one of claims 39-43, wherein the human patient is administered about 100 mg to about 500 mg of the TIGIT antagonist once every 3 weeks. 49. The method of claim 48, wherein the human patient is administered about 50, about 75, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, or about 300 mg of the TIGIT antagonist once every three weeks. Method of administering once. 50. The method of claim 49, wherein the human patient is administered about 200 mg of the TIGIT antagonist once every three weeks. 44. The method of any one of claims 39-43, wherein the human patient is administered about 400 mg of the TIGIT antagonist once every 6 weeks. 52. The method of any one of claims 1-5 and 25-51, wherein the human patient is administered a total of about 3000 mg/m ² to about 4000 mg/m ² 5-fluorouracil per 3-week cycle. How to do it. 53. The method of claim 52, wherein the human patient is administered about 4000 mg/m ² 5-fluorouracil per 3-week cycle. 54. The method of claim 53, wherein the human patient is administered about 800 or about 1000 mg/m ² 5-fluorouracil per day. 53. The method of claim 52, wherein the human patient is administered a total of about 3000 mg/m ² 5-fluorouracil per 3 week cycle. 56. The method of claim 55, wherein the human patient is administered about 600 mg/m ² 5-fluorouracil per day. The method of any one of claims 1 to 5 and 25 to 55, wherein the human patient is administered about 40 mg/m ² to about 100 mg/m ² cisplatin once every 3 weeks. . 58. The method of claim 57, wherein the human patient is administered about 80 mg/m ² cisplatin once every 3 weeks. 58. The method of claim 57, wherein the human patient is administered about 60 mg/m ² cisplatin once every 3 weeks. For human patients requiring treatment for esophageal cancer
(a) about 200 mg pembrolizumab;
(b) about 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;
(c) a total of about 3000 mg/m ² or 4000 mg/m ² of 5-fluorouracil represented by formula (I) per cycle; and
(d) about 60 mg/m ² or 80 mg/m ² of cisplatin represented by formula (II)
A method of treating esophageal cancer comprising administering a therapeutic combination comprising. 61. The method of claim 60, wherein each of (a), (b) and (d) is administered once every three weeks. 62. The method of claim 60 or 61, wherein 5-fluorouracil is administered 5 times every 3 weeks. The method according to any one of claims 60 to 62, wherein (a) and (b) are administered on the same day, and (a) and (b) are administered sequentially or simultaneously. 64. The method of claim 63, wherein (a) and (b) are co-formulated. 64. The method of claim 63, wherein (a) and (b) are in a fixed dose combination. 66. The method of any one of claims 60-65, wherein the esophageal cancer is advanced esophageal cancer. 66. The method of any one of claims 60-65, wherein the esophageal cancer is metastatic esophageal cancer. 66. The method of any one of claims 60-65, wherein the esophageal cancer is locally advanced and unresectable. 66. The method of any one of claims 60-65, wherein the esophageal cancer is metastatic adenocarcinoma. 66. The method of any one of claims 60-65, wherein the esophageal cancer is squamous cell carcinoma of the esophagus (ESCC). An effective amount for human patients in need of cancer treatment.
(a) TIGIT antagonist;
(b) PD-1 antagonist; and
(c) paclitaxel represented by formula (III) or a pharmaceutically acceptable salt thereof

A method of treating cancer comprising administering a therapeutic combination comprising. 72. The method of claim 71, wherein the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, and triple negative breast cancer (TNBC). 73. The method of claim 72, wherein the cancer is TNBC. 74. The method of claim 73, wherein the TNBC is recurrent and unresectable. 74. The method of claim 73, wherein the TNBC is metastatic TNBC. effective amount
(a) TIGIT antagonist;
(b) PD-1 antagonist; and
(c) paclitaxel represented by formula (III) or a pharmaceutically acceptable salt thereof
Kit containing . 77. The kit of claim 76, further comprising instructions for administering the TIGIT antagonist, PD-1 antagonist, and paclitaxel to a human patient in need thereof. Use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination is administered in an effective amount.
(a) TIGIT antagonist;
(b) PD-1 antagonist; and
(c) paclitaxel represented by formula (III) or a pharmaceutically acceptable salt thereof
Uses that include. 79. Use according to claim 78, wherein the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, and triple negative breast cancer (TNBC). 79. Use according to claim 79, wherein the cancer is TNBC. 81. Use according to claim 80, wherein the TNBC is recurrent and unresectable. 81. Use according to claim 80, wherein the TNBC is metastatic TNBC. 83. The method, kit or use according to any one of claims 71 to 82, wherein the PD-1 antagonist and the TIGIT antagonist are in a fixed dose combination. 83. The method, kit or use according to any one of claims 71 to 82, wherein the PD-1 antagonist and the TIGIT antagonist are formulated separately. 83. The method, kit or use according to any one of claims 71 to 82, wherein the PD-1 antagonist and the TIGIT antagonist are co-formulated. 84. The method, kit or use of any one of claims 71 to 83, wherein the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen binding fragment thereof. 84. The method, kit or use according to any one of claims 71 to 83, wherein the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or antigen binding fragment thereof. 87. The method, kit, or use of claim 86, wherein the anti-human PD-1 monoclonal antibody is a humanized antibody. 87. The method, kit, or use of claim 86, wherein the anti-human PD-1 monoclonal antibody is a human antibody. 89. The method, kit or use of any one of claims 71 to 89, wherein the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen binding fragment thereof. 91. The method, kit, or use of claim 90, wherein the anti-human TIGIT monoclonal antibody is a humanized antibody. 91. The method, kit, or use of claim 90, wherein the anti-human TIGIT monoclonal antibody is a human antibody. 87. The method, kit or use of claim 86, wherein the anti-human PD-1 monoclonal antibody is pembrolizumab. 87. The method, kit or use of claim 86, wherein the anti-human PD-1 monoclonal antibody is nivolumab. 87. The method, kit or use of claim 86, wherein the anti-human PD-1 monoclonal antibody is cemiplimab. 91. The method of claim 90, wherein the anti-human TIGIT monoclonal antibody or antigen binding fragment thereof comprises three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: 112 CDRL2 comprising the amino acid sequence and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 154 A method, kit or use comprising a CDRH2 comprising an amino acid sequence as set forth and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 110. 97. The method of claim 96, wherein the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof has a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. A method, kit, or use comprising a light chain variable region comprising: 98. The method of claim 97, wherein the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof comprises or consists of a light chain as set forth in SEQ ID NO: 294 and an amino acid sequence as set forth in SEQ ID NO: 295. A method, kit or use comprising a heavy chain comprising or consisting of. The method according to any one of claims 71 to 83,
(a) the PD-1 antagonist is pembrolizumab;
(b) the TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and SEQ ID NO: Comprising a CDRH3 comprising the amino acid sequence as set forth in 110
Method, kit or use. The method according to any one of claims 71 to 83,
(a) the PD-1 antagonist is nivolumab;
(b) the TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and SEQ ID NO: Comprising a CDRH3 comprising the amino acid sequence as set forth in 110
Method, kit or use. The method according to any one of claims 71 to 83,
(a) the PD-1 antagonist is cemiplimab;
(b) the TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and SEQ ID NO: Comprising a CDRH3 comprising the amino acid sequence as set forth in 110
Method, kit or use. 102. The method of any one of claims 99-101, wherein the TIGIT antagonist comprises a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 152. A method, kit, or use comprising a variable region. 103. The method of claim 103, wherein the TIGIT antagonist comprises a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 294 and a heavy chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 295. method, kit, or use. 104. The method of any one of claims 99, 102, and 103, wherein the human patient is administered about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab once every 3 weeks. 105. The method of claim 104, wherein the human patient is administered about 200 mg pembrolizumab once every 3 weeks. 101. The method of claim 100, wherein the human patient is administered about 240 mg or about 3 mg/kg nivolumab once every two weeks or about 480 mg nivolumab once every four weeks. 102. The method of claim 101, wherein the human patient is administered about 350 mg cemiplimab once every three weeks. 104. The method of any one of claims 99-103, wherein the human patient is administered about 100 mg to about 500 mg of the TIGIT antagonist once every 3 weeks. 109. The method of claim 108, wherein the human patient is administered about 50, about 75, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, or about 300 mg of the TIGIT antagonist once every 3 weeks. Method of administering once. 109. The method of claim 109, wherein the human patient is administered about 200 mg of the TIGIT antagonist once every three weeks. 111. The method of any one of claims 71-75 and 83-110, wherein the human patient is administered about 70 mg/m ² to about 100 mg/m ² paclitaxel once weekly. 112. The method of claim 111, wherein the human patient is administered about 90 mg/m ² paclitaxel once weekly. 112. The method of claim 111, wherein the human patient is administered about 80 mg/m ² paclitaxel once weekly. For human patients requiring treatment for TNBC
(a) about 200 mg pembrolizumab;
(b) about 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110; and
(c) about 80 mg/m ² or 90 mg/m ² of paclitaxel represented by formula (III)
A method of treating TNBC comprising administering a therapeutic combination comprising. 115. The method of claim 114, wherein each of (a) and (b) is administered once every three weeks. 116. The method of claim 114 or 115, wherein (c) is administered once weekly. The method according to any one of claims 114 to 116, wherein (a) and (b) are administered on the same day, and (a) and (b) are administered sequentially or simultaneously. 118. The method of any one of claims 114-117, wherein the TNBC is recurrent unresectable. 118. The method of any one of claims 114-117, wherein the TNBC is metastatic. 117. The method of any one of claims 114-116, wherein (a) and (b) are co-formulated. 117. The method of any one of claims 114-116, wherein (a) and (b) are in a fixed dose combination. An effective amount for human patients in need of cancer treatment.
(a) TIGIT antagonist;
(b) PD-1 antagonist;
(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and

(d) Cisplatin represented by formula (II)

A method of treating cancer comprising administering a therapeutic combination comprising. 123. The method of claim 122, wherein the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, and triple negative breast cancer (TNBC). 124. The method of claim 123, wherein the cancer is biliary tract cancer. The method of claim 124, wherein the biliary tract cancer is metastatic biliary tract cancer. 125. The method of claim 124, wherein the esophageal cancer is locally recurrent and unresectable. effective amount
(a) TIGIT antagonist;
(b) PD-1 antagonist;
(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and
(d) Cisplatin represented by formula (II)
Kit containing . 128. The kit of claim 127, further comprising instructions for administering the TIGIT antagonist, PD-1 antagonist, gemcitabine, and cisplatin to a human patient in need thereof. Use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination is administered in an effective amount.
(a) TIGIT antagonist;
(b) PD-1 antagonist;
(c) gemcitabine or a pharmaceutically acceptable salt thereof represented by formula (IV); and
(d) Cisplatin represented by formula (II)
Uses that include. 129. Use according to claim 129, wherein the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, and triple negative breast cancer (TNBC). The use according to claim 130, wherein the cancer is biliary tract cancer. The use according to claim 131, wherein the biliary tract cancer is metastatic biliary tract cancer. Use according to claim 131, wherein the biliary tract cancer is locally advanced and unresectable. 134. The method, kit or use of any one of claims 122-133, wherein the PD-1 antagonist and the TIGIT antagonist are formulated separately. 134. The method, kit or use of any one of claims 122-133, wherein the PD-1 antagonist and the TIGIT antagonist are in a fixed dose combination. 134. The method, kit or use of any one of claims 122-133, wherein the PD-1 antagonist and the TIGIT antagonist are co-formulated. 137. The method, kit or use of any one of claims 122 to 136, wherein the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen binding fragment thereof. 137. The method, kit or use of any one of claims 122 to 136, wherein the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or antigen binding fragment thereof. 138. The method, kit, or use of claim 137, wherein the anti-human PD-1 monoclonal antibody is a humanized antibody. 138. The method, kit, or use of claim 137, wherein the anti-human PD-1 monoclonal antibody is a human antibody. 141. The method, kit or use of any one of claims 122-140, wherein the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof. 142. The method, kit, or use of claim 141, wherein the anti-human TIGIT monoclonal antibody is a humanized antibody. 142. The method, kit, or use of claim 141, wherein the anti-human TIGIT monoclonal antibody is a human antibody. 138. The method, kit, or use of claim 137, wherein the anti-human PD-1 monoclonal antibody is pembrolizumab. 138. The method, kit, or use of claim 137, wherein the anti-human PD-1 monoclonal antibody is nivolumab. 138. The method, kit, or use of claim 137, wherein the anti-human PD-1 monoclonal antibody is cemiplimab. 138. The method of claim 137, wherein the anti-human TIGIT monoclonal antibody or antigen binding fragment thereof comprises three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: 112 CDRL2 comprising the amino acid sequence and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 154 A method, kit or use comprising a CDRH2 comprising an amino acid sequence as set forth and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 110. 138. The method of claim 137, wherein the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof has a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. A method, kit, or use comprising a light chain variable region comprising: 138. The method of claim 137, wherein the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 294 and a light chain and an amino acid sequence as set forth in SEQ ID NO: 295. A method, kit or use comprising a heavy chain comprising or consisting of. The method according to any one of claims 122 to 143,
(a) the PD-1 antagonist is pembrolizumab;
(b) the TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and SEQ ID NO: Comprising a CDRH3 comprising the amino acid sequence as set forth in 110
Method, kit or use. The method according to any one of claims 122 to 143,
(a) the PD-1 antagonist is nivolumab;
(b) the TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and SEQ ID NO: Comprising a CDRH3 comprising the amino acid sequence as set forth in 110
Method, kit or use. The method according to any one of claims 122 to 143,
(a) the PD-1 antagonist is cemiplimab;
(b) the TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and SEQ ID NO: Comprising a CDRH3 comprising the amino acid sequence as set forth in 110
Method, kit or use. 153. The method of any one of claims 150-152, wherein the TIGIT antagonist comprises a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 152. A method, kit, or use comprising a variable region. 153. The method of claim 153, wherein the TIGIT antagonist comprises a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 294 and a heavy chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 295. method, kit, or use. 155. The method of any one of claims 150, 153, and 154, wherein the human patient is administered about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab once every 3 weeks. 151. The method of claim 150, wherein the human patient is administered about 200 mg pembrolizumab once every 3 weeks. 152. The method of claim 151, wherein the human patient is administered about 240 mg or about 3 mg/kg nivolumab once every two weeks or about 480 mg nivolumab once every four weeks. 153. The method of claim 152, wherein the human patient is administered about 350 mg cemiplimab once every 3 weeks. 159. The method of any one of claims 150-158, wherein the human patient is administered about 100 mg to about 500 mg of the TIGIT antagonist once every 3 weeks. 159. The method of claim 159, wherein the human patient is administered about 50, about 75, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, or about 300 mg of the TIGIT antagonist once every 3 weeks. Method of administering once. 161. The method of claim 160, wherein the human patient is administered about 200 mg of the TIGIT antagonist once every three weeks. 159. The method of any one of claims 150-158, wherein the human patient is administered about 400 mg of the TIGIT antagonist once every 6 weeks. The method of any one of claims 122 to 126 and 134 to 162, wherein the human patient is administered about 800 mg/m ² to about 1000 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof for 3 weeks. A method of administering once each time. The method of claim 163, wherein about 1000 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof is administered to the human patient once every 3 weeks. The method of claim 163, wherein about 800 mg/m ² gemcitabine or a pharmaceutically acceptable salt thereof is administered to the human patient once every 3 weeks. The method of any one of claims 122-126 and 134-165, wherein the human patient is administered about 20 mg/m ² to about 25 mg/m ² cisplatin once every 3 weeks. . 167. The method of claim 166, wherein the human patient is administered about 25 mg/m ² cisplatin once every 3 weeks. 167. The method of claim 166, wherein the human patient is administered about 20 mg/m ² cisplatin once every 3 weeks. For human patients requiring treatment for biliary tract cancer
(a) about 200 mg pembrolizumab;
(b) about 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;
(c) about 800 mg/m ² or 1000 mg/m ² of gemcitabine represented by formula (IV) or a pharmaceutically acceptable salt thereof; and
(d) about 60 mg/m ² or 80 mg/m ² of cisplatin represented by formula (II)
A method of treating biliary tract cancer, comprising administering a therapeutic combination comprising. 169. The method of claim 169, wherein each of (a), (b), (c) and (d) is administered once every three weeks. The method of claim 169 or 170, wherein (a) and (b) are administered on the same day, and (a) and (b) are administered sequentially or simultaneously. 172. The method of claim 171, wherein (a) and (b) are co-formulated. 172. The method of claim 171, wherein (a) and (b) are in a fixed dose combination. The method of any one of claims 169 to 173, wherein the biliary tract cancer is metastatic biliary tract cancer. 174. The method of any one of claims 169-173, wherein the biliary tract cancer is locally recurrent and unresectable. An effective amount for human patients in need of cancer treatment.
(a) TIGIT antagonist;
(b) PD-1 antagonist;
(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and

(d) Oxaliplatin represented by formula (VI)

A method of treating cancer comprising administering a therapeutic combination comprising. 177. The method of claim 176, wherein the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, triple negative breast cancer (TNBC), and gastric cancer. 178. The method of claim 177, wherein the cancer is stomach cancer. 179. The method of claim 178, wherein the gastric cancer is advanced or GEJ adenocarcinoma. 179. The method of claim 178, wherein the gastric cancer is HER2 negative. 179. The method of claim 178, wherein the gastric cancer has not been previously treated. effective amount
(a) TIGIT antagonist;
(b) PD-1 antagonist;
(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and
(d) Oxaliplatin represented by formula (VI)
Kit containing . 184. The kit of claim 183, further comprising instructions for administering the TIGIT antagonist, PD-1 antagonist, capecitabine, and oxaliplatin to a human patient in need thereof. Use of a therapeutic combination for treating cancer in a human patient in need thereof, wherein the therapeutic combination is administered in an effective amount.
(a) TIGIT antagonist;
(b) PD-1 antagonist;
(c) capecitabine or a pharmaceutically acceptable salt thereof represented by formula (V); and
(d) Oxaliplatin represented by formula (VI)
Uses that include. 185. The use of claim 184, wherein the cancer is selected from the group consisting of endometrial cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer (HNSCC), biliary tract cancer, esophageal cancer, triple negative breast cancer (TNBC), and gastric cancer. The use of claim 185, wherein the cancer is stomach cancer. The use of claim 186, wherein the gastric cancer is advanced or GEJ adenocarcinoma. The use of claim 186, wherein the gastric cancer is HER2 negative. 187. Use according to claim 186, wherein the gastric cancer is not previously treated. 189. The method, kit or use of any one of claims 176-189, wherein the PD-1 antagonist and the TIGIT antagonist are formulated separately. 189. The method, kit or use of any one of claims 176-189, wherein the PD-1 antagonist and the TIGIT antagonist are in a fixed dose combination. 189. The method, kit or use of any one of claims 176-189, wherein the PD-1 antagonist and the TIGIT antagonist are co-formulated. 193. The method, kit or use of any one of claims 176 to 192, wherein the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen binding fragment thereof. 193. The method, kit or use of any one of claims 176 to 192, wherein the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or antigen binding fragment thereof. 194. The method, kit, or use of claim 193, wherein the anti-human PD-1 monoclonal antibody is a humanized antibody. 194. The method, kit, or use of claim 193, wherein the anti-human PD-1 monoclonal antibody is a human antibody. 197. The method, kit or use of any one of claims 176 to 196, wherein the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen binding fragment thereof. 198. The method, kit, or use of claim 197, wherein the anti-human TIGIT monoclonal antibody is a humanized antibody. 198. The method, kit, or use of claim 197, wherein the anti-human TIGIT monoclonal antibody is a human antibody. 197. The method, kit, or use of claim 196, wherein the anti-human PD-1 monoclonal antibody is pembrolizumab. 197. The method, kit, or use of claim 196, wherein the anti-human PD-1 monoclonal antibody is nivolumab. 197. The method, kit, or use of claim 196, wherein the anti-human PD-1 monoclonal antibody is cemiplimab. 193. The method of claim 193, wherein the anti-human TIGIT monoclonal antibody or antigen binding fragment thereof comprises three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, as set forth in SEQ ID NO: 112 CDRL2 comprising the amino acid sequence and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 154 A method, kit or use comprising a CDRH2 comprising an amino acid sequence as set forth and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 110. 193. The method of claim 193, wherein the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof has a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. A method, kit, or use comprising a light chain variable region comprising: 193. The method of claim 193, wherein the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 294 and a light chain and an amino acid sequence as set forth in SEQ ID NO: 295. A method, kit or use comprising a heavy chain comprising or consisting of. The method according to any one of claims 176 to 192,
(a) the PD-1 antagonist is pembrolizumab;
(b) the TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and SEQ ID NO: Comprising a CDRH3 comprising the amino acid sequence as set forth in 110
Method, kit or use. The method according to any one of claims 176 to 192,
(a) the PD-1 antagonist is nivolumab;
(b) the TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and SEQ ID NO: Comprising a CDRH3 comprising the amino acid sequence as set forth in 110
Method, kit or use. The method according to any one of claims 176 to 192,
(a) the PD-1 antagonist is cemiplimab;
(b) the TIGIT antagonist has three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 154 and SEQ ID NO: Comprising a CDRH3 comprising the amino acid sequence as set forth in 110
Method, kit or use. 208. The method of any one of claims 206-208, wherein the TIGIT antagonist comprises a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 152. A method, kit, or use comprising a variable region. 209. The method of claim 209, wherein the TIGIT antagonist comprises a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 294 and a heavy chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 295. method, kit, or use. 211. The method of any one of claims 206, 209, and 210, wherein the human patient is administered about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab once every 3 weeks. 212. The method of claim 211, wherein the human patient is administered about 200 mg pembrolizumab once every 3 weeks. 208. The method of claim 207, wherein the human patient is administered about 240 mg or about 3 mg/kg nivolumab once every two weeks or about 480 mg nivolumab once every four weeks. 209. The method of claim 208, wherein the human patient is administered about 350 mg cemiplimab once every 3 weeks. 215. The method of any one of claims 176-214, wherein the human patient is administered about 100 mg to about 500 mg of the TIGIT antagonist once every 3 weeks. The method of claim 215, wherein the human patient is administered about 50, about 75, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, or about 300 mg of the TIGIT antagonist once every 3 weeks. Method of administering once. 217. The method of claim 216, wherein the human patient is administered about 200 mg of the TIGIT antagonist once every three weeks. 215. The method of any one of claims 176-214, wherein the human patient is administered about 400 mg of the TIGIT antagonist once every 6 weeks. The method of any one of claims 176-181 and 190-218, wherein the human patient is administered about 500 mg/m ² to about 1500 mg/m ² capecitabine or a pharmaceutically acceptable salt thereof. Method of administering twice a day. 164. The method of claim 163, wherein the human patient is administered about 750 mg/m ² capecitabine or a pharmaceutically acceptable salt thereof twice daily. 164. The method of claim 163, wherein the human patient is administered about 1000 mg/m ² capecitabine or a pharmaceutically acceptable salt thereof twice daily. The method of any one of claims 176-181 and 190-221, wherein the human patient is administered about 80 mg/m ² to about 150 mg/m ² oxaliplatin once every 3 weeks. . 167. The method of claim 166, wherein the human patient is administered about 100 mg/m ² oxaliplatin once every 3 weeks. 167. The method of claim 166, wherein the human patient is administered about 130 mg/m ² oxaliplatin once every 3 weeks. An effective amount for human patients in need of treatment for gastric cancer.
(a) about 200 mg pembrolizumab;
(b) about 200 mg of three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 comprising the amino acid sequence as set forth in SEQ ID NO: 112 and SEQ ID NO: 113 CDRL3 comprising the amino acid sequence as set forth in and three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 comprising the amino acid sequence as set forth in SEQ ID NO: 154 and SEQ ID NO: Number: An anti-TIGIT antibody or antigen-binding fragment thereof comprising CDRH3 comprising the amino acid sequence as set forth in 110;
(c) about 750 mg/m ² or 1000 mg/m ² of capecitabine represented by formula (V) or a pharmaceutically acceptable salt thereof; and
(d) about 100 mg/m ² or 130 mg/m ² of oxaliplatin represented by formula (VI)
A method of treating gastric cancer comprising administering a therapeutic combination comprising. 227. The method of claim 226, wherein each of (a), (b), and (d) is administered once every three weeks, and (c) is administered twice daily. The method of claim 225 or 226, wherein (a) and (b) are administered on the same day, and (a) and (b) are administered sequentially or simultaneously. 227. The method of claim 227, wherein (a) and (b) are co-formulated. 227. The method of claim 227, wherein (a) and (b) are in a fixed dose combination. 229. The method of any one of claims 225-229, wherein the gastric cancer is advanced or GEJ adenocarcinoma. 229. The method of any one of claims 225-229, wherein the gastric cancer is HER2 negative. 229. The method of any one of claims 225-229, wherein the gastric cancer has not been previously treated. A composition or kit comprising a PD-1 antagonist and/or a TIGIT antagonist and a hyaluronan degrading enzyme. 234. The composition or kit of claim 233, comprising a PD-1 antagonist and a TIGIT antagonist, and further comprising 5-fluorouracil and cisplatin. 234. The composition or kit of claim 233, comprising a PD-1 antagonist and a TIGIT antagonist, and further comprising paclitaxel or a pharmaceutically acceptable salt thereof. The composition or kit of claim 233, comprising a PD-1 antagonist and a TIGIT antagonist, and further comprising gemcitabine or a pharmaceutically acceptable salt thereof and cisplatin. 234. The composition or kit of claim 233, comprising a PD-1 antagonist and a TIGIT antagonist, and further comprising capecitabine or a pharmaceutically acceptable salt thereof and oxaliplatin. A method comprising administering a PD-1 antagonist and/or a TIGIT antagonist and a hyaluronan degrading enzyme. 239. The method of claim 238, comprising administering a PD-1 antagonist and a TIGIT antagonist, and further comprising administering 5-fluorouracil and cisplatin. 239. The method of claim 238, comprising administering a PD-1 antagonist and a TIGIT antagonist, and further comprising administering paclitaxel or a pharmaceutically acceptable salt thereof. 239. The method of claim 238, comprising administering a PD-1 antagonist and a TIGIT antagonist, and further comprising administering gemcitabine or a pharmaceutically acceptable salt thereof and cisplatin. 239. The method of claim 238, comprising administering a PD-1 antagonist and a TIGIT antagonist, and further comprising administering capecitabine or a pharmaceutically acceptable salt thereof and oxaliplatin. 243. The composition or kit of any one of claims 233-242, wherein the PD-1 antagonist and the TIGIT antagonist are formulated separately. A method comprising administering an antagonist. 243. The composition or kit comprising a PD-1 antagonist and a TIGIT antagonist, or PD-1 according to any one of claims 233-242, wherein the PD-1 antagonist and the TIGIT antagonist are in a fixed dose combination. A method comprising administering an antagonist and a TIGIT antagonist. 243. The composition or kit comprising a PD-1 antagonist and a TIGIT antagonist, or a PD-1 antagonist and a TIGIT according to any one of claims 233-242, wherein the PD-1 antagonist and the TIGIT antagonist are co-formulated. A method comprising administering an antagonist. 246. The composition or kit of any one of claims 233 to 245, wherein the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, or a method comprising administering a PD-1 antagonist and a TIGIT antagonist. 246. The composition or kit of any one of claims 233 to 245, wherein the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or antigen-binding fragment thereof, comprising a PD-1 antagonist and a TIGIT antagonist, or a method comprising administering a PD-1 antagonist and a TIGIT antagonist. 247. The composition, kit, or method of claim 246, wherein the anti-human PD-1 monoclonal antibody is a humanized antibody. 247. The composition, kit, or method of claim 246, wherein the anti-human PD-1 monoclonal antibody is a human antibody. 249. The composition or kit comprising a PD-1 antagonist and a TIGIT antagonist, or PD-1 according to any one of claims 233 to 249, wherein the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof. A method comprising administering an antagonist and a TIGIT antagonist. 251. The composition, kit, or method of claim 250, wherein the anti-human TIGIT monoclonal antibody is a humanized antibody. 251. The composition, kit, or method of claim 250, wherein the anti-human TIGIT monoclonal antibody is a human antibody. 247. The composition, kit, or method of claim 246, wherein the anti-human PD-1 monoclonal antibody is pembrolizumab. 247. The composition, kit, or method of claim 246, wherein the anti-human PD-1 monoclonal antibody is nivolumab. 247. The composition, kit, or method of claim 246, wherein the anti-human PD-1 monoclonal antibody is cemiplimab. 251. The method of claim 250, wherein the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof comprises three light chain CDRs: CDRL1 comprising the amino acid sequence as set forth in SEQ ID NO: 111, SEQ ID NO: 112 CDRL2 comprising the amino acid sequence and CDRL3 comprising the amino acid sequence as set forth in SEQ ID NO: 113 and the three heavy chain CDRs: CDRH1 comprising the amino acid sequence as set forth in SEQ ID NO: 108, SEQ ID NO: 154 A composition, kit or method comprising a CDRH2 comprising an amino acid sequence as set forth and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 110. 251. The method of claim 250, wherein the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof has a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and an amino acid sequence as set forth in SEQ ID NO: 152. A composition, kit, or method comprising a light chain variable region comprising: 251. The method of claim 250, wherein the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 294 and a light chain and an amino acid sequence as set forth in SEQ ID NO: 295. A composition, kit or method comprising a heavy chain comprising or consisting of.

Images