Treatment of tumors by means of Anti-tigit antibody in combination with Anti-PD-1 antibody

Abstract

Disclosed in the present invention is the use of an anti-TIGIT antibody or an antigen-binding fragment and an anti-PD-1 antibody or an antigen-binding fragment in the preparation of drugs for treating tumors.

Description

Combination therapy of anti-TIGIT antibody and anti-PD-1 antibody for tumor TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical treatment, in particular to the use or method of anti-TIGIT antibody and anti-PD-1 antibody for treating tumor patients. BACKGROUND

[0002] Tumor is one of the most serious diseases threatening human health and social development. For example, gastric cancer is one of the most common malignant tumors in the world, and is the third leading cause of death from cancer worldwide, and the fifth most common malignant tumor in the world. Gastric cancer is the third leading cause of cancer death worldwide, with about 769,000 patients dying from gastric cancer worldwide each year. The 5-year survival rate of advanced or metastatic gastric cancer is about 5% to 20%, and the median overall survival of patients receiving simple chemotherapy is only about 1 year. However, for a long time, the first-line treatment for gastric cancer mainly relies on surgery or radiotherapy, and the prognosis of patients with locally advanced or metastatic gastric cancer who cannot be surgically resected is poor, and there is a great unmet clinical need.

[0003] However, the development of drugs or treatment methods for treating tumors still faces great challenges. There is still a need in the art to develop clinically effective, safer drugs or treatment methods for treating or prolonging the lives of tumor patients. SUMMARY

[0004] The present application provides a method or use for treating tumor, comprising: administering to a patient in need thereof an effective amount of anti-TIGIT antibody or antigen binding fragment and anti-PD-1 antibody or antigen binding fragment.

[0005] In one aspect, the present application provides the use of anti-TIGIT antibody or antigen binding fragment and anti-PD-1 antibody or antigen binding fragment in the preparation of a medicament for treating tumor. In another aspect, the present application provides the use of anti-TIGIT antibody or antigen binding fragment in the preparation of a medicament for treating tumor in combination with anti-PD-1 antibody or antigen binding fragment. In another aspect, the present application provides the use of anti-PD-1 antibody or antigen binding fragment in the preparation of a medicament for treating tumor in combination with anti-TIGIT antibody or antigen binding fragment.

[0006] In one aspect, the present application provides the use of anti-TIGIT antibody or antigen binding fragment and anti-PD-1 antibody or antigen binding fragment in the preparation of a medicament for treating tumor. In another aspect, the present application provides the use of anti-TIGIT antibody or antigen binding fragment in the preparation of a medicament for treating tumor in combination with anti-PD-1 antibody or antigen binding fragment. In another aspect, the present application provides the use of anti-PD-1 antibody or antigen binding fragment in the preparation of a medicament for treating tumor in combination with anti-TIGIT antibody or antigen binding fragment.

[0007] In one aspect, the present application provides a combination medicament comprising an anti-TIGIT antibody or antigen-binding fragment and an anti-PD-1 antibody or antigen-binding fragment. In another aspect, the present application provides a pharmaceutical composition comprising an anti-TIGIT antibody or antigen-binding fragment and an anti-PD-1 antibody or antigen-binding fragment.

[0008] In one aspect, the present application also provides a kit comprising an anti-TIGIT antibody or antigen-binding fragment and an anti-PD-1 antibody or antigen-binding fragment. In some embodiments, the kit further comprises an instruction.

[0009] In some embodiments, the tumor comprises, but is not limited to, a hematological cancer, a solid tumor. In some embodiments, the hematological cancer comprises, but is not limited to, leukemia, lymphoma and myeloma. In some embodiments, the leukemia comprises acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML) and myeloproliferative disorder / tumor (MPDS). In some embodiments, the lymphoma comprises Hodgkin lymphoma, indolent and aggressive non-Hodgkin lymphoma, Burkitt lymphoma and follicular lymphoma (small cell and large cell). In some embodiments, the myeloma comprises multiple myeloma (MM), giant cell myeloma, heavy chain myeloma and light chain or Bence Jones myeloma. In some embodiments, the solid tumor comprises breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, colon cancer, lung cancer (such as non-small cell lung cancer (NSCLC)), head and neck cancer, bladder cancer, esophageal cancer, liver cancer (such as hepatocellular carcinoma (HCC)), kidney cancer and gastric cancer.

[0010] In some embodiments, the tumor is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myeloproliferative disorder / tumor, Hodgkin lymphoma, indolent and aggressive non-Hodgkin lymphoma, Burkitt lymphoma, follicular lymphoma, multiple myeloma, giant cell myeloma, heavy chain myeloma, light chain or Bence Jones myeloma, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, colon cancer, lung cancer, head and neck cancer, bladder cancer, esophageal cancer, liver cancer, kidney cancer and gastric cancer.

[0011] In some embodiments, the tumor is selected from the group consisting of gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer and hepatocellular carcinoma.

[0012] In some embodiments, the tumor is an advanced solid tumor.

[0013] In some embodiments, the tumor patient comprises a histologically or cytologically confirmed advanced gastric cancer, gastroesophageal junction cancer and esophageal cancer patient who has failed, is intolerant to, or has declined standard therapy. In some embodiments, the standard therapy refers to the standard therapy regimen recommended by NCCN guidelines and CSCO diagnosis and treatment guidelines for the tumor.

[0014] In some embodiments, the tumor patient comprises a locally advanced unresectable or metastatic gastric cancer, gastroesophageal junction cancer and esophageal cancer patient who has never received systemic therapy. In some embodiments, the patient has a PD-L1 combined positive score (CPS) ≥5 and the tumor tissue is HER2 negative.

[0015] In some embodiments, the tumor patient comprises a histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer patient (referring to the eighth edition of the tumor staging manual of the American Joint Committee on Cancer (AJCC)). In some embodiments, the patient can be:

[0016] a. who has progressed after first-line treatment with PD-1 / PD-L1 antibodies and platinum-containing doublet chemotherapy or who is ineligible for standard therapy; or

[0017] b. who has a driver gene mutation and has failed targeted therapy and chemotherapy or is ineligible for standard therapy.

[0018] In some embodiments, the tumor patient comprises a histologically or clinically diagnosed advanced hepatocellular carcinoma patient who has progressed after treatment with PD-1 / PD-L1 antibodies and targeted drug systems or is ineligible for standard therapy. In some embodiments, the patient is a liver function (Child-Pugh) grade A or better B (≤7 points).

[0019] In some embodiments, the anti-TIGIT antibody or antigen binding fragment is an anti-TIGIT antibody or antigen binding fragment disclosed in WO2021 / 043206.

[0020] In some embodiments, the anti-TIGIT antibody or antigen binding fragment comprises at least one of HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, HCDR3 shown in SEQ ID NO: 3, LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6.

[0021] In some embodiments, the anti-TIGIT antibody or antigen binding fragment comprises a HCDR1 set forth in SEQ ID NO: 1, a HCDR2 set forth in SEQ ID NO: 2, a HCDR3 set forth in SEQ ID NO: 3, a LCDR1 set forth in SEQ ID NO: 4, a LCDR2 set forth in SEQ ID NO: 5, and a LCDR3 set forth in SEQ ID NO: 6.

[0022] In some embodiments, the heavy chain variable region of the anti-TIGIT antibody or antigen binding fragment comprises the amino acid sequence set forth in SEQ ID NO: 7, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence set forth in SEQ ID NO: 7, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO: 7.

[0023] In some embodiments, the light chain variable region of the anti-TIGIT antibody or antigen binding fragment comprises the amino acid sequence set forth in SEQ ID NO: 8, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence set forth in SEQ ID NO: 8, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO: 8.

[0024] In some embodiments, the heavy chain variable region of the anti-TIGIT antibody or antigen binding fragment comprises the amino acid sequence set forth in SEQ ID NO: 7, and / or the light chain variable region of the anti-TIGIT antibody or antigen binding fragment comprises the amino acid sequence set forth in SEQ ID NO: 8.

[0025] In some embodiments, the heavy chain of the anti-TIGIT antibody comprises the amino acid sequence set forth in SEQ ID NO: 9, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence set forth in SEQ ID NO: 9, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO: 9.

[0026] In some embodiments, the heavy chain of the anti-TIGIT antibody comprises the amino acid sequence set forth in SEQ ID NO: 9, and / or the light chain of the antibody comprises the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the anti-TIGIT antibody contains two identical sequences of heavy chain and two identical sequences of light chain, respectively.

[0027] In some embodiments, the heavy chain of the anti-TIGIT antibody comprises the amino acid sequence set forth in SEQ ID NO: 9, and / or the light chain of the antibody comprises the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the anti-TIGIT antibody contains two identical sequences of heavy chain and two identical sequences of light chain, respectively.

[0028] In some embodiments, the anti-TIGIT antibody is antibody h10D8OF.

[0029] In some embodiments, the anti-PD-1 antibody or antigen binding fragment is nivolumab (e.g., Opdivo or OPDIVO or a biosimilar thereof), pembrolizumab (e.g., Keytruda or a biosimilar thereof), camrelizumab (e.g., Hanmi or a biosimilar thereof), sintilimab (e.g., or a biosimilar thereof), toripalimab (e.g., Tuoyi or a biosimilar thereof), or tislelizumab (e.g., or a biosimilar thereof).

[0030] In some embodiments, the anti-PD-1 antibody or antigen binding fragment is an anti-PD-1 antibody or antigen binding fragment disclosed in WO2020 / 207432.

[0031] In some embodiments, the anti-PD-1 antibody or antigen binding fragment comprises one or more of HCDR1 set forth in SEQ ID NO: 11, HCDR2 set forth in SEQ ID NO: 12, HCDR3 set forth in SEQ ID NO: 13, LCDR1 set forth in SEQ ID NO: 14, LCDR2 set forth in SEQ ID NO: 15, and LCDR3 set forth in SEQ ID NO: 16.

[0032] In some embodiments, the anti-PD-1 antibody or antigen binding fragment comprises a HCDR1 set forth in SEQ ID NO: 11, a HCDR2 set forth in SEQ ID NO: 12, a HCDR3 set forth in SEQ ID NO: 13, a LCDR1 set forth in SEQ ID NO: 14, a LCDR2 set forth in SEQ ID NO: 15, and a LCDR3 set forth in SEQ ID NO: 16.

[0033] In some embodiments, the heavy chain variable region of the anti-PD-1 antibody or antigen binding fragment comprises the amino acid sequence set forth in SEQ ID NO: 17, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence set forth in SEQ ID NO: 17, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO: 17.

[0034] In some embodiments, the light chain variable region of the anti-PD-1 antibody or antigen binding fragment comprises the amino acid sequence set forth in SEQ ID NO: 18, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence set forth in SEQ ID NO: 18, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO: 18.

[0035] In some embodiments, the heavy chain variable region of the anti-PD-1 antibody or antigen binding fragment comprises the amino acid sequence set forth in SEQ ID NO: 17, and / or the light chain variable region of the anti-PD-1 antibody or antigen binding fragment comprises the amino acid sequence set forth in SEQ ID NO: 18.

[0036] In some embodiments, the heavy chain of the anti-PD-1 antibody comprises the amino acid sequence set forth in SEQ ID NO: 19, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence set forth in SEQ ID NO: 19, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO: 19.

[0037] In some embodiments, the heavy chain of the anti-PD-1 antibody comprises an amino acid sequence as set forth in SEQ ID NO: 19, and / or the light chain of the anti-PD-1 antibody comprises an amino acid sequence as set forth in SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody contains two identical heavy chains and two identical light chains, respectively.

[0038] In some embodiments, the heavy chain of the anti-PD-1 antibody comprises an amino acid sequence as set forth in SEQ ID NO: 19, and / or the light chain of the anti-PD-1 antibody comprises an amino acid sequence as set forth in SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody contains two identical heavy chains and two identical light chains, respectively.

[0039] In some embodiments, the anti-PD-1 antibody is Antibody A.

[0040] In some embodiments, the heavy chain of the anti-TIGIT antibody comprises an amino acid sequence as set forth in SEQ ID NO: 9 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 10, the heavy chain of the anti-PD-1 antibody comprises an amino acid sequence as set forth in SEQ ID NO: 19 and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 20, and the tumor is selected from the group consisting of gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular carcinoma.

[0041] In some embodiments, an effective amount refers to the amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual, or human by a researcher, veterinarian, medical doctor, or other clinician, which includes the treatment of a disease, such as a tumor.

[0042] In some embodiments, the anti-TIGIT antibody or antigen binding fragment is administered at a dose of about 0.01-1200 mg, about 0.01-1 mg, about 1-3 mg, about 1-5 mg, about 1-10 mg, about 3-10 mg, about 10-30 mg, about 10-50 mg, 10-100 mg, about 100-300 mg, about 100-500 mg, about 100-600 mg, about 300-600 mg, about 100-900 mg, about 600-900 mg, about 100-1000 mg, or about 1000-1200 mg per treatment cycle. In some embodiments, the anti-TIGIT antibody or antigen binding fragment is administered at a dose of about 0.01 mg, about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 30 mg, about 50 mg, about 100 mg, about 300 mg, about 500 mg, about 600 mg, about 900 mg, about 1000 mg, or about 1200 mg per treatment cycle, or a range between any two of these values (including endpoints) or any value therein. In some embodiments, the anti-TIGIT antibody or antigen binding fragment is administered at a dose of about 600 mg or about 900 mg per treatment cycle.

[0043] In some embodiments, the anti-TIGIT antibody or antigen binding fragment is administered at a dose of about 0.01 mg / kg-20 mg / kg, about 0.01 mg / kg-0.05 mg / kg, about 0.01 mg / kg-0.06 mg / kg, about 0.1 mg / kg-0.2 mg / kg, about 0.1 mg / kg-0.5 mg / kg, about 0.1 mg / kg-0.6 mg / kg, about 1 mg / kg-2 mg / kg, about 1 mg / kg-5 mg / kg, about 1 mg / kg-6 mg / kg, about 10 mg / kg-12 mg / kg, about 12 mg / kg-15 mg / kg, about 15 mg / kg-18 mg / kg, or about 18 mg / kg-20 mg / kg per treatment cycle. In some embodiments, the anti-TIGIT antibody or antigen binding fragment is administered at a dose of about 0.01 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 6 mg / kg, about 10 mg / kg, about 12 mg / kg, about 15 mg / kg, about 18 mg / kg, or about 20 mg / kg per treatment cycle, or a range between any two of these values (including endpoints) or any value therein. In some embodiments, the anti-TIGIT antibody or antigen binding fragment is administered at a dose of about 12 mg / kg or about 18 mg / kg per treatment cycle.

[0044] In some embodiments, a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values, inclusive of the endpoints, or any value therein. In some embodiments, the anti-TIGIT antibody or antigen binding fragment is administered once daily to once every 7 weeks. In some embodiments, the anti-TIGIT antibody or antigen binding fragment is administered once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, or once every 7 weeks.

[0045] In some embodiments, the anti-TIGIT antibody or antigen binding fragment is administered once daily to once every 7 weeks at a dose of about 0.01-1200 mg, about 0.01-1 mg, about 1-3 mg, about 1-5 mg, about 1-10 mg, about 3-10 mg, about 10-30 mg, about 10-50 mg, 10-100 mg, about 100-300 mg, about 100-500 mg, about 100-600 mg, about 300-600 mg, about 100-900 mg, about 600-900 mg, about 100-1000 mg, or about 1000-1200 mg. In some embodiments, the anti-TIGIT antibody or antigen binding fragment is administered once daily to once every 7 weeks at a dose of about 0.01 mg, about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 30 mg, about 50 mg, about 100 mg, about 300 mg, about 500 mg, about 600 mg, about 900 mg, about 1000 mg, or about 1200 mg, or a range between any two of these values, inclusive of the endpoints, or any value therein.

[0046] In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 0.01-1200 mg, about 0.01-1 mg, about 1-3 mg, about 1-5 mg, about 1-10 mg, about 3-10 mg, about 10-30 mg, about 10-50 mg, 10-100 mg, about 100-300 mg, about 100-500 mg, about 100-600 mg, about 300-600 mg, about 100-900 mg, about 600-900 mg, about 100-1000 mg, or about 1000-1200 mg. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 0.01 mg, about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 30 mg, about 50 mg, about 100 mg, about 300 mg, about 500 mg, about 600 mg, about 900 mg, about 1000 mg, or about 1200 mg, or a range between any two of these values, inclusive of the endpoints, or any value therein. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 600 mg or about 900 mg.

[0047] In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 0.01 mg / kg - 20 mg / kg, about 0.01 mg / kg - 0.05 mg / kg, about 0.01 mg / kg - 0.06 mg / kg, about 0.1 mg / kg - 0.2 mg / kg, about 0.1 mg / kg - 0.5 mg / kg, about 0.1 mg / kg - 0.6 mg / kg, about 1 mg / kg - 2 mg / kg, about 1 mg / kg - 5 mg / kg, about 1 mg / kg - 6 mg / kg, about 10 mg / kg - 12 mg / kg, about 12 mg / kg - 15 mg / kg, about 15 mg / kg - 18 mg / kg, or about 18 mg / kg - 20 mg / kg per dose. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 0.01 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 6 mg / kg, about 10 mg / kg, about 12 mg / kg, about 15 mg / kg, about 18 mg / kg, or about 20 mg / kg per dose, or a range between any two of these values, inclusive and endpoints, or any value therein. In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 12 mg / kg or about 18 mg / kg per dose.

[0048] In some embodiments, the anti-TIGIT antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 600 mg or about 900 mg, the anti-TIGIT antibody or antigen-binding fragment being antibody h10D8OF.

[0049] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 1-1000 mg, about 1-10 mg, about 1-50 mg, about 1-100 mg, about 1-200 mg, about 1-240 mg, about 1-300 mg, about 1-600 mg, about 100-300 mg, about 100-500 mg, about 100-600 mg, 100-900 mg, about 300-600 mg, about 300-900 mg, about 600-900 mg, or about 900-1000 mg per treatment cycle. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 240 mg, about 300 mg, about 500 mg, about 600 mg, about 900 mg, or about 1000 mg per treatment cycle, or a range between any two of these values (including the endpoints) or any value therein. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 300 mg per treatment cycle.

[0050] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 0.01 mg / kg-20 mg / kg, about 0.01 mg / kg-1 mg / kg, about 1 mg / kg-2 mg / kg, about 1 mg / kg-3 mg / kg, about 1 mg / kg-5 mg / kg, about 1 mg / kg-6 mg / kg, about 1 mg / kg-10 mg / kg, about 2 mg / kg-6 mg / kg, about 6 mg / kg-12 mg / kg, about 10 mg / kg-12 mg / kg, about 12 mg / kg-15 mg / kg, or about 12 mg / kg-20 mg / kg per treatment cycle. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 0.01 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 5 mg / kg, about 6 mg / kg, about 10 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 20 mg / kg per treatment cycle, or a range between any two of these values (including the endpoints) or any value therein. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 6 mg / kg per treatment cycle.

[0051] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered once per day to once every 7 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, or once every 7 weeks.

[0052] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered once per day to once every 7 weeks at a dose of about 1-1000 mg, about 1-10 mg, about 1-50 mg, about 1-100 mg, about 1-200 mg, about 1-240 mg, about 1-300 mg, about 1-600 mg, about 100-300 mg, about 100-500 mg, about 100-600 mg, 100-900 mg, about 300-600 mg, about 300-900 mg, about 600-900 mg, or about 900-1000 mg. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered once per day to once every 7 weeks at a dose of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 240 mg, about 300 mg, about 500 mg, about 600 mg, about 900 mg, or about 1000 mg, or a range between any two of these values (including endpoints) or any value therein.

[0053] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 1-1000 mg, about 1-10 mg, about 1-50 mg, about 1-100 mg, about 1-200 mg, about 1-240 mg, about 1-300 mg, about 1-600 mg, about 100-300 mg, about 100-500 mg, about 100-600 mg, 100-900 mg, about 300-600 mg, about 300-900 mg, about 600-900 mg, or about 900-1000 mg. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 240 mg, about 300 mg, about 500 mg, about 600 mg, about 900 mg, or about 1000 mg, or a range between any two of these values (including endpoints) or any value therein. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 300 mg.

[0054] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 0.01 mg / kg - 20 mg / kg, about 0.01 mg / kg - 1 mg / kg, about 1 mg / kg - 2 mg / kg, about 1 mg / kg - 3 mg / kg, about 1 mg / kg - 5 mg / kg, about 1 mg / kg - 6 mg / kg, about 1 mg / kg - 10 mg / kg, about 2 mg / kg - 6 mg / kg, about 6 mg / kg - 12 mg / kg, about 10 mg / kg - 12 mg / kg, about 12 mg / kg - 15 mg / kg, or about 12 mg / kg - 20 mg / kg per dose. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 0.01 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 5 mg / kg, about 6 mg / kg, about 10 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 20 mg / kg per dose, or a range between any two of these values (including the endpoints) or any value therein. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 6 mg / kg per dose.

[0055] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered once about every 3 weeks at a dose of about 300 mg, the anti-PD-1 antibody or antigen-binding fragment is antibody A.

[0056] In some embodiments, the antibody h10D8OF and antibody A are administered once about every 3 weeks, the antibody h10D8OF is administered at a dose of about 600 mg or about 900 mg per dose, the antibody A is administered at a dose of about 300 mg per dose, and the tumor is selected from the group consisting of gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular cancer.

[0057] In some embodiments, the patient receives one treatment cycle of treatment. In some embodiments, the patient receives multiple (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or more, or a range between any two of these values (including the endpoints) or any value therein) treatment cycles of treatment. In some embodiments, the patient receives treatment until the condition is in remission and no longer requires treatment.

[0058] "Combination" as described herein is a mode of administration that includes various scenarios in which two or more drugs are administered sequentially, or simultaneously. In some embodiments, the anti-TIGIT antibody or antigen binding fragment and the anti-PD-1 antibody or antigen binding fragment are prepared as separate pharmaceutical compositions and administered simultaneously to a patient in need thereof. In some embodiments, the anti-TIGIT antibody or antigen binding fragment and the anti-PD-1 antibody or antigen binding fragment are prepared as separate pharmaceutical compositions and administered simultaneously to a patient in need thereof, or at different times during the course of treatment. For example, the anti-TIGIT antibody or antigen binding fragment is administered prior to the anti-PD-1 antibody or antigen binding fragment, or the anti-TIGIT antibody or antigen binding fragment is administered after the anti-PD-1 antibody or antigen binding fragment, or the anti-TIGIT antibody or antigen binding fragment and the anti-PD-1 antibody or antigen binding fragment are administered in an alternating regimen. In the present invention, the anti-TIGIT antibody or antigen binding fragment and the anti-PD-1 antibody or antigen binding fragment are administered to a patient in need thereof in a single dose or in multiple doses.

[0059] In some embodiments, the anti-TIGIT antibody or antigen binding fragment is administered after the anti-PD-1 antibody or antigen binding fragment is administered to a patient in need thereof.

[0060] In some embodiments, the anti-TIGIT antibody or antigen binding fragment is administered after the anti-PD-1 antibody or antigen binding fragment is administered to a patient in need thereof.

[0061] In some embodiments, the anti-TIGIT antibody or antigen binding fragment (or formulation) and / or anti-PD-1 antibody or antigen binding fragment (or formulation) is administered by injection or infusion. In some embodiments, the anti-TIGIT antibody or antigen binding fragment (or formulation) or anti-PD-1 antibody or antigen binding fragment (or formulation) is administered by subcutaneous (s.c.) injection, intraperitoneal (i.p.) injection, parenteral injection, intra-arterial injection, or intravenous (i.v.) infusion (i.e., intravenous infusion). The amount of the anti-TIGIT antibody or antigen binding fragment and anti-PD-1 antibody or antigen binding fragment administered will depend on the nature of the drug, the extent of cell surface-triggered internalization, transport, and release of the drug, and the disease being treated and the condition of the patient (e.g., age, sex, weight, etc.).

[0062] In some embodiments, the anti-TIGIT antibody or antigen binding fragment (or formulation) and / or anti-PD-1 antibody or antigen binding fragment (or formulation) is administered by intravenous infusion.

[0063] In some embodiments, the intravenous infusion of the anti-TIGIT antibody or antigen binding fragment (or formulation) is for a duration of about 30-120 minutes, e.g., about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 105 minutes, about 120 minutes, or a range between any two of these values (including the endpoints) or any of these values. In some embodiments, the intravenous infusion of the anti-TIGIT antibody or antigen binding fragment (or formulation) is for a duration of about 30 to 60 minutes. In some embodiments, the intravenous infusion of the anti-TIGIT antibody or antigen binding fragment (or formulation) is for a duration of 60 (±10) minutes.

[0064] In some embodiments, the intravenous infusion of the anti-PD-1 antibody or antigen binding fragment (or formulation) is for a duration of about 30-120 minutes, e.g., about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 105 minutes, or about 120 minutes, or a range between any two of these values, inclusive of the endpoints, or any value therein. In some embodiments, the intravenous infusion of the anti-PD-1 antibody or antigen binding fragment (or formulation) is for about 30 to 60 minutes. In some embodiments, the intravenous infusion of the anti-PD-1 antibody or antigen binding fragment (or formulation) is for 60 (±10) minutes.

[0065] In some embodiments, the anti-TIGIT antibody or antigen binding fragment, anti-PD-1 antibody or antigen binding fragment can be further used in combination with other therapeutic methods for treating tumors, such as chemotherapy, radiotherapy, and surgical treatment, etc.

[0066] In some embodiments, the anti-TIGIT antibody or antigen binding fragment, anti-PD-1 antibody or antigen binding fragment can be further used in combination with one or more chemotherapeutic agents for treating tumors.

[0067] In some embodiments, the tumor is a hematological cancer or a solid tumor; or, the tumor is selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myeloproliferative disease / neoplasm, Hodgkin’s lymphoma, indolent and aggressive non-Hodgkin’s lymphoma, Burkitt’s lymphoma, follicular lymphoma, multiple myeloma, giant cell myeloma, heavy chain myeloma, light chain or Bence Jones myeloma, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, colon cancer, lung cancer, head and neck cancer, bladder cancer, esophageal cancer, liver cancer, kidney cancer, and stomach cancer.

[0068] In some embodiments, the tumor is selected from the group consisting of gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular carcinoma.

[0069] In some embodiments, the chemotherapeutic agent comprises capecitabine, a taxane, or a platinum-based drug, or a combination thereof. In some embodiments, the platinum-based drug is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, lipoplatin, or satraplatin.

[0070] In some embodiments, the chemotherapeutic agent is a combination of a platinum-based drug and capecitabine.

[0071] In some embodiments, the chemotherapeutic agent is oxaliplatin in combination with capecitabine.

[0072] In some embodiments, the chemotherapeutic agent is capecitabine.

[0073] In some embodiments, the antibodies h10D8OF and A are further combined with oxaliplatin and capecitabine for treating a tumor. In some embodiments, the tumor is selected from the group consisting of gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular cancer.

[0074] In some embodiments, the antibodies h10D8OF and A are further combined with capecitabine for treating a tumor. In some embodiments, the tumor is selected from the group consisting of gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular cancer.

[0075] In some embodiments, the patient receives treatment with antibodies h10D8OF and A plus oxaliplatin and capecitabine for the first 6 cycles. In some embodiments, the patient receives treatment with antibodies h10D8OF and A after receiving treatment with antibodies h10D8OF and A plus oxaliplatin and capecitabine for the first 6 cycles. In some embodiments, the patient receives treatment with antibodies h10D8OF and A plus capecitabine or treatment with capecitabine after receiving treatment with antibodies h10D8OF and A plus oxaliplatin and capecitabine for the first 6 cycles.

[0076] In some embodiments, oxaliplatin is administered at about 50-300 mg / m 2 In some embodiments, oxaliplatin is administered at about 85-130 mg / m 2 In some embodiments, oxaliplatin is administered at about 50 mg / m 2 , about 85 mg / m 2 , about 100 mg / m 2 , about 130 mg / m 2 , about 150 mg / m 2 , about 175 mg / m 2 , about 200 mg / m 2 , about 250 mg / m 2 , or about 300 mg / m 2 per dose, or a range (including endpoints) between any two of these values, or any value therein. In some embodiments, oxaliplatin is administered at about 130 mg / m 2Dosing. In some embodiments, the oxaliplatin is administered once every week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the oxaliplatin is administered once every 3 weeks. In some embodiments, the oxaliplatin is administered at about 130 mg / m2per dose, based on body surface area. 2 Dosing, administered once every 3 weeks.

[0077] In some embodiments, the oxaliplatin is administered at about 130 mg / m2per dose, based on body surface area. 2 , administered as an intravenous infusion, once every 3 weeks.

[0078] In some embodiments, the capecitabine is administered at about 100-2000 mg / m2per dose, based on body surface area. 2 Dosing. In some embodiments, the capecitabine is administered at about 100 mg / m2per dose, based on body surface area. 2 , about 500 mg / m2per dose, based on body surface area. 2 , about 1000 mg / m2per dose, based on body surface area. 2 , about 1250 mg / m2per dose, based on body surface area. 2 , about 1500 mg / m2per dose, based on body surface area. 2 , about 1750 mg / m2per dose, based on body surface area. 2 , or about 2000 mg / m2per dose, based on body surface area. 2 Dosing, or a range between any two of these values, including endpoints, or any value therein. In some embodiments, the capecitabine is administered at about 1000 mg / m2per dose, based on body surface area. 2 Dosing. In some embodiments, the capecitabine is administered once a day for 1 week; once a day for 2 weeks; or once a day for 3 weeks. In some embodiments, the capecitabine is administered twice a day for 2 weeks; twice a day for 2 weeks; or twice a day for 3 weeks. In some embodiments, each 3 weeks is a treatment cycle, and the capecitabine is administered twice a day for 2 weeks, followed by 1 week of rest. In some embodiments, each 3 weeks is a treatment cycle, and the capecitabine is administered at about 1000 mg / m2per dose, based on body surface area, twice a day for 2 weeks, followed by 1 week of rest. 2 Dosing, twice a day for 2 weeks, followed by 1 week of rest.

[0079] In some embodiments, the capecitabine is administered at about 1000 mg / m2per dose, based on body surface area, 2 , orally, twice a day for 1-14 days per cycle, every 3 weeks.

[0080] In some embodiments, the method of treating a tumor or use comprises administering to the patient one or more treatment cycles of the anti-TIGIT antibody or antigen binding fragment and the anti-PD-1 antibody or antigen binding fragment, wherein:

[0081] (1) at least one treatment cycle administering to the patient a composition comprising: the anti-TIGIT antibody or antigen-binding fragment and the anti-PD-1 antibody or antigen-binding fragment; and / or

[0082] (2) at least one treatment cycle administering to the patient a composition comprising: the anti-TIGIT antibody or antigen-binding fragment, the anti-PD-1 antibody or antigen-binding fragment, oxaliplatin, and capecitabine; and / or

[0083] (3) at least one treatment cycle administering to the patient a composition comprising: the anti-TIGIT antibody or antigen-binding fragment, the anti-PD-1 antibody or antigen-binding fragment, and capecitabine.

[0084] In some embodiments, the method of treating a tumor or use comprises administering to the patient one or more treatment cycles of the anti-TIGIT antibody or antigen-binding fragment and the anti-PD-1 antibody or antigen-binding fragment, wherein:

[0085] (1) the first, first to second, first to third, first to fourth, first to fifth, first to sixth, first to seventh, first to eighth, or first to ninth treatment cycle administering to the patient a composition comprising: the anti-TIGIT antibody or antigen-binding fragment, the anti-PD-1 antibody or antigen-binding fragment, oxaliplatin, and capecitabine; and / or

[0086] (2) the second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth and subsequent treatment cycles administering to the patient a composition comprising: the anti-TIGIT antibody or antigen-binding fragment, the anti-PD-1 antibody or antigen-binding fragment, and capecitabine; or

[0087] the second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth and subsequent treatment cycles administering to the patient a composition comprising: the anti-TIGIT antibody or antigen-binding fragment and the anti-PD-1 antibody or antigen-binding fragment.

[0088] In some embodiments, the method of treating a tumor or use comprises administering to the patient one or more treatment cycles of the anti-TIGIT antibody or antigen-binding fragment and the anti-PD-1 antibody or antigen-binding fragment, each 3-weeks being a treatment cycle, wherein:

[0089] (1) at least one treatment cycle administering to the patient a composition comprising: the anti-TIGIT antibody or antigen-binding fragment about once every 3 weeks at a dose of about 600 mg or about 900 mg per administration; the anti-PD-1 antibody or antigen-binding fragment about once every 3 weeks at a dose of about 300 mg per administration; and / or

[0090] (2) Administration to the patient for at least one treatment cycle of the following: the anti-TIGIT antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 600 mg or approximately 900 mg; the anti-PD-1 antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 300 mg; oxaliplatin is administered at a dose of approximately 130 mg / m² per body surface area. 2 Administer once every 3 weeks; capecitabine is administered at a dose of approximately 1000 mg / m² per body surface area. 2 Administer twice daily, on days 1-14 of each cycle; and / or

[0091] (3) At least one treatment cycle, the patient is given the following: the anti-TIGIT antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 600 mg or approximately 900 mg; the anti-PD-1 antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 300 mg; capecitabine is administered at a dose of approximately 1000 mg / m² per body surface area. 2 Dosage: Administer twice daily, on days 1-14 of each cycle.

[0092] In some embodiments, the method or use of treating tumors includes administering to a patient one or more treatment cycles of the anti-TIGIT antibody or antigen-binding fragment and the anti-PD-1 antibody or antigen-binding fragment, with each treatment cycle consisting of 3 weeks, wherein:

[0093] (1) During treatment cycles 1, 1–2, 1–3, 1–4, 1–5, 1–6, 1–7, 1–8, or 1–9, the patient is given the following: the anti-TIGIT antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 600 mg or approximately 900 mg; the anti-PD-1 antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 300 mg; oxaliplatin is administered at a dose of approximately 130 mg / m² per body surface area. 2 Administer once every 3 weeks; capecitabine is administered at a dose of approximately 1000 mg / m² per body surface area. 2 Administer twice daily, on days 1-14 of each cycle; and / or

[0094] (2) During the 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, or 10th treatment cycles and subsequent treatment cycles, the patient shall be administered the following: the anti-TIGIT antibody or antigen-binding fragment approximately every 3 weeks at a dose of approximately 600 mg or approximately 900 mg; the anti-PD-1 antibody or antigen-binding fragment approximately every 3 weeks at a dose of approximately 300 mg; capecitabine at a dose of approximately 1000 mg / m² per body surface area. 2 Dosage: Administer twice daily, on days 1-14 of each cycle; or

[0095] administering to the patient one or more treatment cycles of: the anti-TIGIT antibody or antigen binding fragment about once every 3 weeks at a dose of about 600 mg or about 900 mg per dose; the anti-PD-1 antibody or antigen binding fragment about once every 3 weeks at a dose of about 300 mg per dose.

[0096] In some embodiments, the methods of treating a tumor or uses comprise administering to the patient one or more treatment cycles of the antibody h10D8OF and the antibody A, each 3 weeks being a treatment cycle, wherein:

[0097] (1) administering to the patient for 1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, or 1-9 treatment cycles comprising: the antibody h10D8OF about once every 3 weeks at a dose of about 600 mg or about 900 mg per dose; the antibody A about once every 3 weeks at a dose of about 300 mg per dose; oxaliplatin at about 130 mg / m2per dose based on body surface area, about once every 3 weeks; capecitabine at about 1000 mg / m2per dose based on body surface area, about twice a day on days 1-14 of each cycle. 2 (2) administering to the patient for 2, 3, 4, 5, 6, 7, 8, 9, or 10 and subsequent treatment cycles comprising: the antibody h10D8OF about once every 3 weeks at a dose of about 600 mg or about 900 mg per dose; the antibody A about once every 3 weeks at a dose of about 300 mg per dose; capecitabine at about 1000 mg / m2per dose based on body surface area, about twice a day on days 1-14 of each cycle. 2 (3) administering to the patient for 2, 3, 4, 5, 6, 7, 8, 9, or 10 and subsequent treatment cycles comprising: the antibody h10D8OF about once every 3 weeks at a dose of about 600 mg or about 900 mg per dose; the antibody A about once every 3 weeks at a dose of about 300 mg per dose.

[0098] (2) administering to the patient for 2, 3, 4, 5, 6, 7, 8, 9, or 10 and subsequent treatment cycles comprising: the antibody h10D8OF about once every 3 weeks at a dose of about 600 mg or about 900 mg per dose; the antibody A about once every 3 weeks at a dose of about 300 mg per dose; capecitabine at about 1000 mg / m2per dose based on body surface area, about twice a day on days 1-14 of each cycle. 2 (3) administering to the patient for 2, 3, 4, 5, 6, 7, 8, 9, or 10 and subsequent treatment cycles comprising: the antibody h10D8OF about once every 3 weeks at a dose of about 600 mg or about 900 mg per dose; the antibody A about once every 3 weeks at a dose of about 300 mg per dose.

[0099] (2) administering to the patient for 2, 3, 4, 5, 6, 7, 8, 9, or 10 and subsequent treatment cycles comprising: the antibody h10D8OF about once every 3 weeks at a dose of about 600 mg or about 900 mg per dose; the antibody A about once every 3 weeks at a dose of about 300 mg per dose; capecitabine at about 1000 mg / m2per dose based on body surface area, about twice a day on days 1-14 of each cycle.

[0100] In some embodiments, the methods of treating a tumor or uses comprise administering to the patient one or more treatment cycles of the antibody h10D8OF and the antibody A, each 3 weeks being a treatment cycle, wherein:

[0101] (1) for cycles 1-6, the patient is administered: the antibody h10D8 OF about once every 3 weeks at a dose of about 600 mg or about 900 mg per dose; the antibody A about once every 3 weeks at a dose of about 300 mg per dose; oxaliplatin at about 130 mg / m2per dose based on body surface area; and capecitabine at about 1000 mg / m2per dose based on body surface area, administered every 3 weeks; 2 capecitabine at about 1000 mg / m2per dose based on body surface area, administered every 3 weeks; 2 capecitabine at about 1000 mg / m2per dose based on body surface area, administered every 3 weeks;

[0102] (2) for cycles 7 and beyond, the patient is administered: the antibody h10D8 OF about once every 3 weeks at a dose of about 600 mg or about 900 mg per dose; the antibody A about once every 3 weeks at a dose of about 300 mg per dose; and capecitabine at about 1000 mg / m2per dose based on body surface area, administered every 3 weeks; 2 capecitabine at about 1000 mg / m2per dose based on body surface area, administered every 3 weeks;

[0103] for cycles 7 and beyond, the patient is administered: the antibody h10D8 OF about once every 3 weeks at a dose of about 600 mg or about 900 mg per dose; the antibody A about once every 3 weeks at a dose of about 300 mg per dose;

[0104] wherein the tumor is selected from the group consisting of gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular cancer.

[0105] The term

[0106] Unless otherwise indicated, each of the terms below shall have the meaning set forth herein.

[0107] It should be noted that "a" or "an" entity refers to one or more than one of that entity; for example, "an antibody" shall be understood to mean one or more antibodies, and, alternatively, "one or more" or "at least one" shall be understood to mean one or more than one, depending on the context. Thus, the terms "a" (or "an"), "one or more", and "at least one" can be used interchangeably in this disclosure.

[0108] As used herein, "comprising" or "including" or "having" means that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of, when used to define compositions and methods, excludes other elements of any essential significance to the combination. "Consisting of, when used to define compositions and methods, excludes the presence of other elements.

[0109] "About" means the conventional error range for the relevant technical field of art. In some embodiments, "about" refers to a range of ±10%, ±5%, or ±1% of the stated value.

[0110] “TIGIT” (T cell immunoreceptor with Ig and ITIM domains) is a T cell immunoreceptor with Ig and ITIM domains, which is mainly expressed on activated T cells and NK cells. TIGIT is an immune receptor inhibitory checkpoint, which is of great significance in tumor immune surveillance.

[0111] “PD-1” (Programmed death 1), also known as Programmed Death 1, is an immunoinhibitory receptor expressed on activated T cells, B cells and myeloid cells, which is a member of the CD28 immunoglobulin superfamily. The interaction of PD-1 with its ligand PD-L1 negatively regulates antigen receptor signaling and attenuates T cell responses. So far, a large number of studies have shown that the interaction between PD-1 and PD-L1 leads to a decrease in lymphocytes infiltrating tumors, a decrease in T cell receptor-mediated proliferation and immune evasion of cancer cells. Blocking the interaction between PD-1 and PD-L1 can increase T cell proliferation and cytokine production, improve the immunity of tumor-specific CD8+ T cells, and thus help the immune system to clear tumor cells.

[0112] “Antibody”, “antigen binding fragment” refers to a polypeptide or polypeptide complex that specifically recognizes and binds to an antigen. The antibody can be an intact antibody and any antigen binding fragment or single chain thereof. Therefore, the term “antibody” includes any protein or peptide in the molecule containing at least a part of the immunoglobulin molecule having biological activity of binding to antigen. Antibodies and antigen binding fragments include, but are not limited to, complementarity determining regions (CDRs) of heavy or light chains or ligand binding portions thereof, heavy chain variable regions (VH), light chain variable regions (VL), heavy chain constant regions (CH), light chain constant regions (CL), framework regions (FR) or any part thereof, or at least a part of the binding protein. The CDR region includes the CDR region of the light chain (LCDR1-3) and the CDR region of the heavy chain (HCDR1-3).

[0113] The antibodies, antigen binding fragments or derivatives described herein include, but are not limited to, polyclonal, monoclonal, multispecific, fully human, humanized, primatized, chimeric antibodies, single chain antibodies (scFv), epitope binding fragments (such as Fab, Fab' and F(ab')2).

[0114] DNA encoding the antibodies can be designed and synthesized according to the antibody amino acid sequences described herein using routine methods, inserted into expression vectors, and then transfected into host cells, which are cultured in media that allow production of the monoclonal antibodies by the transfected host cells. In some embodiments, the expression antibody vectors include at least one promoter element, the antibody coding sequence, a transcription termination signal and a poly A tail. Other elements include enhancers, a Kozak sequence, and donor and acceptor sites for RNA splicing flanking the insert. Efficient transcription can be obtained by using the early and late promoters from SV40, the long terminal repeat from retroviruses such as RSV, HTLV1, HIV1, and cytomegalovirus, or other promoters such as the actin promoter. Suitable expression vectors can include pIRES1neo, pRetro-Off, pRetro-On, PLXSN, or Plncx, pcDNA3.1(+ / -), pcDNA3.1 / Zeo(+ / -), pcDNA3.1 / Hygro(+ / -), pcDNA3.1 / G418(+ / -), PSVL, PMSG, pRSVcat, pSV2dhfr, pBC12MI, and pCS2, among others. Commonly used mammalian cells include HEK293 cells, Cos1 cells, Cos7 cells, CV1 cells, murine L cells, and CHO cells, among others.

[0115] "Treatment" refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent, slow down, lessen, ameliorate and stop undesirable physiological changes or disorders, such as the progression of a disease, including but not limited to alleviation or relief of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission, whether partial or total, whether detectable or undetectable. Patients in need of treatment include those already with the condition or disorder, those likely to have the condition or disorder, or those in which the condition or disorder is to be prevented, patients who can or are expected to benefit from administration of the antibodies or compositions of the application for detection, diagnostic procedures, and / or treatment.

[0116] "Need" means that a patient has been identified as in need of a particular method or treatment. In some embodiments, the identification can be made by any diagnostic means. In any of the methods and treatments described herein, a patient can be in need.

[0117] "Patient" refers to any mammal, including humans, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, etc., in need of diagnosis, prognosis, or treatment. In some embodiments, the patient is a human.

[0118] A "combination medicament" includes two or more medicaments, which can each form a separate administration unit or collectively form a combined administration unit. In some embodiments, a combination medicament includes separate anti-TIGIT antibodies or antigen-binding fragments and anti-PD-1 or antigen-binding fragments. In some embodiments, a combination medicament includes a composition of anti-TIGIT antibodies or antigen-binding fragments and anti-PD-1 or antigen-binding fragments. In some embodiments, a combination medicament includes separate anti-TIGIT antibodies or antigen-binding fragments, anti-PD-1 or antigen-binding fragments, and a chemotherapeutic agent. In some embodiments, a combination medicament includes separate anti-TIGIT antibodies or antigen-binding fragments, anti-PD-1 or antigen-binding fragments, oxaliplatin, and capecitabine. In some embodiments, the different medicaments can be administered simultaneously or separately when administering the combination medicament.

[0119] An "effective amount" or "therapeutically effective amount" refers to the amount of a medicament, e.g., an anti-TIGIT antibody or antigen-binding fragment or an anti-PD-1 antibody or antigen-binding fragment, which is sufficient to reduce or improve the severity and / or duration of a disorder, e.g., a tumor, or one or more symptoms thereof; prevent progression of the disorder; cause regression of the disorder; prevent recurrence, development, onset, or progression of one or more symptoms associated with the disorder; detect the disorder; or enhance or improve the prophylactic or therapeutic efficacy of another therapy, e.g., a prophylactic or therapeutic agent. For example, an effective amount of an anti-TIGIT antibody or antigen-binding fragment or an anti-PD-1 antibody or antigen-binding fragment can inhibit tumor growth (e.g., inhibit an increase in tumor volume); reduce tumor growth (e.g., decrease tumor volume); reduce the number of cancer cells; and / or relieve to some extent one or more symptoms associated with the tumor. For example, an effective amount can improve progression-free survival (PFS), improve overall survival (OS), improve objective response rate (ORR), improve duration of response (DoR), improve disease control rate (DCR), or reduce the likelihood of recurrence.

[0120] "Administering" or "administration" refers to the act of applying a substance to achieve a therapeutic goal (e.g., treating a tumor). The mode of administration can be parenteral, enteral, and topical. Parenteral administration is generally by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0121] Anti-tumor efficacy evaluation can be imaging evaluation (CT / MRI), physical examination and survival evaluation; anti-tumor efficacy indicators include: according to the RECIST 1.1 evaluation standard (Eisenhauer, EA et al., Eur J Cancer. 2009; 45(2): 228-247), objective response rate (ORR) of imaging efficacy evaluation by CT / MRI as the main evaluation method, duration of response (DoR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).

[0122] Objective response rate (ORR): refers to the proportion of patients whose tumors shrink to a certain amount and remain for a certain period of time, including cases of complete remission (CR) and partial remission (PR). In some embodiments, the objective response rate is the proportion of patients whose efficacy reaches PR or CR at the end of a certain period of treatment, such as the first 6 cycles of treatment. In some embodiments, the objective response rate is the proportion of patients whose best response efficacy reaches PR or CR during the entire study period.

[0123] Duration of response (DoR): DoR is defined as the time from the first assessment of objective response to the first assessment of progressive disease (PD) or death from any cause before PD, reflecting the duration of ORR.

[0124] Disease control rate (DCR): the proportion of patients whose tumors shrink or remain stable for a certain period of time, including cases of CR, PR and stable disease (SD).

[0125] Progression-free survival (PFS): is the time from the first administration to the occurrence of objective tumor progression or all-cause death (whichever occurs first).

[0126] Overall survival (OS): the time from the date of first administration to the occurrence of death due to any cause. Patients who are still alive at the time of analysis will have the date of their last contact as the cutoff date.

[0127] MTD definition: MTD (maximum tolerated dose) is defined as the highest dose level at which ≤1 / 6 patients in a certain dose group are observed to have dose-limiting toxicity (DLT) during the DLT evaluation period.

[0128] The Eastern Cooperative Oncology Group (ECOG) has developed a simplified activity status score table, which divides the activity status of patients into 0-5 levels, and the ECOG performance status score standard is scored as 0, 1, 2, 3, 4, and 5.

[0129] The PK (pharmacokinetics) parameters used herein are defined as follows:

[0130] Single-dose PK parameters: C max , T max , T 1 / 2 , CL, Vd, Ke, MRT, AUC (0-τ) , AUC (0-∞) :

[0131] Multiple-dose PK parameters: C max,ss , C avg,ss , C min,ss , AUC (0-τ)ss , AUC (0-∞)ss , T max,ss , T 1 / 2,ss , CL, V ss , Ke, MRT, accumulation index (R ac ), fluctuation index DF:

[0132] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. DETAILED DESCRIPTION

[0133] The technical solutions of the present application are further illustrated below by specific examples, which do not represent a limitation on the scope of protection of the present application. Some non-essential modifications and adjustments made by others according to the concept of the present application still fall within the scope of protection of the present application.

[0134] The materials, reagents, etc. used in the following examples can be obtained from commercial channels unless otherwise specified.

[0135] Example 1 Preparation method of antibody

[0136] The DNA sequences encoding the heavy and light chains of the antibody are cloned into an expression vector, then transferred into host cells, cultured and purified to obtain the antibody.

[0137] The amino acid sequences of antibody h10D8OF and antibody A are shown in Tables 1 and 2, respectively, wherein the heavy chain of antibody h10D8OF is shown as SEQ ID NO: 9, and the light chain is shown as SEQ ID NO: 10; the heavy chain of antibody A is shown as SEQ ID NO: 19, and the light chain is shown as SEQ ID NO: 20. In the preparation process, the expression cells used for antibody h10D8OF and antibody A are both CHO cells.

[0138] Table 1 Amino acid sequence of antibody h10D8OF

[0139] Table 2 Amino acid sequence of antibody A

[0140] Example 2 A multicenter, open phase Ib / IIa clinical study of antibody A injection combined with antibody h10D8 OF injection for safety, tolerability, pharmacokinetic characteristics and preliminary clinical efficacy in patients with locally advanced or metastatic solid tumors

[0141] 1. Clinical study drugs:

[0142] Ib phase drugs and doses: antibody A (300 mg) + antibody h10D8 OF (600 mg or 900 mg).

[0143] Antibody A injection is a fixed dose of 300 mg, and antibody h10D8 OF injection is set up in two dose groups, A group (600 mg) and B group (900 mg).

[0144] II phase drugs and doses:

[0145] Antibody A (300 mg) + antibody h10D8 OF (600 mg or 900 mg) + oxaliplatin + capecitabine.

[0146] Table 3 Dosage and usage of oxaliplatin and capecitabine

[0147] Among them, the gastric cancer, gastroesophageal junction cancer and esophageal cancer cohort received antibody A injection combined with antibody h10D8 OF injection plus chemotherapy (oxaliplatin [130 mg / m2 IV Q3W] and oral capecitabine [1000 mg / m 2 BID, days 1-14, Q3W] treatment for the first 6 cycles, and subsequent treatment cycles received antibody A injection combined with antibody h10D8 OF injection ± capecitabine treatment, and whether to use capecitabine after the 6th cycle was adjusted according to the actual situation.

[0148] Antibody A injection administration scheme: intravenous infusion administration, once every 3 weeks (Q3W). The infusion time in the Ib phase study was 60 (±10) minutes; in the II phase study, infusion was performed after chemotherapy administration, and the recommended infusion time was 30-60 minutes.

[0149] Antibody h10D8 OF injection administration scheme: intravenous infusion administration, once every 3 weeks (Q3W), starting 30 (±10) minutes after the completion of antibody A injection infusion. The infusion time in the Ib phase study was 60 (±10) minutes; in the II phase study, the recommended infusion time was 30-60 minutes, and if no infusion-related reactions were observed, the subsequent infusion time could be adjusted to 30 minutes-2 hours to complete the infusion according to the actual clinical situation.

[0150] 2. Study population

[0151] 2.1 Inclusion criteria

[0152] 1) Age ≥ 18 years;

[0153] 2) The following requirements shall be met accordingly for different phases or cohorts:

[0154] Phase Ib: Patients with advanced malignancies who have failed, are intolerant of, or have declined standard therapy, as confirmed by cytology or pathology;

[0155] Cohort 1 of Phase II: Patients with locally advanced unresectable or metastatic gastric, gastroesophageal junction, and esophageal cancer who have not received prior systemic treatment: PD-L1 CPS ≥ 5 and tumor tissue testing is HER2 negative;

[0156] Cohort 2 of Phase II: Patients with histologically or cytologically confirmed locally advanced or metastatic (referring to the AJCC eighth edition of the Manual of Tumor Staging) NSCLC:

[0157] a. Patients who have disease progression after first-line treatment with PD-1 / PD-L1 antibodies and platinum-based doublet chemotherapy or who are ineligible for standard treatment;

[0158] b. Patients with driver gene mutations who have failed targeted therapy and chemotherapy or are ineligible for standard treatment;

[0159] Cohort 3 of Phase II: Patients with pathologically or clinically diagnosed advanced HCC who have disease progression after systemic treatment with PD-1 / PD-L1 antibodies and targeted drugs or are ineligible for standard treatment, and whose liver function is classified as Child-Pugh Class A or better (≤ 7 points) Class B;

[0160] 4) Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;

[0161] 5) The expected survival period is ≥ 12 weeks;

[0162] 6) Adequate organ and bone marrow function.

[0163] 2.2 Exclusion Criteria

[0164] 1) Patients who are receiving or are expected to receive other anti-tumor treatment during the study period, including but not limited to chemotherapy, radiotherapy, immunotherapy, endocrine therapy (except replacement therapy), targeted therapy, biological therapy, and traditional Chinese medicine with anti-tumor effect, etc.

[0165] 2) The first study drug administration is not less than 4 weeks or 5 half-lives (whichever is longer) from the previous anti-tumor treatment (chemotherapy, endocrine therapy, targeted therapy), or less than 4 weeks from the last major radiotherapy, less than 2 weeks from the palliative radiotherapy for bone metastasis, less than 2 weeks from the last traditional Chinese medicine / immune modulating drug (including thymosin, interferon, interleukin, etc.) with anti-tumor indications, or less than 8 weeks from the last radioactive drug;

[0166] 3) Received other unlisted clinical study drugs or treatments within 4 weeks before the first use of the study drug;

[0167] 4) Vaccinated with live / attenuated or mRNA vaccines within 4 weeks before screening or planned to be vaccinated during the study period;

[0168] 5) Pregnant or lactating women;

[0169] 6) Patients with primary central nervous system tumors, those with meningeal metastases, or those with symptomatic central nervous system metastases are excluded. Patients with asymptomatic or symptomatic central nervous system metastases that are clinically under control may be included, but must meet the following conditions: a. Disease stabilization for ≥4 weeks before the first dose; b. No evidence of central nervous system disease progression on MRI scan / enhancement within 4 weeks before the first dose; c. Anti-epileptic drugs have been discontinued for ≥2 weeks before the first dose, and the prednisone dose is ≤10 mg / day or equivalent hormone dose;

[0170] 7) Patients who have undergone major surgical procedures (excluding puncture biopsy) within 4 weeks before the first use of the study drug or have not yet recovered, or those who need to undergo elective surgery during the trial period; patients with a history of gastrointestinal perforation or gastrointestinal fistula within 6 months before the first dose in the expansion cohort may not be included. If the perforation or fistula has been treated by resection or repair, and the disease is judged to have recovered or remitted, they may be allowed to enroll;

[0171] 8) Patients with a history of tissue or organ transplantation surgery;

[0172] 9) Patients who have experienced a severe infection within 4 weeks before the first dose or those with active infection within 2 weeks before the first dose;

[0173] 10) Known history of human immunodeficiency virus (HIV) infection;

[0174] 11) Active hepatitis B without treatment must be excluded; Note: HBV viral load <2000 IU / ml or <104 copies / ml before the first dose of study drug can not exclude, but need to consider giving anti-HBV treatment during the study; Patients who are anti-HBc (+), HBsAg (-), anti-HBs (-) and HBV viral load (-) are not required to routinely give prophylactic anti-HBV treatment, but need to closely monitor viral reactivation;

[0175] 12) Patients with active hepatitis C virus (HCV) infection (defined as: HCV antibody positive and HCV-RNA level higher than the lower limit of detection);

[0176] 13) Patients with untreated or treated tuberculosis, including but not limited to pulmonary tuberculosis; those who have been treated with standard anti-tuberculosis treatment and have been confirmed to have been cured can be included;

[0177] 14) Patients with known history of severe allergies, or patients known to have had ≥ grade 3 allergic reactions to previous macromolecular protein preparations / antibodies;

[0178] 15) Patients with history of autoimmune diseases (excluding vitiligo and thyroid diseases that can be treated with hormone replacement therapy, type I diabetes mellitus);

[0179] 16) Patients who have received systemic glucocorticoid (prednisone >10 mg / day or equivalent dose of similar drugs) or other immunosuppressive therapy within 14 days before the first use of the study drug; The following are excluded: treatment with topical, ocular, intra-articular, intranasal and inhaled glucocorticoids, short-term use of glucocorticoids for prophylactic treatment (e.g. prevention of contrast agent allergy);

[0180] 17) Patients who have had ≥ grade 3 immune-related adverse events (irAE) in the past, or patients who have had ≥ grade 2 irAEs that require permanent discontinuation of immunotherapy according to the Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities (CSCO Guidelines) (2023 version or newer version);

[0181] 18) Severe cardiovascular disease: heart failure of New York Heart Association (NYHA) classification grade III and above, left ventricular ejection fraction (LVEF) <50%, unstable angina pectoris, uncontrolled hypertension (defined in this protocol as systolic blood pressure >160 mmHg and / or diastolic blood pressure >100 mmHg after treatment although the best anti-hypertensive treatment is used), history of myocardial infarction within the past 6 months, severe arrhythmia requiring drug control (atrial fibrillation or supraventricular tachycardia are judged by the investigator whether to be included);

[0182] 19) Patients with a history of substance abuse or drug abuse known to affect study compliance;

[0183] 20) Presence of other active malignancy within 5 years prior to first dose except for adequately treated carcinoma in situ of the cervix, basal cell or squamous cell skin cancer, localized prostate cancer following radical surgery, ductal carcinoma in situ following radical surgery, except for the tumor for which the patient is enrolled in the study;

[0184] 21) Presence of effusion in pericardial, pleural, peritoneal, pelvic or other serosal cavities requiring recent intervention (e.g., paracentesis, thoracentesis, or drainage) (patients with stable effusion following recent intervention may be enrolled).

[0185] 3. Objectives and Endpoints

[0186] 3.1 Primary and Secondary Objectives

[0187] The primary objective of Phase Ib study is to evaluate the safety and tolerability of Antibody A Injection and Antibody h10D8 OF Injection in combination in patients with locally advanced or metastatic solid tumors to provide the recommended dose for subsequent clinical trials. The secondary objectives are to preliminarily evaluate the anti-tumor efficacy of Antibody A Injection and Antibody h10D8 OF Injection in combination; to evaluate the pharmacokinetic (PK) characteristics of Antibody A Injection and Antibody h10D8 OF Injection in combination in single and multiple dosing in patients with advanced solid tumors; to evaluate the immunogenicity of BA1308 and Antibody h10D8 OF Injection in combination.

[0188] The primary objective of Phase II study is to evaluate the safety, anti-tumor preliminary efficacy of Antibody A Injection and Antibody h10D8 OF Injection in combination with chemotherapy in patients with advanced gastric cancer, gastroesophageal junction cancer and esophageal cancer, and the safety, preliminary efficacy of Antibody A Injection and Antibody h10D8 OF Injection in patients with advanced non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) to provide the recommended dose for subsequent clinical trials.

[0189] The secondary objectives are to evaluate the pharmacokinetic (PK) characteristics of Antibody A Injection and Antibody h10D8 OF Injection in combination with chemotherapy in patients with advanced gastric cancer, gastroesophageal junction cancer and esophageal cancer, and Antibody A Injection and Antibody h10D8 OF Injection in single and multiple dosing in patients with advanced non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC); to evaluate the immunogenicity of Antibody A Injection and Antibody h10D8 OF Injection in combination with chemotherapy in patients with advanced gastric cancer, gastroesophageal junction cancer and esophageal cancer, and Antibody A Injection and Antibody h10D8 OF Injection in patients with advanced non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC).

[0190] 3.2 Primary and Secondary Endpoint Indicators

[0191] The primary endpoint is safety endpoint: vital signs and physical examination, adverse events (AEs), clinical laboratory tests, clinical auxiliary examination (such as electrocardiogram, etc.).

[0192] Secondary endpoint indicators:

[0193] 1) Preliminary efficacy according to the Response Evaluation Criteria in Solid Tumors (RECIST V1.1). The main indicators include: objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), etc.

[0194] 2) Pharmacokinetic parameters of antibody A injection and antibody h10D8OF injection under single and multiple dosing of each, including:

[0195] Single dose: C max , T max , T 1 / 2 , CL, Vd, Ke, MRT, AUC(0-t), AUC(0-∞).

[0196] Multiple doses: C max,ss , C avg,ss , C min,ss , AUC (0-τ)ss , AUC (0-∞)ss , T max,ss , T 1 / 2,ss , CL, V ss , Ke, MRT, accumulation index (R ac ), fluctuation index DF.

[0197] 3) Anti-drug antibodies (ADAs) / neutralizing antibodies (NAbs)

[0198] The combined administration mode of the antibody A injection and the antibody h10D8OF injection of the present application is expected to have good safety and tolerability, or to result in at least one improvement selected from the objective response rate (ORR), the duration of response (DoR), the disease control rate (DCR), the progression-free survival (PFS), and the overall survival (OS).

Claims

1. A method for treating a tumor comprising: administering to a patient in need thereof an effective amount of an anti-TIGIT antibody or antigen binding fragment and an anti-PD-1 antibody or antigen binding fragment; wherein the anti-TIGIT antibody or antigen binding fragment comprises a HCDR1 as set forth in SEQ ID NO: 1, a HCDR2 as set forth in SEQ ID NO: 2, a HCDR3 as set forth in SEQ ID NO: 3, a LCDR1 as set forth in SEQ ID NO: 4, a LCDR2 as set forth in SEQ ID NO: 5, and a LCDR3 as set forth in SEQ ID NO:

6. the tumor is a hematological cancer or a solid tumor; or, the tumor is selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myeloproliferative disease / neoplasm, Hodgkin lymphoma, indolent and aggressive non-Hodgkin lymphoma, Burkitt lymphoma, follicular lymphoma, multiple myeloma, giant cell myeloma, heavy chain myeloma, light chain or Bence Jones myeloma, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, colon cancer, lung cancer, head and neck cancer, bladder cancer, esophageal cancer, liver cancer, kidney cancer, and stomach cancer; or the tumor is selected from the group consisting of gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular cancer.

2. A method for treating a tumor, comprising administering to a patient in need thereof an effective amount of an anti-TIGIT antibody or antigen binding fragment, an anti-PD-1 antibody or antigen binding fragment, and one or more chemotherapeutic agents; wherein the anti-TIGIT antibody or antigen binding fragment comprises a HCDR1 as set forth in SEQ ID NO: 1, a HCDR2 as set forth in SEQ ID NO: 2, a HCDR3 as set forth in SEQ ID NO: 3, a LCDR1 as set forth in SEQ ID NO: 4, a LCDR2 as set forth in SEQ ID NO: 5, and a LCDR3 as set forth in SEQ ID NO:

6.

3. The method of claim 2, wherein the chemotherapeutic agent comprises capecitabine, a taxane, or a platinum drug, or a combination thereof.

4. The method of claim 3, wherein the chemotherapeutic agent is oxaliplatin in combination with capecitabine.

5. The method of claim 3, wherein the chemotherapeutic agent is capecitabine.

6. The method of claim 4, wherein the oxaliplatin is administered at about 50-300 mg / m 2 Dosing.

7. The method of any one of claims 4-6, wherein capecitabine is administered at about 100-2000 mg / m2 per dose by body surface area 2 Dosing.

8. The method of any one of claims 4 or 6-7, wherein the oxaliplatin is administered at about 130 mg / m2 per dose by body surface area. 2 Dosing.

9. The method of any one of claims 4-8, wherein capecitabine is administered at about 1000 mg / m2 per dose by body surface area 2 Dosing.

10. The method of any one of claims 4 or 6-9, wherein the oxaliplatin is administered at about 130 mg / m2 per dose by body surface area. 2 as an intravenous infusion once every three weeks.

11. The method of any one of claims 4-10, wherein capecitabine is administered at about 1000 mg / m2 per dose by body surface area 2 , orally, every 3 weeks as a treatment cycle, administered twice daily on days 1-14 of each cycle.

12. The method of any one of claims 2-11, wherein the tumor is a hematological cancer or a solid tumor.

13. The method of any one of claims 2-12, wherein the tumor is selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myeloproliferative disease / neoplasm, Hodgkin lymphoma, indolent and aggressive non-Hodgkin lymphoma, Burkitt lymphoma, follicular lymphoma, multiple myeloma, giant cell myeloma, heavy chain myeloma, light chain or Bence Jones myeloma, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, colon cancer, lung cancer, head and neck cancer, bladder cancer, esophageal cancer, liver cancer, kidney cancer, and stomach cancer.

14. The method of any one of claims 2-13, wherein the tumor is selected from the group consisting of gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular carcinoma.

15. The method of any one of claims 1-14, the anti-TIGIT antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 7, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO: 7, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO: 7; and / or the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO: 8, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO:

8.

16. The method of any one of claims 1-15, the anti-TIGIT antibody or antigen binding fragment comprising a heavy chain and a light chain, wherein: the heavy chain of the anti-TIGIT antibody comprises the amino acid sequence set forth in SEQ ID NO: 9, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO: 9, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO: 9; and / or the light chain of the anti-TIGIT antibody comprises the amino acid sequence set forth in SEQ ID NO: 10, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO: 10, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO:

10.

17. The method of any one of claims 1-16, wherein the anti-PD-1 antibody or antigen binding fragment comprises nivolumab, pembrolizumab, camrelizumab, sintilimab, toripalimab, or tislelizumab.

18. The method of any one of claims 1-16, wherein the anti-PD-1 antibody or antigen binding fragment comprises HCDR1 set forth in SEQ ID NO: 11, HCDR2 set forth in SEQ ID NO: 12, HCDR3 set forth in SEQ ID NO: 13, LCDR1 set forth in SEQ ID NO: 14, LCDR2 set forth in SEQ ID NO: 15, and LCDR3 set forth in SEQ ID NO:

16.

19. The method of any of claims 1-16 or 18, the anti-PD-1 antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 17, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO: 17, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO: 17; and / or the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 18, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO: 18, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO:

18.

20. The method of any one of claims 1-16 or 18-19, the anti-PD-1 antibody or antigen binding fragment comprising a heavy chain and a light chain, wherein: the heavy chain of the anti-PD-1 antibody comprises the amino acid sequence set forth in SEQ ID NO: 19, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO: 19, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO: 19; and / or the light chain of the anti-PD-1 antibody comprises the amino acid sequence set forth in SEQ ID NO: 20, or an amino acid sequence that is at least 80% identical to the sequence set forth in SEQ ID NO: 20, or an amino acid sequence that has one or more conservative amino acid substitutions compared to the sequence set forth in SEQ ID NO:

20.

21. The method of any one of claims 1-20, wherein the anti-TIGIT antibody or antigen binding fragment is administered at a dose of about 0.01 mg, about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 30 mg, about 50 mg, about 100 mg, about 300 mg, about 500 mg, about 600 mg, about 900 mg, about 1000 mg, or about 1200 mg per treatment cycle, or a range between any two of these values (inclusive of the endpoints) or any value therein.

22. The method of any one of claims 1-21, wherein the anti-TIGIT antibody or antigen binding fragment is administered at a dose of about 600 mg or about 900 mg per treatment cycle.

23. The method of any one of claims 1-22, wherein the anti-PD-1 antibody or antigen binding fragment is administered at a dose of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 240 mg, about 300 mg, about 500 mg, about 600 mg, about 900 mg, or about 1000 mg per treatment cycle, or a range between any two of these values (inclusive of the endpoints) or any value therein.

24. The method of any one of claims 1-23, wherein the anti-PD-1 antibody or antigen binding fragment is administered at a dose of about 300 mg per treatment cycle.

25. The method of any one of claims 1-24, wherein the anti-TIGIT antibody or antigen binding fragment and the anti-PD-1 antibody or antigen binding fragment are administered separately or concurrently.

26. The method of any one of claims 1-25, wherein the anti-TIGIT antibody or antigen binding fragment is administered after the anti-PD-1 antibody or antigen binding fragment.

27. The method of any one of claims 1-26, wherein the anti-TIGIT antibody or antigen binding fragment is administered once per day to once every 7 weeks at a dose of about 600 mg or about 900 mg per administration; and / or the anti-PD-1 antibody or antigen binding fragment is administered once per day to once every 7 weeks at a dose of about 300 mg per administration.

28. The method of any one of claims 1-27, wherein the anti-TIGIT antibody or antigen binding fragment is administered once about every 3 weeks at a dose of about 600 mg or about 900 mg per administration; and / or the anti-PD-1 antibody or antigen binding fragment is administered once about every 3 weeks at a dose of about 300 mg per administration. the anti-PD-1 antibody or antigen-binding fragment is administered to the patient about once every 3 weeks at a dose of about 300 mg per administration.

29. The method of any one of claims 1-28, comprising administering to the patient one or more treatment cycles of an anti-TIGIT antibody or antigen-binding fragment and an anti-PD-1 antibody or antigen-binding fragment.

30. The method of any one of claims 1-29, comprising administering to the patient one or more treatment cycles of an anti-TIGIT antibody or antigen-binding fragment and an anti-PD-1 antibody or antigen-binding fragment, wherein: (1) at least one treatment cycle comprises administering to the patient: the anti-TIGIT antibody or antigen-binding fragment and the anti-PD-1 antibody or antigen-binding fragment; and / or (2) at least one treatment cycle comprises administering to the patient: the anti-TIGIT antibody or antigen-binding fragment, the anti-PD-1 antibody or antigen-binding fragment, oxaliplatin, and capecitabine; and / or (3) at least one treatment cycle comprises administering to the patient: the anti-TIGIT antibody or antigen-binding fragment, the anti-PD-1 antibody or antigen-binding fragment, and capecitabine.

31. Use of an anti-TIGIT antibody or antigen-binding fragment and an anti-PD-1 antibody or antigen-binding fragment in the manufacture of a medicament for the treatment of a tumor, wherein the treatment is according to the method of any one of claims 1-30.

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