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WO2023174408A1 - 抗tim-3抗体与抗pd-l1抗体的药物组合 - Google Patents

抗tim-3抗体与抗pd-l1抗体的药物组合 Download PDF

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Publication number
WO2023174408A1
WO2023174408A1 PCT/CN2023/082186 CN2023082186W WO2023174408A1 WO 2023174408 A1 WO2023174408 A1 WO 2023174408A1 CN 2023082186 W CN2023082186 W CN 2023082186W WO 2023174408 A1 WO2023174408 A1 WO 2023174408A1
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WO
WIPO (PCT)
Prior art keywords
antibody
antigen
binding fragment
amino acid
acid sequence
Prior art date
Application number
PCT/CN2023/082186
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English (en)
French (fr)
Inventor
桂在智
于鼎
王训强
孙达
董新军
田心
吕鹏
沈忱
王亮亮
Original Assignee
正大天晴药业集团南京顺欣制药有限公司
正大天晴药业集团股份有限公司
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Application filed by 正大天晴药业集团南京顺欣制药有限公司, 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团南京顺欣制药有限公司
Priority to CN202380027568.XA priority Critical patent/CN118871128A/zh
Publication of WO2023174408A1 publication Critical patent/WO2023174408A1/zh

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the present disclosure belongs to the field of biomedicine, and specifically relates to a pharmaceutical combination of anti-TIM-3 antibodies and anti-PD-L1 antibodies.
  • T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), also known as Hepatitis A Virus Cellular Receptor 2 (HAVCR2) , is a member of the TIM family of immunomodulatory proteins (the human TIM family includes TIM-1, 3, and 4).
  • TIM-3 is selectively expressed on the surface of activated Th1 cells, and is also expressed on myeloid cells, DC cells, NK cells, and macrophages. It is also expressed on a variety of tumor cells, such as melanoma, cervical cancer and renal cancer.
  • TIM-3 has a variety of different ligands, including galectin 9 (Galectin9), phosphatidylserine (PtdSer), high mobility group protein B1 (HMGB1) and carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1).
  • Galectin9 galectin 9
  • PtdSer phosphatidylserine
  • HMGB1 high mobility group protein B1
  • CEACAM1 carcinoembryonic antigen cell adhesion molecule 1
  • TIM-3 As an immune checkpoint, TIM-3's physiological function is to negatively regulate the body's immune function and avoid damage to the body caused by excessive immunity or autoimmunity.
  • TIM-3 protein and/or mRNA is up-regulated on a variety of tumor tissues and tumor-related immune cells, participates in tumor immune evasion and immune response, and promotes tumor development.
  • Programmed death-ligand 1 is a ligand of programmed death molecule 1 (Programmed death, PD-1). It is highly expressed on the surface of various malignant tumor cells, and the expression level is The clinical manifestations and prognosis of the subjects are closely related.
  • PD-L1 on the surface of cancer cells inhibits the activation and proliferation of T cells by binding to PD-1 or CD80 on the surface of T cells, promotes effector T cells to enter a state of exhaustion or anergy, and induces T cell Apoptosis stimulates helper T cells to differentiate into regulatory T cells, thereby preventing T cells from killing tumor cells.
  • Anti-PD-L1 antibodies can prevent the activity of effector T cells in the tumor microenvironment from being inhibited and enhance the endogenous anti-tumor immune effect by blocking the interaction between PD-L1, PD-1 and CD80.
  • TIM-3 is closely related to PD-1/PD-L1, and TIM-3 may be an important molecule that mediates PD-1/PD-L1 to achieve immune evasion.
  • monotherapy with anti-TIM-3 antibodies and anti-PD-L1 antibodies still has certain limitations, and other alternative therapies are needed, such as combining anti-TIM-3 antibodies with anti-PD-L1 antibodies, to improve the anti-tumor effect.
  • the present disclosure provides a pharmaceutical combination comprising an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-L1 antibody, or antigen-binding fragment thereof.
  • the pharmaceutical combination includes a unit dose of 60-1800 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and a unit dose of 10-1800 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination comprises 100-1800 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and 100-2400 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle, comprising 100-1800 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and 100-2400 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof .
  • the pharmaceutical combination is used to treat tumors.
  • the present disclosure provides a pharmaceutical combination for treating tumors, comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof.
  • the present disclosure also provides a method of treating a tumor in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination of the present disclosure.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the preparation of medicaments for treating tumors.
  • the present disclosure also provides the use of anti-TIM-3 antibodies or antigen-binding fragments thereof and anti-PD-L1 antibodies or antigen-binding fragments thereof in the preparation of medicaments for treating tumors.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof may be packaged separately or together. And wherein, the anti-TIM-3 antibody or antigen-binding fragment thereof can be packaged in a single portion or multiple equal portions, and the anti-PD-L1 antibody or antigen-binding fragment thereof can be packaged in a single portion or multiple portions.
  • the pharmaceutical combination is a fixed combination.
  • the fixed combination is in the form of a solid formulation or a liquid formulation.
  • the pharmaceutical combination is a non-fixed combination.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof in the non-fixed combination are each in the form of a pharmaceutical composition.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof can be administered simultaneously, sequentially, and/or alternately.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100-1800 mg each time.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 100-2400 mg each time.
  • kits for treating tumors comprising a pharmaceutical combination of the present disclosure.
  • the kit includes an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the tumor is a solid tumor. In some embodiments, the tumor is lung cancer. In some embodiments, the lung cancer is selected from non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • the present disclosure provides pharmaceutical combinations comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination is used to treat tumors.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the preparation of a medicament for treating tumors.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure to treat tumors.
  • the present disclosure also provides methods of treating tumors, comprising administering to a subject a therapeutically effective amount of a pharmaceutical combination of the present disclosure.
  • kits for treating tumors comprising pharmaceutical combinations of the present disclosure.
  • the kit further includes instructions for treating tumors with the pharmaceutical combination of the present disclosure.
  • the present disclosure also provides anti-TIM-3 antibodies or antigen-binding fragments thereof for treating tumors.
  • the present disclosure also provides the use of an anti-TIM-3 antibody or antigen-binding fragment thereof in the preparation of a medicament for treating tumors.
  • the present disclosure also provides the use of anti-TIM-3 antibodies or antigen-binding fragments thereof to treat tumors.
  • the present disclosure also provides methods of treating tumors, comprising administering to a subject a therapeutically effective amount of an anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure.
  • the tumor is a solid tumor.
  • the tumor is lung cancer.
  • the lung cancer is selected from non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).
  • the present disclosure provides a pharmaceutical combination comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination is packaged in the same kit, which further includes the combination of an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-L1 antibody or antigen-binding fragment thereof to treat tumors. instruction of.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof in the pharmaceutical combination are separately packaged in respective kits, and the kit further includes Instructions for the combined use of anti-TIM-3 antibodies or antigen-binding fragments thereof and anti-PD-L1 antibodies or antigen-binding fragments thereof to treat tumors.
  • the pharmaceutical combination is a fixed combination.
  • the fixed combination is in the form of a solid formulation or a liquid formulation.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof in the fixed combination are formulated in a single formulation.
  • the single formulation is in the form of a liquid formulation or a solid formulation.
  • the single formulation is an injectable solution.
  • the single formulation is a lyophilized formulation.
  • the pharmaceutical combination is a non-fixed combination.
  • the anti-TIM-3 in the non-fixed combination The antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition, and the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof and the pharmaceutical composition containing the anti-PD-L1 antibody or its antigen-binding fragment are each in the form of a pharmaceutical composition.
  • the pharmaceutical composition of the antigen-binding fragment may or may not be present in the same pharmaceutical bag.
  • the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof is a liquid preparation. In some specific embodiments, the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is an injectable solution. In some specific embodiments, pharmaceutical compositions containing anti-TIM-3 antibodies or antigen-binding fragments thereof are lyophilized formulations. In some specific embodiments, in the non-fixed combination, the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is a liquid preparation. In some specific embodiments, the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is an injection. In some specific embodiments, the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is a lyophilized preparation.
  • the unit dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg. In some embodiments, the unit dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 60 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320mg, about 360mg, about 400mg, about 420mg, about 440mg, about 480mg, about 520mg, about 540mg, about 560mg, about 600mg, about 640mg, about 660mg, about 680mg, about 720mg, about 760mg, about 780mg, about 800mg, About 840mg, about 880mg, about 900mg, about 920mg, about 960mg, about 1000mg, about 1020mg
  • the unit dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 240 mg, about 300 mg, about 360 mg, and/or about 600 mg. In some embodiments, the unit dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 240 mg and/or about 600 mg.
  • the unit dosage of the anti-PD-L1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 10-1800 mg, 100-1500 mg, 100-1200 mg, 600-1200 mg, or 100-600 mg. In some embodiments, the unit dose of the anti-PD-L1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 10 mg, about 40 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200mg, about 220mg, about 240mg, about 260mg, about 280mg, about 300mg, about 320mg, about 340mg, about 360mg, about 380mg, about 400mg, about 420mg, about 440mg, about 460mg, about 480mg, about 500mg, about 520mg, About 540mg, about 560mg, about 580mg, about 600mg, about 620mg, about 640mg, about 660mg
  • the pharmaceutical combination includes a unit dose of 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and a unit dose of 10 -1800 mg, 100-1500 mg, 100-1200 mg, 600-1200 mg, or 100-600 mg of anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination includes a unit dose of about 60 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320 mg, about 360 mg, about 400 mg, about 420 mg, About 440mg, about 480mg, about 520mg, about 540mg, about 560mg, about 600mg, about 640mg, about 660mg, about 680mg, about 720mg, about 760mg, about 780mg, about 800mg, about 840mg, about 880mg, about 900mg, about 920mg , about 960mg, about 1000mg, about 1020mg, about 1040mg, about 1080mg, about 1120mg, about 1140mg, about 1160mg, about 1200mg, about 1240mg, about 1260mg, about 1280mg, about 1320mg, about 1360mg, about 1380mg
  • the pharmaceutical combination includes a unit dose of about 240 mg, about 300 mg, about 360 mg, and/or about 600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and a unit dose of about 100 mg and/or about 600 mg.
  • Anti-PD-L1 antibody or antigen-binding fragment thereof the pharmaceutical combination includes a unit dose of about 240 mg and/or about 600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and a unit dose of about 100 mg and/or about 600 mg of an anti-PD-L1 antibody or Its antigen-binding fragment.
  • the pharmaceutical combination comprises 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, An anti-TIM-3 antibody or an antigen-binding fragment thereof in the range of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or any of the above values. In some embodiments, the pharmaceutical combination comprises about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination comprises 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, About 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, or about 2400 mg, or an anti-PD-L1 antibody or its antigen in the range formed by any of the above values Combine fragments. In some embodiments, the pharmaceutical combination comprises about 1200 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination comprises 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, and 100-2400 mg, 600-1800 mg, 1000- 1500 mg, 1000-1200 mg, or 1200-1500 mg of anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination comprises about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, About 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or an anti-TIM-3 antibody or an antigen-binding fragment thereof within a range formed by any of the above values, and about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, About 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg , about 2300 mg, or about 2400 mg, or an anti-PD-L1 antibody or an antigen
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and contains 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle, comprising about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg , about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or an anti-TIM-3 antibody or an antigen-binding fragment thereof within a range formed by any of the above values.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and contains about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and contains 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg of an anti-PD-L1 antibody or antigen thereof Combine fragments.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle, comprising about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg , about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, About 2200 mg, about 2300 mg, or about 2400 mg, or an anti-PD-L1 antibody or an antigen-binding fragment thereof within a range formed by any of the above values.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and contains about 1
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and contains 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, and 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg of anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle, comprising about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg , about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or an anti-TIM-3 antibody or an antigen-binding fragment thereof within a range formed by any of the above values, and about 100 mg, about 200 mg , about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, or about 2400 mg, or
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and comprises about 1200 mg or about 1500 mg of an anti-TIM-3 antibody, or an antigen-binding fragment thereof, and about 1200 mg of an anti-PD-L1 antibody, or an antigen-binding fragment thereof. fragment.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof can be a pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the pharmaceutical composition containing anti-TIM-3 antibody or antigen-binding fragment thereof is a single dose or multiple doses, preferably multiple doses.
  • the multiple doses may consist of a single dose of a pharmaceutical composition containing about 240 mg, about 300 mg, about 360 mg, and/or about 600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the multiple doses may consist of a single dose of a pharmaceutical composition containing about 240 mg and/or about 600 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof may be a pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical composition containing anti-PD-L1 antibody or antigen-binding fragment thereof is a single dose or multiple doses, preferably multiple doses.
  • the multiple doses may consist of a single dose of a pharmaceutical composition containing about 100 mg and/or about 600 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the dosage of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a fixed dosage in the pharmaceutical composition.
  • the pharmaceutical combination contains an anti-TIM-3 antibody or antigen-binding fragment thereof in a daily dose. In some embodiments, the pharmaceutical combination contains the anti-TIM-3 antibody or antigen-binding fragment thereof in a once-daily dose.
  • the pharmaceutical combination contains a uniform dose of the anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination contains an amount of anti-TIM-3 antibody or antigen-binding fragment thereof that is sufficient for one treatment cycle, and each treatment cycle is 21 days (ie, 3 weeks).
  • the dosage of the anti-PD-L1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a fixed dosage in the pharmaceutical composition.
  • the pharmaceutical combination contains a daily dose of the anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination contains the anti-PD-L1 antibody or antigen-binding fragment thereof in a once-daily dose.
  • the pharmaceutical combination contains a uniform dose of the anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the pharmaceutical combination contains an amount of anti-PD-L1 antibody or antigen-binding fragment thereof that is sufficient for one treatment cycle, and each treatment cycle is 21 days (ie, 3 weeks).
  • the mass ratio of the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof is (0.01-30):1, (0.01- 20):1, (0.1-2.5):1, (0.5-1.5):1 or (1-1.25):1; wherein, anti-TIM-3 antibody or antigen-binding fragment thereof and anti-PD-L1 antibody or antigen thereof
  • the combined fragments can be packaged separately or together.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are packaged separately, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof can be performed in single or multiple portions
  • anti-PD-L1 antibodies or antigen-binding fragments thereof can be packaged in single or multiple portions.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof are packaged separately, wherein the anti-TIM-3 antibody, or antigen-binding fragment thereof, can be presented in a single portion or in multiple equal portions.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof can Packed in single or multiple portions.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are packaged separately, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof can be provided in a single portion or in multiple aliquots ( For example, 2 equal parts, 3 equal parts, 4 equal parts, 5 equal parts, 6 equal parts, 7 equal parts, 8 equal parts or more) for packaging, the anti-PD-L1 antibody or its antigen-binding fragment can be packaged in a single Packaging in parts or multiple equal parts (such as 2 equal parts, 3 equal parts, 12 equal parts or other equal parts).
  • an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-L1 antibody, or antigen-binding fragment thereof are packaged together.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is or an antigen-binding fragment thereof, a pharmaceutical composition prepared as a single or multiple dose suitable for administration to a patient of 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, containing
  • the pharmaceutical composition of the anti-PD-L1 antibody or antigen-binding fragment thereof is prepared to be suitable for administering to a patient 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof Single or multiple doses of fragments.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is or an antigen-binding fragment thereof, a pharmaceutical composition prepared suitable for administration to a patient of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about A single dose or multiple doses of an anti-TIM-3 antibody or antigen-binding fragment thereof, containing 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or a range formed by any of the above values, containing anti-PD- Pharmaceutical compositions of L1 antibodies or antigen-binding fragments thereof are prepared suitable for administration to a patient of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg,
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody is or an antigen-binding fragment thereof, a pharmaceutical composition prepared as a single or multiple dose suitable for administering to a patient about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, containing an anti-PD-L1 antibody or an antigen-binding fragment thereof
  • the pharmaceutical composition is formulated to be suitable for administration to a patient in a single or multiple dose of about 1200 mg of an anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the present disclosure also provides the use of a pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating tumors.
  • the present disclosure also provides the use of a pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof to treat tumors.
  • the present disclosure also provides methods of treating tumors in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination comprising an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-L1 antibody, or antigen-binding fragment thereof.
  • the present disclosure provides a kit for treating tumors, the kit comprising a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and a medicament containing an anti-PD-L1 antibody or an antigen-binding fragment thereof.
  • the present disclosure provides a kit for treating tumors, the kit comprising a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof, and using Description of the pharmaceutical composition for treating tumors.
  • the present disclosure also provides a pharmaceutical package for treating tumors, which contains individually packaged pharmaceutical compositions in independent containers, wherein one container includes an anti-TIM-3 antibody or an antigen thereof. a pharmaceutical composition that binds the fragment, and includes in a second container a pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof.
  • the present disclosure also provides a pharmaceutical package for treating tumors, which contains individually packaged pharmaceutical compositions in independent containers, wherein the container includes an anti-TIM-3 antibody or an antigen-binding agent thereof. fragments and pharmaceutical compositions of anti-PD-L1 antibodies or antigen-binding fragments thereof.
  • the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is a liquid preparation or a solid preparation.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is an injectable solution.
  • pharmaceutical compositions containing anti-TIM-3 antibodies or antigen-binding fragments thereof are lyophilized formulations.
  • the pharmaceutical composition containing the anti-PD-L1 antibody or its antigen-binding fragment is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is an injection. In some specific embodiments, the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is a lyophilized preparation.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof is a liquid preparation or a solid preparation.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-L1 antibody or antigen-binding fragment thereof is an injection.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-L1 antibody or antigen-binding fragment thereof is a lyophilized preparation.
  • the tumor is a solid tumor.
  • the solid tumor is lung cancer.
  • the lung cancer includes non-small cell lung cancer or small cell lung cancer.
  • the non-small cell lung cancer is squamous cell non-small cell lung cancer (also known as squamous cell carcinoma, squamous cell carcinoma, squamous non-small cell lung cancer, or squamous cell carcinoma).
  • the non-small cell lung cancer is non-squamous non-small cell lung cancer.
  • the non-small cell lung cancer is an adenocarcinoma (also known as lung adenocarcinoma).
  • the non-small cell lung cancer is large cell carcinoma (also known as lung large cell carcinoma).
  • the small cell lung cancer is extensive stage small cell lung cancer. In some embodiments, the small cell lung cancer is limited stage small cell lung cancer.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof can be administered simultaneously, sequentially, and/or alternately. In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered sequentially. In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition, which can be simultaneously, sequentially and/or or alternate administration.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition and administered sequentially. In some embodiments, in the above uses or methods of treatment, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered first, and then the anti-TIM-3 antibody or antigen-binding fragment thereof is administered. In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition, and the anti-PD-L1 antibody or antigen-binding fragment thereof is first administered.
  • a pharmaceutical composition containing an L1 antibody or an antigen-binding fragment thereof and then administering a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof are formulated in a single formulation and administered simultaneously.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered in the same or different dosage regimens respectively. In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered in different dosage regimens respectively. In some embodiments, in the above uses or treatment methods, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered in the same dosage regimen respectively.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) Administer once.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 4 weeks.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg each time.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg each time , about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or a dosage within the range formed by any of the above values.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of about 1200 mg or about 1500 mg per administration.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks at 100-1800 mg, 600-1800 mg, 600- A dose of 1500 mg, or 1200-1500 mg of anti-TIM-3 antibody or antigen-binding fragment thereof is administered.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, at about 1200 mg or about 1500 mg of anti-TIM-3 antibody each time or antigen-binding fragments thereof.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of about 1200 mg or about 1500 mg of the anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) Administer once.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every 3 weeks.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every 4 weeks.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at 100-2400 mg, 600-1800 mg, 1000- Doses of 1500 mg, 1000-1200 mg, or 1200-1500 mg are administered.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg each time , about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg, about 2300mg, or about 2400mg, or any of the above values range of doses administered.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of about 1200 mg per administration. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks at 100-2400 mg, 600-1800 mg, 1000- A dose of 1500 mg, 1000-1200 mg, or 1200-1500 mg of anti-PD-L1 antibody or antigen-binding fragment thereof is administered. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, at about 1200 mg of the anti-PD-L1 antibody or antigen thereof. Dosage administration of combined fragments. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every 3 weeks at a dose of about 1200 mg of anti-PD-L1 antibody or antigen-binding fragment thereof.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof have the same or different treatment cycles, respectively.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof have the same treatment cycle, such as every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks is a treatment cycle.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof have the same treatment cycle, for example, every 3 weeks is a treatment cycle.
  • every 3 weeks is a treatment cycle, and the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered in each treatment cycle. In some embodiments, in the above use or treatment method, every 3 weeks is a treatment cycle, and the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered once in each treatment cycle. .
  • every 3 weeks is a treatment cycle, and the anti-TIM-3 antibody or antigen-binding fragment thereof is administered on the 1st day of each treatment cycle, and the anti-TIM-3 antibody or antigen-binding fragment thereof is administered on the 1st day of each treatment cycle.
  • every 3 weeks is a treatment cycle, and the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once on the 1st day of each treatment cycle, and once on the 1st day of each treatment cycle.
  • Anti-PD-L1 antibodies or antigen-binding fragments thereof were administered once a day.
  • every 3 weeks is a treatment cycle, and 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of anti-TIM-3 is administered in each treatment cycle.
  • Antibody or antigen-binding fragment thereof 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg of anti-PD-L1 antibody or antigen-binding fragment thereof is administered in each treatment cycle.
  • every 3 weeks is a treatment cycle, and about 1200 mg or about 1500 mg of anti-TIM-3 antibody or antigen-binding fragment thereof is administered in each treatment cycle, and in each treatment cycle Approximately 1200 mg of anti-PD-L1 antibody or antigen-binding fragment thereof is administered per cycle.
  • every 3 weeks is a treatment cycle, and about 1200 mg or about 1500 mg of anti-TIM-3 antibody or antigen-binding fragment thereof is administered on the first day of each treatment cycle, Approximately 1200 mg of anti-PD-L1 antibody or antigen-binding fragment thereof is administered on Day 1 of each treatment cycle.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof are administered in multiple doses or in a single dose.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof are each administered in multiple doses.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof can be selected from 0.01 to 50 mg/kg, 0.1 to 40 mg/kg, 0.1 to 35 mg/kg, 0.1 to 30 mg/kg kg, 0.1 to 25mg/kg, 0.1 to 20mg/kg, 0.1 to 15mg/kg, 0.1 to 10mg/kg, 1 to 40mg/kg, 1 to 35mg/kg, 1 to 30mg/kg, 1 to 25mg/kg, 1 to 20mg/kg, 1 to 15mg/kg, 1 to 10mg/kg, 1 to 3mg/kg, 3 to 40mg/kg, 3 to 35mg/kg, 3 to 30mg/kg, 3 to 25mg/kg, 3 to administered to the subject at a dose of 20 mg/kg, 3 to 15 mg/kg, 3 to 10 mg/kg, 10 to 40 mg/kg, 10 to 30 mg/kg, 10 to 25 mg/kg, or 20 to 25 mg/kg;
  • the anti-PD-L1 antibody or antigen-binding fragment thereof can be selected from 0.01 to 50 mg/kg, 0.1 to 40 mg/kg, 0.1 to 35 mg/kg, 0.1 to 30 mg/kg kg, 0.1 to 25mg/kg, 0.1 to 20mg/kg, 0.1 to 15mg/kg, 0.1 to 10mg/kg, 1 to 40mg/kg, 1 to 35mg/kg, 1 to 30mg/kg, 1 to 25mg/kg, 1 to 20mg/kg, 1 to 15mg/kg, 1 to 10mg/kg, 1 to 3mg/kg, 3 to 40mg/kg, 3 to 35mg/kg, 3 to 30mg/kg, 3 to 25mg/kg, 3 to administered to the subject at a dose of 20 mg/kg, 3 to 15 mg/kg, 3 to 10 mg/kg, 10 to 40 mg/kg, 10 to 30 mg/kg, 10 to 25 mg/kg, or 20 to 25 mg/kg/
  • the dosing regimen (e.g., dosing cycle, dosing dose) of the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof and dose adjustments) may be adjusted based on disease severity, disease response, any treatment-related toxicities, and the patient's age and health status.
  • a treatment cycle of anti-TIM-3 antibody or antigen-binding fragment thereof and/or anti-PD-L1 antibody or antigen-binding fragment thereof can be adjusted to 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks. , 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks or 15 weeks.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof described in the present disclosure includes: heavy chain CDR1 (HCDR1) of the amino acid sequence shown in SEQ ID NO:1, HCDR2 of the amino acid sequence shown in SEQ ID NO:2, SEQ ID NO: HCDR3 with the amino acid sequence shown in SEQ ID NO: 4, LCDR2 with the amino acid sequence shown in SEQ ID NO: 5, and LCDR3 with the amino acid sequence shown in SEQ ID NO: 6.
  • the CDR sequences of anti-TIM-3 antibodies or antigen-binding fragments thereof are shown in Table 1.
  • CDR complementarity determining region
  • Table 1 has shown CDR sequences (wherein the CDR regions shown in SEQ ID NO: 1-6 are defined by the AbM numbering system), however, when it comes to defining antibodies with specific CDR sequences defined by certain divisions of this disclosure, The scope of the antibody also includes antibodies defined by CDR sequences converted into any other numbering system definition (such as one or a combination of one or more definitions such as Kabat, Chothia, IMGT or Contact, which are well known in the art).
  • anti-TIM-3 antibodies or antigen-binding fragments thereof comprising the following amino acid sequences are also encompassed within the scope of the anti-TIM-3 antibodies or antigen-binding fragments thereof of the present disclosure: HCDR1 of the amino acid sequence shown in SEQ ID NO: 1, HCDR2 with the amino acid sequence shown in SEQ ID NO:2, HCDR3 with the amino acid sequence shown in ARRYYGYDAMDY (SEQ ID NO:31), LCDR1 with the amino acid sequence shown in SEQ ID NO:4, LCDR2 with the amino acid sequence shown in SEQ ID NO:5 , and LCDR3 of the amino acid sequence shown in SEQ ID NO:6.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO:7 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the heavy chain
  • the variable region, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% of the amino acid sequence shown in SEQ ID NO:8 %, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the light chain variable region.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO:7, and a light chain variable region of the amino acid sequence set forth in SEQ ID NO:8 district.
  • the amino acid sequence of the heavy chain variable region of the anti-TIM-3 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 7, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO. NO:8 shown.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof may further comprise an immunoglobulin constant region, or a fragment, analog, variant or derivative of the constant region.
  • the heavy chain constant region is derived from a human immunoglobulin heavy chain, such as IgG1, IgG2, IgG3 and IgG4, or a heavy chain of another class of immunoglobulin, preferably an IgG4 heavy chain.
  • the light chain constant region is from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin.
  • the constant region may comprise any modification described herein, such as insertion, deletion, substitution, or chemical modification of amino acids.
  • the constant region contains mutations that alter effector function.
  • any amino acid residue of the constant region may be substituted with an amino acid residue of any allotype.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO:9 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the heavy chain , and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% with the amino acid sequence shown in SEQ ID NO:10 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the light chain.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence set forth in SEQ ID NO:9, and a light chain of the amino acid sequence set forth in SEQ ID NO:10.
  • the amino acid sequence of the heavy chain of the anti-TIM-3 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO:9
  • the amino acid sequence of the light chain is set forth in SEQ ID NO:10.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure is mAb 50B5 or antigen-binding fragment thereof described in patent application documents with publication number WO2020041520 or CN112566936, or a chimeric antibody of mAb 50B5 or its antigen-binding fragment.
  • Antigen-binding fragments, or humanized antibodies of mAb 50B5 or antigen-binding fragments thereof are examples of antibodies 50B5 or antigen-binding fragment thereof.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure is mAb 15B4 or antigen-binding fragment thereof described in patent application documents with publication number WO2020041520 or CN112566936, or a chimeric antibody of mAb 15B4 or An antigen-binding fragment thereof, or a humanized antibody of mAb 15B4, or an antigen-binding fragment thereof.
  • the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure is selected from Sabatolimab, Cobolimab, Surzebiclimab, Roche's RG-7769, Hengrui Medicine's SHR-1702, Agenus' INCAGN-2390, WuXi BC-3402 from Biology, LBL-003 from Verizhibo, LNL-005 from Jianxin Biotech, or BMS-986258 from BMS.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof described in the present disclosure includes: heavy chain CDR1 (HCDR1) of the amino acid sequence shown in SEQ ID NO: 11 or SEQ ID NO: 21, SEQ ID NO: 12 or SEQ ID NO: HCDR2 with the amino acid sequence shown in SEQ ID NO:13 or HCDR3 with the amino acid sequence shown in SEQ ID NO:23, light chain CDR1 (LCDR1) with the amino acid sequence shown in SEQ ID NO:14 or SEQ ID NO:24, SEQ LCDR2 with the amino acid sequence shown in ID NO:15 or SEQ ID NO:25, and LCDR3 with the amino acid sequence shown in SEQ ID NO:16 or SEQ ID NO:26.
  • HCDR1 heavy chain CDR1
  • LCDR2 light chain CDR1
  • LCDR2 with the amino acid sequence shown in SEQ ID NO:14 or SEQ ID NO:24
  • SEQ LCDR2 with the amino acid sequence shown in ID NO:15 or SEQ ID NO:25
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: the amino acid sequence shown in SEQ ID NO: 11 HCDR1, HCDR2 with the amino acid sequence shown in SEQ ID NO: 12, HCDR3 with the amino acid sequence shown in SEQ ID NO: 13, LCDR1 with the amino acid sequence shown in SEQ ID NO: 14, LCDR2 with the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 with the amino acid sequence shown in SEQ ID NO:16; or HCDR1 with the amino acid sequence shown in SEQ ID NO:21, HCDR2 with the amino acid sequence shown in SEQ ID NO:22, HCDR3 with the amino acid sequence shown in SEQ ID NO:23, LCDR1 with the amino acid sequence shown in SEQ ID NO:24, LCDR2 with the amino acid sequence shown in SEQ ID NO:25, and LCDR3 with the amino acid sequence shown in SEQ ID NO:26.
  • the CDR sequences of anti-PD-L1 antibodies or antigen-binding fragments thereof are provided in
  • CDR complementarity determining region
  • a given antibody or region thereof e.g., variable region
  • CDR regions have been shown in Table 2, when it comes to defining an antibody with specific CDR sequences, the scope of the antibody encompasses any numbering system definition (such as AbM, Kabat, Chothia, IMGT or Contact, etc., which are well known in the art).
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, or 83% identical to the amino acid sequence set forth in SEQ ID NO: 17 or SEQ ID NO: 27 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100 % identity of the heavy chain variable region, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86% with the amino acid sequence shown in SEQ ID NO: 18 or SEQ ID NO: 28 Light chain variable of %, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity district.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises the heavy chain variable region of the amino acid sequence set forth in SEQ ID NO: 17 or SEQ ID NO: 27, and SEQ ID NO: 18 or SEQ The light chain variable region of the amino acid sequence shown in ID NO:28.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO: 17 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the heavy chain
  • the variable region, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% of the amino acid sequence shown in SEQ ID NO:18 %, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the light chain variable region.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO:27. %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity chain variable region, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, A light chain variable region that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO: 17, and a light chain variable region of the amino acid sequence set forth in SEQ ID NO: 18 district. In other embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO: 27, and a light chain variable region of the amino acid sequence set forth in SEQ ID NO: 28. Change area.
  • the amino acid sequence of the heavy chain variable region of the anti-PD-L1 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 17, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO. :18.
  • the amino acid sequence of the heavy chain variable region of the anti-PD-L1 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 27, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO. Shown in NO:28.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof may further comprise a constant region of an immunoglobulin, or a fragment, analog, variant or derivative of the constant region.
  • the heavy chain constant region is from a human immunoglobulin heavy chain, such as IgG1, IgG2, IgG3 and IgG4 or a heavy chain of another class of immunoglobulin, preferably an IgG1 heavy chain.
  • the light chain constant region is from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin.
  • the constant region may comprise any modification described herein, such as insertion, deletion, substitution, or chemical modification of amino acids.
  • the constant region contains mutations that alter effector function.
  • any amino acid residue of the constant region may be substituted with an amino acid residue of any allotype, preferably with an amino acid residue of G1m(3) and/or nG1m(1).
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, or 83% identical to the amino acid sequence set forth in SEQ ID NO: 19 or SEQ ID NO: 29 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100 % identity of the heavy chain, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% with the amino acid sequence shown in SEQ ID NO:20 or SEQ ID NO:30 %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the light chain.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence set forth in SEQ ID NO: 19 or SEQ ID NO: 29, and SEQ ID NO: 20 or SEQ ID NO: 30 The light chain of the amino acid sequence shown.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO: 19 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the heavy chain , and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% with the amino acid sequence shown in SEQ ID NO:20 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity of the light chain.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence set forth in SEQ ID NO:29. %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity chain, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, A light chain that is 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence set forth in SEQ ID NO: 19, and a light chain of the amino acid sequence set forth in SEQ ID NO: 20.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence set forth in SEQ ID NO:29, and a light chain of the amino acid sequence set forth in SEQ ID NO:30.
  • the heavy chain amino acid sequence of the anti-PD-L1 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 19, and the light chain amino acid sequence is set forth in SEQ ID NO: 20.
  • the heavy chain amino acid sequence of the anti-PD-L1 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO:29, and the light chain amino acid sequence is set forth in SEQ ID NO:30.
  • the anti-PD-L1 antibodies or antigen fragments thereof of the present disclosure include, but are not limited to, 13C5, 5G11, ch13C5-hlgG1, ch13C5-hlgG4, ch5G11-hlgG1, ch5G11-hlgG4, and hu13C5 described in the patent application documents with publication number WO2016022630 or CN107001463. - hIgG1, hu13C5-hlgG4, hu5G11-hlgG1 or hu5G11-hlgG4 monoclonal antibodies or antigen-binding fragments thereof.
  • compositions containing antibodies or antigen-binding fragments thereof are provided.
  • an anti-TIM-3 antibody, or antigen-binding fragment thereof, and an anti-PD-L1 antibody, or antigen-binding fragment thereof are formulated for parenteral administration.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof are formulated for administration by intravenous, intramuscular, subcutaneous, or other parenteral routes, For example, for injection or infusion. In some specific embodiments, for intravenous, intramuscular or subcutaneous administration. In some specific embodiments, for intravenous injection or infusion.
  • Anti-TIM-3 antibodies or antigen-binding fragments thereof and anti-PD-L1 antibodies or antigen-binding fragments thereof can be formulated into suitable dosage forms, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules) , enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (i.e. preparations suitable for injection, such as intramuscular, intravenous, intraperitoneal, subcutaneous), granules, emulsions, suspensions, solutions, Dispersions and dosage forms for sustained-release preparations for oral or parenteral administration.
  • suitable dosage forms including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules) , enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (i.e. preparations suitable for injection, such as intramuscular, intrave
  • anti-TIM-3 antibodies or antigen-binding fragments thereof and anti-PD-L1 antibodies or antigen-binding fragments thereof can be formulated as injections.
  • anti-TIM-3 antibodies or antigen-binding fragments thereof and anti-PD-L1 antibodies or antigen-binding fragments thereof can be formulated into preparations suitable for intravenous injection (eg, injection solutions or lyophilized preparations).
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof are formulated in a single formulation.
  • anti-TIM-3 antibodies or antigen-binding fragments thereof, anti-PD-L1 antibodies or antigen-binding fragments thereof are formulated with one or more pharmaceutically acceptable excipients to form a suitable medicament combination.
  • the anti-TIM-3 antibody, or antigen-binding fragment thereof, and the anti-PD-L1 antibody, or antigen-binding fragment thereof are formulated separately (i.e., each is in the form of a pharmaceutical composition).
  • an anti-TIM-3 antibody, or antigen-binding fragment thereof is formulated with one or more pharmaceutically acceptable excipients to form a suitable pharmaceutical composition.
  • an anti-PD-L1 antibody or antigen-binding fragment thereof is formulated with one or more pharmaceutically acceptable excipients to form a suitable pharmaceutical composition.
  • the unit dosage of the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, 240-600 mg or other amounts.
  • Anti-TIM-3 antibody or antigen-binding fragment thereof for example, about 60 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320 mg, about 360 mg, about 400 mg, about 420 mg, about 440 mg , about 480mg, about 520mg, about 540mg, about 560mg, about 600mg, about 640mg, about 660mg, about 680mg, about 720mg, about 760mg, about 780mg, about 800mg, about 840mg, about 880mg, about 900mg, about 920mg, about 960mg, about 1000mg, about 1020mg, about 1040mg, about 1080mg
  • the unit dose of the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is 10-1800 mg, 100-1500 mg, 100-1200 mg, 600-1200 mg, 100-600 mg or other amounts of anti-PD-L1 antibody or antigen-binding fragment thereof, such as about 10 mg, about 40 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160mg, about 180mg, about 200mg, about 220mg, about 240mg, about 260mg, about 280mg, about 300mg, about 320mg, about 340mg, about 360mg, about 380mg, about 400mg, about 420mg, about 440mg, about 460mg, about 480mg, About 500mg, about 520mg, about 540mg, about 560mg, about 580mg, about 600mg, about 620mg, about 640mg, about 660mg, about 680mg,
  • excipient is used to describe any ingredient other than a compound of the present disclosure. The choice of excipient will depend largely on factors such as the particular mode of administration, the excipient's effect on solubility and stability, and the nature of the dosage form.
  • pharmaceutically acceptable excipients include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Some examples of pharmaceutically acceptable excipients are water, saline, dextrose, glycerol, ethanol, etc., and combinations thereof. In many cases, pharmaceutically acceptable excipients include isotonic agents. Other examples of pharmaceutically acceptable excipients are wetting agents or minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives or buffers, which increase the storage life or effectiveness of the antibody.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof is an aqueous injection.
  • the pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof is an aqueous injection.
  • the aqueous injection includes, but is not limited to, aqueous preparations that have not been lyophilized or aqueous preparations reconstituted with lyophilized powder.
  • the pharmaceutical composition containing an anti-TIM-3 antibody or antigen-binding fragment thereof is a lyophilized preparation.
  • the pharmaceutical composition containing an anti-PD-L1 antibody or antigen-binding fragment thereof is a lyophilized preparation.
  • the freeze-dried preparation refers to a preparation prepared from an aqueous solution undergoing a freeze-drying process, in which the substance is first frozen, and then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (secondary drying). process) until the amount of solvent is such that it no longer supports biological activity or chemical reaction. Lyophilized formulations of the present disclosure may also be dried by other methods known in the art, such as spray drying and bubble drying.
  • the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof in the pharmaceutical composition containing anti-PD-L1 antibody or antigen-binding fragment thereof is 1-200 mg/mL, 2-150 mg/mL, 4.5 -100mg/mL, 5-80mg/mL, 10-60mg/mL, 10-50mg/mL, or 10-30mg/mL. In some specific embodiments, the concentration of the anti-PD-L1 antibody or antigen-binding fragment thereof is about 4.8 mg/mL, about 5 mg/mL, about 10 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL.
  • the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof is about 4.8 mg/mL. In some embodiments, the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof is about 10 mg/mL. In some embodiments, the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof is about 30 mg/mL. In some embodiments, the concentration of anti-PD-L1 antibody or antigen-binding fragment thereof is about 60 mg/mL.
  • the pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof includes: a mass volume concentration of about 1-150 mg/mL anti-PD-L1 antibody or an antigen-binding fragment thereof, and a buffer of 3-50 mM solution, 2-150mg/mL isotonicity regulator/stabilizer and 0.01-0.8mg/mL surfactant, and the pH is about 4.5-6.8.
  • the pharmaceutical composition containing an anti-PD-L1 antibody or an antigen-binding fragment thereof includes: (a) an anti-PD-L1 antibody with a mass volume concentration of about 10 mg/mL or about 30 mg/mL, ( b) sucrose at a mass volume concentration of approximately 80 mg/mL, (c) polysorbate 80 at a mass volume concentration of approximately 0.2 mg/mL, (d) histidine at a molar concentration of approximately 10 mM, (e) optionally hydrochloric acid In an appropriate amount, adjust the pH value of the composition to about 5.5.
  • the components of the pharmaceutical combinations of the present disclosure may be administered individually, or part or all thereof, together, by any suitable route, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). ) application.
  • the components of the pharmaceutical combinations of the present disclosure may be administered individually, or part or all thereof may be administered together orally or by injection, such as intravenously or subcutaneously. injection.
  • the components in the pharmaceutical combination of the present disclosure may be formulated independently, or part or all thereof, together into suitable dosage forms, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal, subcutaneous), granules, emulsions, suspensions, solutions, dispersions and preparations for oral or parenteral use Sustained-release formulations for oral administration.
  • each component of the pharmaceutical combination of the present disclosure may be administered independently, or some or all of them may be co-formulated into an injection.
  • the components in the pharmaceutical combination of the present disclosure may each independently, or some or all of them may jointly contain pharmaceutically acceptable excipients.
  • compositions of the present disclosure may also include additional therapeutic agents.
  • the additional therapeutic agent may be a tumor therapeutic agent known in the art.
  • a tumor of the present disclosure is a malignant tumor (i.e., a cancer); by malignant tumor is any malignant and/or invasive growth caused by abnormal cell growth.
  • the tumor is a solid tumor.
  • the tumor is a refractory, unresectable, recurrent, advanced and/or metastatic solid tumor.
  • the tumor is an advanced solid tumor.
  • the solid tumor is lung cancer.
  • the lung cancer is refractory, unresectable, recurrent, advanced, and/or metastatic lung cancer.
  • the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
  • the non-small cell lung cancer is squamous cell non-small cell lung cancer (also known as squamous cell carcinoma, squamous cell carcinoma, squamous non-small cell lung cancer, or squamous cell carcinoma).
  • the non-small cell lung cancer is non-small cell lung cancer whose histology is predominantly squamous cell carcinoma.
  • the non-small cell lung cancer is non-squamous non-small cell lung cancer.
  • the non-small cell lung cancer is an adenocarcinoma (also known as lung adenocarcinoma).
  • the non-small cell lung cancer is large cell carcinoma (also known as lung large cell carcinoma).
  • the non-small cell lung cancer is adenosquamous carcinoma.
  • the small cell lung cancer is limited stage small cell lung cancer or extensive stage small cell lung cancer.
  • the lung cancer is locally advanced or advanced non-small cell lung cancer. In some embodiments, the lung cancer is recurrent and/or metastatic non-small cell lung cancer. In some embodiments, the lung cancer is advanced, recurrent and/or metastatic non-small cell lung cancer. In some embodiments, the lung cancer is locally advanced, recurrent, and/or metastatic non-small cell lung cancer. In some embodiments, the lung cancer is stage IIIB, stage IIIC or stage IV non-small cell lung cancer.
  • the lung cancer is advanced, recurrent and/or metastatic squamous non-small cell lung cancer or non-squamous non-small cell lung cancer (eg, lung adenocarcinoma). In some embodiments, the lung cancer is locally advanced, recurrent and/or metastatic squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer (eg, lung adenocarcinoma). In some embodiments, the lung cancer is stage IIIB, stage IIIC or stage IV squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer (eg, lung adenocarcinoma).
  • the lung cancer is locally advanced or advanced small cell lung cancer. In some embodiments, the lung cancer is recurrent and/or metastatic small cell lung cancer. In some embodiments, the lung cancer is advanced, recurrent, and/or metastatic small cell lung cancer. In some embodiments, the lung cancer is locally advanced, recurrent, and/or metastatic small cell lung cancer. In some embodiments, the lung cancer is recurrent and/or metastatic extensive-stage small cell lung cancer. In some embodiments, the lung cancer is recurrent extensive-stage small cell lung cancer.
  • the lung cancer is free of driver gene mutations, including but not limited to: EGFR, ALK, ROS1, BRAF, NTRK, MET, and/or KRAS. In some embodiments, the lung cancer is free of EGFR mutations. In some embodiments, the lung cancer does not contain ALK fusion. In some embodiments, the lung cancer is free of ROS1 mutations.
  • the non-small cell lung cancer is free of driver gene mutations, including but not limited to: EGFR, ALK, ROS1, BRAF, NTRK, MET, and/or KRAS.
  • the non-small cell lung cancer is free of EGFR mutations.
  • the non-small cell lung cancer is free of ALK fusion.
  • the non-small cell lung cancer is free of ROS1 mutations.
  • the squamous non-small cell lung cancer or non-squamous non-small cell lung cancer is free of EGFR mutations.
  • the squamous non-small cell lung cancer or non-squamous non-small cell lung cancer does not have an ALK fusion. In some embodiments, the squamous non-small cell lung cancer or non-squamous non-small cell lung cancer is free of ROS1 mutations.
  • the subject with lung cancer has not previously been treated for lung cancer (eg, lacks effective treatment options).
  • the subject with lung cancer has not previously received systemic therapy to treat lung cancer.
  • the subject with lung cancer has not previously received surgery, radiation therapy, induction chemotherapy, concurrent chemoradiotherapy, adjuvant chemotherapy, and/or immunotherapy to treat lung cancer.
  • the subject with lung cancer is not suitable for surgical treatment and is not suitable for curative concurrent chemoradiotherapy.
  • the subject with lung cancer has previously been treated for lung cancer with one or more different anti-tumor treatments (eg, treatment failed or was not suitable).
  • the subject with lung cancer has previously been treated for lung cancer with one or more of surgery, radiation therapy, chemotherapy, and immunotherapy (eg, treatment failed or was not suitable).
  • the subject with lung cancer has previously been treated for lung cancer with one or more of induction chemotherapy, concurrent chemoradiotherapy, adjuvant chemotherapy, and/or immunotherapy (eg, treatment failure or incompatibility).
  • the subject with lung cancer has previously received neoadjuvant or adjuvant therapy (eg, chemotherapy or radiation therapy) to treat lung cancer (eg, treatment failed or was not suitable).
  • neoadjuvant or adjuvant therapy eg, chemotherapy or radiation therapy
  • the subject with lung cancer has already had lung cancer treated with chemotherapy (eg, treatment failed or was not suitable).
  • the subject with lung cancer has already had lung cancer treated with concurrent chemoradiotherapy (eg, treatment failed or was not suitable).
  • the subject with lung cancer has not previously received systemic chemotherapy, but has received surgery, radiation therapy, induction chemotherapy, concurrent chemoradiotherapy, and/or adjuvant chemotherapy to treat lung cancer.
  • the subject of lung cancer obtains complete remission or partial remission and then develops disease progression again after undergoing surgical treatment, radiotherapy, induction chemotherapy, concurrent chemoradiotherapy, and/or adjuvant chemotherapy.
  • the subject with lung cancer has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemoradiotherapy, and/or adjuvant chemotherapy to treat lung cancer, and after stopping treatment for 6 months (e.g., 6, 7, 8, 9, or 10 months) disease progression occurs.
  • the subject with non-small cell lung cancer has not previously received systemic chemotherapy, but has received surgery, radiation therapy, induction chemotherapy, concurrent chemoradiotherapy, and/or adjuvant chemotherapy to treat non-small cell lung cancer.
  • the subject of non-small cell lung cancer obtains complete remission or partial remission and then develops disease progression again after undergoing surgical treatment, radiotherapy, induction chemotherapy, concurrent chemoradiotherapy and/or adjuvant chemotherapy.
  • the subject with non-small cell lung cancer has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemoradiotherapy, and/or adjuvant chemotherapy to treat non-small cell lung cancer, and 6 months after discontinuing treatment (e.g., 6, 7, 8, 9, or 10 months).
  • the subject with lung cancer has already had lung cancer treated with at least one first-line systemic chemotherapy regimen (eg, treatment failed or was not suitable). In some embodiments, the subject with lung cancer has already been treated for lung cancer with a first-line systemic chemotherapy regimen (eg, treatment failed or was not suitable). In some embodiments, the subject with lung cancer has been treated for lung cancer with first or second line treatment regimens (eg, treatment failed or was not suitable).
  • the subject with lung cancer has previously received an immune checkpoint (e.g., PD-1, PD-L1, CTLA-4, or PD-L2) inhibitor alone or in combination with platinum-based chemotherapy. (e.g., treatment fails or is not suitable).
  • the immune checkpoint (e.g., PD-1, PD-L1, CTLA-4, or PD-L2) inhibitor is an antibody directed against an immune checkpoint or an antigen-binding fragment thereof (e.g., targeting PD -1, PD-L1, CTLA-4 or PD-L2 antibodies or antigen-binding fragments thereof).
  • the subject with lung cancer has previously received platinum-based chemotherapy (eg, treatment failed or was not suitable).
  • the subject of the lung cancer is PD-L1 expression-positive lung cancer. In some embodiments, the subject of the lung cancer is non-small cell lung cancer with positive PD-L1 expression.
  • the subject of lung cancer is a non-small cell lung cancer patient without EGFR mutations, ALK fusions, and/or ROS1 mutations.
  • the subject of lung cancer is a patient with advanced, metastatic or recurrent non-small cell lung cancer in the absence of driver gene mutations (including EGFR mutations, ALK fusions and/or ROS1 mutations).
  • the subject of the lung cancer is locally advanced (stage IIIB/IIIC), metastatic or recurrent (stage IV) non-cancerous disease without driver gene mutations (including EGFR mutations, ALK fusions and/or ROS1 mutations). Patients with small cell lung cancer.
  • the subject of the lung cancer is a locally advanced (stage IIIB/IIIC), metastatic or metastatic disease that is positive for PD-L1 expression and does not have driver gene mutations (including EGFR mutations, ALK fusions and/or ROS1 mutations).
  • Stage IV non-small cell lung cancer.
  • the subject with lung cancer is a patient with extensive-stage small cell lung cancer who has previously received platinum-based chemotherapy (eg, failed or was ineligible for treatment).
  • the subject of the lung cancer is a patient with extensive-stage small cell lung cancer who has failed first-line chemotherapy based on platinum-based drugs or is not suitable for first-line chemotherapy based on platinum-based drugs.
  • the subject of the lung cancer is a patient with recurrent extensive-stage small cell lung cancer who has failed first-line chemotherapy based on platinum-based drugs or is not suitable for first-line chemotherapy based on platinum-based drugs.
  • Embodiment 1 A pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-L1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody or an antigen-binding fragment thereof comprises: SEQ HCDR1 with the amino acid sequence shown in ID NO:1, HCDR2 with the amino acid sequence shown in SEQ ID NO:2, HCDR3 with the amino acid sequence shown in SEQ ID NO:3, LCDR1 with the amino acid sequence shown in SEQ ID NO:4, SEQ ID NO LCDR2 with the amino acid sequence shown in SEQ ID NO: 5, and LCDR3 with the amino acid sequence shown in SEQ ID NO: 6.
  • Embodiment 2 The pharmaceutical combination according to Embodiment 1, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO:7. chain variable region, and a light chain variable region whose amino acid sequence is at least 95% identical to the amino acid sequence shown in SEQ ID NO:8.
  • Embodiment 3 The pharmaceutical combination according to embodiment 1 or 2, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: an amino acid sequence having at least 95% identity with the amino acid sequence shown in SEQ ID NO: 9
  • Embodiment 4 The pharmaceutical combination according to any one of embodiments 1-3, wherein the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200mg, or 240-600mg.
  • Embodiment 5 The pharmaceutical combination according to any one of embodiments 1-4, wherein the unit dose of the anti-PD-L1 antibody or antigen-binding fragment thereof is 10-1800 mg, 100-1500 mg, 100-1200 mg, 600-1200mg, or 100-600mg.
  • Embodiment 6 The pharmaceutical combination according to any one of embodiments 1-5, wherein the mass ratio of the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof is ( 0.01-30):1, (0.01-20):1, (0.1-2.5):1, (0.5-1.5):1 or (1-1.25):1.
  • Embodiment 7 The pharmaceutical combination according to any one of embodiments 1-6, wherein the pharmaceutical combination is suitable for administration in a single treatment cycle, which includes 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of anti-TIM-3 antibody or antigen-binding fragment thereof.
  • Embodiment 8 The pharmaceutical combination according to Embodiment 7, wherein the pharmaceutical combination includes 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg of anti-PD-L1 antibody or antigen thereof Combine fragments.
  • Embodiment 9 The pharmaceutical combination according to any one of embodiments 1-8, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises:
  • HCDR1 with the amino acid sequence shown in SEQ ID NO:11
  • HCDR2 with the amino acid sequence shown in SEQ ID NO:12
  • HCDR3 with the amino acid sequence shown in SEQ ID NO:13
  • LCDR1 with the amino acid sequence shown in SEQ ID NO:14
  • LCDR2 of the amino acid sequence shown in SEQ ID NO:15
  • LCDR3 of the amino acid sequence shown in SEQ ID NO:16;
  • HCDR1 with the amino acid sequence shown in SEQ ID NO:21
  • HCDR2 with the amino acid sequence shown in SEQ ID NO:22
  • HCDR3 with the amino acid sequence shown in SEQ ID NO:23
  • LCDR1 with the amino acid sequence shown in SEQ ID NO:24
  • LCDR2 with the amino acid sequence shown in SEQ ID NO:25
  • LCDR3 with the amino acid sequence shown in SEQ ID NO:26.
  • Embodiment 10 The pharmaceutical combination according to any one of embodiments 1-9, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises:
  • Embodiment 11 The pharmaceutical combination according to any one of embodiments 1-10, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises:
  • Embodiment 12 The pharmaceutical combination according to any one of embodiments 1-11, wherein the pharmaceutical combination is used to treat tumors.
  • Embodiment 13 The pharmaceutical combination of embodiment 12, wherein the tumor is a solid tumor.
  • Embodiment 14 The pharmaceutical combination according to embodiment 13, wherein the solid tumor is lung cancer.
  • Embodiment 15 The pharmaceutical combination according to embodiment 14, wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
  • Embodiment 16 Use of the pharmaceutical combination according to any one of embodiments 1-11 in the preparation of a medicament for treating tumors.
  • Embodiment 17 The use of embodiment 16, wherein the tumor is a solid tumor.
  • Embodiment 18 The use of embodiment 17, wherein the solid tumor is lung cancer.
  • Embodiment 19 The use of embodiment 18, wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
  • Embodiment 20 The use according to any one of embodiments 16-19, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof can be used simultaneously, sequentially and /or alternate administration.
  • Embodiment 21 The use according to embodiment 20, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered sequentially.
  • Embodiment 22 The use of any one of embodiments 16-21, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks
  • the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once, optionally, at a dose of 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg each time.
  • Embodiment 23 The use of any one of embodiments 16-22, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered once, optionally, at a dose of 100-2400 mg, 600-1800 mg, 1000-1500 mg, 1000-1200 mg, or 1200-1500 mg each time.
  • Embodiment 24 A kit for treating tumors, comprising the pharmaceutical combination according to any one of embodiments 1-15.
  • the disclosed drug combination and treatment plan have good curative effects in the treatment of lung cancer (including non-small cell lung cancer and small cell lung cancer). It has a beneficial effect in at least one of ORR, DCR, DOR, PFS, OS, tolerability and side effects.
  • the term "pharmaceutical combination” refers to the simultaneous or sequential administration of two or more active ingredients (including administration as the respective active ingredients themselves, or as their respective pharmaceutically acceptable salts or esters). such as derivatives, prodrugs or compositions).
  • the active ingredients may each be administered to the subject simultaneously as a single formulation, or each as a single formulation sequentially in any order. Alternatively, all of the active ingredients are formulated in a single formulation and administered to the subject simultaneously.
  • fixed combination refers to the active components (e.g., anti-TIM-3 antibody or antigen-binding fragment thereof and anti-PD-L1 antibody or antigen-binding fragment thereof) in a fixed total dose or dose ratio, or as a single entity, drug combination
  • the drug or preparation is administered to the subject at the same time.
  • non-fixed combination refers to two or more active components administered to a subject simultaneously, concurrently or sequentially as independent entities (e.g. pharmaceutical compositions, preparations), wherein the active components administered to the subject achieve therapeutic effectiveness. quantity level.
  • non-fixed combinations include cocktail therapy, for example, administration of three or more active ingredients.
  • the individual active ingredients may be packaged, sold or administered as entirely separate pharmaceutical compositions.
  • the "non-fixed combination” also includes the combined use of "fixed combinations” between “fixed combinations” or “fixed combinations” with any one or more independent entities of the active ingredients.
  • the term "antibody” refers to an antigen-binding protein having at least one antigen-binding domain.
  • Antibodies and fragments thereof of the present disclosure A segment may be an entire antibody or any fragment thereof.
  • the antibodies and fragments thereof of the present disclosure include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof.
  • Examples of antibodies and antigen-binding fragments thereof include monospecific antibodies, bispecific antibodies, multispecific antibodies, Fab fragments, Fab' fragments, F(ab)' 2 fragments, Fv fragments, isolated CDR regions, single-chain Fv molecules (scFv) and other antibody fragments known in the art.
  • the anti-TIM-3 antibodies and anti-PD-L1 antibodies and antigen-binding fragments thereof disclosed herein can be of the IgGl, IgG2, IgG3 or IgG4 isotype.
  • the term "isotype" refers to the class of antibody encoded by the heavy chain constant region genes.
  • the anti-TIM-3 antibodies and antigen-binding fragments thereof and the anti-PD-L1 antibodies and antigen-binding fragments thereof of the present disclosure can be derived from any species, including but not limited to mouse, rat, rabbit, primate, llama, and people.
  • anti-TIM-3 antibodies and antigen-binding fragments thereof and the anti-PD-L1 antibodies and antigen-binding fragments thereof of the present disclosure may be murine antibodies, chimeric antibodies, humanized antibodies, or fully human antibodies.
  • antibodies in this disclosure include entire antibodies and any antigen-binding fragments (or “antigen-binding portions") or single chains thereof.
  • a conventional "whole antibody” is a glycoprotein containing two heavy (H) chains and two light (L) chains linked by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region consists of three domains, namely CH1, CH2 and CH3.
  • Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL).
  • the light chain constant region consists of one domain, CL.
  • the VH and VL regions can also be divided into hypervariable regions, namely complementarity determining regions (CDR), and framework regions (FR) with relatively conserved sequences.
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL are composed of three CDRs and four FRs respectively, from the amino end to the carboxyl end: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain binding domains that interact with the antigen.
  • the constant region of an antibody can mediate binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system.
  • various cells of the immune system eg, effector cells
  • Clq first component of the classical complement system.
  • special “whole antibodies”, such as Nanobodies have only heavy (H) chains and no light (L) chains.
  • an “antigen-binding fragment” or “antibody-binding portion” of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding an antigen (eg, TIM-3 or PD-L1). It has been demonstrated that the antigen-binding function of an antibody can be performed by fragments of the entire antibody.
  • Examples encompassed by the term "antigen-binding portion/fragment" of an antibody include: (i) Fab fragments: monovalent fragments consisting of VL, VH , CL and CH1 domains; ( ii) F(ab')2 fragments , a bivalent fragment containing two Fab fragments connected by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of an antibody single arm ; (v) a dAb fragment consisting of a VH domain (see Ward et al., Nature.
  • a Nanobody A heavy chain variable region containing a single variable domain and two constant domains.
  • the two domains VL and VH of the Fv fragment are encoded by different genes, recombinant methods can be used to connect VH and VL into a single protein chain through synthetic linkers, in which VL and VH pair to form a monovalent molecule (called a single-chain Fv (scFv); see, for example, Bird et al., Science. 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85:5879-5883 (1988)).
  • scFv single-chain Fv
  • antigen-binding portion/fragment single chain antibodies are also encompassed by the term antigen-binding portion/fragment.
  • recombinant polypeptides, fusion proteins and immunoconjugates comprising such antigen-binding portions/fragments are also encompassed by the term antigen-binding portions/fragments.
  • a “chimeric antibody” is an antibody that has at least a portion of a heavy chain variable region derived from one species and at least a portion of a light chain variable region; and at least a portion of a constant region derived from another species.
  • a chimeric antibody may comprise a murine variable region and a human constant region.
  • a “humanized antibody” is an antibody that contains complementarity determining regions (CDRs) derived from a non-human antibody; and framework and constant regions derived from a human antibody.
  • CDRs complementarity determining regions
  • anti-TIM-3 antibodies and anti-PD-L1 antibodies can comprise CDRs derived from one or more murine antibodies and human framework and constant regions.
  • Provided herein are exemplary humanized antibodies. Additional anti-TIM-3 antibodies or variants thereof comprising the HCDR and LCDR provided herein can be generated using any human framework sequences and are also included in the present disclosure. Additional anti-PD-L1 antibodies or variants thereof comprising the HCDR and LCDR provided herein can be generated using any human framework sequences and are also included in the present disclosure.
  • framework sequences suitable for use in the present disclosure include those that are structurally similar to the framework sequences provided herein. Additional modifications can be made in the framework regions to improve the properties of the antibodies provided herein. Such additional framework modifications may include chemical modifications; point mutations to reduce immunogenicity or remove T cell epitopes; or mutations back to residues in the original germline sequence. In some embodiments, such modifications include those corresponding to mutations exemplified herein, including back mutations to germline sequences. For example, in one embodiment, one or more amino acids in the human framework regions of the VH and/or VL of the humanized antibodies provided herein are backmutated to the corresponding amino acids in the parent murine antibody.
  • identity is also called consistency.
  • Percent (%) identity refers to the sequence to be compared after aligning it with the specific amino acid sequence shown herein and introducing gaps if necessary to achieve the maximum percent sequence identity, and without regard to When any conservative substitution is included as part of sequence identity, the percentage of amino acid residues in the aligned sequence that are identical to the amino acid residues of the specific amino acid sequence shown herein. Alignment of amino acid sequences for identity can be performed using various methods within the scope of the art, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. One skilled in the art can determine appropriate parameters for aligning sequences, including Any algorithm required to obtain maximal alignment over the full length of the compared sequences.
  • treatment refers to an attempt to alter the natural course of a disease in a treated individual, and may be a clinical intervention performed for prevention or during the course of clinical pathology.
  • desired effects of treatment include but are not limited to preventing the occurrence or recurrence of the disease, alleviating the symptoms of the disease, reducing any direct or indirect pathological consequences of the disease, preventing the metastasis of the disease, slowing down the progression rate of the disease, improving or alleviating the state of the disease, and prolonging the disease. Frequency and duration of asymptomatic periods, and prognosis for resolution or improvement of disease.
  • terapéuticaally effective amount means (i) treating a specified disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying as used herein
  • the amount of active material e.g., an antibody or antigen-binding fragment thereof of the present disclosure
  • therapeutically effective amounts may also be routinely determined by those skilled in the art based on their own knowledge and this disclosure.
  • administering means the physical introduction to a subject of a pharmaceutical composition containing a therapeutic agent using any of a variety of methods and delivery systems known to those skilled in the art.
  • Routes of administration of the antibody or antigen-binding fragment thereof include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other gastric Parenteral route of administration, such as by injection or infusion.
  • parenteral administration refers to modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic , intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion , and in vivo electroporation. Administration may also be performed, eg, once, multiple times, and/or over one or more extended time periods.
  • flat dose is used to mean the dose administered to a patient without regard to the patient's weight or body surface area (BSA).
  • a unified dose is therefore stated as an absolute amount of agent (eg, anti-TIM-3 antibody or antigen-binding fragment thereof or anti-PD-L1 antibody or antigen-binding fragment thereof) rather than as a mg/kg dose.
  • agent eg, anti-TIM-3 antibody or antigen-binding fragment thereof or anti-PD-L1 antibody or antigen-binding fragment thereof
  • mg/kg dose eg, a 60 kg person and a 100 kg person will receive the same dose of antibody (eg, 1200 mg or 1500 mg of anti-TIM-3 antibody or antigen-binding fragment thereof, 1200 mg of anti-PD-L1 antibody or antigen-binding fragment thereof).
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the terms “subject,” “patient,” or “subject” are used interchangeably.
  • “Subject,” “patient,” or “subject” includes any human or non-human animal.
  • the term “non-human animals” includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs.
  • the term “subject,” “patient,” or “subject” is a mammal.
  • the subject, patient or subject is a mouse.
  • the subject, patient or subject is human.
  • “about” means within the range of error that one of ordinary skill in the art would determine is acceptable for a particular value, which depends in part on how the value is measured or determined, ie, the limitations of the measurement system. For example, “about” may mean within 1 or more than 1 standard deviation in accordance with practice in the art. Alternatively, “about” may mean up to ⁇ 5%, such as ⁇ 2%, ⁇ 1%, or ⁇ 0.5% of a given numerical range. When a specific value is given in the disclosure or claims, unless otherwise stated, the meaning of "about” shall be considered to be within an acceptable error range for that specific value. In this article, unless otherwise stated, the values of step parameters or conditions are modified by "about” by default.
  • “combination” or “used in combination” means that two or more active substances may be administered to a subject simultaneously, each as a single formulation, or each as a single formulation, sequentially in any order. Alternatively, all of the active ingredients are formulated in a single formulation and administered to the subject simultaneously.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven tablets, one tablet is a single dose; or a bottle of injection is a single dose.
  • multiple doses consists of a plurality of single doses.
  • Unit dose refers to the dose of active ingredient contained in the smallest packaging unit containing a certain amount of medicine. For example, the dose of antibody contained in a bottle of antibody injection is a unit dose.
  • pharmaceutical composition refers to a mixture of one or more active ingredients of the present disclosure or a pharmaceutical combination thereof and a pharmaceutically acceptable excipient.
  • the purpose of pharmaceutical compositions is to facilitate administration to a subject of a compound of the present disclosure or a pharmaceutical combination thereof.
  • pharmaceutical composition and “preparation” have the same meaning and are used interchangeably.
  • recurrent cancer is a cancer that reappears at the original site or at a distant site after responding to initial treatment, such as surgery.
  • a “locally recurrent” cancer is a cancer that appears after treatment in the same location as a previously treated cancer.
  • metalstatic cancer refers to cancer that has spread from one part of the body, such as the lungs, to another part of the body.
  • refractory refers to a situation in which a subject or mammal has residual cancer cells in its body even after intensive treatment.
  • first-line treatment refers to the first or standard choice of drug treatment based on the patient's condition.
  • treatment failure is defined as disease progression or recurrence during or after the last treatment.
  • PD-L1 positive or “PD-L1 expression positive” referring to cell surface PD-L1 expression refers to the proportion of cells in a test tissue sample containing tumor cells and tumor-infiltrating immune cells above which the Samples were assessed as expressing cell surface PD-L1.
  • PD-L1 positive tumors or tumors positive for PD-L1 expression means at least about 0.01%, at least about 0.5%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, or at least about 30% of the total cells express PD-L1.
  • PD-L1 positive tumors or PD-L1 expression positive tumors may also be described herein as PD-L1 expressing tumors.
  • PD-L1 positive tumors or PD-L1 expression positive tumors mean, at least about 0.1%-20%, at least about 0.1%-10%, at least about 1%, at least about 5%, at least about 1% % or a range of 1%-5% of the total cells express PD-L1 on the cell surface.
  • PD-L1 positive tumor or PD-L1 expression positive tumor means that at least about 1% of the total cells express PD-L1 on the cell surface.
  • PD-L1 positive tumor or PD-L1 expression positive tumor means that at least about 1% of the total number of tumor cells or tumor-infiltrating immune cells express PD-L1 on the cell surface.
  • Figure 1 shows the tumor volume (mm 3 ) of mice in each group on D11. P values are compared by Mann-Whitney test. * indicates P ⁇ 0.05, and P ⁇ 0.05 is defined as a statistically significant difference;
  • Figure 2 shows the tumor weight (g) of mice in each group on D11. P values are compared by Mann-Whitney test. * indicates P ⁇ 0.05, and P ⁇ 0.05 is defined as a statistically significant difference.
  • the entire contents of WO2020041520 or CN112566936 patent application documents are incorporated into this disclosure.
  • the heavy chain amino acid sequence of the anti-TIM-3 antibody in the following examples is as shown in SEQ ID NO: 9 of the present disclosure, and the light chain amino acid sequence is as shown in SEQ ID NO: 10 of the present disclosure.
  • the preparation and purification methods of the anti-PD-L1 antibodies in the present disclosure have been recorded in the patent application documents with publication numbers WO2016022630 or CN107001463, and the entire contents of the WO2016022630 or CN107001463 patent application documents are incorporated into the present disclosure.
  • the hu5G11-hlgG1 in the following examples is the hu5G11-hlgG1 in WO2016022630 or CN107001463.
  • the heavy chain amino acid sequence of hu5G11-hlgG1 is as shown in SEQ ID NO:19 of the present disclosure, and the light chain amino acid sequence is as shown in SEQ ID of the present disclosure. NO:20 shown.
  • Example 1 The efficacy of anti-TIM-3 antibodies and anti-PD-L1 antibodies on lung cancer HCC827 subcutaneous transplanted tumors
  • HCC827 cells were purchased from the Cell Bank of the Chinese Academy of Sciences. The cells were cultured in RPMI-1640 medium containing 10% fetal calf serum to the exponential growth phase. The cells were collected for later use. Human peripheral blood mononuclear cells (HuPBMC) were purchased from Shanghai Rubai Biotechnology Co., Ltd. The cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, and then the cells were collected for use. NCG mice (NOD/ShiLtJ Gpt-Prkdc em26Cd52Il2rgem26Cd22/Gpt Gpt) aged 6-7 weeks were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.
  • each NCG mouse was subcutaneously inoculated with 8 ⁇ 10 6 HCC827 cells. After the tumors grew to 100-200 mm 3 , they were divided into 5 groups according to the tumor volume, with 8 mice in each group. Each mouse was injected intravenously (IV) with 5 ⁇ 10 6 HuPBMC, and the next day each mouse was intraperitoneally injected with hIgG4 (purchased from Sino Biological), anti-TIM-3 antibody, hu5G11-hlgG1, or anti-TIM-3 antibody. +hu5G11-hIgG1, administered once each on D0, D3, D7, and D10 for a total of 4 times. The administration volume is 10 mg/kg body weight. D0 indicates the time of the first administration. The dosage is as shown in Table 3. Show.
  • mice in each group tolerated the drugs well, and no symptoms such as obvious weight loss occurred.
  • the results are shown in Table 3 and Figure 1-2.
  • the average tumor volumes of mice in groups 2 and 3 were 589.7 ⁇ 59.6mm 3 and 703.4 ⁇ 58.9mm 3 respectively, and the tumor inhibition rates were 35% and 35%, respectively.
  • the tumor weight of mice in group 5 was not only significantly lower than that of mice in group 1, but also significantly lower than that of mice in groups 2, 3 and 4.
  • the tumor weight of mice indicates that the combination of anti-TIM-3 antibody and hu5G11-hlgG1 has a synergistic anti-tumor effect.
  • the expected survival period is more than 3 months.
  • Cohort 1 patients with advanced first-line NSCLC with positive PD-L1 expression
  • stage IIIB/IIIC Patients with locally advanced (stage IIIB/IIIC), recurrent or metastatic (stage IV) NSCLC who are not suitable for surgical treatment and are not suitable for radical concurrent chemoradiation and chemotherapy confirmed by histology or cytology;
  • testing proves that there is no EGFR mutation, ALK fusion, or ROS1 mutation (for squamous non-small cell lung cancer, patients with known gene mutations are excluded, and testing is not mandatory for those with unknown status);
  • Cohort 1 advanced first-line patients have not received systemic anti-tumor treatment for advanced disease. Patients are allowed to have received neoadjuvant/adjuvant chemotherapy or radiotherapy or concurrent chemoradiotherapy in the past, but the interval between disease recurrence and completion of the last treatment must be at least 6 months;
  • Routine blood examination standards no blood transfusion or correction with hematopoietic stimulating factor drugs within 7 days before the examination:
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • APTT Activated partial thrombin time
  • ILR international normalized ratio
  • PT prothrombin time
  • Thyroid function tests must meet the following standards:
  • LVEF left ventricular ejection fraction
  • Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study period and within 6 months after the end of the study; serum pregnancy / The urine pregnancy test is negative and must be non-lactating subjects; male subjects must agree to use contraceptive measures during the study period and within 6 months after the end of the study period.
  • contraceptive measures such as intrauterine devices, birth control pills or condoms
  • the hu5G11-hIgG1 injection was infused first, and then the anti-TIM-3 antibody injection was infused.
  • hu5G11-hIgG1 injection (specification: 600mg/20mL/bottle, and/or 100mg/10mL/bottle): 3 weeks is a treatment cycle, through intravenous infusion, on the first day of each treatment cycle, 1200mg hu5G11-hIgG1 The dose is administered once.
  • Anti-TIM-3 antibody injection (specification: 240mg/4mL/bottle, and/or 600mg/10mL/bottle): 3 weeks is a treatment cycle, through intravenous infusion, 1200mg, 1500mg on the first day of each treatment cycle or a dose of 1800 mg anti-TIM-3 antibody administered once.
  • the efficacy evaluation standard is based on RECIST 1.1, and the iRECIST standard is used to confirm the efficacy.
  • ORR Objective response rate
  • PFS progression-free survival
  • DCR disease control rate
  • DOR duration of response
  • OS overall survival
  • Pharmacokinetic/pharmacodynamic related indicators pharmacokinetic (PK) parameters, immunogenicity (ADA) incidence, receptor occupancy (RO), etc.;
  • Adverse event incidence the occurrence of all adverse events (AE), serious adverse events (SAE) and treatment-related adverse events (TEAEs), as well as abnormal laboratory test indicators.
  • Brain metastasis must be asymptomatic or treated and the disease has been stable for at least 1 month after stopping steroids and anticonvulsants (before treatment in this study). Patients suspected of having brain metastases during the screening period should undergo brain CT/MRI before entering this study;
  • Routine blood examination standards no blood transfusion or correction with hematopoietic stimulating factor drugs within 7 days before the examination:
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • Coagulation function must meet the following standards: activated partial thrombin time (APTT), international normalized ratio (INR), prothrombin time (PT) ⁇ 1.5 ⁇ ULN (not receiving anticoagulant therapy);
  • APTT activated partial thrombin time
  • ILR international normalized ratio
  • PT prothrombin time
  • Thyroid function tests must meet the following standards:
  • LVEF left ventricular ejection fraction
  • the hu5G11-hIgG1 injection was infused first, and then the anti-TIM-3 antibody injection was infused.
  • hu5G11-hIgG1 injection (specification: 600mg/20mL/bottle, and/or 100mg/10mL/bottle): 3 weeks is a treatment cycle, through intravenous infusion, 1200mg hu5G11-hIgG1 on the first day of each treatment cycle The dose is administered once (dosing time window: ⁇ 3 days).
  • Anti-TIM-3 antibody injection (specification: 240mg/4mL/bottle, and/or 600mg/10mL/bottle): 3 weeks is a treatment cycle, through intravenous infusion, on the first day of each treatment cycle, 1200mg or A dose of 1500 mg of anti-TIM-3 antibody was administered once (dosing time window: ⁇ 3 days).
  • the efficacy evaluation standard is based on RECIST 1.1, and the iRECIST standard is used to confirm the efficacy.
  • ORR Objective response rate
  • PFS progression-free survival
  • DCR disease control rate
  • DOR duration of response
  • OS overall survival
  • Pharmacokinetic/pharmacodynamic related indicators pharmacokinetic (PK) parameters, immunogenicity (ADA) incidence, receptor occupancy (RO), etc.;
  • Adverse event incidence the occurrence of all adverse events (AE), serious adverse events (SAE) and treatment-related adverse events (TEAEs), as well as abnormal laboratory test indicators.
  • anti-TIM-3 antibody combined with hu5G11-hIgG1 can safely and effectively treat extensive-stage small cell lung cancer (especially extensive-stage small cell lung cancer that has failed or is intolerant to first-line platinum-containing chemotherapy regimens).
  • extensive-stage small cell lung cancer especially extensive-stage small cell lung cancer that has failed or is intolerant to first-line platinum-containing chemotherapy regimens.
  • the clinical efficacy and survival benefit of the patient can be significantly improved, the patient's condition can be relieved and controlled, the progression of the disease can be slowed down, and the patient's progression-free survival and overall survival can be prolonged. At this stage, some patients can achieve partial response PR, and the overall disease control rate is high DCR.
  • the advantages of anti-TIM-3 antibody combined with hu5G11-hIgG1 in the treatment of extensive-stage small cell lung cancer are shown. Specific exemplary results are as follows:
  • Treatment plan Every 3 weeks is a treatment cycle. On the first day of each treatment cycle, 1200 mg of hu5G11-hIgG1 injection is first intravenously infused, and then 1200 mg of anti-TIM-3 antibody injection is intravenously infused.
  • the patient’s best treatment effect is PR (partial remission).

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Abstract

提供抗TIM-3抗体与抗PD-L1抗体的药物组合，其包括抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段。还提供用于治疗肿瘤的试剂盒，其包含所述药物组合。此外，还提供所述药物组合在制备用于治疗肿瘤的药物中的用途以及所述药物组合治疗肿瘤的方法。

Description

抗TIM-3抗体与抗PD-L1抗体的药物组合 技术领域
本公开属于生物医药领域，具体涉及抗TIM-3抗体与抗PD-L1抗体的药物组合。
背景技术
近年来肿瘤发病率呈上升趋势，恶性肿瘤治疗效果差，晚期转移率高。目前临床上采用的常规治疗方法如放疗、化疗和手术治疗虽然能够缓解病痛，延长生存时间，但均存在局限。因此通过对免疫检查点的抑制、实现免疫细胞的再次活化、避免肿瘤细胞的免疫逃逸、从而杀伤肿瘤细胞的免疫治疗，已逐渐成为肿瘤治疗领域的热点。
T细胞免疫球蛋白和粘蛋白结构域蛋白3(T cell immunoglobulin and mucin domain-containing protein 3，TIM-3)，也称为甲型肝炎病毒细胞受体2(Hepatitis A Virus Cellular Receptor 2，HAVCR2)，是免疫调节蛋白TIM家族成员(人TIM家族包括TIM-1、3、4)，TIM-3选择性地表达于活化的Th1细胞表面，还在髓细胞、DC细胞、NK细胞、巨噬细胞上表达，同时也在多种肿瘤细胞上表达，例如黑色素瘤、宫颈癌和肾癌。TIM-3具有多种不同的配体，包括半乳凝素9(Galectin9)、磷酯酰丝氨酸(PtdSer)、高迁移族蛋白B1(HMGB1)和癌胚抗原细胞黏附分子1(CEACAM1)。TIM-3作为一种免疫检查点，其生理功能为负向调节机体的免疫作用，避免过强的免疫作用或自身免疫作用对机体的损伤。越来越多的证据表明，TIM-3蛋白和/或mRNA在多种肿瘤组织和肿瘤相关的免疫细胞上表达上调，参与肿瘤免疫逃逸和免疫应答，促进肿瘤的发展。
程序性死亡配体1(Programmed death-ligand 1，PD-L1)是程序性死亡分子1(Programmed death，PD-1)的一个配体，高表达于多种恶性肿瘤细胞表面，且表达水平和受试者的临床表现及预后紧密相关。在肿瘤微环境中，癌症细胞表面的PD-L1通过与T细胞表面的PD-1或CD80的结合，抑制T细胞的激活和增殖，促进效应T细胞进入衰竭或无反应状态，诱导T细胞的凋亡，刺激辅助T细胞分化为调节性T细胞，从而阻止T细胞对肿瘤细胞的杀伤作用。抗PD-L1抗体可以通过阻断PD-L1与PD-1及CD80的相互作用，避免肿瘤微环境中的效应T细胞的活性被抑制，增强内源性抗肿瘤免疫效应。
TIM-3与PD-1/PD-L1密切相关，TIM-3可能是介导PD-1/PD-L1实现免疫逃逸的重要分子。而抗TIM-3抗体和抗PD-L1抗体的单药治疗仍存在一定的局限性，需要其他替代疗法，例如将抗TIM-3抗体与抗PD-L1抗体联合，以提高抗肿瘤效果。
发明概述
在一方面，本公开提供药物组合，其包括抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合包括单位剂量为60-1800mg的抗TIM-3抗体或其抗原结合片段和单位剂量为10-1800mg的抗PD-L1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合包含100-1800mg的抗TIM-3抗体或其抗原结合片段和100-2400mg的抗PD-L1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包含100-1800mg的抗TIM-3抗体或其抗原结合片段和100-2400mg的抗PD-L1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合用于治疗肿瘤。
在另一方面，本公开提供用于治疗肿瘤的药物组合，其包含抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段。
在另一方面，本公开还提供在受试者中治疗肿瘤的方法，其包括向受试者给予治疗有效量的本公开的药物组合。另外，本公开还提供了本公开的药物组合在制备用于治疗肿瘤的药物中的用途。或者，本公开还提供了抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段在制备用于治疗肿瘤的药物中的用途。
在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段可分开包装或包装在一起。并且其中，所述抗TIM-3抗体或其抗原结合片段能够以单份或多个等份进行包装，所述抗PD-L1抗体或其抗原结合片段能够以单份或多份进行包装。
在一些实施方案中，所述药物组合是固定组合。在一些实施方案中，所述固定组合呈固体制剂的形式或液体制剂的形式。
在一些实施方案中，所述药物组合是非固定组合。在一些实施方案中，所述非固定组合中的抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段各自呈药物组合物的形式。
在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段，可同时、先后和/或交替给药。
在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每次以100-1800mg的剂量施用。
在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次。在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段每次以100-2400mg的剂量施用。
在另一方面，本公开提供用于治疗肿瘤的试剂盒，其包括本公开的药物组合。在一些具体的实施方案中，所述试剂盒包括抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段。
在一些实施方案中，所述肿瘤为实体瘤。在一些实施方案中，所述肿瘤为肺癌。在一些实施方案中，所述肺癌选自非小细胞肺癌(NSCLC)或小细胞肺癌(SCLC)。
发明详述
本公开提供药物组合，其包括抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述药物组合用于治疗肿瘤。
本公开还提供本公开的药物组合在制备用于治疗肿瘤的药物中的用途。本公开还提供本公开的药物组合治疗肿瘤的用途。本公开还提供治疗肿瘤的方法，包括向受试者给予治疗有效量的本公开的药物组合。
本公开还提供用于治疗肿瘤的试剂盒，所述试剂盒包括本公开的药物组合。在一些实施方案中，所述试剂盒还包括本公开的药物组合治疗肿瘤的说明。
此外，本公开还提供用于治疗肿瘤的抗TIM-3抗体或其抗原结合片段。本公开还提供抗TIM-3抗体或其抗原结合片段在制备用于治疗肿瘤的药物中的用途。本公开还提供抗TIM-3抗体或其抗原结合片段治疗肿瘤的用途。本公开还提供治疗肿瘤的方法，包括向受试者给予治疗有效量的本公开的抗TIM-3抗体或其抗原结合片段。
在一些实施方案中，所述肿瘤为实体瘤。在一些实施方案中，所述肿瘤为肺癌。在一些实施方案中，所述肺癌选自非小细胞肺癌(NSCLC)或小细胞肺癌(SCLC)。
药物组合
在一方面，本公开提供一种药物组合，其包括抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合包装于同一试剂盒中，所述试剂盒还包括将抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段联合使用以治疗肿瘤的说明。在另一些实施方案中，所述药物组合中的抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段分开包装于各自的药盒中，所述药盒还包括将抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段联合使用以治疗肿瘤的说明。
在一些实施方案中，所述药物组合是固定组合。在一些实施方案中，所述固定组合呈固体制剂的形式或液体制剂的形式。在一些实施方案中，所述固定组合中的抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段配制在单一制剂中。在一些实施方案中，所述单一制剂呈液体制剂的形式或固体制剂的形式。在一些具体实施方案中，所述单一制剂为注射液。在一些具体实施方案中，所述单一制剂为冻干制剂。
在一些实施方案中，所述药物组合是非固定组合。在一些实施方案中，所述非固定组合中的抗TIM-3 抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段各自呈药物组合物的形式，且含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-L1抗体或其抗原结合片段的药物组合物存在于或不存在于同一个药袋。
在一些具体实施方案中，所述非固定组合中，含抗TIM-3抗体或其抗原结合片段的药物组合物为液体制剂。在一些具体实施方案中，含抗TIM-3抗体或其抗原结合片段的药物组合物为注射液。在一些具体实施方案中，含抗TIM-3抗体或其抗原结合片段的药物组合物为冻干制剂。在一些具体实施方案中，所述非固定组合中，含抗PD-L1抗体或其抗原结合片段的药物组合物为液体制剂。在一些具体实施方案中，含抗PD-L1抗体或其抗原结合片段的药物组合物为注射液。在一些具体实施方案中，含抗PD-L1抗体或其抗原结合片段的药物组合物为冻干制剂。
在一些实施方案中，所述药物组合中抗TIM-3抗体或其抗原结合片段的单位剂量为60-1800mg、100-1600mg、120-1600mg、180-1200mg、或240-600mg。在一些实施方案中，所述药物组合中抗TIM-3抗体或其抗原结合片段的单位剂量为约60mg、约120mg、约160mg、约180mg、约200mg、约240mg、约280mg、约300mg、约320mg、约360mg、约400mg、约420mg、约440mg、约480mg、约520mg、约540mg、约560mg、约600mg、约640mg、约660mg、约680mg、约720mg、约760mg、约780mg、约800mg、约840mg、约880mg、约900mg、约920mg、约960mg、约1000mg、约1020mg、约1040mg、约1080mg、约1120mg、约1140mg、约1160mg、约1200mg、约1240mg、约1260mg、约1280mg、约1320mg、约1360mg、约1380mg、约1400mg、约1440mg、约1480mg、约1500mg、约1520mg、约1560mg、约1600mg、约1620mg、约1640mg、约1680mg、约1720mg、约1740mg、约1760mg和/或约1800mg、或上述任意值形成的范围。在一些实施方案中，所述药物组合中抗TIM-3抗体或其抗原结合片段的单位剂量为约240mg、约300mg、约360mg和/或约600mg。在一些实施方案中，所述药物组合中抗TIM-3抗体或其抗原结合片段的单位剂量为约240mg和/或约600mg。
在一些实施方案中，所述药物组合中抗PD-L1抗体或其抗原结合片段的单位剂量为10-1800mg、100-1500mg、100-1200mg、600-1200mg、或100-600mg。在一些实施方案中，所述药物组合中抗PD-L1抗体或其抗原结合片段的单位剂量为约10mg、约40mg、约80mg、约100mg、约120mg、约140mg、约160mg、约180mg、约200mg、约220mg、约240mg、约260mg、约280mg、约300mg、约320mg、约340mg、约360mg、约380mg、约400mg、约420mg、约440mg、约460mg、约480mg、约500mg、约520mg、约540mg、约560mg、约580mg、约600mg、约620mg、约640mg、约660mg、约680mg、约700mg、约720mg、约740mg、约760mg、约780mg、约800mg、约820mg、约840mg、约860mg、约880mg、约900mg、约920mg、约940mg、约960mg、约980mg、约1000mg、约1020mg、约1040mg、约1060mg、约1080mg、约1100mg、约1120mg、约1140mg、约1160mg、约1180mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg和/或约1800mg、或上述任意值形成的范围。在一些实施方案中，所述药物组合中抗PD-L1抗体或其抗原结合片段的单位剂量为约100mg和/或约600mg。
在一些实施方案中，所述药物组合包括单位剂量为60-1800mg、100-1600mg、120-1600mg、180-1200mg、或240-600mg的抗TIM-3抗体或其抗原结合片段和单位剂量为10-1800mg、100-1500mg、100-1200mg、600-1200mg、或100-600mg的抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括单位剂量为约60mg、约120mg、约160mg、约180mg、约200mg、约240mg、约280mg、约300mg、约320mg、约360mg、约400mg、约420mg、约440mg、约480mg、约520mg、约540mg、约560mg、约600mg、约640mg、约660mg、约680mg、约720mg、约760mg、约780mg、约800mg、约840mg、约880mg、约900mg、约920mg、约960mg、约1000mg、约1020mg、约1040mg、约1080mg、约1120mg、约1140mg、约1160mg、约1200mg、约1240mg、约1260mg、约1280mg、约1320mg、约1360mg、约1380mg、约1400mg、约1440mg、约1480mg、约1500mg、约1520mg、约1560mg、约1600mg、约1620mg、约1640mg、约1680mg、约1720mg、约1740mg、约1760mg和/或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段，和单位剂量为约10mg、约40mg、约80mg、约100mg、约120mg、约140mg、约160mg、约180mg、约200mg、约220mg、约240mg、约260mg、约280mg、约300mg、约320mg、约340mg、约360mg、约380mg、约400mg、约420mg、 约440mg、约460mg、约480mg、约500mg、约520mg、约540mg、约560mg、约580mg、约600mg、约620mg、约640mg、约660mg、约680mg、约700mg、约720mg、约740mg、约760mg、约780mg、约800mg、约820mg、约840mg、约860mg、约880mg、约900mg、约920mg、约940mg、约960mg、约980mg、约1000mg、约1020mg、约1040mg、约1060mg、约1080mg、约1100mg、约1120mg、约1140mg、约1160mg、约1180mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg和/或约1800mg、或上述任意值形成的范围的抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括单位剂量为约240mg、约300mg、约360mg和/或约600mg的抗TIM-3抗体或其抗原结合片段和单位剂量为约100mg和/或约600mg的抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包括单位剂量为约240mg和/或约600mg的抗TIM-3抗体或其抗原结合片段和单位剂量为约100mg和/或约600mg的抗PD-L1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合包含100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段。在一些实施方案中，所述药物组合包含约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段。在一些实施方案中，所述药物组合包含约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段。
在一些实施方案中，所述药物组合包含100-2400mg、600-1800mg、1000-1500mg、1000-1200mg、或1200-1500mg的抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包含约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、约2200mg、约2300mg、或约2400mg、或上述任意值形成的范围的抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包含约1200mg的抗PD-L1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合包含100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段，和100-2400mg、600-1800mg、1000-1500mg、1000-1200mg、或1200-1500mg的抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包含约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段，和约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、约2200mg、约2300mg、或约2400mg、或上述任意值形成的范围的抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述药物组合包含约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，和约1200mg的抗PD-L1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包含100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包含约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包含约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包含100-2400mg、600-1800mg、1000-1500mg、1000-1200mg、或1200-1500mg的抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包含约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、 约2200mg、约2300mg、或约2400mg、或上述任意值形成的范围的抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包含约1200mg的抗PD-L1抗体或其抗原结合片段。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包含100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段，和100-2400mg、600-1800mg、1000-1500mg、1000-1200mg、或1200-1500mg的抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包含约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段，和约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、约2200mg、约2300mg、或约2400mg、或上述任意值形成的范围的抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包含约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，和约1200mg的抗PD-L1抗体或其抗原结合片段。
在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段可以是含抗TIM-3抗体或其抗原结合片段的药物组合物。其中，含抗TIM-3抗体或其抗原结合片段的药物组合物为单剂量或多剂量，优选为多剂量。在一些实施方案中，所述多剂量可以由单剂量为含约240mg、约300mg、约360mg和/或约600mg抗TIM-3抗体或其抗原结合片段的药物组合物组成。在一些实施方案中，所述多剂量可以由单剂量为含约240mg和/或约600mg抗TIM-3抗体或其抗原结合片段的药物组合物组成。
在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段可以是含抗PD-L1抗体或其抗原结合片段的药物组合物。其中，含抗PD-L1抗体或其抗原结合片段的药物组合物为单剂量或多剂量，优选为多剂量。在一些实施方案中，所述多剂量可以由单剂量为含约100mg和/或约600mg抗PD-L1抗体或其抗原结合片段的药物组合物组成。
在一些实施方案中，所述药物组合中，抗TIM-3抗体或其抗原结合片段的剂量是药物组合物中的固定剂量。
在一些实施方案中，所述药物组合中，抗TIM-3抗体或其抗原结合片段的含量为一日剂量。在一些实施方案中，所述药物组合中，抗TIM-3抗体或其抗原结合片段的含量为一日一次剂量。
在一些实施方案中，所述药物组合中，抗TIM-3抗体或其抗原结合片段的含量为统一剂量。
在一些实施方案中，所述药物组合中，抗TIM-3抗体或其抗原结合片段的含量为一个治疗周期的剂量，每个治疗周期为21天(即3周)。
在一些实施方案中，所述药物组合中，抗PD-L1抗体或其抗原结合片段的剂量是药物组合物中的固定剂量。
在一些实施方案中，所述药物组合中，抗PD-L1抗体或其抗原结合片段的含量为一日剂量。在一些实施方案中，所述药物组合中，抗PD-L1抗体或其抗原结合片段的含量为一日一次剂量。
在一些实施方案中，所述药物组合中，抗PD-L1抗体或其抗原结合片段的含量为统一剂量。
在一些实施方案中，所述药物组合中，抗PD-L1抗体或其抗原结合片段的含量为一个治疗周期的剂量，每个治疗周期为21天(即3周)。
在一些实施方案中，所述药物组合中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段的质量比为(0.01-30):1、(0.01-20):1、(0.1-2.5):1、(0.5-1.5):1或(1-1.25):1；其中，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段可分开包装或包装在一起。在一些实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段分开包装，其中，抗TIM-3抗体或其抗原结合片段能够以单份或多份进行包装，抗PD-L1抗体或其抗原结合片段能够以单份或多份进行包装。在一些实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段分开包装，其中，抗TIM-3抗体或其抗原结合片段能够以单份或多个等份(例如2等份、3等份、4等份、5等份、6等份、7等份、8等份或更多等份)进行包装，抗PD-L1抗体或其抗原结合片段能够以单份或多份进行包装。在一些 实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段分开包装，其中，抗TIM-3抗体或其抗原结合片段能够以单份或多个等份(例如2等份、3等份、4等份、5等份、6等份、7等份、8等份或更多等份)进行包装，抗PD-L1抗体或其抗原结合片段能够以单份或多个等份(例如2等份、3等份、12等份或其他等份)进行包装。在一些实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段包装在一起。
在一些实施方案中，所述药物组合包括含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-L1抗体或其抗原结合片段的药物组合物，其中含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合向患者给予100-1800mg、600-1800mg、600-1500mg、或1200-1500mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-L1抗体或其抗原结合片段的药物组合物被制备为适合向患者给予100-2400mg、600-1800mg、1000-1500mg、1000-1200mg、或1200-1500mg抗PD-L1抗体或其抗原结合片段的单剂量或多剂量。在一些实施方案中，所述药物组合包括含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-L1抗体或其抗原结合片段的药物组合物，其中含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-L1抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、约2200mg、约2300mg、或约2400mg、或上述任意值形成的范围的抗PD-L1抗体或其抗原结合片段的单剂量或多剂量。在一些实施方案中，所述药物组合包括含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-L1抗体或其抗原结合片段的药物组合物，其中含抗TIM-3抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约1200mg或约1500mg抗TIM-3抗体或其抗原结合片段的单剂量或多剂量，含抗PD-L1抗体或其抗原结合片段的药物组合物被制备为适合向患者给予约1200mg抗PD-L1抗体或其抗原结合片段的单剂量或多剂量。
在另一方面，本公开还提供包括抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段的药物组合在制备用于治疗肿瘤的药物中的用途。本公开还提供包括抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段的药物组合治疗肿瘤的用途。本公开还提供在受试者中治疗肿瘤的方法，包括向受试者给予治疗有效量的包含抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段的药物组合。
在另一方面，本公开提供用于治疗肿瘤的试剂盒，所述试剂盒包括含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-L1抗体或其抗原结合片段的药物组合物，以及将含抗TIM-3抗体或其抗原结合片段的药物组合物和含抗PD-L1抗体或其抗原结合片段的药物组合物联合使用以治疗肿瘤的说明。
在另一方面，本公开提供用于治疗肿瘤的试剂盒，所述试剂盒包括含抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段的药物组合物，以及使用所述药物组合物治疗肿瘤的说明。
在另一方面，本公开还提供一种用于治疗肿瘤的药物包，其在独立的容器中分别包含单包装的药物组合物，其中，在一个容器中包括含抗TIM-3抗体或其抗原结合片段的药物组合物，并在第二个容器中包括含抗PD-L1抗体或其抗原结合片段的药物组合物。
在另一方面，本公开还提供一种用于治疗肿瘤的药物包，其在独立的容器中分别包含单包装的药物组合物，其中，所述容器包括含抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段的药物组合物。
在一些具体实施方案中，所述试剂盒或药物包中，含抗TIM-3抗体或其抗原结合片段的药物组合物为为液体制剂或固体制剂。在一些具体实施方案中，含抗TIM-3抗体或其抗原结合片段的药物组合物为注射液。在一些具体实施方案中，含抗TIM-3抗体或其抗原结合片段的药物组合物为冻干制剂。
在一些具体实施方案中，所述试剂盒或药物包中，含抗PD-L1抗体或其抗原结合片段的药物组合物为为液体制剂或固体制剂。在一些具体实施方案中，含抗PD-L1抗体或其抗原结合片段的药物组合物为注射液。在一些具体实施方案中，含抗PD-L1抗体或其抗原结合片段的药物组合物为冻干制剂。
在一些具体实施方案中，所述试剂盒或药物包中，含抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段的药物组合物为液体制剂或固体制剂。在一些具体实施方案中，含抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段的药物组合物为注射液。在一些具体实施方案中，含抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段的药物组合物为冻干制剂。
在一些实施方案中，所述肿瘤为实体瘤。在一些实施方案中，所述实体瘤为肺癌。在一些实施方案中，所述肺癌包括非小细胞肺癌或小细胞肺癌。在一些实施方案中，所述非小细胞肺癌为鳞状细胞非小细胞肺癌(也称为鳞癌、鳞状细胞癌、鳞状非小细胞肺癌或鳞状上皮细胞癌)。在一些实施方案中，所述非小细胞肺癌为非鳞状细胞非小细胞肺癌。在一些实施方案中，所述非小细胞肺癌为腺癌(也称为肺腺癌)。在一些实施方案中，所述非小细胞肺癌为大细胞癌(也称为肺大细胞癌)。在一些实施方案中，所述小细胞肺癌为广泛期小细胞肺癌。在一些实施方案中，所述小细胞肺癌为局限期小细胞肺癌。
药物组合的给药/治疗方案
在一些实施方案中，上述用途或治疗方法中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段，可同时、先后和/或交替给药。在一些实施方案中，上述用途或治疗方法中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段先后给药。在一些实施方案中，上述用途或治疗方法中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段各自呈药物组合物的形式，可同时、先后和/或交替给药。在一些实施方案中，上述用途或治疗方法中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段各自呈药物组合物的形式，先后给药。在一些实施方案中，上述用途或治疗方法中，先施用抗PD-L1抗体或其抗原结合片段，再施用抗TIM-3抗体或其抗原结合片段。在一些实施方案中，上述用途或治疗方法中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段各自呈药物组合物的形式，先施用含抗PD-L1抗体或其抗原结合片段的药物组合物，再施用含抗TIM-3抗体或其抗原结合片段的药物组合物。在一些实施方案中，在所述方法或用途中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段配制在单一制剂中，同时给药。
在一些实施方案中，上述用途或治疗方法中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段分别以相同或不同的给药方案进行给药。在一些实施方案中，上述用途或治疗方法中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段分别以不同的给药方案进行给药。在一些实施方案中，上述用途或治疗方法中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段分别以相同的给药方案进行给药。
在一些实施方案中，上述用途或治疗方法中，所述抗TIM-3抗体或其抗原结合片段每1周(q1w)、每2周(q2w)、每3周(q3w)、或每4周(q4w)施用一次。在一个具体的实施方案中，抗TIM-3抗体或其抗原结合片段每3周施用一次。在一个具体的实施方案中，抗TIM-3抗体或其抗原结合片段每4周施用一次。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每次以100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的剂量施用。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每次以约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、或约1800mg、或上述任意值形成的范围的剂量施用。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每次以约1200mg或约1500mg的剂量施用。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次，每次以100-1800mg、600-1800mg、600-1500mg、或1200-1500mg抗TIM-3抗体或其抗原结合片段的剂量施用。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次，每次以约1200mg或约1500mg抗TIM-3抗体或其抗原结合片段的剂量施用。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段每3周施用一次，每次以约1200mg或约1500mg抗TIM-3抗体或其抗原结合片段的剂量施用。
在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体或其抗原结合片段每1周(q1w)、每2周(q2w)、每3周(q3w)、或每4周(q4w)施用一次。在一个具体的实施方案中，抗PD-L1抗体或其抗原结合片段每3周施用一次。在一个具体的实施方案中，抗PD-L1抗体或其抗原结合片段每4周施用一次。在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段每次以100-2400mg、600-1800mg、1000- 1500mg、1000-1200mg、或1200-1500mg的剂量施用。在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段每次以约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、约2200mg、约2300mg、或约2400mg、或上述任意值形成的范围的剂量施用。在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段每次以约1200mg的剂量施用。在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次，每次以100-2400mg、600-1800mg、1000-1500mg、1000-1200mg、或1200-1500mg抗PD-L1抗体或其抗原结合片段的剂量施用。在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次，每次以约1200mg抗PD-L1抗体或其抗原结合片段的剂量施用。在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段每3周施用一次，每次以约1200mg抗PD-L1抗体或其抗原结合片段的剂量施用。
在一些实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段分别具有相同或不同的治疗周期。在一些具体的实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段具有相同的治疗周期，例如每1周、每2周、每3周、或每4周为一个治疗周期。在一些具体的实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段具有相同的治疗周期，例如每3周为一个治疗周期。
在一些实施方案中，上述用途或治疗方法中，每3周为一个治疗周期，在每个治疗周期给予抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段。在一些实施方案中，上述用途或治疗方法中，每3周为一个治疗周期，在每个治疗周期分别给予抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段一次。在一些实施方案中，上述用途或治疗方法中，每3周为一个治疗周期，在每个治疗周期的第1天给予抗TIM-3抗体或其抗原结合片段，在每个治疗周期第1天给予抗PD-L1抗体或其抗原结合片段。在一些实施方案中，上述用途或治疗方法中，每3周为一个治疗周期，在每个治疗周期的第1天给予抗TIM-3抗体或其抗原结合片段一次，在每个治疗周期第1天给予抗PD-L1抗体或其抗原结合片段一次。
在一些具体的实施方案中，上述用途或治疗方法中，每3周为一个治疗周期，在每个治疗周期给予100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段，在每个治疗周期给予100-2400mg、600-1800mg、1000-1500mg、1000-1200mg、或1200-1500mg的抗PD-L1抗体或其抗原结合片段。在一些具体的实施方案中，上述用途或治疗方法中，每3周为一个治疗周期，在每个治疗周期给予约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，在每个治疗周期给予约1200mg的抗PD-L1抗体或其抗原结合片段。在一些具体的实施方案中，上述用途或治疗方法中，每3周为一个治疗周期，在每个治疗周期的第1天给予约1200mg或约1500mg的抗TIM-3抗体或其抗原结合片段，在每个治疗周期的第1天给予约1200mg的抗PD-L1抗体或其抗原结合片段。
在一些实施方案中，在每一个治疗周期中，以(0.01-30):1、(0.01-20):1、(0.1-2.5):1、(0.5-1.5):1或(1-1.25):1的抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段的质量比，向受试者给予抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段以多剂量或单剂量给予。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段均以多剂量给予。
在一些实施方案中，上述用途或治疗方法中，所述抗TIM-3抗体或其抗原结合片段可以选自0.01至50mg/kg、0.1至40mg/kg、0.1至35mg/kg、0.1至30mg/kg、0.1至25mg/kg、0.1至20mg/kg、0.1至15mg/kg、0.1至10mg/kg、1至40mg/kg、1至35mg/kg、1至30mg/kg、1至25mg/kg、1至20mg/kg、1至15mg/kg、1至10mg/kg、1至3mg/kg、3至40mg/kg、3至35mg/kg、3至30mg/kg、3至25mg/kg、3至20mg/kg、3至15mg/kg、3至10mg/kg、10至40mg/kg、10至30mg/kg、10至25mg/kg、或20至25mg/kg的剂量给予受试者；或者以1-2400mg、20-1800mg、100-1800mg、300-1800mg、600-1600mg、700-1600mg、800-1600mg、900-1600mg、1000-1600mg、1100-1600mg、1200-1600mg、1300-1600mg、1400-1600mg、1500-1600mg、600-1500mg、800-1500mg、1000-1500mg、1200-1500mg、600-1200mg、800-1200mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、 1700mg、或1800mg的统一剂量施用于受试者。
在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体或其抗原结合片段可以选自0.01至50mg/kg、0.1至40mg/kg、0.1至35mg/kg、0.1至30mg/kg、0.1至25mg/kg、0.1至20mg/kg、0.1至15mg/kg、0.1至10mg/kg、1至40mg/kg、1至35mg/kg、1至30mg/kg、1至25mg/kg、1至20mg/kg、1至15mg/kg、1至10mg/kg、1至3mg/kg、3至40mg/kg、3至35mg/kg、3至30mg/kg、3至25mg/kg、3至20mg/kg、3至15mg/kg、3至10mg/kg、10至40mg/kg、10至30mg/kg、10至25mg/kg、或20至25mg/kg的剂量给予受试者；或者以1-2400mg、20-1800mg、100-1800mg、300-1800mg、600-1600mg、700-1600mg、800-1600mg、900-1600mg、1000-1600mg、1100-1600mg、1200-1600mg、1300-1600mg、1400-1600mg、1500-1600mg、600-1500mg、800-1500mg、1000-1500mg、1200-1500mg、600-1200mg、800-1200mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、或1800mg的统一剂量施用于受试者。
在一些实施方案中，上述用途或治疗方法中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段的给药方案(例如，给药周期、给药剂量及剂量调整)可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态进行调整。例如，可以将抗TIM-3抗体或其抗原结合片段和/或抗PD-L1抗体或其抗原结合片段的一个治疗周期调整为4周、5周、6周、7周、8周、9周、10周、11周、12周、13周、14周或15周。
抗TIM-3抗体或其抗原结合片段
本公开所述的抗TIM-3抗体或其抗原结合片段包含：SEQ ID NO:1所示氨基酸序列的重链CDR1(HCDR1)，SEQ ID NO:2所示氨基酸序列的HCDR2，SEQ ID NO:3所示氨基酸序列的HCDR3，SEQ ID NO:4所示氨基酸序列的轻链CDR1(LCDR1)，SEQ ID NO:5所示氨基酸序列的LCDR2，和SEQ ID NO:6所示氨基酸序列的LCDR3。抗TIM-3抗体或其抗原结合片段的CDR序列于表1中示出。
表1.抗TIM-3抗体或其抗原结合片段的CDR序列
本领域技术人员应当理解的是，除非另有规定，否则术语给定抗体或其区(例如可变区)的“CDR”及“互补决定区”应理解为涵盖通过任何一种已知方案界定的互补决定区。虽然表1已经示出了CDR序列(其中，SEQ ID NO:1-6所示的CDR区由AbM编号系统定义)，然而，在涉及用本公开某些划分定义的具体CDR序列限定抗体时，所述抗体的范围还涵盖了转换为其他任意编号系统定义(例如本领域所公知的Kabat、Chothia、IMGT或Contact等定义中的一种或几种的结合)的CDR序列限定的抗体。例如，包含下述氨基酸序列的抗TIM-3抗体或其抗原结合片段也涵盖在本公开的抗TIM-3抗体或其抗原结合片段的范围内：SEQ ID NO:1所示氨基酸序列的HCDR1，SEQ ID NO:2所示氨基酸序列的HCDR2，ARRYYGYDAMDY(SEQ ID NO:31)所示氨基酸序列的HCDR3，SEQ ID NO:4所示氨基酸序列的LCDR1，SEQ ID NO:5所示氨基酸序列的LCDR2，和SEQ ID NO:6所示氨基酸序列的LCDR3。
在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段包含氨基酸序列与SEQ ID NO:7所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链可变区，和氨基酸序列与SEQ ID NO:8所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链可变区。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段包含SEQ ID NO:7所示氨基酸序列的重链可变区，和SEQ ID NO:8所示氨基酸序列的轻链可变区。在一些具体的实施方案中，所述抗TIM-3抗体或其抗原结合片段的重链可变区的氨基酸序列如SEQ ID NO:7所示，和轻链可变区的氨基酸序列如SEQ ID NO:8所示。

在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段还可包含免疫球蛋白的恒定区，或所述恒定区的片段、类似物、变体或衍生物。在一些实施方案中，所述重链恒定区来自人免疫球蛋白重链，例如IgG1、IgG2、IgG3和IgG4或其他类别免疫球蛋白的重链，优选为IgG4的重链。在一些实施方案中，所述轻链恒定区来自人免疫球蛋白轻链，例如人免疫球蛋白的κ轻链或λ轻链。在一些实施方案中，所述恒定区可包含任何文本所述的修饰，例如氨基酸的插入、缺失、取代或化学修饰。在一些实施方案中，所述恒定区包含改变效应功能的突变。在一些实施方案中，所述恒定区的任意氨基酸残基可用任意同种异型(allotype)的氨基酸残基取代。
在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段包含氨基酸序列与SEQ ID NO:9所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链，和氨基酸序列与SEQ ID NO:10所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链。在一些实施方案中，所述抗TIM-3抗体或其抗原结合片段包含SEQ ID NO:9所示氨基酸序列的重链，和SEQ ID NO:10所示氨基酸序列的轻链。在一些具体的实施方案中，所述抗TIM-3抗体或其抗原结合片段的重链的氨基酸序列如SEQ ID NO:9所示，和轻链的氨基酸序列如SEQ ID NO:10所示。
在一些实施方案中，本公开的抗TIM-3抗体或其抗原结合片段是公开号为WO2020041520或CN112566936的专利申请文件中记载的mAb 50B5或其抗原结合片段，或mAb 50B5的嵌合抗体或其抗原结合片段，或mAb 50B5的人源化抗体或其抗原结合片段。
在另一些实施方案中，本公开的抗TIM-3抗体或其抗原结合片段是公开号为WO2020041520或CN112566936的专利申请文件中记载的mAb 15B4或其抗原结合片段，或mAb 15B4的嵌合抗体或其抗原结合片段，或mAb 15B4的人源化抗体或其抗原结合片段。
在另一些实施方案中，本公开的抗TIM-3抗体或其抗原结合片段选自Sabatolimab、Cobolimab、Surzebiclimab、Roche的RG-7769、恒瑞医药的SHR-1702、Agenus的INCAGN-2390、药明生物的BC-3402、维立志博的LBL-003、健信生物的LNL-005、或BMS的BMS-986258。
抗PD-L1抗体或其抗原结合片段
本公开所述的抗PD-L1抗体或其抗原结合片段包含：SEQ ID NO:11或SEQ ID NO:21所示氨基酸序列的重链CDR1(HCDR1)，SEQ ID NO:12或SEQ ID NO:22所示氨基酸序列的HCDR2，SEQ ID NO:13或SEQ ID NO:23所示氨基酸序列的HCDR3，SEQ ID NO:14或SEQ ID NO:24所示氨基酸序列的轻链CDR1(LCDR1)，SEQ ID NO:15或SEQ ID NO:25所示氨基酸序列的LCDR2，和SEQ ID NO:16或SEQ ID NO:26所示氨基酸序列的LCDR3。
在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含：SEQ ID NO:11所示氨基酸序列的 HCDR1，SEQ ID NO:12所示氨基酸序列的HCDR2，SEQ ID NO:13所示氨基酸序列的HCDR3，SEQ ID NO:14所示氨基酸序列的LCDR1，SEQ ID NO:15所示氨基酸序列的LCDR2，和SEQ ID NO:16所示氨基酸序列的LCDR3；或SEQ ID NO:21所示氨基酸序列的HCDR1，SEQ ID NO:22所示氨基酸序列的HCDR2，SEQ ID NO:23所示氨基酸序列的HCDR3，SEQ ID NO:24所示氨基酸序列的LCDR1，SEQ ID NO:25所示氨基酸序列的LCDR2，和SEQ ID NO:26所示氨基酸序列的LCDR3。抗PD-L1抗体或其抗原结合片段CDR序列提供与下表2中。
表2.抗PD-L1抗体或其抗原结合片段的CDR序列
本领域技术人员应当理解的是，除非另有规定，否则术语给定抗体或其区(例如可变区)的“CDR”或“互补决定区”应理解为涵盖通过任何一种已知方案界定的互补决定区。虽然表2中已经示出了CDR区，然而，在涉及用具体CDR序列限定抗体时，所述抗体的范围涵盖任意编号系统定义(例如本领域所公知的AbM、Kabat、Chothia、IMGT或Contact等定义中的一种或几种的结合)的CDR序列限定的抗体。
在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含氨基酸序列与SEQ ID NO:17或SEQ ID NO:27所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链可变区，和氨基酸序列与SEQ ID NO:18或SEQ ID NO:28所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链可变区。在一些的实施方案中，所述抗PD-L1抗体或其抗原结合片段包含SEQ ID NO:17或SEQ ID NO:27所示氨基酸序列的重链可变区，和SEQ ID NO:18或SEQ ID NO:28所示氨基酸序列的轻链可变区。在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含氨基酸序列与SEQ ID NO:17所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链可变区，和氨基酸序列与SEQ ID NO:18所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链可变区。在另一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含氨基酸序列与SEQ ID NO:27所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链可变区，和氨基酸序列与SEQ ID NO:28所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链可变区。在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含SEQ ID NO:17所示氨基酸序列的重链可变区，和SEQ ID NO:18所示氨基酸序列的轻链可变区。在另一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含SEQ ID NO:27所示氨基酸序列的重链可变区，和SEQ ID NO:28所示氨基酸序列的轻链可变区。在一些具体的实施方案中，所述抗PD-L1抗体或其抗原结合片段重链可变区的氨基酸序列如SEQ ID NO:17所示，和轻链可变区的氨基酸序列如SEQ ID NO:18所示。在另一些具体的实施方案中，所述抗PD-L1抗体或其抗原结合片段重链可变区的氨基酸序列如SEQ ID NO:27所示，和轻链可变区的氨基酸序列如SEQ ID NO:28所示。

在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段还可包含免疫球蛋白的恒定区，或所述恒定区的片段、类似物、变体或衍生物。在一些实施方案中，所述重链恒定区来自人免疫球蛋白重链，例如IgG1、IgG2、IgG3和IgG4或其他类别免疫球蛋白的重链，优选为IgG1的重链。在一些实施方案中，所述轻链恒定区来自人免疫球蛋白轻链，例如人免疫球蛋白的κ轻链或λ轻链。在一些实施方案中，所述恒定区可包含任何文本所述的修饰，例如氨基酸的插入、缺失、取代或化学修饰。在一些实施方案中，所述恒定区包含改变效应功能的突变。在一些实施方案中，所述恒定区的任意氨基酸残基可用任意同种异型(allotype)的氨基酸残基取代，优选地，用G1m(3)和/或nG1m(1)的氨基酸残基取代。
在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含氨基酸序列与SEQ ID NO:19或SEQ ID NO:29所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链，和氨基酸序列与SEQ ID NO:20或SEQ ID NO:30所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链。在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含SEQ ID NO:19或SEQ ID NO:29所示氨基酸序列的重链，和SEQ ID NO:20或SEQ ID NO:30所示氨基酸序列的轻链。在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含氨基酸序列与SEQ ID NO:19所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链，和氨基酸序列与SEQ ID NO:20所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链。在另一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含氨基酸序列与SEQ ID NO:29所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链，和氨基酸序列与SEQ ID NO:30所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链。在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含SEQ ID NO:19所示氨基酸序列的重链，和SEQ ID NO:20所示氨基酸序列的轻链。在另一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含SEQ ID NO:29所示氨基酸序列的重链，和SEQ ID NO:30所示氨基酸序列的轻链。在一些具体的实施方案中，所述抗PD-L1抗体或其抗原结合片段的重链氨基酸序列如SEQ ID NO:19所示，和轻链氨基酸序列如SEQ ID NO:20所示。在另一些具体的实施方案中，所述抗PD-L1抗体或其抗原结合片段的重链氨基酸序列如SEQ ID NO:29所示，和轻链氨基酸序列如SEQ ID NO:30所示。

本公开的抗PD-L1抗体或其抗原片段包括但不限于公开号为WO2016022630或CN107001463的专利申请文件中记载的13C5、5G11、ch13C5-hIgG1、ch13C5-hIgG4、ch5G11-hIgG1、ch5G11-hIgG4、hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4单克隆抗体或其抗原结合片段。
含抗体或其抗原结合片段的药物组合物
在一些实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段配制为用于胃肠外途径施用的制剂。在一些具体的实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段配制为用于静脉内、肌肉内、皮下或其它胃肠外途径施用的制剂，例如用于注射或输注。在一些具体的实施方案中，用于静脉内、肌肉内或皮下施用。在一些具体的实施方案中，用于静脉注射或输注。
抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段可以配制成适合的剂型，包括但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(即适合注射的制剂，例如肌肉内、静脉内、腹腔内、皮下)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。在一些具体的实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段可以配制成注射剂。在一些具体的实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段可以配制成适合静脉注射的制剂(例如，注射液或者冻干制剂)。
在一些实施方案中，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段配制在单一制剂中。在一些实施方案中，抗TIM-3抗体或其抗原结合片段、抗PD-L1抗体或其抗原结合片段与一种或多种药学上可接受的赋形剂配制在一起以制成合适的药物组合物。
在一些实施方案中，抗TIM-3抗体或其抗原结合片段与抗PD-L1抗体或其抗原结合片段分开配制(即，各自呈药物组合物的形式)。在一些实施方案中，抗TIM-3抗体或其抗原结合片段与一种或多种药学上可接受的赋形剂配制在一起以制成合适的药物组合物。在一些实施方案中，抗PD-L1抗体或其抗原结合片段与一种或多种药学上可接受的赋形剂配制在一起以制成合适的药物组合物。
在一些实施方案中，所述含抗TIM-3抗体或其抗原结合片段的药物组合物的单位剂量为60-1800mg、100-1600mg、120-1600mg、180-1200mg、240-600mg或其他量的抗TIM-3抗体或其抗原结合片段，例如约60mg、约120mg、约160mg、约180mg、约200mg、约240mg、约280mg、约300mg、约320mg、约360mg、约400mg、约420mg、约440mg、约480mg、约520mg、约540mg、约560mg、约600mg、约640mg、约660mg、约680mg、约720mg、约760mg、约780mg、约800mg、约840mg、约880mg、约900mg、约920mg、约960mg、约1000mg、约1020mg、约1040mg、约1080mg、约1120mg、约1140mg、约1160mg、约1200mg、约1240mg、约1260mg、约1280mg、约1320mg、约1360mg、约1380mg、约1400mg、约1440mg、约1480mg、约1500mg、约1520mg、约1560mg、约1600mg、约1620mg、约1640mg、约1680mg、约1720mg、约1740mg、约1760mg、或约1800mg、或上述任意值形成的范围的抗TIM-3抗体或其抗原结合片段。在一些实施方案中，所述含抗TIM-3抗体或其抗原结合片段的药物组合物的单位剂量为约240mg或约600mg的抗TIM-3抗体或其抗原结合片段。
在一些实施方案中，所述含抗PD-L1抗体或其抗原结合片段的药物组合物的单位剂量为10-1800mg、 100-1500mg、100-1200mg、600-1200mg、100-600mg或其他量的抗PD-L1抗体或其抗原结合片段，例如约10mg、约40mg、约80mg、约100mg、约120mg、约140mg、约160mg、约180mg、约200mg、约220mg、约240mg、约260mg、约280mg、约300mg、约320mg、约340mg、约360mg、约380mg、约400mg、约420mg、约440mg、约460mg、约480mg、约500mg、约520mg、约540mg、约560mg、约580mg、约600mg、约620mg、约640mg、约660mg、约680mg、约700mg、约720mg、约740mg、约760mg、约780mg、约800mg、约820mg、约840mg、约860mg、约880mg、约900mg、约920mg、约940mg、约960mg、约980mg、约1000mg、约1020mg、约1040mg、约1060mg、约1080mg、约1100mg、约1120mg、约1140mg、约1160mg、约1180mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、或上述任意值形成的范围的抗PD-L1抗体或其抗原结合片段。在一些实施方案中，所述含抗PD-L1抗体或其抗原结合片段的药物组合物的单位剂量为约100mg或约600mg的抗PD-L1抗体或其抗原结合片段。
本文所用的“赋形剂”用于描述除了本公开的化合物以外的任何成分。赋形剂的选择，在很大程度上将取决于诸如特定的施用方式、赋形剂对溶解度和稳定性的功效以及剂型的性质等因素。如本文所用的，“药学上可接受的赋形剂”包括生理上相容的任何和全部的溶剂、分散介质、包衣、抗细菌和抗真菌剂、等渗剂和吸收延迟剂等等。药学上可接受的赋形剂的一些实例为水、盐水、右旋糖、甘油、乙醇等及其组合。在许多情况下，药学上可接受的赋形剂包含等渗剂。药学上可接受的赋形剂的其他实例为润湿剂或少量的辅助物质，诸如润湿剂或乳化剂，防腐剂或缓冲剂，其提高抗体的储存期或有效性。
在一个具体实施方案中，所述含抗TIM-3抗体或其抗原结合片段的药物组合物为水性注射液。在一个具体实施方案中，所述含抗PD-L1抗体或其抗原结合片段的药物组合物为水性注射液。所述水性注射液包括但不限于未经冻干的水性制剂或冻干粉重构的水性制剂。
在另一些实施方案中，所述含抗TIM-3抗体或其抗原结合片段的药物组合物为冻干制剂。在另一些实施方案中，所述含抗PD-L1抗体或其抗原结合片段的药物组合物为冻干制剂。所述冻干制剂是指水溶液经历冻干过程制备的制剂，在该过程中物质首先被冷冻，然后先通过升华降低溶剂数量(初级干燥过程)，然后通过脱附作用降低溶剂数量(二级干燥过程)，直到溶剂数量为不再支持生物学活性或化学反应的值。本公开的冻干制剂还可以通过本领域已知的其它方法干燥，如喷雾干燥和鼓泡干燥(bubble drying)。
在一些实施方案中，所述含抗PD-L1抗体或其抗原结合片段的药物组合物中抗PD-L1抗体或其抗原结合片段的浓度为1-200mg/mL、2-150mg/mL、4.5-100mg/mL、5-80mg/mL、10-60mg/mL、10-50mg/mL、或10-30mg/mL。在一些具体的实施方案中，抗PD-L1抗体或其抗原结合片段的浓度为约4.8mg/mL、约5mg/mL、约10mg/mL、约20mg/mL、约25mg/mL、约30mg/mL、约35mg/mL、约40mg/mL、约45mg/mL、约50mg/mL、约55mg/mL、约60mg/mL、约80mg/mL、约100mg/mL、或约120mg/mL。在一些实施方案中，抗PD-L1抗体或其抗原结合片段的浓度为约4.8mg/mL。在一些实施方案中，抗PD-L1抗体或其抗原结合片段的浓度为约10mg/mL。在一些实施方案中，抗PD-L1抗体或其抗原结合片段的浓度为约30mg/mL。在一些实施方案中，抗PD-L1抗体或其抗原结合片段的浓度为约60mg/mL。
在一些实施方案中，所述含抗PD-L1抗体或其抗原结合片段的药物组合物包含：质量体积浓度为约1-150mg/mL抗PD-L1抗体或其抗原结合片段、3-50mM缓冲液、2-150mg/mL等渗调节剂/稳定剂和0.01-0.8mg/mL表面活性剂，且pH为约4.5-6.8。
在一个具体实施方案中，所述含抗PD-L1抗体或其抗原结合片段的药物组合物包含：(a)质量体积浓度为约10mg/mL或约30mg/mL的抗PD-L1抗体，(b)质量体积浓度为约80mg/mL的蔗糖，(c)质量体积浓度为约0.2mg/mL的聚山梨酯80，(d)摩尔浓度为约10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为约5.5。
施用方式
下述内容并非限制本公开的药物组合的施用方式。
本公开的药物组合中的组分可以各自独立地、或者其中的部分或全部共同以适合的各种途径施用，包括但不限于，口服或肠胃外(通过静脉内、肌内、局部或皮下途径)施用。在一些实施方案中，本公开的药物组合的组分可以各自独立地、或者其中的部分或全部共同口服施用或注射施用，例如静脉注射或皮下 注射。
本公开的药物组合中的组分可以各自独立地、或者其中的部分或全部共同配制成合适的剂型，包括但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(肌肉内、静脉内、腹腔内、皮下)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。在一些实施方案中，本公开的药物组合的各组分可以各自独立地、或者其中的部分或全部共同配制成注射剂。
本公开的药物组合中的组分可以各自独立地、或者其中的部分或全部共同含有药学上可接受的赋形剂。
本公开的药物组合还可以包含另外的治疗剂。在一个实施方案中，所述另外的治疗剂可以是本领域已知的肿瘤治疗剂。
肿瘤
在某些方面，本公开所述肿瘤为恶性肿瘤(即癌症)；所述恶性肿瘤是指由异常细胞生长引起的任何恶性和/或侵袭性生长。在一些实施方案中，所述肿瘤是实体瘤。在一些实施方案中，所述肿瘤是难治性的、不可切除的、复发性的、晚期的和/或转移性的实体瘤。在一些实施方案中，所述肿瘤为晚期实体瘤。
在一些实施方案中，所述实体瘤为肺癌。在一些实施方案中，所述肺癌是难治性的、不可切除的、复发性的、晚期的和/或转移性的肺癌。
在一些实施方案中，所述肺癌选自非小细胞肺癌或小细胞肺癌。
在一些实施方案中，所述非小细胞肺癌为鳞状细胞非小细胞肺癌(也称为鳞癌、鳞状细胞癌、鳞状非小细胞肺癌或鳞状上皮细胞癌)。在一些实施方案中，所述非小细胞肺癌是组织学以鳞状细胞癌为主的非小细胞肺癌。在一些实施方案中，所述非小细胞肺癌为非鳞状细胞非小细胞肺癌。在一些实施方案中，所述非小细胞肺癌为腺癌(也称为肺腺癌)。在一些实施方案中，所述非小细胞肺癌为大细胞癌(也称为肺大细胞癌)。在一些实施方案中，所述非小细胞肺癌为腺鳞癌。
在一些实施方案中，所述小细胞肺癌为局限期小细胞肺癌或广泛期小细胞肺癌。
在一些实施方案中，所述肺癌为局部晚期或晚期非小细胞肺癌。在一些实施方案中，所述肺癌为复发性和/或转移性非小细胞肺癌。在一些实施方案中，所述肺癌为晚期、复发性和/或转移性非小细胞肺癌。在一些实施方案中，所述肺癌为局部晚期、复发性和/或转移性非小细胞肺癌。在一些实施方案中，所述肺癌为ⅢB期、ⅢC期或IV期非小细胞肺癌。
在一些实施方案中，所述肺癌为晚期、复发性和/或转移性鳞状细胞非小细胞肺癌或非鳞状细胞非小细胞肺癌(例如肺腺癌)。在一些实施方案中，所述的肺癌为局部晚期、复发性和/或转移性鳞状细胞非小细胞肺癌或非鳞状细胞非小细胞肺癌(例如肺腺癌)。在一些实施方案中，所述肺癌为ⅢB期、ⅢC期或IV期鳞状细胞非小细胞肺癌或非鳞状细胞非小细胞肺癌(例如肺腺癌)。
在一些实施方案中，所述肺癌为局部晚期或晚期小细胞肺癌。在一些实施方案中，所述肺癌为复发性和/或转移性小细胞肺癌。在一些实施方案中，所述肺癌为晚期、复发性和/或转移性小细胞肺癌。在一些实施方案中，所述肺癌为局部晚期、复发性和/或转移性小细胞肺癌。在一些实施方案中，所述肺癌为复发性和/或转移性的广泛期小细胞肺癌。在一些实施方案中，所述肺癌为复发性的广泛期小细胞肺癌。
在一些实施方案中，所述肺癌不存在驱动基因突变，所述驱动基因包括但不限于：EGFR、ALK、ROS1、BRAF、NTRK、MET和/或KRAS。在一些实施方案中，所述肺癌不存在EGFR突变。在一些实施方案中，所述肺癌不存在ALK融合。在一些实施方案中，所述肺癌不存在ROS1突变。
在一些实施方案中，所述非小细胞肺癌不存在驱动基因突变，所述驱动基因包括但不限于：EGFR、ALK、ROS1、BRAF、NTRK、MET和/或KRAS。在一些实施方案中，所述非小细胞肺癌不存在EGFR突变。在一些实施方案中，所述非小细胞肺癌不存在ALK融合。在一些实施方案中，所述非小细胞肺癌不存在ROS1突变。在一些实施方案中，所述鳞状细胞非小细胞肺癌或非鳞状细胞非小细胞肺癌不存在EGFR突变。在一些实施方案中，所述鳞状细胞非小细胞肺癌或非鳞状细胞非小细胞肺癌不存在ALK融合。在一些实施方案中，所述鳞状细胞非小细胞肺癌或非鳞状细胞非小细胞肺癌不存在ROS1突变。
在一些实施方案中，所述肺癌的主体先前未治疗过肺癌(例如，缺乏有效治疗方案)。
在一些实施方案中，所述肺癌的主体先前未接受过系统治疗以治疗肺癌。
在一些实施方案中，所述肺癌的主体先前未接受过手术治疗、放射疗法、诱导化疗、同步放化疗、辅助化疗和/或免疫疗法以治疗肺癌。在一些实施方案中，所述肺癌的主体不适合接受手术治疗且不适合接受根治性同步放化疗。
在一些实施方案中，所述肺癌的主体先前已经用一种或多种不同的抗肿瘤治疗方法治疗过肺癌(例如，治疗失败或不适用)。
在一些实施方案中，所述肺癌的主体先前已经用手术治疗、放射疗法、化学疗法和免疫疗法中的一种或多种治疗过肺癌(例如治疗失败或不适用)。在一些实施方案中，所述肺癌的主体先前已经用诱导化疗、同步放化疗、辅助化疗和/或免疫疗法中的一种或多种治疗过肺癌(例如治疗失败或不适用)。
在一些实施方案中，所述肺癌的主体先前接受过新辅助或辅助疗法(例如化疗或放疗)以治疗肺癌(例如，治疗失败或不适用)。在一些实施方案中，所述肺癌的主体已经用化学疗法治疗过肺癌(例如，治疗失败或不适用)。在一些实施方案中，所述肺癌的主体已经用同步放化疗法治疗过肺癌(例如，治疗失败或不适用)。
在一些具体实施方式中，所述肺癌的主体先前未接受过系统化疗，但是接受过手术治疗、放射治疗、诱导化疗、同步放化疗和/或辅助化疗以治疗肺癌。在一些具体实施方式中，所述肺癌的主体经手术治疗、放射治疗、诱导化疗、同步放化疗和/或辅助化疗后，获完全缓解或部分缓解后再次出现疾病进展。在一些具体实施方式中，所述肺癌的主体先前接受过手术治疗、放射治疗、诱导化疗、同步放化疗和/或辅助化疗以治疗肺癌，且在停止治疗6个月后(例如6、7、8、9或10个月)出现疾病进展。
在一些具体实施方式中，所述非小细胞肺癌的主体先前未接受过系统化疗，但是接受过手术治疗、放射治疗、诱导化疗、同步放化疗和/或辅助化疗以治疗非小细胞肺癌。在一些具体实施方式中，所述非小细胞肺癌的主体经手术治疗、放射治疗、诱导化疗、同步放化疗和/或辅助化疗后，获完全缓解或部分缓解后再次出现疾病进展。在一些具体实施方式中，所述非小细胞肺癌的主体先前接受过手术治疗、放射治疗、诱导化疗、同步放化疗和/或辅助化疗以治疗非小细胞肺癌，且在停止治疗6个月后(例如6、7、8、9或10个月)出现疾病进展。
在一些实施方案中，所述肺癌的主体已经用至少一线系统化疗方案治疗过肺癌(例如，治疗失败或不适用)。在一些实施方案中，所述肺癌的主体已经用一线系统化疗方案治疗过肺癌(例如，治疗失败或不适用)。在一些实施方案中，所述肺癌的主体已经用一线或二线治疗方案治疗过肺癌(例如，治疗失败或不适用)。
在一些实施方案中，所述肺癌的主体既往接受过免疫检查点(例如，PD-1、PD-L1、CTLA-4或PD-L2)抑制剂单药或联合以铂类药物为基础的化疗(例如，治疗失败或不适用)。在一些实施方案中，所述免疫检查点(例如，PD-1、PD-L1、CTLA-4或PD-L2)抑制剂为针对免疫检查点的抗体或其抗原结合片段(例如，靶向PD-1、PD-L1、CTLA-4或PD-L2的抗体或其抗原结合片段)。
在一些实施方案中，所述肺癌的主体既往接受过以铂类药物为基础的化疗(例如，治疗失败或不适用)。
在一些实施方案中，所述肺癌的主体为PD-L1表达阳性的肺癌。在一些实施方案中，所述肺癌的主体为PD-L1表达阳性的非小细胞肺癌。
在一些实施方案中，所述肺癌的主体是不存在EGFR突变、ALK融合和/或ROS1突变的非小细胞肺癌患者。在一些实施方案中，所述肺癌的主体是不存在驱动基因突变(包括EGFR突变，ALK融合和/或ROS1突变)的晚期、转移性或复发性非小细胞肺癌患者。在一些实施方案中，所述肺癌的主体是不存在驱动基因突变(包括EGFR突变，ALK融合和/或ROS1突变)的局部晚期(ⅢB/ⅢC期)、转移性或复发性(Ⅳ期)非小细胞肺癌患者。在一些实施方案中，所述肺癌的主体是PD-L1表达阳性，且不存在驱动基因突变(包括EGFR突变，ALK融合和/或ROS1突变)的局部晚期(ⅢB/ⅢC期)、转移性或复发性(Ⅳ期)非小细胞肺癌患者。
在一些实施方案中，所述肺癌的主体是既往接受过以铂类药物为基础的化疗(例如，治疗失败或不适用)的广泛期小细胞肺癌患者。在一些实施方案中，所述肺癌的主体是以铂类药物为基础的一线化疗失败或不适用以铂类药物为基础的一线化疗的广泛期小细胞肺癌患者。在一些实施方案中，所述肺癌的主体是以铂类药物为基础的一线化疗失败或不适用以铂类药物为基础的一线化疗的复发性的广泛期小细胞肺癌患者。
本公开还提供了以下一些具体的实施方案，但本公开的保护范围不限于此：
实施方案1.一种药物组合，其包括抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段，其中，所述抗TIM-3抗体或其抗原结合片段包含：SEQ ID NO:1所示氨基酸序列的HCDR1，SEQ ID NO:2所示氨基酸序列的HCDR2，SEQ ID NO:3所示氨基酸序列的HCDR3，SEQ ID NO:4所示氨基酸序列的LCDR1，SEQ ID NO:5所示氨基酸序列的LCDR2，和SEQ ID NO:6所示氨基酸序列的LCDR3。
实施方案2.根据实施方案1所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段包含：氨基酸序列与SEQ ID NO:7所示氨基酸序列具有至少95％同一性的重链可变区，和氨基酸序列与SEQ ID NO:8所示氨基酸序列具有至少95％同一性的轻链可变区。
实施方案3.根据实施方案1或2所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段包含：氨基酸序列与SEQ ID NO:9所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:10所示氨基酸序列具有至少95％同一性的轻链。
实施方案4.根据实施方案1-3中任一项所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段的单位剂量为60-1800mg、100-1600mg、120-1600mg、180-1200mg、或240-600mg。
实施方案5.根据实施方案1-4中任一项所述的药物组合，其中，所述抗PD-L1抗体或其抗原结合片段的单位剂量为10-1800mg、100-1500mg、100-1200mg、600-1200mg、或100-600mg。
实施方案6.根据实施方案1-5中任一项所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段的质量比为(0.01-30):1、(0.01-20):1、(0.1-2.5):1、(0.5-1.5):1或(1-1.25):1。
实施方案7.根据实施方案1-6中任一项所述的药物组合，其中，所述药物组合适用于在单个治疗周期内施用，其包括100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段。
实施方案8.根据实施方案7所述的药物组合，其中，所述药物组合包括100-2400mg、600-1800mg、1000-1500mg、1000-1200mg、或1200-1500mg的抗PD-L1抗体或其抗原结合片段。
实施方案9.根据实施方案1-8中任一项所述的药物组合，其中，所述抗PD-L1抗体或其抗原结合片段包含：
(a)SEQ ID NO:11所示氨基酸序列的HCDR1，SEQ ID NO:12所示氨基酸序列的HCDR2，SEQ ID NO:13所示氨基酸序列的HCDR3，SEQ ID NO:14所示氨基酸序列的LCDR1，SEQ ID NO:15所示氨基酸序列的LCDR2，和SEQ ID NO:16所示氨基酸序列的LCDR3；或
(b)SEQ ID NO:21所示氨基酸序列的HCDR1，SEQ ID NO:22所示氨基酸序列的HCDR2，SEQ ID NO:23所示氨基酸序列的HCDR3，SEQ ID NO:24所示氨基酸序列的LCDR1，SEQ ID NO:25所示氨基酸序列的LCDR2，和SEQ ID NO:26所示氨基酸序列的LCDR3。
实施方案10.根据实施方案1-9中任一项所述的药物组合，其中，所述抗PD-L1抗体或其抗原结合片段包含：
(a)氨基酸序列与SEQ ID NO:17所示氨基酸序列具有至少95％同一性的重链可变区，和氨基酸序列与SEQ ID NO:18所示氨基酸序列具有至少95％同一性的轻链可变区；或
(b)氨基酸序列与SEQ ID NO:27所示氨基酸序列具有至少95％同一性的重链可变区，和氨基酸序列与SEQ ID NO:28所示氨基酸序列具有至少95％同一性的轻链可变区。
实施方案11.根据实施方案1-10中任一项所述的药物组合，其中，所述抗PD-L1抗体或其抗原结合片段包含：
(a)氨基酸序列与SEQ ID NO:19所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:20所示氨基酸序列具有至少95％同一性的轻链；或
(b)氨基酸序列与SEQ ID NO:29所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:30所示氨基酸序列具有至少95％同一性的轻链。
实施方案12.根据实施方案1-11中任一项所述的药物组合，其中，所述药物组合用于治疗肿瘤。
实施方案13.根据实施方案12所述的药物组合，其中，所述肿瘤为实体瘤。
实施方案14.根据实施方案13所述的药物组合，其中，所述实体瘤为肺癌。
实施方案15.根据实施方案14所述的药物组合，其中，所述肺癌选自非小细胞肺癌或小细胞肺癌。
实施方案16.实施方案1-11中任一项所述的药物组合在制备用于治疗肿瘤的药物中的用途。
实施方案17.根据实施方案16所述的用途，其中，所述肿瘤为实体瘤。
实施方案18.根据实施方案17所述的用途，其中，所述实体瘤为肺癌。
实施方案19.根据实施方案18所述的用途，其中，所述肺癌选自非小细胞肺癌或小细胞肺癌。
实施方案20.根据实施方案16-19中任一项所述的用途，其中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段，可同时、先后和/或交替给药。
实施方案21.根据实施方案20所述的用途，其中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段先后给药。
实施方案22.根据实施方案16-21中任一项所述的用途，其中，所述抗TIM-3抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次，可选地，每次以100-1800mg、600-1800mg、600-1500mg、或1200-1500mg抗TIM-3抗体或其抗原结合片段的剂量施用。
实施方案23.根据实施方案16-22中任一项所述的用途，其中，所述抗PD-L1抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次，可选地，每次以100-2400mg、600-1800mg、1000-1500mg、1000-1200mg、或1200-1500mg抗PD-L1抗体或其抗原结合片段的剂量施用。
实施方案24.一种用于治疗肿瘤的试剂盒，其包含实施方案1-15中任一项所述的药物组合。
技术效果
通常，使用上述的本公开的药物组合将有助于：
(1)与单独给予该组合中的任一药物相比，在减少肿瘤的生长或甚至消除肿瘤方面产生更好的疗效；
(2)与该组合中的任一药物单独给药相比，提供更少量的给药；
(3)提供在患者中具有良好耐受的治疗，与单一给予的任一药物相比，其不良反应和/或并发症更少；
(4)提供在所治疗患者之中的更好的疾病控制率；
(5)提供在所治疗的患者具有更长的生存期(例如中位生存期、无进展生存期或总生存期)；
(6)提供相比于标准的化疗而言，所治疗患者具有更长的生存期(例如中位生存期、无进展生存期或总生存期)；
(7)提供更长时间的疾病缓解持续时间(DOR)；和/或
(8)与单独给予该组合中的任一药物相比，具有良好的抗肿瘤的活性，表现出更优异的抗肿瘤协同效果。
本公开的药物组合及治疗方案，在治疗肺癌(包括非小细胞肺癌和小细胞肺癌)中具有较好的疗效。其中至少在ORR、DCR、DOR、PFS、OS、耐受性和副作用中的至少一方面具有有益的效果。
定义和说明
除非另有说明，本公开中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本公开中出现商品名时，意在指代其对应的商品或其活性成分。
如文本所用，术语“药物组合”是指同时或先后施用的两种或两种以上的活性成分(包括以各自的活性成分本身的形式施用，或者以其各自的药学上可接受的盐或酯等衍生物、前药或组合物的形式施用)的组合。所述活性成分可以各自作为单一制剂同时地、或各自作为单一制剂以任何顺序依次地施用于受试者。或者，所述活性成分的全部配制在单一制剂中，同时施用于受试者。
术语“固定组合”指活性组分(例如，抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段)以固定的总剂量或剂量比例，或以单一实体、药物组合物或制剂的形式同时给予受试者。
术语“非固定组合”指两种以上活性组分作为独立的实体(例如药物组合物、制剂)同时、并行或依序地给予受试者，其中所述给予受试者的活性成份达到治疗有效量水平。非固定组合可列举的例子是鸡尾酒疗法，例如给予3种或以上之活性组分。在非固定组合中，所述各个活性组分可以作为完全独立的药物组合物进行包装、销售或给药。所述“非固定组合”也包括“固定组合”之间、或“固定组合”与任一或多种活性组分的独立实体的联合使用。
如本文所用，术语“抗体”是指具有至少一个抗原结合结构域的抗原结合蛋白。本公开的抗体和其片 段可以是整个抗体或其任何片段。因此，本公开的抗体和其片段包括单克隆抗体或其片段和抗体变体或其片段。抗体和其抗原结合片段片段的实例包括单特异性抗体、双特异性抗体、多特异性抗体、Fab片段、Fab'片段、F(ab)'2片段、Fv片段、分离的CDR区、单链Fv分子(scFv)和本领域已知的其它抗体片段。本文公开的抗TIM-3抗体和抗PD-L1抗体和其抗原结合片段可以是IgG1、IgG2、IgG3或IgG4同种型。术语“同种型”是指由重链恒定区基因编码的抗体种类。本公开的抗TIM-3抗体和其抗原结合片段以及抗PD-L1抗体和其抗原结合片段可以衍生自任何物种，包括但不限于小鼠、大鼠、兔、灵长类动物、美洲驼和人。本公开的抗TIM-3抗体和其抗原结合片段以及抗PD-L1抗体和其抗原结合片段可以是鼠类抗体、嵌合抗体、人源化抗体或全人源抗体。除非另有说明，否则本公开的“抗体”包括整个抗体及其任何抗原结合片段(或“抗原结合部分”)或单链。常规的“整个抗体”是包含两条重(H)链和两条轻(L)链的糖蛋白，重链和轻链通过二硫键连接。每条重链由重链可变区(VH)和重链恒定区(CH)组成。重链恒定区由三个结构域组成，即CH1，CH2和CH3。每条轻链由轻链可变区(VL)和轻链恒定区(CL)组成。轻链恒定区由一个结构域CL组成。VH和VL区还可以划分为高变区，即互补决定区(CDR)，和序列较为保守的框架区(FR)。每个VH和VL分别由三个CDR和四个FR组成，从氨基端到羧基端分别为：FR1，CDR1，FR2，CDR2，FR3，CDR3，FR4。重链和轻链的可变区包含与抗原相互作用的结合域。抗体的恒定区可以介导免疫球蛋白与宿主组织或因子的结合，所述宿主组织或因子包括免疫系统的多种细胞(例如，效应细胞)和经典补体系统的第一成分(C1q)。与此同时，如本领域技术人员所了解的，特殊的“整个抗体”，例如纳米抗体，其仅只有重(H)链而没有轻(L)链。
抗体的“抗原结合片段”或“抗体结合部分”是指抗体的一个或多个片段，其保留特异性结合抗原(例如，TIM-3或PD-L1)的功能。已证实，抗体的抗原结合功能可以通过整个抗体的片段来实施。涵盖在术语抗体的“抗原结合部分/片段”中的实例包括：(i)Fab片段：由VL、VH、CL和CH1结构域组成的单价片段；(ii)F(ab')2片段，包含在铰链区二硫桥连接的两个Fab片段的二价片段；(iii)由VH和CH1结构域组成的Fd片段；(iv)由抗体单臂的VL和VH结构域组成的Fv片段；(v)由VH结构域组成的dAb片段(参见Ward et al.,Nature.341:544-546(1989))；(vi)分离的互补决定区(CDR)；以及(vii)纳米抗体，一种包含单可变结构域和两个恒定结构域的重链可变区。此外，尽管Fv片段的两个结构域VL和VH由不同基因编码，但可以采用重组的方法通过合成接头将VH和VL连接成单蛋白链，其中VL和VH配对形成单价分子(称单链Fv(scFv)；参见例如Bird et al.,Science.242:423-426(1988)；Huston et al.,Proc.Natl.Acad.Sci.85:5879-5883(1988))。这些单链抗体也涵盖在术语抗原结合部分/片段中。此外，包含该抗原结合部分/片段的重组多肽、融合蛋白和免疫缀合物也涵盖在术语抗原结合部分/片段中。
“嵌合抗体”是下述抗体：所述抗体具有衍生自一种物种的重链可变区的至少一部分和轻链可变区的至少一部分；以及衍生自另一物种的恒定区的至少一部分。例如，在一个实施方案中，嵌合抗体可以包含鼠类可变区和人恒定区。
“人源化抗体”是下述抗体：所述抗体含有衍生自非人抗体的互补决定区(CDR)；和衍生自人抗体的框架区以及恒定区。例如，抗TIM-3抗体以及抗PD-L1抗体可以包含衍生自一种或多种鼠类抗体的CDR以及人框架区和恒定区。本文提供了示例性人源化抗体。包含本文提供的HCDR和LCDR的另外的抗TIM-3抗体或其变体可以使用任何人框架序列产生，并且也包括在本公开中。包含本文提供的HCDR和LCDR的另外的抗PD-L1抗体或其变体可以使用任何人框架序列产生，并且也包括在本公开中。在一个实施方案中，适用于在本公开中使用的框架序列包括在结构上与本文提供的框架序列类似的那些框架序列。可以在框架区中进行另外修饰以改进本文提供的抗体的特性。此类另外的框架修饰可以包括化学修饰；点突变以降低免疫原性或去除T细胞表位；或使突变回复为原始种系序列中的残基。在一些实施方案中，此类修饰包括对应于本文示例的突变的那些修饰，包括对种系序列的回复突变。例如，在一个实施方案中，本文提供的人源化抗体的VH和/或VL的人框架区中的一个或多个氨基酸被回复突变为亲本鼠类抗体中对应的氨基酸。
术语“同一性”，也称一致性。氨基酸序列的“同一性百分数(％)”是指将待比对序列与本文中所示的具体氨基酸序列进行比对并且如有必要的话为达到最大序列同一性百分数而引入空位后，并且不考虑任何保守置换作为序列同一性的一部分时，待比对序列中与本文中所示的具体氨基酸序列的氨基酸残基相同的氨基酸残基百分数。同一性的氨基酸序列比对可以采用本领域范围内的多种方式进行，例如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员可决定用于比对序列的适宜参数，包括 在比较序列的全长里获得最大比对需要的任何算法。
术语“治疗”指试图改变治疗个体中疾病的自然进程，并且可以是为了预防或在临床病理学的过程期间实施的临床干预。治疗的期望效果包括但不限于预防疾病的发生或复发，缓解疾病的症状，降低疾病的任何直接或间接病理学后果，预防疾病的转移，减缓疾病的进展率，改善或减轻疾病的状态，延长无症状期频率和持续时间，及消退或改善疾病的预后。
术语“治疗有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本公开化合物的用量。构成“治疗有效量”的活性物质(例如本公开的抗体或其抗原结合片段)的量可根据一些因素而变化，诸如个体的疾病状态、年龄、性别和重量，以及治疗剂或治疗剂组合在个体中引发所需应答的能力。治疗有效量也可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“施用”或“给予”表示，使用本领域技术人员已知的多种方法和递送系统中的任一种，向主体物理引入包含治疗剂的药物组合物。
抗体或其抗原结合片段(例如，抗TIM-3抗体或其抗原结合片段或抗PD-L1抗体或其抗原结合片段)的施用途径包括静脉内、肌肉内、皮下、腹膜内、脊柱或其它胃肠外施用途径，例如通过注射或输注。本文中使用的短语“胃肠外施用”是指，通常通过注射进行的除了肠内和局部施用以外的施用模式，且包括但不限于，静脉内、肌肉内、动脉内、鞘内、淋巴管内、病灶内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注、以及体内电穿孔。还可以执行施用，例如，一次、多次，和/或在一个或多个延长的时间段中。
术语“统一剂量(flat dose)”的应用是指，不考虑患者的重量或体表面积(BSA)施用给患者的剂量。因此将统一剂量规定为药剂(例如，抗TIM-3抗体或其抗原结合片段或抗PD-L1抗体或其抗原结合片段)的绝对量，而不是规定为mg/kg剂量。例如，60kg人和100kg人将接受相同剂量的抗体(例如，1200mg或1500mg抗TIM-3抗体或其抗原结合片段，1200mg抗PD-L1抗体或其抗原结合片段)。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
在本文中，术语“受试者”、“患者”或“主体”可互换使用。“受试者”、“患者”或“主体”包括任何人或非人动物。术语“非人动物”包括但不限于脊椎动物诸如非人灵长类动物、绵羊、狗，和啮齿类动物诸如小鼠、大鼠和豚鼠。在一些实施方案中，术语“受试者”、“患者”或“主体”是哺乳动物。在部分实施方案中，所述受试者、患者或主体是小鼠。在部分实施方案中，所述受试者、患者或主体是人。
如本文所用，“约”表示在本领域普通技术人员判定的对特定值可以接受的误差范围内，其部分取决于如何测量或测定该值，即测量系统的限制。例如，“约”按照本领域实践可表示1倍或超过1倍标准偏差以内。或者，“约”可以表示多至±5％的范围，例如在所给定的具体数值范围±2％范围内、±1％范围内或±0.5％范围内波动。当本公开或权利要求中给出特定值时，除非另有说明，“约”的含义应认为是在该特定值的可接受的误差范围内。在本文中，除非另有说明，步骤参数或条件的值默认均由“约”修饰。
如本文所用，“联用”或“联合使用”意指两种或更多种活性物质可以各自作为单一制剂同时地、或各自作为单一制剂以任何顺序依次地施用于受试者。或者，所述活性成分的全部配制在单一制剂中，同时施用于受试者。
术语“单剂量”是指含有一定量药品的最小包装单元，例如一盒药有七粒药片，则一粒药片为单剂量；或者一瓶注射液为单剂量。术语“多剂量”由多个单剂量组成。“单位剂量”是指含有一定量药品的最小包装单元中所含的活性成分的剂量，例如，一瓶抗体注射液中所含的抗体的剂量为单位剂量。
术语“药物组合物”是指一种或多种本公开的活性成分或其药物组合与药学上可接受的赋形剂组成的混合物。药物组合物的目的是有利于对受试者给予本公开的化合物或其药物组合。在本文中，术语“药物组合物”和“制剂”具有相同的含义，并可互换使用。
术语“复发性”癌症是在对初始治疗(例如手术)产生应答后，在初始部位或远处部位再生的癌症。“局部复发性”癌症是在治疗后，在与先前治疗的癌症相同的位置出现的癌症。
术语“转移性”癌症是指从身体的一部分(例如肺部)扩散到身体的另一部分的癌症。
术语“难治性”是指受试者或哺乳动物即使在强烈治疗后在其体内也具有残留癌细胞的情况。
术语“一线治疗”是指是指根据患者病情可以首先选择或者标准选择的药物进行治疗。
术语“治疗失败”的定义为在治疗过程中或末次治疗后出现疾病进展或复发。
涉及细胞表面PD-L1表达的术语“PD-L1阳性”或“PD-L1表达阳性”指在包含肿瘤细胞和肿瘤浸润性免疫细胞的供试组织样品中的细胞比例，高于这个比例，该样品评定为表达细胞表面PD-L1。对于通过免疫组织化学(IHC)测定(例如，用mAb 28-8)的细胞表面表达，PD-L1阳性肿瘤或PD-L1表达阳性肿瘤意指，至少约0.01％、至少约0.5％、至少约1％、至少约2％、至少约3％、至少约4％、至少约5％、至少约6％、至少约7％、至少约8％、至少约9％、至少约10％、至少约15％、至少约20％、至少约25％或至少约30％总数的细胞表达PD-L1。PD-L1阳性肿瘤或PD-L1表达阳性肿瘤也可以在本文中表述为表达PD-L1的肿瘤。在其他实施方案中，PD-L1阳性肿瘤或PD-L1表达阳性肿瘤意指，至少约0.1％-20％，至少约0.1％-10％，至少约1％，至少约5％，至少约1％或1％-5％范围内总数的细胞在细胞表面上表达PD-L1。在一个实施方案中，PD-L1阳性肿瘤或PD-L1表达阳性肿瘤意指至少约1％总数的细胞在细胞表面上表达PD-L1。在一个实施方案中，PD-L1阳性肿瘤或PD-L1表达阳性肿瘤意指至少约1％总数的肿瘤细胞或肿瘤浸润性免疫细胞在细胞表面上表达PD-L1。
在本文中，除非上下文另有明确规定，否则单数术语涵盖复数指代物，反之亦然。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本公开的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
附图说明
图1示出了D11天各组小鼠的肿瘤体积(mm3)，P值是通过Mann-Whitney检验进行比较，*表示P<0.05，P<0.05定义为有统计学显著性差异；
图2示出了D11天各组小鼠的肿瘤重量(g)，P值是通过Mann-Whitney检验进行比较，*表示P<0.05，P<0.05定义为有统计学显著性差异。
实施例
为清楚起见，进一步用实施例来阐述本公开，但是实施例并非限制本公开的范围。
WO2020041520或CN112566936专利申请文件的全部内容均引入本公开。下述实施例中抗TIM-3抗体的重链氨基酸序列如本公开的SEQ ID NO:9所示，和轻链氨基酸序列如本公开的SEQ ID NO:10所示。
本公开中抗PD-L1抗体的制备、纯化方法已在公开号为WO2016022630或CN107001463的专利申请文件中记载，WO2016022630或CN107001463专利申请文件的全部内容均引入本公开。下述实施例中的hu5G11-hIgG1为WO2016022630或CN107001463中的hu5G11-hIgG1，hu5G11-hIgG1的重链氨基酸序列如本公开的SEQ ID NO:19所示，和轻链氨基酸序列如本公开的SEQ ID NO:20所示。
实施例1：抗TIM-3抗体和抗PD-L1抗体对肺癌HCC827皮下移植瘤的疗效
HCC827细胞购买自中国科学院细胞库，细胞在含10％胎牛血清的RPMI-1640培养基中培养至指数生长期，收集细胞待用。人外周血单个核细胞(HuPBMC)购买自上海儒佰生物技术有限公司，细胞培养于含10％胎牛血清的RPMI-1640培养基中，然后收集细胞待用。6-7周龄的NCG小鼠(NOD/ShiLtJ Gpt-Prkdc em26Cd52Il2rgem26Cd22/Gpt Gpt)购买自江苏集萃药康生物科技股份有限公司，于SPF级屏障环境饲养。待NCG小鼠适应环境之后，每只NCG小鼠皮下接种8×106个HCC827细胞，待肿瘤长到100-200mm3之后根据肿瘤体积分成5组，每组8只。每只小鼠静脉注射(IV)5×106个HuPBMC，第二天每只小鼠通过腹腔注射hIgG4(购买自Sino Biological)、抗TIM-3抗体、hu5G11-hIgG1、或抗TIM-3抗体+hu5G11-hIgG1，于D0、D3、D7、D10天各给药一次，共给药4次，给药体积为10mg/kg体重，D0表示第一次给药时间，给药剂量如表3所示。
每1周用游标卡尺测量肿瘤直径2次，通过下列公式计算T/C(％)或抑瘤率TGI(％)，考察药物对肿 瘤生长的影响。实验结束、达到实验终点、或肿瘤体积达到1500mm3，CO2麻醉处死动物，随后解剖取出肿瘤。肿瘤体积(V)计算公式为：V＝1/2×a×b2，其中a、b分别表示肿瘤长、宽；T/C(％)＝(T-T0)/(C-C0)×100，其中T、C为实验结束时的治疗组、hIgG4组肿瘤体积，T0、C0为实验开始时的治疗组、hIgG4组肿瘤体积；抑瘤率(TGI)(％)＝100-T/C(％)。
实验期间，各组荷瘤小鼠对药物均能较好耐受，没有明显体重减轻等症状发生。结果如表3和图1-2所示，在D11，第2组和第3组小鼠的平均肿瘤体积分别为589.7±59.6mm3和703.4±58.9mm3，抑瘤率分别为35％和19％；第4组小鼠的平均肿瘤体积为546.4±58.2mm3，抑瘤率为42％；第5组小鼠的平均肿瘤体积为488.7±70.7mm3，抑瘤率为51％(P<0.05，与第1组进行比较)；此外，第5组小鼠的肿瘤重量不仅显著低于第1组小鼠的肿瘤重量，而且显著低于第2组、第3组和第4组小鼠的肿瘤重量(见图2)；表明抗TIM-3抗体与hu5G11-hIgG1的联用具有增效的抗肿瘤作用。
表3.抗TIM-3抗体和抗PD-L1抗体对肺癌HCC827皮下移植瘤的疗效

注：P值是通过双尾Student’s t检验与第1组进行比较，P<0.05定义为有统计学显著性差异。
实施例2：非小细胞肺癌的临床试验
1.入选标准：
满足以下所有入选标准者才能入组本试验：
(1)受试者自愿加入本研究，签署知情同意书。
(2)年龄：18-75周岁(签署知情同意书时)。
(3)ECOG PS评分：0-1分。
(4)预计生存期超过3个月。
(5)入组患者符合下列标准：
队列1：PD-L1表达阳性的晚期一线NSCLC患者，
队列2：PD-L1表达阳性的晚期免疫耐药后NSCLC患者，
1)组织学或细胞学证实的不适合接受手术治疗且不适合接受根治性同步放化疗的局部晚期(ⅢB/ⅢC期)、复发性或转移性(IV期)NSCLC患者；
2)对于非鳞非小细胞肺癌，检测证明不存在EGFR突变、ALK融合、ROS1突变(对于鳞状非小细胞肺癌，已知存在上述基因突变的患者排除，状态未知者不强制要求检测)；
3)PD-L1表达阳性比例≥1％[TC(肿瘤细胞)或IC(免疫细胞)≥1％]；
4)队列1晚期一线患者：未接受过针对晚期疾病的系统抗肿瘤治疗。允许患者既往接受过新辅助/辅助化疗或放疗或同步放化疗，但疾病复发与完成末次治疗必须间隔至少6个月；
5)队列2晚期免疫耐药后患者：既往至少接受过免疫检查点(包括但不限于PD-1或PD-L1)抑制剂治疗失败或不耐受(允许联合或序贯或单药，序贯指：先接受含铂化疗后进行免疫检查点抑制剂治疗维持)。既往针对晚期疾病的治疗线数：1-2。对于新辅助/辅助化疗或放疗或同步放化疗，如果在治疗期间或停止治疗后6个月内疾病进展，应将其算作一线治疗方案。
(6)根据RECIST 1.1标准证实具有至少一个可测量病灶。
(7)主要器官功能正常，即符合下列标准：
1)血常规检查标准(检查前7天内未输血、未使用造血刺激因子类药物纠正)：
a.血红蛋白(HGB)≥90g/L；
b.中性粒细胞绝对值(NEUT)≥1.5×109/L；
c.血小板计数(PLT)≥90×109/L；
2)生化检查需符合以下标准：
a.总胆红素(TBIL)≤1.5倍正常值上限(ULN)(Gilbert综合症患者：TBIL≤3×ULN)；
b.丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)≤2.5×ULN。原发肝胆肿瘤或肿瘤肝脏转移者：ALT、AST≤5×ULN；
c.血清肌酐(CR)≤1.5×ULN或肌酐清除率(CCR)≥60mL/min；
3)凝血功能需符合以下标准：
活化部分凝血酶时间(APTT)、国际标准化比值(INR)、凝血酶原时间(PT)≤1.5×ULN(未接受过抗凝治疗)；
4)甲状腺功能检查需符合以下标准：
促甲状腺激素(TSH)≤ULN；如果异常应考察三碘甲状腺原氨酸(T3)和甲状腺素(T4)的水平，T3和T4水平正常则可以入选；
5)心脏彩超评估：左室射血分数(LVEF)≥50％。
(8)育龄女性受试者应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器、避孕药或避孕套)；在研究入组前的7天内血清妊娠/尿妊娠试验阴性，且必须为非哺乳期受试者；男性受试者应同意在研究期间和研究期结束后6个月内必须采用避孕措施。
2.试验药物与给药方案
先进行hu5G11-hIgG1注射液输注，再进行抗TIM-3抗体注射液输注。
hu5G11-hIgG1注射液(规格：600mg/20mL/瓶，和/或100mg/10mL/瓶)：3周为1个治疗周期，通过静脉滴注，每个治疗周期第1天以1200mg hu5G11-hIgG1的剂量给药一次。
抗TIM-3抗体注射液(规格：240mg/4mL/瓶，和/或600mg/10mL/瓶)：3周为1个治疗周期，通过静脉滴注，每个治疗周期第1天以1200mg、1500mg或1800mg抗TIM-3抗体的剂量给药一次。
3.评价标准
疗效评估标准依据RECIST 1.1，同时使用iRECIST标准对疗效进行确认。
4.终点指标
客观缓解率(ORR)、无进展生存期(PFS)、疾病控制率(DCR)、缓解持续时间(DOR)、总生存期(OS)等；
药代/药效学相关指标：药代动力学(PK)参数、免疫原性(ADA)发生率、受体占位(RO)等；
不良事件发生率：所有不良事件(AE)、严重不良事件(SAE)和治疗相关不良事件(TEAEs)的发生情况，以及异常实验室检查指标。
5.结果
初步研究结果表明，抗TIM-3抗体联合hu5G11-hIgG1可以安全、有效地治疗晚期非小细胞肺癌(尤其是PD-L1表达阳性的晚期非小细胞肺癌)。经抗TIM-3抗体+hu5G11-hIgG1联合治疗后，可显著提升患者的临床疗效和生存获益，使患者的病情得到缓解和控制，减缓疾病的进展，延长患者的无进展生存期和总生存期。显示了抗TIM-3抗体联合hu5G11-hIgG1联合治疗晚期非小细胞肺癌的优势。
实施例3：小细胞肺癌的临床试验
1.入选标准：
满足以下所有入选标准者才能入组本试验：
(1)受试者自愿加入本研究，签署知情同意书；
(2)年龄：18-75周岁(签署知情同意书时)；ECOG PS评分：0-1分；预计生存期超过3个月；
(3)经病理学证实的广泛期小细胞肺癌患者(按照美国退伍军人肺癌协会Veterans Administration Lung  Study Group，VALG分期)；
(4)既往针对广泛期小细胞肺癌至少接受过一线含铂化疗方案治疗失败或不耐受；
(5)允许既往暴露于免疫介导治疗，包括但不限于其他抗CTLA-4抗体、抗PD-1抗体、抗PD-L1抗体以及抗PD-L2抗体，不包括治疗性抗癌疫苗；
(6)脑转移：必须是无症状的或经过治疗的且在停用类固醇和抗惊厥药物后疾病稳定至少1个月(本研究治疗之前)。在筛选期怀疑存在脑部转移的患者应在进入本研究前进行脑部CT/MRI检查；
(7)根据RECIST 1.1标准证实具有至少一个可测量病灶；
(8)主要器官功能正常，即符合下列标准：
1)血常规检查标准(检查前7天内未输血、未使用造血刺激因子类药物纠正)：
a.血红蛋白(HGB)≥90g/L；
b.中性粒细胞绝对值(NEUT)≥1.5×109/L；
c.血小板计数(PLT)≥100×109/L；
2)生化检查需符合以下标准：
a.总胆红素(TBIL)≤1.5倍正常值上限(ULN)(Gilbert综合症患者：TBIL≤3×ULN)；
b.丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)≤2.5×ULN；原发肝胆肿瘤或肿瘤肝脏转移者：ALT、AST≤5×ULN；
c.血清肌酐(CR)≤1.5×ULN或肌酐清除率(CCR)≥60mL/min。
3)凝血功能需符合以下标准：活化部分凝血酶时间(APTT)、国际标准化比值(INR)、凝血酶原时间(PT)≤1.5×ULN(未接受过抗凝治疗)；
4)甲状腺功能检查需符合以下标准：
促甲状腺激素(TSH)≤ULN；如果异常应考察T3和T4水平，T3和T4水平正常则可以入选。
5)心脏彩超评估：左室射血分数(LVEF)≥50％。
(9)育龄女性受试者应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器、避孕药或避孕套)；在研究入组前的7天内血清妊娠/尿妊娠试验阴性，且必须为非哺乳期受试者；男性受试者应同意在研究期间和研究期结束后6个月内必须采用避孕措施。
2.试验药物与给药方案
先进行hu5G11-hIgG1注射液输注，再进行抗TIM-3抗体注射液输注。
hu5G11-hIgG1注射液(规格：600mg/20mL/瓶，和/或100mg/10mL/瓶)：3周为1个治疗周期，通过静脉滴注，每个治疗周期的第1天以1200mg hu5G11-hIgG1的剂量给药一次(给药时间窗：±3天)。
抗TIM-3抗体注射液(规格：240mg/4mL/瓶，和/或600mg/10mL/瓶)：3周为1个治疗周期，通过静脉滴注，每个治疗周期的第1天以1200mg或1500mg抗TIM-3抗体的剂量给药一次(给药时间窗：±3天)。
3.评价标准
疗效评估标准依据RECIST 1.1，同时使用iRECIST标准对疗效进行确认。
4.终点指标
客观缓解率(ORR)、无进展生存期(PFS)、疾病控制率(DCR)、缓解持续时间(DOR)、总生存期(OS)等；
药代/药效学相关指标：药代动力学(PK)参数、免疫原性(ADA)发生率、受体占位(RO)等；
不良事件发生率：所有不良事件(AE)、严重不良事件(SAE)和治疗相关不良事件(TEAEs)的发生情况，以及异常实验室检查指标。
5.结果
初步研究结果表明，抗TIM-3抗体联合hu5G11-hIgG1可以安全、有效地治疗广泛期小细胞肺癌(尤其是一线含铂化疗方案治疗失败或不耐受的广泛期小细胞肺癌)。经抗TIM-3抗体+hu5G11-hIgG1联合治疗后，可显著提升患者的临床疗效和生存获益，使患者的病情得到缓解和控制，减缓疾病的进展，延长患者的无进展生存期和总生存期，部分患者可达到部分缓解PR，整体具有较高的疾病控制率DCR。显示了抗TIM-3抗体联合hu5G11-hIgG1联合治疗广泛期小细胞肺癌的优势，具体示例性结果如下所述：
(1)示例性结果
1)诊断结果：患者诊断为右肺上叶小细胞肺癌，广泛期。
2)既往治疗：患者此前经EC(依托泊苷+卡铂)方案治疗6个周期后，疾病进展。
3)治疗方案：每3周为1个治疗周期，每个治疗周期的第1天，先静脉输注hu5G11-hIgG1注射液1200mg，再静脉输注抗TIM-3抗体注射液1200mg。
4)治疗效果及评估：
筛选期：靶病灶71mm；
治疗2个周期：靶病灶40mm；
根据疗效评估标准，截止到目前，患者的最佳治疗效果为PR(部分缓解)。

Claims (15)

  1. 一种药物组合，其包括抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段，其中，所述抗TIM-3抗体或其抗原结合片段包含：SEQ ID NO:1所示氨基酸序列的HCDR1，SEQ ID NO:2所示氨基酸序列的HCDR2，SEQ ID NO:3所示氨基酸序列的HCDR3，SEQ ID NO:4所示氨基酸序列的LCDR1，SEQ ID NO:5所示氨基酸序列的LCDR2，和SEQ ID NO:6所示氨基酸序列的LCDR3。
  2. 根据权利要求1所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段包含：氨基酸序列与SEQ ID NO:7所示氨基酸序列具有至少95％同一性的重链可变区，和氨基酸序列与SEQ ID NO:8所示氨基酸序列具有至少95％同一性的轻链可变区。
  3. 根据权利要求1或2所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段包含：氨基酸序列与SEQ ID NO:9所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:10所示氨基酸序列具有至少95％同一性的轻链。
  4. 根据权利要求1-3中任一项所述的药物组合，其中，所述抗PD-L1抗体或其抗原结合片段包含：
    (a)SEQ ID NO:11所示氨基酸序列的HCDR1，SEQ ID NO:12所示氨基酸序列的HCDR2，SEQ ID NO:13所示氨基酸序列的HCDR3，SEQ ID NO:14所示氨基酸序列的LCDR1，SEQ ID NO:15所示氨基酸序列的LCDR2，和SEQ ID NO:16所示氨基酸序列的LCDR3；或
    (b)SEQ ID NO:21所示氨基酸序列的HCDR1，SEQ ID NO:22所示氨基酸序列的HCDR2，SEQ ID NO:23所示氨基酸序列的HCDR3，SEQ ID NO:24所示氨基酸序列的LCDR1，SEQ ID NO:25所示氨基酸序列的LCDR2，和SEQ ID NO:26所示氨基酸序列的LCDR3。
  5. 根据权利要求1-4中任一项所述的药物组合，其中，所述抗PD-L1抗体或其抗原结合片段包含：
    (a)氨基酸序列与SEQ ID NO:17所示氨基酸序列具有至少95％同一性的重链可变区，和氨基酸序列与SEQ ID NO:18所示氨基酸序列具有至少95％同一性的轻链可变区；或
    (b)氨基酸序列与SEQ ID NO:27所示氨基酸序列具有至少95％同一性的重链可变区，和氨基酸序列与SEQ ID NO:28所示氨基酸序列具有至少95％同一性的轻链可变区。
  6. 根据权利要求1-5中任一项所述的药物组合，其中，所述抗PD-L1抗体或其抗原结合片段包含：
    (a)氨基酸序列与SEQ ID NO:19所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:20所示氨基酸序列具有至少95％同一性的轻链；或
    (b)氨基酸序列与SEQ ID NO:29所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:30所示氨基酸序列具有至少95％同一性的轻链。
  7. 根据权利要求1-6中任一项所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段配制为用于胃肠外途径施用的制剂，优选地，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段配制为用于静脉内、肌肉内或皮下施用的制剂；可选地，
    所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段配制在单一制剂中，或所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段分开配制。
  8. 根据权利要求1-7中任一项所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段的单位剂量为60-1800mg、100-1600mg、120-1600mg、180-1200mg、或240-600mg；
    可选地，所述抗PD-L1抗体或其抗原结合片段的单位剂量为10-1800mg、100-1500mg、100-1200mg、600-1200mg、或100-600mg。
  9. 根据权利要求1-8中任一项所述的药物组合，其中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段的质量比为(0.01-30):1、(0.01-20):1、(0.1-2.5):1、(0.5-1.5):1或(1-1.25):1。
  10. 根据权利要求1-9中任一项所述的药物组合，其中，所述药物组合适用于在单个治疗周期内施用，其包括100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的抗TIM-3抗体或其抗原结合片段，和100-2400mg、600-1800mg、1000-1500mg、1000-1200mg、或1200-1500mg的抗PD-L1抗体或其抗原结合片段。
  11. 权利要求1-10中任一项所述的药物组合在制备用于治疗肿瘤的药物中的用途。
  12. 根据权利要求11所述的用途，其中，所述肿瘤为实体瘤；优选地，所述实体瘤为肺癌；更优选地，所 述肺癌为非小细胞肺癌或小细胞肺癌。
  13. 根据权利要求11或12所述的用途，其中，所述抗TIM-3抗体或其抗原结合片段和抗PD-L1抗体或其抗原结合片段，可同时、先后和/或交替给药。
  14. 根据权利要求11-13中任一项所述的用途，其中，所述抗TIM-3抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次；可选地，所述抗TIM-3抗体或其抗原结合片段每次以100-1800mg、600-1800mg、600-1500mg、或1200-1500mg的剂量施用。
  15. 根据权利要求11-14中任一项所述的用途，其中，所述抗PD-L1抗体或其抗原结合片段每1周、每2周、每3周、或每4周施用一次；可选地，所述抗PD-L1抗体或其抗原结合片段每次以100-2400mg、600-1800mg、1000-1500mg、1000-1200mg、或1200-1500mg的剂量施用。
PCT/CN2023/082186 2022-03-18 2023-03-17 抗tim-3抗体与抗pd-l1抗体的药物组合 WO2023174408A1 (zh)

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