WO2025242190A1 - Traitement de tumeurs au moyen d'un anticorps anti-tigit en combinaison avec un anticorps anti-pd-1 - Google Patents

Traitement de tumeurs au moyen d'un anticorps anti-tigit en combinaison avec un anticorps anti-pd-1

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Publication number
WO2025242190A1
WO2025242190A1 PCT/CN2025/096706 CN2025096706W WO2025242190A1 WO 2025242190 A1 WO2025242190 A1 WO 2025242190A1 CN 2025096706 W CN2025096706 W CN 2025096706W WO 2025242190 A1 WO2025242190 A1 WO 2025242190A1
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WIPO (PCT)
Prior art keywords
antibody
antigen
binding fragment
seq
approximately
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Pending
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PCT/CN2025/096706
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English (en)
Chinese (zh)
Inventor
巢传琦
王昊
李胜峰
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Bio Thera Solutions Ltd
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Bio Thera Solutions Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515—Complete light chain, i.e. VL + CL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]

Definitions

  • This invention relates to the field of drug therapy, and more specifically to the use or method of using anti-TIGIT antibodies and anti-PD-1 antibodies to treat cancer patients.
  • Gastric cancer is one of the most serious threats to human health and social development.
  • gastric cancer is one of the most common malignant tumors worldwide, the third leading cause of cancer death globally, and the fifth most common malignant tumor.
  • Gastric cancer is the third leading cause of cancer death worldwide, with approximately 769,000 patients dying from it each year.
  • the 5-year survival rate for advanced or metastatic gastric cancer is approximately 5% to 20%, and the median overall survival for patients receiving chemotherapy alone is only about one year.
  • first-line treatment for gastric cancer has mainly consisted of surgery or radiotherapy and chemotherapy, and patients with locally advanced or metastatic gastric cancer that cannot be surgically resected have a poor prognosis, indicating a significant unmet clinical need.
  • the present invention provides a method or use for treating tumors, the method or use comprising: administering an effective amount of an anti-TIGIT antibody or antigen-binding fragment and an anti-PD-1 antibody or antigen-binding fragment to a patient in need.
  • the present invention provides the use of anti-TIGIT antibodies or antigen-binding fragments and anti-PD-1 antibodies or antigen-binding fragments in the preparation of medicaments for treating tumors.
  • the present invention provides the use of anti-TIGIT antibodies or antigen-binding fragments in the preparation of medicaments for treating tumors in combination with anti-PD-1 antibodies or antigen-binding fragments.
  • the present invention provides the use of anti-PD-1 antibodies or antigen-binding fragments in the preparation of medicaments for treating tumors in combination with anti-TIGIT antibodies or antigen-binding fragments.
  • the present invention provides the use of anti-TIGIT antibody or antigen-binding fragment and anti-PD-1 antibody or antigen-binding fragment in the treatment of tumors.
  • the present invention provides the use of anti-TIGIT antibody or antigen-binding fragment and anti-PD-1 antibody or antigen-binding fragment in combination for the treatment of tumors.
  • the present invention provides the use of anti-TIGIT antibody or antigen-binding fragment in combination with anti-PD-1 antibody or antigen-binding fragment for the treatment of tumors.
  • the present invention provides a combination drug comprising an anti-TIGIT antibody or antigen-binding fragment and an anti-PD-1 antibody or antigen-binding fragment.
  • the present invention provides a pharmaceutical composition comprising an anti-TIGIT antibody or antigen-binding fragment and an anti-PD-1 antibody or antigen-binding fragment.
  • the present invention also provides a kit comprising an anti-TIGIT antibody or antigen-binding fragment and an anti-PD-1 antibody or antigen-binding fragment.
  • the kit further includes instructions for use.
  • the tumor includes, but is not limited to, hematologic malignancies and solid tumors.
  • hematologic malignancies include, but are not limited to, leukemia, lymphoma, and myeloma.
  • leukemia includes acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and myeloproliferative disorders/tumors (MPDS).
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • MPDS myeloproliferative disorders/tumors
  • lymphoma includes Hodgkin lymphoma, painless and aggressive non-Hodgkin lymphoma, Burkitt lymphoma, and follicular lymphoma (small cell and large cell).
  • myeloma includes multiple myeloma (MM), giant cell myeloma, heavy chain myeloma, and light chain or Bens-Jones myeloma.
  • solid tumors include 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 stomach cancer.
  • lung cancer such as non-small cell lung cancer (NSCLC)
  • head and neck cancer such as non-small cell lung cancer (NSCLC)
  • bladder cancer such as hepatocellular carcinoma (HCC)
  • HCC hepatocellular carcinoma
  • the tumor is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myeloproliferative disorders/tumors, Hodgkin lymphoma, painless and aggressive non-Hodgkin lymphoma, Burkitt lymphoma, follicular lymphoma, multiple myeloma, giant cell myeloma, heavy chain myeloma, light chain or Bens-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.
  • the tumor is selected from gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular carcinoma.
  • the tumor is an advanced solid tumor.
  • the tumor patients include those with advanced malignant tumors diagnosed by cytology or pathology who have failed standard treatment, have no standard treatment available, are intolerant to standard treatment, or refuse standard treatment.
  • the standard treatment refers to the standard treatment regimens recommended by the NCCN and CSCO guidelines for the tumors.
  • the tumor patients include those with locally advanced, unresectable, or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal cancer who have not previously received systemic therapy.
  • the patient has a combined PD-L1 positive score (CPS) ⁇ 5 and the tumor tissue is HER2 negative.
  • the tumor patient includes a patient with histologically or cytologically confirmed locally advanced or metastatic (refer to the American Joint Committee on Cancer (AJCC) 8th Edition Staging Manual) non-small cell lung cancer.
  • the patient may be:
  • the tumor patients include those with pathologically or clinically diagnosed advanced hepatocellular carcinoma who have experienced disease progression or are ineligible for standard treatment after systemic therapy with PD-1/PD-L1 antibodies and targeted therapies.
  • the patients are those with a Child-Pugh liver function classification of A or a better B ( ⁇ 7 points).
  • the anti-TIGIT antibody or antigen-binding fragment is the anti-TIGIT antibody or antigen-binding fragment disclosed in WO2021/043206.
  • the anti-TIGIT antibody or antigen-binding fragment comprises at least one or more 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.
  • the anti-TIGIT antibody or antigen-binding fragment comprises 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.
  • the heavy chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises the amino acid sequence shown in SEQ ID NO:7, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the sequence shown in SEQ ID NO:7, or an amino acid sequence having one or more conserved amino acid substitutions with the sequence shown in SEQ ID NO:7.
  • the light chain variable region of the anti-TIGIT antibody or antigen-binding fragment comprises the amino acid sequence shown in SEQ ID NO:8, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the sequence shown in SEQ ID NO:8, or an amino acid sequence having one or more conserved amino acid substitutions with the sequence shown in SEQ ID NO:8.
  • the heavy chain variable region of the anti-TIGIT antibody or antigen-binding fragment contains the amino acid sequence shown in SEQ ID NO:7, and/or the light chain variable region of the anti-TIGIT antibody or antigen-binding fragment contains the amino acid sequence shown in SEQ ID NO:8.
  • the heavy chain of the anti-TIGIT antibody comprises the amino acid sequence shown in SEQ ID NO:9, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the sequence shown in SEQ ID NO:9, or an amino acid sequence having one or more conserved amino acid substitutions with the sequence shown in SEQ ID NO:9.
  • the light chain of the anti-TIGIT antibody comprises the amino acid sequence shown in SEQ ID NO:10, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the sequence shown in SEQ ID NO:10, or an amino acid sequence having one or more conserved amino acid substitutions with the sequence shown in SEQ ID NO:10.
  • the heavy chain of the anti-TIGIT antibody comprises the amino acid sequence shown in SEQ ID NO:9, and/or the light chain of the antibody comprises the amino acid sequence shown in SEQ ID NO:10. In some embodiments, the anti-TIGIT antibody comprises two identical heavy chains and two identical light chains.
  • the anti-TIGIT antibody is antibody h10D8OF.
  • the anti-PD-1 antibody or antigen-binding fragment is nivolumab (such as Opdivo or OPDIVO or their biosimilars), pembrolizumab (such as Keytruda or their biosimilars), camrelizumab (such as Eryka or their biosimilars), or sintilimab (such as). (or its biosimilars), toripalimab (e.g., Tuoyi or its biosimilars), or tislelizumab (e.g., ... (or its biosimilars).
  • nivolumab such as Opdivo or OPDIVO or their biosimilars
  • pembrolizumab such as Keytruda or their biosimilars
  • camrelizumab such as Eryka or their biosimilars
  • sintilimab such as. (or its biosimilars)
  • toripalimab e.g., Tuoyi or its biosimilars
  • tislelizumab e.g.
  • the anti-PD-1 antibody or antigen-binding fragment is the anti-PD-1 antibody or antigen-binding fragment disclosed in WO2020/207432.
  • the anti-PD-1 antibody or antigen-binding fragment comprises one or more of HCDR1 shown in SEQ ID NO:11, HCDR2 shown in SEQ ID NO:12, HCDR3 shown in SEQ ID NO:13, LCDR1 shown in SEQ ID NO:14, LCDR2 shown in SEQ ID NO:15, and LCDR3 shown in SEQ ID NO:16.
  • the anti-PD-1 antibody or antigen-binding fragment comprises HCDR1 shown in SEQ ID NO:11, HCDR2 shown in SEQ ID NO:12, HCDR3 shown in SEQ ID NO:13, LCDR1 shown in SEQ ID NO:14, LCDR2 shown in SEQ ID NO:15, and LCDR3 shown in SEQ ID NO:16.
  • the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises the amino acid sequence shown in SEQ ID NO:17, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the sequence shown in SEQ ID NO:17, or an amino acid sequence having one or more conserved amino acid substitutions with the sequence shown in SEQ ID NO:17.
  • the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment comprises the amino acid sequence shown in SEQ ID NO:18, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the sequence shown in SEQ ID NO:18, or an amino acid sequence having one or more conserved amino acid substitutions with the sequence shown in SEQ ID NO:18.
  • the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment contains the amino acid sequence shown in SEQ ID NO:17, and/or the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment contains the amino acid sequence shown in SEQ ID NO:18.
  • the heavy chain of the anti-PD-1 antibody comprises an amino acid sequence as shown in SEQ ID NO:19, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the sequence shown in SEQ ID NO:19, or an amino acid sequence having one or more conserved amino acid substitutions with the sequence shown in SEQ ID NO:19.
  • the light chain of the anti-PD-1 antibody comprises an amino acid sequence as shown in SEQ ID NO:20, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the sequence shown in SEQ ID NO:20, or an amino acid sequence having one or more conserved amino acid substitutions with the sequence shown in SEQ ID NO:20.
  • the heavy chain of the anti-PD-1 antibody comprises the amino acid sequence shown in SEQ ID NO:19, and/or the light chain of the anti-PD-1 antibody comprises the amino acid sequence shown in SEQ ID NO:20. In some embodiments, the anti-PD-1 antibody comprises two identical heavy chains and two identical light chains.
  • the anti-PD-1 antibody is antibody A.
  • the heavy chain of the anti-TIGIT antibody comprises the amino acid sequence shown in SEQ ID NO:9 and the light chain comprises the amino acid sequence shown in SEQ ID NO:10
  • the heavy chain of the anti-PD-1 antibody comprises the amino acid sequence shown in SEQ ID NO:19 and the light chain comprises the amino acid sequence shown in SEQ ID NO:20
  • the tumor is selected from gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer and hepatocellular carcinoma.
  • the effective amount refers to the amount of an active compound or agent that elicits a biological or pharmaceutical response in an tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician, including the treatment of a disease such as cancer.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at doses 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.
  • 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 (including endpoints) of any two of these values, or any value thereof.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at a dose of about 600 mg or about 900 mg per treatment cycle.
  • the anti-TIGIT antibody or antigen-binding fragment is administered at doses of about 0.01 mg/kg to 20 mg/kg, about 0.01 mg/kg to 0.05 mg/kg, about 0.01 mg/kg to 0.06 mg/kg, about 0.1 mg/kg to 0.2 mg/kg, about 0.1 mg/kg to 0.5 mg/kg, about 0.1 mg/kg to 0.6 mg/kg, about 1 mg/kg to 2 mg/kg, about 1 mg/kg to 5 mg/kg, about 1 mg/kg to 6 mg/kg, about 10 mg/kg to 12 mg/kg, about 12 mg/kg to 15 mg/kg, about 15 mg/kg to 18 mg/kg, or about 18 mg/kg to 20 mg/kg per treatment cycle.
  • 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 (including endpoints) of any two of these values, or any value therein.
  • 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.
  • a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range (including endpoints) between any two of these values, or any value therein.
  • the anti-TIGIT antibody or antigen-binding fragment is administered once daily to once every 7 weeks.
  • the anti-TIGIT antibody or antigen-binding fragment is administered once weekly, 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.
  • the anti-TIGIT antibody or antigen-binding fragment is administered once daily to once every 7 weeks, with each dose being 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.
  • the anti-TIGIT antibody or antigen-binding fragment is administered once daily to once every 7 weeks, with each dose being 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 (including endpoints) of any two of these values, or any value therein.
  • the anti-TIGIT antibody or antigen-binding fragment is administered approximately every 3 weeks, with each dose being approximately 0.01-1200 mg, approximately 0.01-1 mg, approximately 1-3 mg, approximately 1-5 mg, approximately 1-10 mg, approximately 3-10 mg, approximately 10-30 mg, approximately 10-50 mg, 10-100 mg, approximately 100-300 mg, approximately 100-500 mg, approximately 100-600 mg, approximately 300-600 mg, approximately 100-900 mg, approximately 600-900 mg, approximately 100-1000 mg, or approximately 1000-1200 mg.
  • the anti-TIGIT antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 0.01 mg, approximately 1 mg, approximately 3 mg, approximately 5 mg, approximately 10 mg, approximately 30 mg, approximately 50 mg, approximately 100 mg, approximately 300 mg, approximately 500 mg, approximately 600 mg, approximately 900 mg, approximately 1000 mg, or approximately 1200 mg, or a range (including endpoints) of any two of these values, or any value thereof.
  • 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-TIGIT antibody or antigen-binding fragment is administered approximately every 3 weeks at doses of approximately 0.01 mg/kg-20 mg/kg, approximately 0.01 mg/kg-0.05 mg/kg, approximately 0.01 mg/kg-0.06 mg/kg, approximately 0.1 mg/kg-0.2 mg/kg, approximately 0.1 mg/kg-0.5 mg/kg, approximately 0.1 mg/kg-0.6 mg/kg, approximately 1 mg/kg-2 mg/kg, approximately 1 mg/kg-5 mg/kg, approximately 1 mg/kg-6 mg/kg, approximately 10 mg/kg-12 mg/kg, approximately 12 mg/kg-15 mg/kg, approximately 15 mg/kg-18 mg/kg, or approximately 18 mg/kg-20 mg/kg.
  • the anti-TIGIT antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 0.01 mg/kg, approximately 0.05 mg/kg, approximately 0.06 mg/kg, approximately 0.1 mg/kg, approximately 0.2 mg/kg, approximately 0.5 mg/kg, approximately 0.6 mg/kg, approximately 1 mg/kg, approximately 2 mg/kg, approximately 5 mg/kg, approximately 6 mg/kg, approximately 10 mg/kg, approximately 12 mg/kg, approximately 15 mg/kg, approximately 18 mg/kg, or approximately 20 mg/kg, or a range (including endpoints) of any two of these values, or any value thereof.
  • the anti-TIGIT antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 12 mg/kg or approximately 18 mg/kg.
  • the anti-TIGIT antibody or antigen-binding fragment is administered approximately every 3 weeks, with each dose being approximately 600 mg or approximately 900 mg, wherein the anti-TIGIT antibody or antigen-binding fragment is antibody h10D8OF.
  • the anti-PD-1 antibody or antigen-binding fragment is administered at doses 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.
  • 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 (including endpoints) of any two of these values, or any value thereof. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered at a dose of about 300 mg per treatment cycle.
  • the dosage of the anti-PD-1 antibody or antigen-binding fragment is 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.
  • 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 (including endpoints) of any two of these values, or any value thereof. 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.
  • the anti-PD-1 antibody or antigen-binding fragment is administered once daily to once every 7 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered once weekly, 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.
  • the anti-PD-1 antibody or antigen-binding fragment is administered once daily to once every 7 weeks, with each dose being 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.
  • the anti-PD-1 antibody or antigen-binding fragment is administered once daily to once every 7 weeks, with each dose being 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 (including endpoints) of any two of these values, or any value therein.
  • the anti-PD-1 antibody or antigen-binding fragment is administered approximately every 3 weeks, with each dose being approximately 1-1000 mg, approximately 1-10 mg, approximately 1-50 mg, approximately 1-100 mg, approximately 1-200 mg, approximately 1-240 mg, approximately 1-300 mg, approximately 1-600 mg, approximately 100-300 mg, approximately 100-500 mg, approximately 100-600 mg, 100-900 mg, approximately 300-600 mg, approximately 300-900 mg, approximately 600-900 mg, or approximately 900-1000 mg.
  • the anti-PD-1 antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 1 mg, approximately 10 mg, approximately 50 mg, approximately 100 mg, approximately 200 mg, approximately 240 mg, approximately 300 mg, approximately 500 mg, approximately 600 mg, approximately 900 mg, or approximately 1000 mg, or a range (including endpoints) of any two of these values, or any value thereof. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 300 mg.
  • the anti-PD-1 antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 0.01 mg/kg-20 mg/kg, approximately 0.01 mg/kg-1 mg/kg, approximately 1 mg/kg-2 mg/kg, approximately 1 mg/kg-3 mg/kg, approximately 1 mg/kg-5 mg/kg, approximately 1 mg/kg-6 mg/kg, approximately 1 mg/kg-10 mg/kg, approximately 2 mg/kg-6 mg/kg, approximately 6 mg/kg-12 mg/kg, approximately 10 mg/kg-12 mg/kg, approximately 12 mg/kg-15 mg/kg, or approximately 12 mg/kg-20 mg/kg.
  • the anti-PD-1 antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 0.01 mg/kg, approximately 1 mg/kg, approximately 2 mg/kg, approximately 3 mg/kg, approximately 5 mg/kg, approximately 6 mg/kg, approximately 10 mg/kg, approximately 12 mg/kg, approximately 15 mg/kg, or approximately 20 mg/kg, or a range (including endpoints) of any two of these values, or any value thereof. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered approximately every 3 weeks at a dose of approximately 6 mg/kg.
  • the anti-PD-1 antibody or antigen-binding fragment is administered approximately every 3 weeks, with each dose being approximately 300 mg, wherein the anti-PD-1 antibody or antigen-binding fragment is antibody A.
  • the antibody h10D8OF and antibody A are administered approximately every 3 weeks, with each dose of antibody h10D8OF being approximately 600 mg or approximately 900 mg and each dose of antibody A being approximately 300 mg.
  • the tumor is selected from gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular carcinoma.
  • the patient receives one treatment cycle. In some implementations, the patient receives multiple treatment cycles (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 endpoints) or any of these values). In some implementations, the patient receives treatment until the symptoms are relieved and treatment is no longer required.
  • the term "combination" as used herein refers to a route of administration that includes various situations in which two or more drugs are administered sequentially or simultaneously.
  • the anti-TIGIT antibody or antigen-binding fragment and the anti-PD-1 antibody or antigen-binding fragment are prepared as a single pharmaceutical composition and administered simultaneously to a patient in need.
  • 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, or administered at different times during treatment.
  • the anti-TIGIT antibody or antigen-binding fragment may be administered before, after, or in an alternating manner with the anti-PD-1 antibody or antigen-binding fragment.
  • the anti-TIGIT antibody or antigen-binding fragment and the anti-PD-1 antibody or antigen-binding fragment may be administered to patients in need in a single dose or multiple doses.
  • the anti-PD-1 antibody or antigen-binding fragment is administered after the patient in need has been given the anti-TIGIT antibody or antigen-binding fragment.
  • an anti-TIGIT antibody or antigen-binding fragment wherein the anti-TIGIT antibody or antigen-binding fragment is antibody h10D8OF, is administered approximately every 3 weeks at a dose of approximately 600 mg or approximately 900 mg, and wherein the anti-PD-1 antibody or antigen-binding fragment is antibody A, is administered approximately every 3 weeks at a dose of approximately 300 mg.
  • the anti-TIGIT antibody or antigen-binding fragment (or formulation) and/or anti-PD-1 antibody or antigen-binding fragment (or formulation) are administered by injection or infusion.
  • the anti-TIGIT antibody or antigen-binding fragment (or formulation) or anti-PD-1 antibody or antigen-binding fragment (or formulation) is administered via subcutaneous (s.c.) injection, intraperitoneal (i.p.) injection, parenteral injection, intra-arterial injection, or intravenous (i.v.) infusion (i.e., intravenous infusion).
  • the dosage of the anti-TIGIT antibody or antigen-binding fragment and the anti-PD-1 antibody or antigen-binding fragment will depend on the nature of the drug, the extent to which cell surface triggers drug internalization, transport, and release, and the disease being treated and the patient's condition (e.g., age, sex, weight, etc.).
  • the anti-TIGIT antibody or antigen-binding fragment (or formulation) and/or anti-PD-1 antibody or antigen-binding fragment (or formulation) are administered by intravenous infusion.
  • the intravenous infusion duration of the anti-TIGIT antibody or antigen-binding fragment (or formulation) is approximately 30 to 120 minutes, for example, approximately 30 minutes, approximately 35 minutes, approximately 40 minutes, approximately 45 minutes, approximately 50 minutes, approximately 55 minutes, approximately 60 minutes, approximately 65 minutes, approximately 70 minutes, approximately 75 minutes, approximately 80 minutes, approximately 85 minutes, approximately 90 minutes, approximately 95 minutes, approximately 100 minutes, approximately 105 minutes, approximately 110 minutes, approximately 105 minutes, approximately 120 minutes, or a range (including endpoints) of any two of these values, or any value thereof.
  • the intravenous infusion time of the anti-TIGIT antibody or antigen-binding fragment (or formulation) is approximately 30 to 60 minutes. In some embodiments, the intravenous infusion time of the anti-TIGIT antibody or antigen-binding fragment (or formulation) is 60 ( ⁇ 10) minutes.
  • the intravenous infusion duration of the anti-PD-1 antibody or antigen-binding fragment (or formulation) is approximately 30 to 120 minutes, for example, approximately 30 minutes, approximately 35 minutes, approximately 40 minutes, approximately 45 minutes, approximately 50 minutes, approximately 55 minutes, approximately 60 minutes, approximately 65 minutes, approximately 70 minutes, approximately 75 minutes, approximately 80 minutes, approximately 85 minutes, approximately 90 minutes, approximately 95 minutes, approximately 100 minutes, approximately 105 minutes, approximately 110 minutes, approximately 105 minutes, or approximately 120 minutes, or a range (including endpoints) between any two of these values, or any value therein.
  • the intravenous infusion time of the anti-PD-1 antibody or antigen-binding fragment (or formulation) is approximately 30 to 60 minutes. In some embodiments, the intravenous infusion time of the anti-PD-1 antibody or antigen-binding fragment (or formulation) is 60 ( ⁇ 10) minutes.
  • the anti-TIGIT antibody or antigen-binding fragment, or the anti-PD-1 antibody or antigen-binding fragment can be further used in combination with other treatment methods for treating tumors, such as chemotherapy, radiotherapy, and surgery.
  • the anti-TIGIT antibody or antigen-binding fragment, or the anti-PD-1 antibody or antigen-binding fragment may be further used in combination with one or more chemotherapeutic agents for the treatment of tumors.
  • the tumor is a hematologic cancer or a solid tumor; or, the tumor is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myeloproliferative disorders/tumors, Hodgkin lymphoma, painless and aggressive non-Hodgkin lymphoma, Burkitt lymphoma, follicular lymphoma, multiple myeloma, giant cell myeloma, heavy chain myeloma, light chain or Bens-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.
  • acute lymphoblastic leukemia acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelop
  • the tumor is selected from gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular carcinoma.
  • the chemotherapeutic agent includes capecitabine, taxane, or platinum-based drugs or combinations thereof.
  • the platinum-based drug is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatinum tetranitrate, phenanthreneplatin, pyridine, lipopyram, or saxaplatin.
  • the chemotherapeutic agent is a combination of platinum-based drugs and capecitabine.
  • the chemotherapeutic agent is oxaliplatin in combination with capecitabine.
  • the chemotherapeutic agent is capecitabine.
  • the antibody h10D8OF and antibody A are further combined with oxaliplatin and capecitabine for the treatment of tumors.
  • the tumor is selected from gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular carcinoma.
  • the antibody h10D8OF and antibody A are further combined with capecitabine for the treatment of tumors.
  • the tumor is selected from gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular carcinoma.
  • patients receive the first 6 cycles of treatment with antibody h10D8OF and antibody A plus oxaliplatin and capecitabine. In some implementations, after the first 6 cycles of treatment with antibody h10D8OF and antibody A plus oxaliplatin and capecitabine, patients receive antibody h10D8OF and antibody A treatment, or receive capecitabine treatment alone.
  • oxaliplatin is administered at a dose of approximately 50-300 mg/ m2 of body surface area. In some embodiments, oxaliplatin is administered at a dose of approximately 85-130 mg/ m2 of body surface area. In some embodiments, oxaliplatin is administered at a dose of approximately 50 mg/ m2 , approximately 85 mg/ m2 , approximately 100 mg/ m2 , approximately 130 mg/ m2 , approximately 150 mg/ m2 , approximately 175 mg/ m2 , approximately 200 mg/ m2 , approximately 250 mg/ m2 , or approximately 300 mg/ m2 of body surface area, or a range (including endpoints) or any of these values.
  • oxaliplatin is administered at a dose of approximately 130 mg/ m2 of body surface area. In some embodiments, oxaliplatin is administered once weekly, every 2 weeks, every 3 weeks, or every 4 weeks. In some implementations, oxaliplatin is administered once every 3 weeks. In some implementations, oxaliplatin is administered at a dose of approximately 130 mg/ m2 per body surface area, once every 3 weeks.
  • oxaliplatin is administered intravenously at a dose of approximately 130 mg/ m2 per body surface area, once every 3 weeks.
  • capecitabine is administered at a dose of approximately 100-2000 mg/ m2 of body surface area. In some embodiments, capecitabine is administered at a dose of approximately 100 mg/ m2 , approximately 500 mg/ m2 , approximately 1000 mg/ m2 , approximately 1250 mg/ m2 , approximately 1500 mg/ m2 , approximately 1750 mg/ m2 , or approximately 2000 mg/ m2 of body surface area, or a range (including endpoints) or any of these values. In some embodiments, capecitabine is administered at a dose of approximately 1000 mg/ m2 of body surface area. In some embodiments, capecitabine is administered once daily for 1 week; once daily for 2 weeks; or once daily for 3 weeks.
  • capecitabine is administered twice daily for 2 weeks; twice daily for 2 weeks; or twice daily for 3 weeks.
  • a treatment cycle consists of 3 weeks, with capecitabine administered twice daily for 2 weeks, followed by a 1-week rest period.
  • a treatment cycle consists of 3 weeks, with capecitabine administered at a dose of approximately 1000 mg/ m2 per body surface area, twice daily for 2 weeks, followed by a 1-week rest period.
  • capecitabine is administered orally at a dose of approximately 1000 mg/ m2 per body surface area, with each treatment cycle lasting 3 weeks, administered twice daily on days 1-14 of each cycle.
  • 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, wherein:
  • the patient is administered a combination of: the anti-TIGIT antibody or antigen-binding fragment and the anti-PD-1 antibody or antigen-binding fragment; and/or
  • the patient is given at least one treatment cycle the following: the anti-TIGIT antibody or antigen-binding fragment, the anti-PD-1 antibody or antigen-binding fragment, and capecitabine.
  • 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, wherein:
  • the patient is administered a combination of: the anti-TIGIT antibody or antigen-binding fragment, the anti-PD-1 antibody or antigen-binding fragment, oxaliplatin, and capecitabine; and/or
  • the patient is administered a combination of: the anti-TIGIT antibody or antigen-binding fragment, the anti-PD-1 antibody or antigen-binding fragment, and capecitabine; or
  • the patient is administered an anti-TIGIT antibody or antigen-binding fragment and an anti-PD-1 antibody or antigen-binding fragment.
  • 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:
  • the patient is given the following medications for at least one treatment cycle: 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; and capecitabine is administered at a dose of approximately 1000 mg/ m2 per body surface area, twice daily on days 1-14 of each cycle.
  • 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:
  • 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 of body surface area every 3 weeks; capecitabine is administered at a dose of approximately 1000 mg/ m2 of body surface area twice daily on days 1–14 of each cycle; and/or
  • 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 of body surface area, administered twice daily on days 1-14 of each cycle; or
  • 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.
  • the method or use of treating tumors includes administering one or more treatment cycles of the antibody h10D8OF and antibody A to a patient, with each treatment cycle consisting of 3 weeks, wherein:
  • the patient is given the following: the antibody h10D8OF is administered approximately every 3 weeks at a dose of approximately 600 mg or approximately 900 mg; the antibody A is administered approximately every 3 weeks at a dose of approximately 300 mg; oxaliplatin is administered at a dose of approximately 130 mg/ m2 of body surface area every 3 weeks; capecitabine is administered at a dose of approximately 1000 mg/ m2 of body surface area twice daily on days 1–14 of each cycle; and/or
  • the patient shall be administered the following: the antibody h10D8OF, administered approximately every 3 weeks at a dose of approximately 600 mg or approximately 900 mg; the antibody A, administered approximately every 3 weeks at a dose of approximately 300 mg; capecitabine , administered at a dose of approximately 1000 mg/m2 per body surface area, twice daily on days 1-14 of each cycle; or
  • the patient is given the following: the antibody h10D8OF is administered approximately every 3 weeks at a dose of approximately 600 mg or approximately 900 mg; the antibody A is administered approximately every 3 weeks at a dose of approximately 300 mg.
  • the method or use of treating tumors includes administering one or more treatment cycles of antibody h10D8OF and antibody A to a patient, with each treatment cycle consisting of 3 weeks, wherein:
  • the patient is administered the following: the antibody h10D8OF is administered approximately every 3 weeks at a dose of approximately 600 mg or approximately 900 mg; the antibody A is administered approximately every 3 weeks at a dose of approximately 300 mg; oxaliplatin is administered at a dose of approximately 130 mg/ m2 of body surface area every 3 weeks; capecitabine is administered at a dose of approximately 1000 mg/ m2 of body surface area twice daily on days 1–14 of each cycle; and/or
  • the patient is administered the following: the antibody h10D8OF is administered approximately every 3 weeks at a dose of approximately 600 mg or approximately 900 mg; the antibody A is administered approximately every 3 weeks at a dose of approximately 300 mg; capecitabine is administered at a dose of approximately 1000 mg/ m2 of body surface area, twice daily on days 1-14 of each cycle; or
  • the patient is administered the following: the antibody h10D8OF is administered approximately every 3 weeks at a dose of approximately 600 mg or approximately 900 mg; the antibody A is administered approximately every 3 weeks at a dose of approximately 300 mg.
  • the tumor is selected from gastric cancer, gastroesophageal junction cancer, esophageal cancer, non-small cell lung cancer, and hepatocellular carcinoma.
  • an entity “a” refers to one or more of the same entity.
  • an antibody should be understood as one or more antibodies. Therefore, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably in this document.
  • compositions and methods include the listed elements, such as components or steps, but do not exclude others. “consistently composed of” means that compositions and methods exclude other elements that have a fundamental effect on the characteristics of the composition, but do not exclude elements that do not substantially affect the composition or method. “composed of” means excluding elements not specifically listed.
  • Approximately refers to a typical error range for a given value that is readily known to those skilled in the art. In some embodiments, “approximately” as used herein refers to the described value and its range of ⁇ 10%, ⁇ 5%, or ⁇ 1%.
  • TIGIT T cell immunoreceptor with Ig and ITIM domains
  • Ig immunoglobulin
  • ITIM tyrosine inhibitor motif
  • PD-1 Programmed death 1
  • programmed death receptor 1 also known as programmed death receptor 1
  • PD-1 and PD-L1 are members of the CD28 immunoglobulin superfamily.
  • the interaction between PD-1 and its ligand PD-L1 negatively regulates antigen receptor signaling and weakens T cell responses.
  • Numerous studies to date have shown that the interaction between PD-1 and PD-L1 leads to a reduction in lymphocytes infiltrating tumors, a decrease in T cell receptor-mediated proliferation, and immune evasion by cancer cells.
  • Blocking the interaction between PD-1 and PD-L1 has been shown to increase T cell proliferation and cytokine production, enhance the immunity of tumor-specific CD8+ T cells, and thus help the immune system clear tumor cells.
  • Antibody or "antigen-binding fragment” refers to a polypeptide or polypeptide complex that specifically recognizes and binds to an antigen.
  • An antibody can be a complete antibody, any antigen-binding fragment, or a single chain thereof. Therefore, the term “antibody” includes any protein or peptide containing at least a portion of an immunoglobulin molecule that has biological activity of binding to an antigen.
  • Antibody and antigen-binding fragments include, but are not limited to, the complementarity-determining region (CDR), heavy chain variable region (VH), light chain variable region (VL), heavy chain constant region (CH), light chain constant region (CL), framework region (FR), or any portion thereof of the heavy chain or light chain or its ligand-binding moiety, or at least a portion of the binding protein.
  • the CDR region includes the CDR regions of the light chain (LCDR1-3) and the CDR regions of the heavy chain (HCDR1-3).
  • the antibodies, antigen-binding fragments or derivatives described herein include, but are not limited to, polyclonal, monoclonal, multispecific, fully human, humanized, primate-derived, chimeric antibodies, single-chain antibodies (scFv), and epitope-binding fragments (e.g., Fab, Fab', and F(ab') 2 ).
  • DNA encoding the antibody can be designed and synthesized according to the antibody amino acid sequence described herein using conventional methods. This DNA can then be placed into an expression vector, transfected into host cells, and cultured in a culture medium to produce monoclonal antibodies.
  • the antibody expression vector includes at least one promoter element, an antibody-coding sequence, a transcription termination signal, and a polyA tail. Other elements include an enhancer, a Kozak sequence, and donor and acceptor sites for RNA splicing flanking the insert sequence.
  • Efficient transcription can be achieved using early and late promoters of SV40, early promoters from long terminal repeat sequences of retroviruses such as RSV, HTLV1, HIV, and cytomegalovirus, or other cellular promoters such as the actin promoter.
  • Suitable expression vectors may 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, etc.
  • Commonly used mammalian cell lines include HEK293 cells, Cos1 cells, Cos7 cells, CV1 cells, mouse L cells, and CHO cells, etc.
  • Treatment refers to therapeutic treatments and preventative or preventative measures aimed at preventing, mitigating, improving, and stopping adverse physiological changes or disorders, such as disease progression, including but not limited to the following, whether detectable or undetectable: symptom relief, reduction in disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or mitigation of the disease state, reduction or disappearance (whether partial or complete), and prolongation of expected survival without treatment.
  • Patients requiring treatment include those already suffering from the condition or disorder, those susceptible to the condition or disorder, or those needing prevention of the condition or disorder, as well as those who can or are expected to benefit from the application of the antibodies or compositions of the present invention for detection, diagnostic procedures, and/or treatment.
  • Need means that the patient has been identified as requiring a specific method or treatment. In some embodiments, this identification can be made through any diagnostic approach. The patient may require any of the methods and treatments described herein.
  • Patient refers to any mammal requiring diagnosis, prognosis, or treatment, including humans, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, etc. In some implementations, the patient is a human.
  • Combination therapy includes two or more drugs, which may form independent dosing units or together form a combined dosing unit.
  • combination therapy includes separate anti-TIGIT antibody or antigen-binding fragments and anti-PD-1 or antigen-binding fragments.
  • combination therapy includes a composition of anti-TIGIT antibody or antigen-binding fragments and anti-PD-1 or antigen-binding fragments.
  • combination therapy includes separate anti-TIGIT antibody or antigen-binding fragments, anti-PD-1 or antigen-binding fragments, and a chemotherapeutic agent.
  • combination therapy includes separate anti-TIGIT antibody or antigen-binding fragments, anti-PD-1 or antigen-binding fragments, oxaliplatin, and capecitabine.
  • the different drugs when administering combination therapy, may be administered simultaneously or separately.
  • Effective dose refers to the amount of a drug, such as an anti-TIGIT antibody or antigen-binding fragment or an anti-PD-1 antibody or antigen-binding fragment, sufficient to reduce or improve the severity and/or duration of a condition (e.g., cancer) or one or more of its symptoms; prevent disease progression; induce disease remission; prevent recurrence, development, onset, or progression of one or more symptoms associated with the condition; detect the condition; or enhance or improve the preventive or therapeutic effect of another therapy (e.g., a prophylactic or therapeutic agent).
  • a condition e.g., cancer
  • an effective dose 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 the increase in tumor volume); reduce tumor growth (e.g., reduce tumor volume); reduce the number of cancer cells; and/or alleviate one or more symptoms associated with the cancer to some extent.
  • an effective dose 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 relapse.
  • PFS progression-free survival
  • OS overall survival
  • ORR improve objective response rate
  • DoR improve duration of response
  • DCR disease control rate
  • Administration refers to the application of a substance to achieve a therapeutic purpose (e.g., treating a tumor).
  • Administration can be parenteral, intravenous, or local.
  • Parenteral administration is typically via injection, including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-bursal, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.
  • the evaluation of antitumor efficacy can be carried out by imaging assessment (CT/MRI), physical examination and survival assessment; the indicators of antitumor efficacy include: objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) based on imaging efficacy assessment using CT/MRI as the main evaluation means, according to RECIST 1.1 evaluation criteria (Eisenhauer, EA et al., Eur J Cancer. 2009; 45(2):228-247).
  • ORR objective response rate
  • DoR duration of response
  • DCR disease control rate
  • PFS progression-free survival
  • OS overall survival
  • Objective response rate This refers to the proportion of patients whose tumors shrink to a certain extent and remain so for a certain period of time, including cases of complete response (CR) and partial response (PR).
  • the objective response rate is the proportion of patients who achieve PR or CR at the end of a certain treatment period, such as the first 6 cycles of treatment.
  • the objective response rate is the proportion of patients who achieve PR or CR with the best response throughout the study period.
  • DoR Duration of Response
  • DCR Disease control rate
  • PFS Progression-free survival
  • OS Overall survival
  • MTD Maximum Tolerated Dose
  • DLT dose-limiting toxicity
  • the Eastern Cooperative Oncology Group (ECOG) has developed a simplified activity status scoring system that classifies patients’ activity status into 6 levels from 0 to 5.
  • the ECOG activity status scoring system is scored as 0, 1, 2, 3, 4, and 5.
  • PK pharmacokinetic
  • Example 1 Method for preparing antibodies
  • the DNA sequences encoding the heavy and light chains of the antibody are cloned into an expression vector, then transformed into host cells, cultured, and purified to obtain the antibody.
  • the amino acid sequences of antibody h10D8OF and antibody A are shown in Tables 1 and 2, respectively.
  • the heavy chain of antibody h10D8OF is shown in SEQ ID NO:9, and the light chain in SEQ ID NO:10; the heavy chain of antibody A is shown in SEQ ID NO:19, and the light chain in SEQ ID NO:20. Both antibody h10D8OF and antibody A were expressed using CHO cells during preparation.
  • Example 2 A multicenter, open-label phase Ib/IIa clinical study of the safety, tolerability, pharmacokinetic characteristics, and preliminary clinical efficacy of antibody A injection combined with antibody h10D8OF injection in patients with locally advanced or metastatic solid tumors.
  • Antibody A 300mg
  • Antibody h10D8OF 600mg or 900mg
  • Antibody A injection is administered at a fixed dose of 300 mg.
  • Antibody h10D8OF injection is administered in two dose groups: Group A (600 mg) and Group B (900 mg).
  • Antibody A 300mg
  • Antibody h10D8OF 600mg or 900mg
  • Oxaliplatin Capecitabine
  • patients with gastric cancer, gastroesophageal junction cancer, and esophageal cancer received antibody A injection combined with antibody h10D8OF injection plus chemotherapy (oxaliplatin [130mg/m2 IV Q3W] and oral capecitabine [1000mg/ m2 BID, days 1-14, Q3W]) for the first 6 cycles.
  • Subsequent treatment cycles received antibody A injection combined with antibody h10D8OF injection ⁇ capecitabine. Whether capecitabine was used after the 6th cycle was adjusted according to the actual situation.
  • Antibody A injection administration regimen Intravenous infusion, once every 3 weeks (Q3W). In phase Ib studies, the infusion time is 60 ( ⁇ 10) minutes; in phase II studies, chemotherapy should be administered first before infusion, and the recommended infusion time is 30–60 minutes.
  • Dosage regimen for antibody h10D8OF injection Intravenous infusion should begin 30 ( ⁇ 10) minutes after the completion of antibody A injection, administered once every 3 weeks (Q3W). In Phase Ib studies, the infusion duration was 60 ( ⁇ 10) minutes; in Phase II studies, an infusion duration of 30–60 minutes is recommended. If no infusion-related reactions are observed, subsequent infusion times can be adjusted to 30 minutes to 2 hours based on clinical circumstances.
  • Stage Ib Patients with advanced malignant tumors diagnosed by cytology or pathology who have failed standard treatment, have no standard treatment available, are intolerant to standard treatment, or refuse standard treatment;
  • Phase II Cohort 1 Locally advanced unresectable or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal cancer that have not previously received systemic therapy: PD-L1 CPS ⁇ 5 and HER2 negative tumor tissue test;
  • Phase II Cohort 2 Patients with histologically or cytologically confirmed locally advanced or metastatic (refer to AJCC 8th Edition Manual of Tumor Staging) NSCLC:
  • Phase II Cohort 3 Patients with advanced HCC diagnosed by pathology or clinical diagnosis who have experienced disease progression or are unable to receive standard treatment after systemic therapy with PD-1/PD-L1 antibodies and targeted drugs, and whose Child-Pugh liver function is grade A or better grade B ( ⁇ 7 points).
  • Eastern Cooperative Oncology Group (ECOG) performance status score is 0 or 1;
  • the first study dose is given within 4 weeks or 5 half-lives (whichever is longer) of the previous anti-tumor treatment (chemotherapy, endocrine therapy, targeted therapy), or within 4 weeks of the last large-area radiotherapy (2 weeks for palliative radiotherapy for bone metastases), or within 2 weeks of the last treatment with traditional Chinese medicine/immunomodulatory drugs with anti-tumor indications (including thymopeptide, interferon, interleukin, etc.), or within 8 weeks of the last radiotherapy.
  • Patients with primary central nervous system tumors, those with meningeal metastases, or those with symptomatic central nervous system metastases must be excluded.
  • Asymptomatic patients with clinically controlled central nervous system metastases, or those with symptomatic but stable conditions, may be included, provided they meet the following criteria: a. Disease stability ⁇ 4 weeks prior to first administration; b. No evidence of central nervous system disease progression on plain/enhanced MRI within 4 weeks prior to first administration; c. Discontinuation of antiepileptic drugs and prednisone dosage ⁇ 10 mg/day or equivalent dose of hormones ⁇ 2 weeks prior to first administration.
  • HIV human immunodeficiency virus
  • HBV Hepatitis B virus
  • HCV hepatitis C virus
  • tuberculosis Patients with tuberculosis who are either untreated or under treatment, including but not limited to pulmonary tuberculosis; those who have undergone standard anti-tuberculosis treatment and have been confirmed to be cured may be included;
  • Severe cardiovascular disease New York Heart Association (NYHA) class III or higher heart failure, left ventricular ejection fraction (LVEF) ⁇ 50%, unstable angina, uncontrolled hypertension (defined in this protocol as systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg after optimal antihypertensive treatment), history of myocardial infarction within the past 6 months, or severe arrhythmia requiring medication (atrial fibrillation or supraventricular tachycardia will be determined by the investigator for inclusion).
  • NYHA New York Heart Association
  • LVEF left ventricular ejection fraction
  • the primary objective of the Phase Ib study was to evaluate the safety and tolerability of the combined administration of antibody A injection and antibody h10D8OF injection in patients with locally advanced or metastatic solid tumors, providing recommended dosages for subsequent clinical trials. Secondary objectives included: preliminary evaluation of the antitumor efficacy of antibody A injection and antibody h10D8OF injection in the combined administration regimen; evaluation of the pharmacokinetic (PK) characteristics of single-dose and multiple-dose administration of antibody A injection and antibody h10D8OF injection in patients with advanced solid tumors in the combined administration regimen; and evaluation of the immunogenicity of BA1308 and antibody h10D8OF injection in the combined administration regimen.
  • PK pharmacokinetic
  • the primary objective of the Phase II study was to evaluate the safety and preliminary antitumor efficacy of antibody A injection and antibody h10D8OF injection in combination with chemotherapy in advanced gastric cancer, gastroesophageal junction cancer, and esophageal cancer, as well as the safety and preliminary efficacy of antibody A injection and antibody h10D8OF injection in advanced non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), and to provide recommended dosages for subsequent clinical trials.
  • NSCLC non-small cell lung cancer
  • HCC hepatocellular carcinoma
  • the secondary objective was to evaluate the pharmacokinetic (PK) characteristics of single-dose and multiple-dose administration of antibody A injection and antibody h10D8OF injection in combination with chemotherapy in patients with advanced gastric cancer, gastroesophageal junction cancer, and esophageal cancer, as well as in patients with advanced non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC); and to evaluate the immunogenicity of antibody A injection and antibody h10D8OF injection in combination with chemotherapy in patients with advanced gastric cancer, gastroesophageal junction cancer, and esophageal cancer, as well as in patients with advanced non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC).
  • PK pharmacokinetic
  • the primary endpoint was a safety endpoint: vital signs and physical examination, adverse events (AEs), clinical laboratory tests, and clinical ancillary tests (such as electrocardiogram).
  • AEs adverse events
  • clinical laboratory tests such as electrocardiogram
  • Preliminary efficacy evaluation based on the RECIST V1.1 criteria for evaluating the efficacy of treatment in solid tumors Key endpoints include: objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
  • ORR objective response rate
  • DoR duration of response
  • DCR disease control rate
  • PFS progression-free survival
  • OS overall survival
  • the combined administration regimen of antibody A injection and antibody h10D8OF injection of the present invention is expected to have good safety and tolerability, or result in improvements selected from at least one of the following: objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
  • ORR objective response rate
  • DoR duration of response
  • DCR disease control rate
  • PFS progression-free survival
  • OS overall survival

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Abstract

La présente invention concerne l'utilisation d'un anticorps anti-TIGIT ou d'un fragment de liaison à l'antigène et d'un anticorps anti-PD-1 ou d'un fragment de liaison à l'antigène dans la préparation de médicaments pour le traitement de tumeurs.
PCT/CN2025/096706 2024-05-24 2025-05-23 Traitement de tumeurs au moyen d'un anticorps anti-tigit en combinaison avec un anticorps anti-pd-1 Pending WO2025242190A1 (fr)

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CN202410659012.9A CN121003695A (zh) 2024-05-24 2024-05-24 抗tigit抗体和抗pd-1抗体联合治疗肿瘤

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018204405A1 (fr) * 2017-05-02 2018-11-08 Merck Sharp & Dohme Corp. Formulations stables d'anticorps anti-tigit seuls et en association avec des anticorps du récepteur de mort programmée 1 (pd-1) et leurs procédés d'utilisation
WO2020020281A1 (fr) * 2018-07-25 2020-01-30 信达生物制药(苏州)有限公司 Anticorps anti-tigit et ses utilisations
CN111744013A (zh) * 2019-03-29 2020-10-09 江苏恒瑞医药股份有限公司 抗tigit抗体联合pd-1抑制剂治疗疾病的方法和药物组合
CN114206929A (zh) * 2019-09-03 2022-03-18 百奥泰生物制药股份有限公司 一种抗tigit免疫抑制剂及应用
CN114984227A (zh) * 2021-03-02 2022-09-02 百奥泰生物制药股份有限公司 抗tigit抗体在联合用药中的应用
CN115315256A (zh) * 2020-01-27 2022-11-08 基因泰克公司 用抗tigit拮抗剂抗体治疗癌症的方法
CN117177770A (zh) * 2021-01-21 2023-12-05 百济神州有限公司 使用抗tigit抗体与抗pd1抗体组合治疗癌症的方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018204405A1 (fr) * 2017-05-02 2018-11-08 Merck Sharp & Dohme Corp. Formulations stables d'anticorps anti-tigit seuls et en association avec des anticorps du récepteur de mort programmée 1 (pd-1) et leurs procédés d'utilisation
WO2020020281A1 (fr) * 2018-07-25 2020-01-30 信达生物制药(苏州)有限公司 Anticorps anti-tigit et ses utilisations
CN111744013A (zh) * 2019-03-29 2020-10-09 江苏恒瑞医药股份有限公司 抗tigit抗体联合pd-1抑制剂治疗疾病的方法和药物组合
CN114206929A (zh) * 2019-09-03 2022-03-18 百奥泰生物制药股份有限公司 一种抗tigit免疫抑制剂及应用
CN115315256A (zh) * 2020-01-27 2022-11-08 基因泰克公司 用抗tigit拮抗剂抗体治疗癌症的方法
CN117177770A (zh) * 2021-01-21 2023-12-05 百济神州有限公司 使用抗tigit抗体与抗pd1抗体组合治疗癌症的方法
CN114984227A (zh) * 2021-03-02 2022-09-02 百奥泰生物制药股份有限公司 抗tigit抗体在联合用药中的应用

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