Pharmaceutical composition for treating tumors

Abstract

The invention belongs to the field of biological medicine, and particularly provides a medicine composition for treating tumors, and the medicine composition comprises an anti-TIM-3 antibody or an antigen binding fragment thereof, an anti-PD-1 antibody or an antigen binding fragment thereof, and anlotinib or pharmaceutically acceptable salt thereof. The invention further provides application of the medicine composition in preparation of medicines for treating tumors.

Description

Technical Field

[0001] The present application belongs to the field of biomedicine, and specifically relates to a drug combination of an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and anlotinib or a pharmaceutically acceptable salt thereof, and its use in treating tumors. Background Art

[0002] T cell immunoglobulin and mucindomain-containing protein 3 (TIM-3), also known as Hepatitis A Virus Cellular Receptor 2 (HAVCR2), is a member of the TIM family of immunoregulatory 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, macrophages, and also on a variety of tumor cells. TIM-3 has a variety of different ligands, including galectin 9, phosphatidylserine (PtdSer), high mobility group protein B1 (HMGB1), and carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1). As an immune checkpoint, TIM-3 has the physiological function of negatively regulating the body's immune response to avoid damage to the body caused by excessive immune or autoimmune responses. Increasing evidence shows that TIM-3 protein and / or mRNA is upregulated in a variety of tumor tissues and tumor-associated immune cells, participating in tumor immune escape and immune response, and promoting tumor development.

[0003] PD-1 (Programmed death-1) is a key immune checkpoint receptor expressed by activated T lymphocytes and B lymphocytes and mediates immunosuppression, and its ligands include PD-L1 and PD-L2. Chinese patent document CN106977602A discloses an anti-PD-1 monoclonal antibody 14C12H1L1, which can effectively block the binding of PD-1 and PD-L1 and show good anti-tumor activity.

[0004] Anlotinib is a quinoline derivative tyrosine kinase inhibitor. As a multi-target tyrosine kinase inhibitor, it plays a role in affecting tumor angiogenesis and proliferation signal transduction. Its main targets include: receptor tyrosine kinases VEGFR1 (FLT1), VEGFR2 (KDR), VEGFR3 (FLT4), EGFR, FGFR1-4, PDGFRα and β, and stem cell factor receptors (SCFR) 7, 8 and 9.

[0005] Primary liver cancer is the seventh most common malignant tumor in the world, of which hepatocellular carcinoma (HCC) accounts for 80-85%. China is the region with the highest incidence of HCC, accounting for about 45% of global cases. Because liver cancer patients are diagnosed at a late stage, about 70% of patients lose the opportunity for surgical treatment, with a short survival period and poor prognosis.

[0006] In 2020, the number of new cases of colorectal cancer in China reached 555,000, and the number of deaths from colorectal cancer reached 286,000, ranking second in incidence and fifth in mortality among malignant tumors. About 21% of colorectal cancer patients have distant metastasis at the time of initial diagnosis, and 50%-60% of patients will develop metastasis as the disease progresses, resulting in a low survival rate.

[0007] Therefore, there is an urgent need to explore other drugs that can treat patients with hepatocellular carcinoma or colorectal cancer and improve the treatment effect. SUMMARY OF THE INVENTION

[0009] In one aspect, the present application provides a drug combination, which includes an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is anlotinib or a pharmaceutically acceptable salt thereof, such as anlotinib hydrochloride. In some embodiments, the drug combination includes an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and anlotinib or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the drug combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof at a unit dose of 60-1800 mg, an anti-PD-1 antibody or an antigen-binding fragment thereof at a unit dose of 10-500 mg, and anlotinib or a pharmaceutically acceptable salt thereof at a unit dose of 6 mg, 8 mg, 10 mg and / or 12 mg.

[0011] In some embodiments, the drug combination includes 100-1800 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, 10-800 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 6 mg, 8 mg, 10 mg or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 100-1800 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, 10-800 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the drug combination is used to treat a tumor.

[0014] In another aspect, the present application also provides use of the drug combination of the present application for treating a tumor in a subject.

[0015] On the other hand, the present application also provides the use of the drug combination of the present application in the preparation of a drug for treating a tumor in a subject. In some specific embodiments, the present application also provides the use of the drug combination of the present application in the preparation of a drug for first-line treatment of a tumor in a subject. In some specific embodiments, the present application also provides the use of the drug combination of the present application in the preparation of a drug for fourth-line treatment or later lines of treatment of a tumor in a subject.

[0016] On the other hand, the present application also provides a method for treating a tumor in a subject, comprising administering to the subject a drug combination of the present application. On the other hand, the present application also provides a method for treating a tumor in a subject, comprising administering to the subject a therapeutically effective amount of a drug combination of the present application. In some specific embodiments, the present application provides a method for first-line treatment of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of a drug combination of the present application. In some specific embodiments, the present application provides a method for treating a tumor in a subject in a fourth line of treatment or a later line of treatment of a subject, comprising administering to the subject a therapeutically effective amount of a drug combination of the present application.

[0017] In some embodiments, the anti-TIM-3 antibody or an antigen-binding fragment thereof, the anti-PD-1 antibody or an antigen-binding fragment thereof, and anlotinib or a pharmaceutically acceptable salt thereof can be administered simultaneously, sequentially and / or alternately.

[0018] In some embodiments, 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. In some embodiments, 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.

[0019] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10-800 mg, 50-500 mg, or 100-200 mg each time.

[0020] In some embodiments, the anlotinib or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, the anlotinib or a pharmaceutically acceptable salt thereof is administered at a dose of 6 mg, 8 mg, 10 mg, or 12 mg each time.

[0021] On the other hand, the present application provides a kit for treating a tumor, which includes the drug combination of the present application. In some embodiments, the kit includes an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is anlotinib or a pharmaceutically acceptable salt thereof, such as anlotinib hydrochloride. In some embodiments, the kit includes an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and anlotinib or a pharmaceutically acceptable salt thereof.

[0022] In addition, the present application also provides a method for treating a tumor in a subject, comprising administering to the subject a therapeutically effective amount of the anti-TIM-3 antibody or antigen-binding fragment thereof of the present application. The present application also provides a method for first-line treatment of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of the anti-TIM-3 antibody or antigen-binding fragment thereof of the present application. The present application also provides the use of anti-TIM-3 antibodies or antigen-binding fragments thereof in the preparation of a medicament for treating a tumor in a subject. The present application also provides the use of anti-TIM-3 antibodies or antigen-binding fragments thereof in the preparation of a medicament for first-line treatment of a tumor in a subject. The present application also provides the use of anti-TIM-3 antibodies or antigen-binding fragments thereof in the treatment of tumors.

[0023] The present application also provides a method for treating a tumor in a subject, comprising administering to the subject a therapeutically effective amount of the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application. The present application also provides the use of anti-TIM-3 antibody or its antigen-binding fragment and anti-PD-1 antibody or its antigen-binding fragment in the preparation of a medicament for treating a tumor in a subject. The present application also provides the use of anti-TIM-3 antibody or its antigen-binding fragment and anti-PD-1 antibody or its antigen-binding fragment in treating tumors.

[0024] In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is liver cancer. In some embodiments, the tumor is hepatocellular carcinoma. In some embodiments, the tumor is advanced hepatocellular carcinoma. In some embodiments, the tumor is recurrent and / or metastatic hepatocellular carcinoma. In some embodiments, the tumor is colorectal cancer. In some embodiments, the tumor is advanced colorectal cancer. In some embodiments, the tumor is recurrent and / or metastatic colorectal cancer. DETAILED DESCRIPTION OF THE INVENTION

[0026] Drug combinations

[0027] In one aspect, the present application provides a drug combination, which includes an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is anlotinib or a pharmaceutically acceptable salt thereof, such as anlotinib hydrochloride. In some embodiments, the drug combination includes an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and anlotinib or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the drug combination is packaged in the same kit, and the kit further includes instructions for the combined use of anti-TIM-3 antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof to treat tumors. In other embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof in the drug combination are separately packaged in respective medicine boxes, and the medicine box further includes instructions for the combined use of anti-TIM-3 antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof to treat tumors.

[0029] In some embodiments, the pharmaceutical combination is a non-fixed combination.

[0030] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and anlotinib or a pharmaceutically acceptable salt thereof in the non-fixed combination are each in the form of a pharmaceutical composition.

[0031] In some embodiments, in the non-fixed combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is an injection. In some specific embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is a lyophilized preparation.

[0032] In some embodiments, in the non-fixed combination, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is an injection. In some specific embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is a lyophilized preparation.

[0033] In some embodiments, in the non-fixed combination, the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated in a single preparation. In some embodiments, in the non-fixed combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment is an injection. In some specific embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment is a lyophilized preparation.

[0034] In some embodiments, in the non-fixed combination, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is a solid preparation. In some specific embodiments, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is a capsule.

[0035] In some embodiments, the unit dose of the anti-TIM-3 antibody or its antigen-binding fragment 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 dose of the anti-TIM-3 antibody or its antigen-binding fragment in the pharmaceutical combination is 60 mg, 120 mg, 160 mg, 180 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 360 mg, 400 mg, 420 mg, 440 mg, 480 mg, 520 mg, 540 mg, 560 mg, 600 mg, 640 mg, 660 mg, 680 mg, 720 mg, 760 mg, 780 mg, 800 mg, 840 mg, 880 mg, 900 mg, 920 mg, 960 mg, In some embodiments, the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 240 mg, 300 mg, 360 mg and / or 600 mg. In some embodiments, the unit dose of the anti-TIM-3 antibody or its antigen-binding fragment in the pharmaceutical combination is 240 mg and / or 600 mg. In some embodiments, the unit dose of the anti-TIM-3 antibody or its antigen-binding fragment in the pharmaceutical combination is 600 mg.

[0036] In some embodiments, the unit dose of the anti-PD-1 antibody or its antigen-binding fragment in the pharmaceutical combination is 10-500 mg, 50-500 mg, 50-200 mg, or 100-200 mg. In some embodiments, the unit dose of the anti-PD-1 antibody or its antigen-binding fragment in the pharmaceutical combination is 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg , 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg and / or 500mg, or a range formed by any of the above values. In some embodiments, the unit dose of the anti-PD-1 antibody or its antigen-binding fragment in the drug combination is 100mg and / or 200mg. In some embodiments, the unit dose of the anti-PD-1 antibody or its antigen-binding fragment in the drug combination is 100mg.

[0037] In some embodiments, the unit dose of anlotinib or a pharmaceutically acceptable salt thereof in the drug combination is 6 mg, 8 mg, 10 mg and / or 12 mg.

[0038] In some embodiments, the drug combination includes an anti-TIM-3 antibody or an antigen-binding fragment thereof at a unit dose of 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg, an anti-PD-1 antibody or an antigen-binding fragment thereof at a unit dose of 10-500 mg, 50-500 mg, 50-200 mg, or 100-200 mg, and anlotinib or a pharmaceutically acceptable salt thereof at a unit dose of 6 mg, 8 mg, 10 mg and / or 12 mg. In some embodiments, the pharmaceutical combination comprises a unit dose of 60 mg, 120 mg, 160 mg, 180 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 360 mg, 400 mg, 420 mg, 440 mg, 480 mg, 520 mg, 540 mg, 560 mg, 600 mg, 640 mg, 660 mg, 680 mg, 720 mg, 760 mg, 780 mg, 800 mg, 840 mg, 880 mg, 900 mg, 920 mg, 960 mg, 1500mg, 1520mg, 1560mg, 1600mg, 1620mg, 1640mg, 1680mg, 1720mg, 1740mg, 1760mg and / or 1800mg. g, or an anti-TIM-3 antibody or antigen-binding fragment thereof in a range of any of the above values, wherein the unit dose is 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg g, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg and / or 500 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof, and a unit dose of 6 mg, 8 mg, 10 mg and / or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.In some embodiments, the drug combination includes an anti-TIM-3 antibody or an antigen-binding fragment thereof at a unit dose of 240 mg, 300 mg, 360 mg and / or 600 mg, an anti-PD-1 antibody or an antigen-binding fragment thereof at a unit dose of 100 mg and / or 200 mg, and an anlotinib or a pharmaceutically acceptable salt thereof at a unit dose of 6 mg, 8 mg, 10 mg and / or 12 mg. In some embodiments, the drug combination includes an anti-TIM-3 antibody or an antigen-binding fragment thereof at a unit dose of 240 mg and / or 600 mg, an anti-PD-1 antibody or an antigen-binding fragment thereof at a unit dose of 100 mg, and an anlotinib or a pharmaceutically acceptable salt thereof at a unit dose of 6 mg, 8 mg and / or 10 mg. In some embodiments, the drug combination includes a unit dose of 240 mg and / or 600 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, a unit dose of 100 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and a unit dose of 6 mg, 8 mg, 10 mg and / or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the drug combination includes 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of anti-TIM-3 antibodies or antigen-binding fragments thereof. In some embodiments, the drug combination includes 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg or 1800 mg, or an anti-TIM-3 antibody or antigen-binding fragment thereof in a range formed by any of the above values. In some embodiments, the drug combination includes 1200 mg or 1500 mg of anti-TIM-3 antibodies or antigen-binding fragments thereof. In some embodiments, the drug combination includes 1200 mg of anti-TIM-3 antibodies or antigen-binding fragments thereof.

[0040] In some embodiments, the drug combination includes 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination includes 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof in a range formed by any of the above values. In some embodiments, the drug combination includes 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0041] In some embodiments, the drug combination includes 6 mg, 8 mg, 10 mg or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination includes 6 mg, 8 mg or 10 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination includes 8 mg, 10 mg or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination includes 10 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination includes 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the drug combination includes 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 6 mg, 8 mg, 10 mg or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg or 1800 mg, or a range formed by any of the above values ​​of an anti-TIM-3 antibody or an antigen-binding fragment thereof, 10 mg, 50 mg, 100 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg or 1800 mg, or a range formed by any of the above values. 20mg, 140mg, 160mg, 180mg, 200mg, 220mg, 240mg, 260mg, 280mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg or 800mg, or an anti-PD-1 antibody or antigen-binding fragment thereof in a range formed by any of the above values, and 6mg, 8mg, 10mg or 12mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination includes 1200mg or 1500mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, 200mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 6mg, 8mg or 10mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination includes 1200mg or 1500mg of anti-TIM-3 antibody or antigen binding fragment thereof, 200mg of anti-PD-1 antibody or antigen binding fragment thereof, and 8mg, 10mg or 12mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination includes 1200mg of anti-TIM-3 antibody or antigen binding fragment thereof, 200mg of anti-PD-1 antibody or antigen binding fragment thereof, and 10mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination includes 1200mg of anti-TIM-3 antibody or antigen binding fragment thereof, 200mg of anti-PD-1 antibody or antigen binding fragment thereof, and 12mg of anlotinib or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the content of the anti-TIM-3 antibody or its antigen-binding fragment in the pharmaceutical combination is a daily dose. In some embodiments, the content of the anti-TIM-3 antibody or its antigen-binding fragment in the pharmaceutical combination is a once-a-day dose.

[0044] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is present in a uniform dose.

[0045] In some embodiments, the content of the anti-TIM-3 antibody or its antigen-binding fragment in the drug combination is a dose for one treatment cycle, and each treatment cycle is 3 weeks.

[0046] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment in the pharmaceutical combination is a daily dose. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment in the pharmaceutical combination is a once-a-day dose.

[0047] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is contained in a uniform dose.

[0048] In some embodiments, the content of the anti-PD-1 antibody or its antigen-binding fragment in the drug combination is a dose for one treatment cycle, and each treatment cycle is 3 weeks.

[0049] In some embodiments, in the drug combination, the content of anlotinib or a pharmaceutically acceptable salt thereof is a daily dose. In some embodiments, in the drug combination, the content of anlotinib or a pharmaceutically acceptable salt thereof is a once-a-day dose.

[0050] In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or its antigen-binding fragment. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg or 1800 mg, or an anti-TIM-3 antibody or its antigen-binding fragment in a range formed by any of the above values. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 1200 mg or 1500 mg of an anti-TIM-3 antibody or its antigen-binding fragment. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof.

[0051] In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof in a range formed by any of the above values. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0052] In some embodiments, the drug combination is suitable for administration in a single treatment cycle, including 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, including 84-140 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, including 112-168 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, including 140 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, including 168 mg of anlotinib or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the drug combination is suitable for administration in a single treatment cycle, comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, comprising 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg or 1800 mg, or a range formed by any of the above values ​​of an anti-TIM-3 antibody or an antigen-binding fragment thereof, 10 mg, 50mg, 100mg, 120mg, 140mg, 160mg, 180mg, 200mg, 220mg, 240mg, 260mg, 280mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg or 800mg, or an anti-PD-1 antibody or its antigen-binding fragment in the range formed by any of the above values, and 84-140mg of anlotinib or its pharmaceutically acceptable salt. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, which includes 1200mg or 1500mg of anti-TIM-3 antibody or its antigen-binding fragment, 200mg of anti-PD-1 antibody or its antigen-binding fragment, and 84-140mg of anlotinib or its pharmaceutically acceptable salt. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, comprising 1200 mg or 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 112-168 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, comprising 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 84-140 mg of anlotinib or a pharmaceutically acceptable salt thereof.In some embodiments, the drug combination is suitable for administration in a single treatment cycle, including 1200 mg of anti-TIM-3 antibody or antigen binding fragment thereof, 200 mg of anti-PD-1 antibody or antigen binding fragment thereof, and 112-168 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, including 1200 mg or 1500 mg of anti-TIM-3 antibody or antigen binding fragment thereof, 200 mg of anti-PD-1 antibody or antigen binding fragment thereof, and 140 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, including 1200 mg or 1500 mg of anti-TIM-3 antibody or antigen binding fragment thereof, 200 mg of anti-PD-1 antibody or antigen binding fragment thereof, and 168 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, comprising 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 140 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, comprising 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 168 mg of anlotinib or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the anti-TIM-3 antibody or its antigen-binding fragment may be a pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment. Wherein, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is a single dose or multiple doses, preferably multiple doses. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing 240 mg, 300 mg, 360 mg and / or 600 mg of an anti-TIM-3 antibody or its antigen-binding fragment. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing 240 mg and / or 600 mg of an anti-TIM-3 antibody or its antigen-binding fragment.

[0055] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof may be a pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof. Wherein, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof is a single dose or multiple doses, preferably multiple doses. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing 100 mg and / or 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing 100 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.

[0056] In some embodiments, the anlotinib or a pharmaceutically acceptable salt thereof may be a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof. Wherein, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, preferably multiple doses. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing 6 mg, 8 mg, 10 mg and / or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing 6 mg, 8 mg and / or 10 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing 8 mg, 10 mg and / or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, in the drug combination, the mass ratio of the anti-TIM-3 antibody or its antigen-binding fragment: the anti-PD-1 antibody or its antigen-binding fragment is (0.1-180):1, (0.2-50):1, (0.5-9):1, (3-7.5):1, (4-7.5):1 or (6-7.5):1; wherein the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment can be packaged separately or together.

[0058] In some embodiments, in the drug combination, the mass ratio of the anti-TIM-3 antibody or its antigen-binding fragment: anlotinib or its pharmaceutically acceptable salt is (0.1-50):1, (1-30):1, (3-20):1, (6-18):1, (8-12):1 or (8-9):1.

[0059] In some embodiments, in the drug combination, the mass ratio of the anti-TIM-3 antibody or its antigen-binding fragment: anlotinib or its pharmaceutically acceptable salt is (0.1-50):1, (1-30):1, (3-20):1, (7-15):1, (7-11):1 or (7-8):1.

[0060] In some embodiments, in the drug combination, the mass ratio of the anti-PD-1 antibody or its antigen-binding fragment: anlotinib or its pharmaceutically acceptable salt is (0.01-10):1, (0.1-10):1, (0.1-5):1, (0.2-4):1, (0.5-2):1 or (1-2):1.

[0061] In some embodiments, the drug combination includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, and a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof. In some specific embodiments, in the drug combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment to the patient, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 10-800 mg, 50-500 mg, or 100-200 mg of the anti-PD-1 antibody or its antigen-binding fragment to the patient, and the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for administering 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof to the patient. In some specific embodiments, in the drug combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 1200 mg or 1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment to the patient, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 200 mg of the anti-PD-1 antibody or its antigen-binding fragment to the patient, and the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for administering 84-140 mg of anlotinib or a pharmaceutically acceptable salt thereof to the patient. In some specific embodiments, in the drug combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 1200 mg or 1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment to the patient, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 200 mg of the anti-PD-1 antibody or its antigen-binding fragment to the patient, and the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for administering 112-168 mg of anlotinib or a pharmaceutically acceptable salt thereof to the patient. In some specific embodiments, in the drug combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 1200 mg of the anti-TIM-3 antibody or its antigen-binding fragment to the patient, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 200 mg of the anti-PD-1 antibody or its antigen-binding fragment to the patient, and the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for administering 140 mg of anlotinib or a pharmaceutically acceptable salt thereof to the patient.In some specific embodiments, in the drug combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 1200 mg of the anti-TIM-3 antibody or its antigen-binding fragment to the patient, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 200 mg of the anti-PD-1 antibody or its antigen-binding fragment to the patient, and the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for administering 168 mg of anlotinib or a pharmaceutically acceptable salt thereof to the patient.

[0062] In some specific embodiments, in the drug combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment to the patient each time, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 10-800 mg, 50-500 mg, or 100-200 mg of the anti-PD-1 antibody or its antigen-binding fragment to the patient each time, and the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for administering 6 mg, 8 mg, 10 mg or 12 mg of anlotinib or its pharmaceutically acceptable salt to the patient each time. In some specific embodiments, in the drug combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is prepared as multiple doses suitable for administering 1200 mg or 1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment to the patient each time, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is prepared as multiple doses suitable for administering 200 mg of the anti-PD-1 antibody or its antigen-binding fragment to the patient each time, and the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared as a single dose suitable for administering 6 mg, 8 mg or 10 mg of anlotinib or its pharmaceutically acceptable salt to the patient each time. In some specific embodiments, in the drug combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is prepared as multiple doses suitable for administering 1200 mg or 1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment to the patient each time, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is prepared as multiple doses suitable for administering 200 mg of the anti-PD-1 antibody or its antigen-binding fragment to the patient each time, and the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared as a single dose suitable for administering 8 mg, 10 mg or 12 mg of anlotinib or its pharmaceutically acceptable salt to the patient each time. In some specific embodiments, in the drug combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 1200 mg of the anti-TIM-3 antibody or its antigen-binding fragment to the patient each time, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 200 mg of the anti-PD-1 antibody or its antigen-binding fragment to the patient each time, and the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared as a single dose suitable for administering 10 mg of anlotinib or a pharmaceutically acceptable salt thereof to the patient each time.In some specific embodiments, in the drug combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 1200 mg of the anti-TIM-3 antibody or its antigen-binding fragment to the patient each time, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering 200 mg of the anti-PD-1 antibody or its antigen-binding fragment to the patient each time, and the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared as a single dose suitable for administering 12 mg of anlotinib or a pharmaceutically acceptable salt thereof to the patient each time.

[0063] On the other hand, the present application provides a kit for treating tumors, comprising a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, and a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof, as well as instructions for using the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof, the pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, and the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof in combination to treat tumors.

[0064] On the other hand, the present application provides a kit for treating tumors, comprising a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, and a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof, and instructions for using the pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof in combination with a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof to treat tumors.

[0065] The present application also provides a drug package, which contains single-packaged pharmaceutical compositions in separate containers, wherein the first container includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof, the second container includes a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, and the third container includes a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug package is used to treat tumors.

[0066] The present application also provides a drug package, which contains single-packaged pharmaceutical compositions in separate containers, wherein the first container includes a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, and the second container includes a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the drug package is used to treat tumors.

[0067] In some embodiments, in the kit or drug package, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is an injection. In some specific embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is a lyophilized preparation.

[0068] In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment in the kit or drug package is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is an injection. In some specific embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is a lyophilized preparation.

[0069] In some embodiments, in the kit or drug package, the pharmaceutical composition containing anti-TIM-3 antibody or its antigen-binding fragment and anti-PD-1 antibody or its antigen-binding fragment is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing anti-TIM-3 antibody or its antigen-binding fragment and anti-PD-1 antibody or its antigen-binding fragment is an injection. In some specific embodiments, the pharmaceutical composition containing anti-TIM-3 antibody or its antigen-binding fragment and anti-PD-1 antibody or its antigen-binding fragment is a lyophilized preparation.

[0070] In some embodiments, in the kit or drug package, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is a solid preparation. In some specific embodiments, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is a capsule.

[0071] In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is liver cancer. In some embodiments, the tumor is hepatocellular carcinoma. In some embodiments, the tumor is advanced hepatocellular carcinoma. In some embodiments, the tumor is recurrent and / or metastatic hepatocellular carcinoma. In some embodiments, the tumor is colorectal cancer. In some embodiments, the tumor is advanced colorectal cancer. In some embodiments, the tumor is recurrent and / or metastatic colorectal cancer.

[0072] use

[0073] The present application also provides the use of the drug combination of the present application for treating a tumor in a subject. In some specific embodiments, the present application also provides the use of the drug combination of the present application for first-line treatment of a tumor in a subject. In some specific embodiments, the present application also provides the use of the drug combination of the present application for fourth-line treatment or later lines of treatment of a tumor in a subject. On the other hand, the present application also provides a method for treating a tumor in a subject, which includes administering a therapeutically effective amount of the drug combination of the present application to the subject. The present application provides a method for first-line treatment of a tumor in a subject, which includes administering a therapeutically effective amount of the drug combination of the present application to the subject. The present application provides a method for fourth-line treatment or later lines of treatment of a tumor in a subject, which includes administering a therapeutically effective amount of the drug combination of the present application to the subject. On the other hand, the present application also provides the use of the drug combination of the present application in the preparation of a drug for treating a tumor in a subject. In some specific embodiments, the present application also provides the use of the drug combination of the present application in the preparation of a drug for first-line treatment of a tumor in a subject. In some specific embodiments, the present application also provides the use of the drug combination of the present application in the preparation of a drug for fourth-line treatment or later lines of treatment of a tumor in a subject.

[0074] In some embodiments, in the method or use, the drug combination includes an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and anlotinib or a pharmaceutically acceptable salt thereof.

[0075] The present application also provides the use of the anti-TIM-3 antibody or its antigen-binding fragment of the present application in the preparation of a drug for treating a tumor in a subject, wherein the drug is used in combination with the anti-PD-1 antibody or its antigen-binding fragment of the present application and anlotinib or a pharmaceutically acceptable salt thereof. The present application also provides the use of the anti-TIM-3 antibody or its antigen-binding fragment of the present application in the preparation of a drug for first-line treatment of a tumor in a subject, wherein the drug is used in combination with the anti-PD-1 antibody or its antigen-binding fragment of the present application and anlotinib or a pharmaceutically acceptable salt thereof. The present application also provides the use of the anti-TIM-3 antibody or its antigen-binding fragment of the present application in the preparation of a drug for fourth-line treatment or later line treatment of a tumor in a subject, wherein the drug is used in combination with the anti-PD-1 antibody or its antigen-binding fragment of the present application and anlotinib or a pharmaceutically acceptable salt thereof.

[0076] The present application also provides the use of the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a drug for treating a tumor in a subject, wherein the drug is used in combination with anlotinib or a pharmaceutically acceptable salt thereof. The present application also provides the use of the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a drug for first-line treatment of a tumor in a subject, wherein the drug is used in combination with anlotinib or a pharmaceutically acceptable salt thereof. The present application also provides the use of the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a drug for fourth-line treatment or later lines of treatment of a tumor in a subject, wherein the drug is used in combination with anlotinib or a pharmaceutically acceptable salt thereof.

[0077] The present application also provides the use of the anti-TIM-3 antibody or its antigen-binding fragment, anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt for treating a tumor in a subject. In some specific embodiments, the present application also provides the use of the anti-TIM-3 antibody or its antigen-binding fragment, anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt for first-line treatment of a tumor in a subject. In some specific embodiments, the present application also provides the use of the anti-TIM-3 antibody or its antigen-binding fragment, anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt for fourth-line treatment or later treatment of a tumor in a subject.

[0078] The present application also provides the use of the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt in the preparation of a drug for treating a tumor in a subject. In some specific embodiments, the present application also provides the use of the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt in the preparation of a drug for first-line treatment of a tumor in a subject. In some specific embodiments, the present application also provides the use of the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt in the preparation of a drug for fourth-line treatment or later lines of treatment of a tumor in a subject.

[0079] The present application also provides a method for treating a tumor in a subject, comprising administering to the subject an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof. On the other hand, the present application also provides a method for treating a tumor in a subject, comprising administering to the subject a therapeutically effective amount of an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof. In some specific embodiments, the present application provides a method for first-line treatment of a tumor in a subject, comprising administering to the subject an effective amount of an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof. In some specific embodiments, the present application provides a method for treating a tumor in a subject in a fourth-line treatment or a later line of treatment of a subject, comprising administering to the subject a therapeutically effective amount of an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof and anlotinib or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, in the method or use, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt can be administered simultaneously, successively and / or alternately. In some embodiments, in the method or use, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt are each in the form of a pharmaceutical composition and can be administered simultaneously, successively and / or alternately. In some embodiments, in the method or use, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt are administered successively. In some embodiments, in the method or use, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt are each in the form of a pharmaceutical composition and administered successively. In some embodiments, in the method or use, the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated in a single formulation, and the single formulation and anlotinib or its pharmaceutically acceptable salt can be administered simultaneously, sequentially and / or alternately. In some embodiments, in the method or use, the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated in a single formulation, and the single formulation and anlotinib or its pharmaceutically acceptable salt are administered sequentially. In some embodiments, in the method or use, the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated in a single formulation, and the single formulation and a pharmaceutical composition containing anlotinib or its pharmaceutically acceptable salt can be administered simultaneously, sequentially and / or alternately. In some embodiments, in the method or use, the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated in a single formulation, and the single formulation and the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof are administered sequentially.

[0081] In some embodiments, in the method or use, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt are administered in the same or different dosing regimens. In some specific embodiments, in the method or use, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt are administered in different dosing regimens.

[0082] In some embodiments, in the method or use, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In some specific embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks. In some embodiments, 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. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg or 1800 mg, or a range formed by any of the above values. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg or 1500 mg each time. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg each time. In some embodiments, the anti-TIM-3 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of anti-TIM-3 antibody or its antigen-binding fragment. In some embodiments, the anti-TIM-3 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 1200-1500 mg of anti-TIM-3 antibody or its antigen-binding fragment. In some embodiments, the anti-TIM-3 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 1200 mg or 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 1200 mg or 1500 mg of the anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 1200 mg of the anti-TIM-3 antibody or antigen-binding fragment thereof.

[0083] In some embodiments, in the method or use, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10-800 mg, 50-500 mg, or 100-200 mg each time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or a range formed by any of the above values. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 200 mg each time. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 10-800 mg, 50-500 mg, or 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 200 mg of anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 3 weeks, each time at a dose of 200 mg of anti-PD-1 antibody or its antigen-binding fragment.

[0084] In some embodiments, in the method or use, the anlotinib or a pharmaceutically acceptable salt thereof is administered in a regimen of continuous medication for 2 weeks and 1 week of drug withdrawal. In some embodiments, the anlotinib or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 6 mg, 8 mg, 10 mg or 12 mg each time. In some embodiments, the anlotinib or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 6 mg, 8 mg or 10 mg each time. In some embodiments, the anlotinib or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 8 mg, 10 mg or 12 mg each time. In some embodiments, the anlotinib or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 10 mg each time. In some embodiments, the anlotinib or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 12 mg each time. In some embodiments, the anlotinib or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 6 mg, 8 mg, 10 mg or 12 mg each time, administered once a day, continuously administered for 2 weeks, and 1 week of drug withdrawal. In some embodiments, in the method or use, the anlotinib or a pharmaceutically acceptable salt thereof is administered at a dose of 6 mg, 8 mg or 10 mg each time, once a day, for 2 consecutive weeks, and 1 week of drug suspension. In some embodiments, in the method or use, the anlotinib or a pharmaceutically acceptable salt thereof is administered at a dose of 8 mg, 10 mg or 12 mg each time, once a day, for 2 consecutive weeks, and 1 week of drug suspension. In some embodiments, in the method or use, the anlotinib or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg each time, once a day, for 2 consecutive weeks, and 1 week of drug suspension. In some embodiments, in the method or use, the anlotinib or a pharmaceutically acceptable salt thereof is administered at a dose of 12 mg each time, once a day, for 2 consecutive weeks, and 1 week of drug suspension.

[0085] In some embodiments, in the method or use, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt have the same or different treatment cycles. In some specific embodiments, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt have the same treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks is a treatment cycle. In some specific embodiments, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt have the same treatment cycle, for example, every 3 weeks is a treatment cycle.

[0086] In some embodiments, in the method or use, every 3 weeks is a treatment cycle, and anti-TIM-3 antibody or its antigen-binding fragment, anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt are administered in each treatment cycle. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, and anti-TIM-3 antibody or its antigen-binding fragment and anti-PD-1 antibody or its antigen-binding fragment are administered once in each treatment cycle, and anlotinib or its pharmaceutically acceptable salt is administered 14 times. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, and anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and anlotinib or its pharmaceutically acceptable salt is administered on days 1-14 of each treatment cycle. In some embodiments, in the method or use, one treatment cycle is 3 weeks, and an anti-TIM-3 antibody or an antigen-binding fragment thereof is administered once on day 1 of each treatment cycle, an anti-PD-1 antibody or an antigen-binding fragment thereof is administered once on day 1 of each treatment cycle, and anlotinib or a pharmaceutically acceptable salt thereof is administered once a day on days 1 to 14 of each treatment cycle.

[0087] In some embodiments, in the method or use, the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated in a single formulation. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, and the single formulation and anlotinib or a pharmaceutically acceptable salt thereof are administered in each treatment cycle. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, the single formulation is administered once in each treatment cycle, and anlotinib or a pharmaceutically acceptable salt thereof is administered 14 times. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, the single formulation is administered on the 1st day of each treatment cycle, and anlotinib or a pharmaceutically acceptable salt thereof is administered on the 1st-14th day of each treatment cycle. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, the single formulation is administered once on the 1st day of each treatment cycle, and anlotinib or a pharmaceutically acceptable salt thereof is administered once a day on the 1st-14th day of each treatment cycle.

[0088] In some specific embodiments, in the method or use, 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 antibody or its antigen-binding fragment is administered in each treatment cycle, 10-800 mg, 50-500 mg, or 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle, and 84-168 mg of anlotinib or its pharmaceutically acceptable salt is administered in each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg or 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered in each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle, and 84-140 mg of anlotinib or its pharmaceutically acceptable salt is administered in each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg or 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered in each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle, and 112-168 mg of anlotinib or its pharmaceutically acceptable salt is administered in each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered in each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle, and 84-140 mg of anlotinib or its pharmaceutically acceptable salt is administered in each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered in each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle, and 112-168 mg of anlotinib or its pharmaceutically acceptable salt is administered in each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered in each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle, and 140 mg of anlotinib or its pharmaceutically acceptable salt is administered in each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered in each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle, and 168 mg of anlotinib or its pharmaceutically acceptable salt is administered in each treatment cycle.In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg or 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 84-140 mg of anlotinib or its pharmaceutically acceptable salt is administered on days 1-14 of each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg or 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 112-168 mg of anlotinib or its pharmaceutically acceptable salt is administered on days 1-14 of each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 84-140 mg of anlotinib or its pharmaceutically acceptable salt is administered on days 1-14 of each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 112-168 mg of anlotinib or its pharmaceutically acceptable salt is administered on days 1-14 of each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 140 mg of anlotinib or its pharmaceutically acceptable salt is administered on days 1-14 of each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 168 mg of anlotinib or its pharmaceutically acceptable salt is administered on days 1-14 of each treatment cycle.In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg or 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 6 mg, 8 mg, 10 mg or 12 mg of anlotinib or its pharmaceutically acceptable salt is administered daily on days 1-14 of each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg or 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 6 mg, 8 mg or 10 mg of anlotinib or its pharmaceutically acceptable salt is administered daily on days 1-14 of each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg or 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 8 mg, 10 mg or 12 mg of anlotinib or its pharmaceutically acceptable salt is administered daily on days 1-14 of each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 6 mg, 8 mg or 10 mg of anlotinib or its pharmaceutically acceptable salt is administered daily on days 1-14 of each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 8 mg, 10 mg or 12 mg of anlotinib or its pharmaceutically acceptable salt is administered daily on days 1-14 of each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 10 mg of anlotinib or its pharmaceutically acceptable salt is administered daily on days 1-14 of each treatment cycle.In some specific embodiments, in the method or use, one treatment cycle is 3 weeks, 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 12 mg of anlotinib or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 14 of each treatment cycle.

[0089] In some embodiments, in each treatment cycle, the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are administered to the subject at a mass ratio of anti-TIM-3 antibody or its antigen-binding fragment: anti-PD-1 antibody or its antigen-binding fragment of (0.1-180):1, (0.2-50):1, (0.5-9):1, (3-7.5):1, (4-7.5):1, or (6-7.5):1, and anlotinib or a pharmaceutically acceptable salt thereof is administered to the subject.

[0090] In some embodiments, in each treatment cycle, the anti-TIM-3 antibody or its antigen-binding fragment and anlotinib or a pharmaceutically acceptable salt thereof are administered to the subject at a mass ratio of (0.1-50):1, (1-30):1, (3-20):1, (6-18):1, (8-12):1 or (8-9):1 of anti-TIM-3 antibody or its antigen-binding fragment: anlotinib or a pharmaceutically acceptable salt thereof, and the anti-PD-1 antibody or its antigen-binding fragment is administered to the subject.

[0091] In some embodiments, in each treatment cycle, the anti-TIM-3 antibody or its antigen-binding fragment and anlotinib or a pharmaceutically acceptable salt thereof are administered to the subject at a mass ratio of (0.1-50):1, (1-30):1, (3-20):1, (7-15):1, (7-11):1 or (7-8):1 of anti-TIM-3 antibody or its antigen-binding fragment: anlotinib or a pharmaceutically acceptable salt thereof, and the anti-PD-1 antibody or its antigen-binding fragment is administered to the subject.

[0092] In some embodiments, in each treatment cycle, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or a pharmaceutically acceptable salt thereof are administered to the subject at a mass ratio of (0.01-10):1, (0.1-10):1, (0.1-5):1, (0.2-4):1, (0.5-2):1 or (1-2):1 of anti-PD-1 antibody or its antigen-binding fragment: anlotinib or a pharmaceutically acceptable salt thereof, and the anti-TIM-3 antibody or its antigen-binding fragment is administered to the subject.

[0093] In some embodiments, in each treatment cycle, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt are administered in multiple doses or a single dose. In some embodiments, in each treatment cycle, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or its pharmaceutically acceptable salt are administered in multiple doses.

[0094] In some embodiments, in the methods or uses, 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, 0.1 to 25 mg / kg, 0.1 to 20 mg / kg, 0.1 to 15 mg / kg, 0.1 to 10 mg / kg, 1 to 40 mg / kg, 1 to 35 mg / 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 20mg / kg, 3 to 15mg / kg, 3 to 10mg / kg, 10 to 40mg / kg, 10 to 30mg / kg, 10 to 25mg / kg, or 1-2400 mg, 20-1800 mg, 100-1800 mg, 300-1800 mg, 600-1600 mg, 700-1600 mg, 800-1600 mg, 900-1600 mg, 1000-1600 mg, 1100-1600 mg, 1200-1600 mg, 1300-1600 mg, 1400 -1600 mg, 1500-1600 mg, 600-1500 mg, 800-1500 mg, 1000-1500 mg, 1200-1500 mg, 600-1200 mg, 800-1200 mg, 1200 mg to 1800 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg or 1800 mg is administered to the subject.

[0095] In some embodiments, in the methods or uses, the anti-PD-1 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, 0.1 to 25 mg / kg, 0.1 to 20 mg / kg, 0.1 to 15 mg / kg, 0.1 to 10 mg / kg, 1 to 30 mg / kg, 1 to 25 mg / kg, 1 to 20 mg / kg, 1 to 15 mg / kg, 1 to 10 mg / kg, 1 to 8 mg / kg, 1 to 5 mg / kg, 1 to 3 mg / kg, 3 to 30 mg / kg, 3 to 25 mg / kg, 3 to 20 mg / kg , 3 to 15 mg / kg, 3 to 10 mg / kg, 3 to 8 mg / kg, or 3 to 5 mg / kg; or administered to a subject at a uniform dose of 1-1000 mg, 10-1000 mg, 10-800 mg, 20-800 mg, 40-800 mg, 50-700 mg, 50-600 mg, 50-500 mg, 60-500 mg, 80-500 mg, 100-500 mg, 200-500 mg, 100-500 mg, 100-400 mg, 50-350 mg, 100-300 mg, 50-200 mg, 100-200 mg, 100 mg or 200 mg.

[0096] In some embodiments, in the method or use, anlotinib or a pharmaceutically acceptable salt thereof is administered in an interval administration manner, and the interval administration includes an administration period and a drug-free period, and can be administered once or more per day during the administration period. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered continuously for 2 weeks and stopped for 1 week. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is orally administered once a day, at a dose of 6 mg, 8 mg, 10 mg or 12 mg each time, for 2 consecutive weeks and 1 week of drug suspension. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is orally administered once a day, at a dose of 10 mg each time, for 2 consecutive weeks and 1 week of drug suspension. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is orally administered once a day, at a dose of 12 mg each time, for 2 consecutive weeks and 1 week of drug suspension.

[0097] In some embodiments, in the method or use, the dosage regimen (e.g., dosage cycle, dosage time, dosage and dosage adjustment) of the anti-TIM-3 antibody or its antigen-binding fragment, anti-PD-1 antibody or its antigen-binding fragment and / or anlotinib or its pharmaceutically acceptable salt can be adjusted according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. For example, a treatment cycle of an anti-TIM-3 antibody or its antigen-binding fragment and / or an anti-PD-1 antibody or its antigen-binding fragment can be adjusted to 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks or 15 weeks. For example, the dosage of anlotinib or its pharmaceutically acceptable salt can be adjusted from 10 mg to 8 mg, or further adjusted from 8 mg to 6 mg; and the dosage adjustment of anlotinib or its pharmaceutically acceptable salt can occur once or more in one treatment cycle. For example, a treatment cycle of anlotinib or its pharmaceutically acceptable salt can be adjusted to 5 weeks, 6 weeks or 7 weeks. For another example, within a treatment cycle, the administration of anlotinib or a pharmaceutically acceptable salt thereof can be delayed by 1 day, 2 days, 3 days, 4 days or 5 days.

[0098] Anti-TIM-3 antibody or antigen-binding fragment thereof

[0099] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof described herein comprises: a heavy chain CDR1 (HCDR1) of the amino acid sequence shown in SEQ ID NO: 1 or 21, a HCDR2 of the amino acid sequence shown in SEQ ID NO: 2 or 22, a HCDR3 of the amino acid sequence shown in SEQ ID NO: 3 or 23, a light chain CDR1 (LCDR1) of the amino acid sequence shown in SEQ ID NO: 4 or 24, a LCDR2 of the amino acid sequence shown in SEQ ID NO: 5 or 25, and a LCDR3 of the amino acid sequence shown in SEQ ID NO: 6 or 26. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof described herein comprises: a HCDR1 of the amino acid sequence shown in SEQ ID NO: 1, a HCDR2 of the amino acid sequence shown in SEQ ID NO: 2, a HCDR3 of the amino acid sequence shown in SEQ ID NO: 3, a LCDR1 of the amino acid sequence shown in SEQ ID NO: 4, a LCDR2 of the amino acid sequence shown in SEQ ID NO: 5, and a LCDR3 of the amino acid sequence shown in SEQ ID NO: 6. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof described herein comprises: HCDR1 of the amino acid sequence shown in SEQ ID NO: 21, HCDR2 of the amino acid sequence shown in SEQ ID NO: 22, HCDR3 of the amino acid sequence shown in SEQ ID NO: 23, LCDR1 of the amino acid sequence shown in SEQ ID NO: 24, LCDR2 of the amino acid sequence shown in SEQ ID NO: 25, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 26. The CDR sequences of the anti-TIM-3 antibody or antigen-binding fragment thereof are shown in Table 1.

[0100] Table 1. CDR sequences of anti-TIM-3 antibodies or antigen-binding fragments thereof

[0101]

[0102] It will be understood by those skilled in the art that, unless otherwise specified, the term "CDR" or "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass complementarity determining regions defined by any known scheme. Although Table 1 has shown CDR sequences (wherein the CDR regions shown in SEQ ID NOs: 1-6 are defined by the AbM numbering system), however, when referring to antibodies defined by specific CDR sequences of the present application, the scope of the antibodies also encompasses antibodies defined by CDR sequences defined by any other numbering system (e.g., a combination of one or more of the definitions of Kabat, Chothia, CCG, IMGT or Contact, etc., which are well known in the art). For example, an anti-TIM-3 antibody or an antigen-binding fragment thereof comprising the following amino acid sequence is also within the scope of the anti-TIM-3 antibody or antigen-binding fragment thereof of the present application: HCDR1 of the amino acid sequence shown in SEQ ID NO: 1, HCDR2 of the amino acid sequence shown in SEQ ID NO: 2, HCDR3 of the amino acid sequence shown in ARRYYGYDAMDY (SEQ ID NO: 31), LCDR1 of the amino acid sequence shown in SEQ ID NO: 4, LCDR2 of the amino acid sequence shown in SEQ ID NO: 5, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 6.

[0103] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7 or 27. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8 or 28. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region as shown in SEQ ID NO: 7. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a light chain variable region as shown in SEQ ID NO: 8. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:7 or 27, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:8 or 28. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence shown in SEQ ID NO: 7, and a light chain variable region of the amino acid sequence shown in SEQ ID NO: 8. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence shown in SEQ ID NO: 27, and a light chain variable region of the amino acid sequence shown in SEQ ID NO: 28. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-TIM-3 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 7, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 8.In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-TIM-3 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: 28.

[0104] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof described herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 1, HCDR2 comprises the amino acid sequence of SEQ ID NO: 2, HCDR3 comprises the amino acid sequence of SEQ ID NO: 3, LCDR1 comprises the amino acid sequence of SEQ ID NO: 4, LCDR2 comprises the amino acid sequence of SEQ ID NO: 5, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 6; and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7. NO:7 having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical, and the light chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:8.

[0105] QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYTINWVRQAPGQGLEWMGLFNPYNGGTTYAQKF QGRVTMTVDKSTSTVYMELSSLRSEDTAVYYCARRYYGYDAMDYWGQGTLVTVSS(SEQ ID NO:7);

[0106] DIQMTQSPSSSLSASVGDRVTITCKSSQSVLYSSNQKNHLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYLSSYTFGQGTKLEIK(SEQ ID NO:8);

[0107] EVQLQQSGAEVVRPGALVKLSCKASGFNIKDYYMHWVRQRPEQGLEWIGWIDPENDNTIYDPKFQ DRASITADTSSNTAYLQLSSLTSEDTAVYYCARDFGYVAWLVYWGQGTLVTVSA(SEQ ID NO:27);

[0108] DIVMTQSQEFMSTSVGDRVSITCKASQNVDTAVAWYQQKPGQSPKLLIYSASNRYTGVPDRFTGTGSGTTDFTLTINNMQSEDLADYFCQQYSSYPTFGGRTKLEIK (SEQ ID NO: 28).

[0109] In some embodiments, the anti-TIM-3 antibody or its antigen-binding fragment may also include a constant region of an immunoglobulin, or a fragment, analog, variant or derivative of the constant region. In some embodiments, the constant region includes a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is from a human immunoglobulin heavy chain, such as IgG1, IgG2, IgG3 and IgG4 or other classes of immunoglobulin heavy chains, preferably IgG4 heavy chains. In some embodiments, the light chain constant region is from a human immunoglobulin light chain, such as a κ light chain or a λ light chain of a human immunoglobulin. In some embodiments, the constant region may include any modification described in the text, such as insertion, deletion, substitution or chemical modification of amino acids. In some embodiments, the constant region includes a mutation that changes the effector function. In some embodiments, any amino acid residue in the constant region may be substituted with an amino acid residue of any allotype.

[0110] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 9 or 29. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 10 or 30. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain as shown in SEQ ID NO: 9. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a light chain as shown in SEQ ID NO: 10. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10 or 30. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence shown in SEQ ID NO: 9, and a light chain of the amino acid sequence shown in SEQ ID NO: 10. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence shown in SEQ ID NO: 29, and a light chain of the amino acid sequence shown in SEQ ID NO: 30. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-TIM-3 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 9, and the amino acid sequence of the light chain is as shown in SEQ ID NO: 10. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-TIM-3 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 29, and the amino acid sequence of the light chain is as shown in SEQ ID NO: 30.Among them, the terminal amino acid K of SEQ ID NO: 9 and 29 may be present or absent.

[0111] QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYTINWVRQAPGQGLEWMGLFNPYNGGTTYAQKFQGRVTMTVDKSTSTVYMELSSLRSEDTAVYYCARRYYGYDAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 9);

[0112] DIQMTQSPSSLSASVGDRVTITCKSSQSVLYSSNQKNHLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYLSSYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10);

[0113] EVQLQQSGAEVVRPGALVKLSCKASGFNIKDYYMHWVRQRPEQGLEWIGWIDPENDNTIYDPKFQDRASITADTSSNTAYLQLSSLTSEDTAVYYCARDFGYVAWLVYWGQG TLVTVSAASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:29);

[0114] DIVMTQSQEFMSTSVGDRVSITCKASQNVDTAVAWYQQKPGQSPKLLIYSASNRYTGVPDRFTGTGSGTDFTLTINNMQSEDLADYFCQQYSSYPTFGGRTKLEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:30).

[0115] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof of the present application is mAb 50B5 or an antigen-binding fragment thereof described in the patent application document with publication number WO2020041520 or CN112566936, or a chimeric antibody or an antigen-binding fragment thereof of mAb 50B5, or a humanized antibody or an antigen-binding fragment thereof of mAb 50B5.

[0116] In other embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof of the present application is mAb 15B4 or an antigen-binding fragment thereof described in the patent application document with publication number WO2020041520 or CN112566936, or a chimeric antibody or an antigen-binding fragment thereof of mAb 15B4, or a humanized antibody or an antigen-binding fragment thereof of mAb 15B4.

[0117] In other embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof of the present application is selected from Sabatolimab, Cobolimab, Surzebiclimab, Roche's Lomvastomig (RG-7769), Hengrui Medicine's SHR-1702, Agenus' Verzistobart (INCAGN-2390), WuXi Biologics' BC-3402, Wellizhibo's LBL-003, Jianxin Bio's LNL-005, or BMS's BMS-986258.

[0118] Anti-PD-1 antibody or antigen-binding fragment thereof

[0119] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof described herein comprises: HCDR1 of the amino acid sequence shown in SEQ ID NO: 11, HCDR2 of the amino acid sequence shown in SEQ ID NO: 12, HCDR3 of the amino acid sequence shown in SEQ ID NO: 13, LCDR1 of the amino acid sequence shown in SEQ ID NO: 14, LCDR2 of the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 16. The CDR sequences of the anti-PD-1 antibody or antigen-binding fragment thereof are shown in Table 2.

[0120] Table 2. CDR sequences of anti-PD-1 antibodies or antigen-binding fragments thereof

[0121] HCDR1 GFAFSSYD SEQ ID NO:11 HCDR2 ISGGGRYT SEQ ID NO:12 HCDR3 ANRYGEAWFAY SEQ ID NO:13 LCDR1 QDINTY SEQ ID NO:14 LCDR2 RAN SEQ ID NO:15 LCDR3 LQYDEFPLT SEQ ID NO:16

[0122] It will be understood by those skilled in the art that, unless otherwise specified, the term "CDR" or "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass complementarity determining regions defined by any known scheme. Although CDR regions have been shown in Table 2, however, when referring to antibodies defined by specific CDR sequences of the present application, the scope of the antibodies encompasses antibodies defined by CDR sequences defined by any numbering system (e.g., a combination of one or more of the definitions of AbM, Kabat, Chothia, CCG, IMGT or Contact, etc., which are well known in the art).

[0123] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region as shown in SEQ ID NO: 17. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region as shown in SEQ ID NO:18. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 18. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 17, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 18.

[0124] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof described herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 11, HCDR2 comprises the amino acid sequence of SEQ ID NO: 12, HCDR3 comprises the amino acid sequence of SEQ ID NO: 13, LCDR1 comprises the amino acid sequence of SEQ ID NO: 14, LCDR2 comprises the amino acid sequence of SEQ ID NO: 15, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 16; and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 17. NO:17 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical, and the light chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:18.

[0125] EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKG RFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSS(SEQ ID NO:17);

[0126] DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELK (SEQ ID NO: 18).

[0127] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment may further comprise a constant region of an immunoglobulin, or a fragment, analog, variant or derivative of the constant region. In some embodiments, the constant region comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is from a human immunoglobulin heavy chain, such as a heavy chain of IgG1, IgG2, IgG3 and IgG4 or other classes of immunoglobulins, preferably a heavy chain of IgG1. In some embodiments, the light chain constant region is from a human immunoglobulin light chain, such as a κ light chain or a λ light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any modification described in the text, such as insertion, deletion, substitution or chemical modification of amino acids. In some embodiments, the constant region comprises a mutation that changes effector function. In some embodiments, any amino acid residue in the constant region may be substituted with an amino acid residue of any allotype.

[0128] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 19. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain as set forth in SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19, and a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO: 19, and a light chain having an amino acid sequence as shown in SEQ ID NO: 20. In some specific embodiments, the heavy chain amino acid sequence of the anti-PD-1 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 19, and the light chain amino acid sequence is as shown in SEQ ID NO: 20. The terminal amino acid K of SEQ ID NO: 19 may be present or absent.

[0129] EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEKPKSCDKTHT CPPCPAPEAAGAPSVFLPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLPGK(SEQ ID NO:19);

[0130] DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:20).

[0131] In some other embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the present application is selected from nivolumab, pembrolizumab, toripalimab, sintilimab, camrelizumab, tislelizumab, zimberelimab, balstilimab, geptanolimab, Lipustobart (LZ M-009), Cemiplimab, Serplulimab, Prolgolimab, Pucotenlimab, Nofazinlimab, Finotonlimab, Dostarlimab, Cetrelimab, Qilu Pharmaceutical's QL1604, Spartalizumab, Retifanlimab, Sasanlimab, Shandong New Times Pharmaceutical's Rulonilimab (F520), or Shangjian Bio's Enlonstobart (SG001).

[0132] Pharmaceutical composition containing antibody or antigen-binding fragment thereof

[0133] Anti-TIM-3 antibodies or antigen-binding fragments thereof and / or anti-PD-1 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 preparations suitable for intramuscular, intravenous, intraperitoneal, subcutaneous injection), granules, emulsions, suspensions, solutions, dispersions, and sustained-release preparations for oral or non-oral administration. In some embodiments, anti-TIM-3 antibodies or antigen-binding fragments thereof and / or anti-PD-1 antibodies or antigen-binding fragments thereof are formulated as preparations for parenteral administration. In some specific embodiments, anti-TIM-3 antibodies or antigen-binding fragments thereof and / or anti-PD-1 antibodies or antigen-binding fragments thereof are formulated as preparations for intravenous, intramuscular, subcutaneous or other parenteral administration, such as for injection or infusion. In some specific embodiments, the anti-TIM-3 antibody or its antigen-binding fragment and / or the anti-PD-1 antibody or its antigen-binding fragment is formulated as a preparation for intravenous, intramuscular or subcutaneous administration. In some specific embodiments, the anti-TIM-3 antibody or its antigen-binding fragment and / or the anti-PD-1 antibody or its antigen-binding fragment can be formulated as an injection. In some specific embodiments, the anti-TIM-3 antibody or its antigen-binding fragment and / or the anti-PD-1 antibody or its antigen-binding fragment is formulated as a preparation for intravenous injection or infusion.

[0134] In some embodiments, the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated in a single formulation. In some embodiments, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment are formulated together with one or more pharmaceutically acceptable excipients to prepare a suitable pharmaceutical composition.

[0135] In some embodiments, the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated separately (ie, each in the form of a pharmaceutical composition). In some embodiments, the anti-TIM-3 antibody or its antigen-binding fragment is formulated together with one or more pharmaceutically acceptable excipients to prepare a suitable pharmaceutical composition. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is formulated together with one or more pharmaceutically acceptable excipients to prepare a suitable pharmaceutical composition.

[0136] In some embodiments, the unit dose of the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg of the anti-TIM-3 antibody or its antigen-binding fragment, for example, 60 mg, 120 mg, 160 mg, 180 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 360 mg, 400 mg, 420 mg, 440 mg, 480 mg, 520 mg, 540 mg, 560 mg, 600 mg, 640 mg, 660 mg, 680 mg, 720 mg, 760 mg, 780 mg, 800 mg. 1600 mg, 1620 mg, 1640 mg, 1680 mg, 1720 mg, 1740 mg, 1760 mg and / or 1800 mg, or an anti-TIM-3 antibody or antigen-binding fragment thereof, or a range formed by any value thereof. In some embodiments, the unit dose of the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is 240 mg, 300 mg, 360 mg and / or 600 mg of the anti-TIM-3 antibody or its antigen-binding fragment. In some embodiments, the unit dose of the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is 240 mg and / or 600 mg of the anti-TIM-3 antibody or its antigen-binding fragment. In some embodiments, the unit dose of the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is 600 mg of the anti-TIM-3 antibody or its antigen-binding fragment.

[0137] In some embodiments, the unit dose of the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is 10-500 mg, 50-500 mg, 50-200 mg, or 100-200 mg of the anti-PD-1 antibody or its antigen-binding fragment, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 In some embodiments, the unit dose of the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is 100 mg and / or 200 mg of the anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the unit dose of the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is 100 mg and / or 200 mg of the anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the unit dose of the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is 100 mg of the anti-PD-1 antibody or its antigen-binding fragment.

[0138] In some embodiments, the pharmaceutical composition containing anti-TIM-3 antibody or antigen-binding fragment thereof is a water-soluble injection. In some embodiments, the pharmaceutical composition containing anti-PD-1 antibody or antigen-binding fragment thereof is a water-soluble injection. In some embodiments, the pharmaceutical composition containing anti-TIM-3 antibody or antigen-binding fragment thereof and anti-PD-1 antibody or antigen-binding fragment thereof is a water-soluble injection. The water-soluble injection includes but is not limited to a water-soluble preparation that has not been lyophilized or a water-soluble preparation reconstituted with a lyophilized powder.

[0139] In other embodiments, the pharmaceutical composition containing anti-TIM-3 antibodies or antigen-binding fragments thereof is a lyophilized preparation. In other embodiments, the pharmaceutical composition containing anti-PD-1 antibodies or antigen-binding fragments thereof is a lyophilized preparation. In some specific embodiments, the pharmaceutical composition containing anti-TIM-3 antibodies or antigen-binding fragments thereof and anti-PD-1 antibodies or antigen-binding fragments thereof is a lyophilized preparation. The lyophilized preparation refers to a preparation prepared by a freeze-drying process of an aqueous solution, 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 a value that no longer supports biological activity or chemical reaction. The lyophilized preparation of the present application can also be dried by other methods known in the art, such as spray drying and bubbling drying (bubbledrying).

[0140] In some embodiments, the concentration of the anti-PD-1 antibody or its antigen-binding fragment in the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is 0.1-50 mg / mL, 0.5-30 mg / mL, 0.8-20 mg / mL, 1-15 mg / mL, 1-10 mg / mL, 1-5 mg / mL, 2-20 mg / mL, 2-15 mg / mL, 2-10 mg / mL, or 2-5 mg / mL. In some specific embodiments, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 0.8 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 15 mg / mL, or 20 mg / mL. In some embodiments, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 1 mg / mL. In some embodiments, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 2 mg / mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 10 mg / mL.

[0141] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is in the form of a pharmaceutical composition, which comprises an anti-PD-1 antibody or antigen-binding fragment thereof, a buffer, an isotonicity regulator / stabilizer, and a surfactant. In a specific embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is in the form of a liquid preparation (e.g., an injection), which comprises an anti-PD-1 antibody or antigen-binding fragment thereof, sodium acetate trihydrate, glacial acetic acid, sorbitol, and polysorbate 80.

[0142] Anlotinib or its pharmaceutically acceptable salt

[0143] As used in this application, the chemical name of anlotinib is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine, which has the structural formula (I):

[0144]

[0145] As used in this application, anlotinib can be administered in the form of its free base or in the form of its pharmaceutically acceptable salt. The pharmaceutically acceptable salt of anlotinib is within the scope of this application, and the salt can be produced by different organic acids and inorganic acids according to methods known in the art, for example, the inorganic acid can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, and the organic acid can be selected from succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid or methanesulfonic acid. In some embodiments, the pharmaceutically acceptable salt of anlotinib can be the hydrochloride of anlotinib (i.e., anlotinib hydrochloride). In some embodiments, the pharmaceutically acceptable salt of anlotinib is the dihydrochloride of anlotinib.

[0146] In some embodiments of the present application, anlotinib is administered in the form of its hydrochloride. In some embodiments of the present application, anlotinib is administered in the form of its dihydrochloride.

[0147] The dosage of anlotinib or its pharmaceutically acceptable salts involved in the present application, unless otherwise specified, is based on the molecular weight of the compound of formula (I).

[0148] Pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof

[0149] In some embodiments of the present application, the unit dose of the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is 6 mg, 8 mg, 10 mg or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the pharmaceutical composition includes but is not limited to preparations suitable for oral, parenteral, and topical administration; in some embodiments, the pharmaceutical composition is a preparation suitable for oral administration; in some embodiments, the pharmaceutical composition is a solid preparation suitable for oral administration; in some embodiments, the pharmaceutical composition includes but is not limited to tablets and capsules.

[0151] Tyrosine kinase inhibitors

[0152] As used herein, tyrosine kinase inhibitors (TKI) refer to substances or agents that inhibit (e.g., block, destroy or inactivate) tyrosine kinases or downstream signaling from tyrosine kinases. Tyrosine kinases are enzymes responsible for adding phosphate groups (phosphorylation) to the tyrosine of proteins (this is a step that TKIs directly or indirectly inhibit). Tyrosine phosphorylation leads to activation of intracellular signal transduction cascades. Many TKIs can be used for cancer treatment. In one embodiment, the tyrosine kinase inhibitor refers to a substance or agent that specifically inhibits the protein phosphorylation activity of tyrosine kinases.

[0153] In some embodiments, the tyrosine kinase inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some specific embodiments, the tyrosine kinase inhibitor is the hydrochloride of anlotinib. In some specific embodiments, the tyrosine kinase inhibitor is the dihydrochloride of anlotinib.

[0154] Mode of administration

[0155] The following content does not limit the administration mode of the drug combination of the present application.

[0156] Each component in the drug combination of the application can be used independently of each other or part or all of them together with suitable various routes, including but not limited to oral, parenteral route (for example, by intravenous, intramuscular, topical or subcutaneous route). In some embodiments, each component of the drug combination of the application can be used independently of each other or part or all of them together by injection, for example, by intravenous injection or subcutaneous injection. In some embodiments, each component of the drug combination of the application can be used independently of each other or part or all of them together by oral administration.

[0157] The components in the drug combination of the present application can be each independently, or part or all of them 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 preparations suitable for intramuscular, intravenous, intraperitoneal, subcutaneous injections), granules, emulsions, suspensions, solutions, dispersants and sustained-release preparations for oral or parenteral administration. In some embodiments, the components of the drug combination of the present application can be each independently, or part or all of them can be formulated into injections. In some embodiments, the components of the drug combination of the present application can be each independently, or part or all of them can be formulated into capsules.

[0158] The pharmaceutical combination of the present application may further comprise an additional therapeutic agent. In some embodiments, the additional therapeutic agent may be a tumor therapeutic agent known in the art.

[0159] Tumor

[0160] In certain aspects, the tumor described herein is a malignant tumor (ie, cancer); the malignant tumor refers to any malignant and / or invasive growth caused by abnormal cell growth.

[0161] In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is a newly treated, unresectable, refractory, advanced, recurrent and / or metastatic solid tumor. In some embodiments, the tumor is a recurrent and / or metastatic solid tumor. In some embodiments, the tumor is a refractory solid tumor. In some embodiments, the tumor is an unresectable solid tumor. In some embodiments, the tumor is an advanced solid tumor. In some embodiments, the tumor is a locally advanced solid tumor. In some embodiments, the tumor is a newly treated advanced solid tumor.

[0162] In some embodiments, the tumor is liver cancer. In some embodiments, the tumor is treatment-naive, unresectable, refractory, advanced, recurrent and / or metastatic liver cancer. In some embodiments, the tumor is recurrent and / or metastatic liver cancer. In some embodiments, the tumor is refractory liver cancer. In some embodiments, the tumor is unresectable liver cancer. In some embodiments, the tumor is advanced liver cancer. In some embodiments, the tumor is locally advanced liver cancer. In some embodiments, the tumor is treatment-naive advanced liver cancer.

[0163] In some embodiments, the tumor is hepatocellular carcinoma. In some embodiments, the tumor is treatment-naive, unresectable, refractory, advanced, recurrent and / or metastatic hepatocellular carcinoma. In some embodiments, the tumor is recurrent and / or metastatic hepatocellular carcinoma. In some embodiments, the tumor is refractory hepatocellular carcinoma. In some embodiments, the tumor is unresectable hepatocellular carcinoma. In some embodiments, the tumor is advanced hepatocellular carcinoma. In some embodiments, the tumor is locally advanced hepatocellular carcinoma. In some embodiments, the tumor is treatment-naive advanced hepatocellular carcinoma.

[0164] In some embodiments, the tumor is hepatocellular carcinoma with a Chinese Liver Cancer Clinical Stage (CNLC) stage III or II. In some embodiments, the tumor is hepatocellular carcinoma with a Chinese Liver Cancer Clinical Stage III. In some embodiments, the tumor is hepatocellular carcinoma with a Chinese Liver Cancer Clinical Stage II and is not suitable for surgery and / or local treatment.

[0165] In some embodiments, the tumor is hepatocellular carcinoma with Barcelona Clinic Liver Cancer (BCLC) stage B or C. In some embodiments, the tumor is hepatocellular carcinoma with BCLC stage C. In some embodiments, the tumor is hepatocellular carcinoma with BCLC stage B and is not suitable for surgery and / or local treatment.

[0166] In some embodiments, the subject with liver cancer has not been previously treated for liver cancer (eg, lacks an effective treatment regimen). In some embodiments, the subject with liver cancer has not previously received systemic therapy to treat liver cancer.

[0167] In some embodiments, the subject of hepatocellular carcinoma has not been previously treated for hepatocellular carcinoma (e.g., lack of an effective treatment regimen). In some embodiments, the subject of hepatocellular carcinoma has not previously received systemic treatment for hepatocellular carcinoma. In some embodiments, the subject of hepatocellular carcinoma has not previously received immune checkpoint (e.g., PD-1, PD-L1, TIM-3) inhibitors for the treatment of hepatocellular carcinoma. In some embodiments, the subject of hepatocellular carcinoma has not previously received cellular immunity for the treatment of hepatocellular carcinoma. In some embodiments, the subject of hepatocellular carcinoma has not previously received surgical treatment and / or local treatment (such as local chemotherapy) for the treatment of hepatocellular carcinoma.

[0168] In some embodiments, the subject of the hepatocellular carcinoma has not previously been treated for advanced or locally advanced hepatocellular carcinoma (e.g., lack of an effective treatment regimen). In some embodiments, the subject of the hepatocellular carcinoma has not previously received systemic therapy to treat advanced or locally advanced hepatocellular carcinoma. In some embodiments, the subject of the hepatocellular carcinoma has not previously received immune checkpoint (e.g., PD-1, PD-L1, TIM-3) inhibitors to treat advanced or locally advanced hepatocellular carcinoma. In some embodiments, the subject of the hepatocellular carcinoma has not previously received cellular immunity to treat advanced or locally advanced hepatocellular carcinoma.

[0169] In some embodiments, the subject of hepatocellular carcinoma with a Chinese liver cancer clinical stage of III has not been previously treated for advanced or locally advanced hepatocellular carcinoma (e.g., lack of effective treatment regimen). In some embodiments, the subject of hepatocellular carcinoma with a Chinese liver cancer clinical stage of III has not previously received systemic treatment for advanced or locally advanced hepatocellular carcinoma.

[0170] In some embodiments, the subject of hepatocellular carcinoma whose clinical stage of Chinese liver cancer is stage II and is not suitable for surgery and / or local treatment has not been previously treated for advanced or locally advanced hepatocellular carcinoma (e.g., lack of effective treatment options). In some embodiments, the subject of hepatocellular carcinoma whose clinical stage of Chinese liver cancer is stage II and is not suitable for surgery and / or local treatment has not previously received systemic treatment for advanced or locally advanced hepatocellular carcinoma.

[0171] In some embodiments, the subject with BCLC stage C hepatocellular carcinoma has not been previously treated for advanced or locally advanced hepatocellular carcinoma (e.g., lacks an effective treatment regimen). In some embodiments, the subject with BCLC stage C hepatocellular carcinoma has not previously received systemic therapy for advanced or locally advanced hepatocellular carcinoma.

[0172] In some embodiments, the subject with hepatocellular carcinoma of BCLC stage B who is not suitable for surgery and / or local treatment has not been previously treated for advanced or locally advanced hepatocellular carcinoma (e.g., lacks effective treatment options). In some embodiments, the subject with hepatocellular carcinoma of BCLC stage B who is not suitable for surgery and / or local treatment has not previously received systemic treatment for advanced or locally advanced hepatocellular carcinoma.

[0173] In some embodiments, patients who are "not suitable for surgery and / or local treatment" include patients who cannot benefit from surgery and / or local treatment.

[0174] In some embodiments, the local treatment includes but is not limited to surgery, transarterial chemoembolization (TACE), hepatic arterial chemotherapy (HAIC), transcatheter arterial chemotherapy (TAI), radiofrequency or microwave ablation, and anhydrous alcohol injection.

[0175] In some embodiments, the tumor is colorectal cancer. In some embodiments, the tumor is newly treated, unresectable, refractory, advanced, recurrent and / or metastatic colorectal cancer. In some embodiments, the tumor is recurrent colorectal cancer. In some embodiments, the tumor is metastatic colorectal cancer. In some embodiments, the tumor is recurrent and / or metastatic colorectal cancer. In some embodiments, the tumor is refractory colorectal cancer. In some embodiments, the tumor is unresectable colorectal cancer. In some embodiments, the tumor is advanced colorectal cancer. In some embodiments, the tumor is locally advanced colorectal cancer. In some embodiments, the tumor is recurrent and / or metastatic advanced colorectal cancer.

[0176] In some embodiments, the subject with colorectal cancer has not been previously treated for colorectal cancer (eg, lacks an effective treatment regimen). In some embodiments, the subject with colorectal cancer has not previously received systemic therapy to treat colorectal cancer.

[0177] In some embodiments, the subject of colorectal cancer has been previously treated for colorectal cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of colorectal cancer has previously received one or more different anti-tumor treatments for colorectal cancer (e.g., treatment failure or intolerance).

[0178] In some embodiments, the subject of colorectal cancer has previously received one or more of surgery, radiotherapy, chemotherapy, and immunotherapy to treat colorectal cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of colorectal cancer has previously received systemic treatment to treat colorectal cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of colorectal cancer has previously received immune checkpoint inhibitors to treat colorectal cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of colorectal cancer has previously received drugs targeting EGFR to treat colorectal cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of colorectal cancer has previously received BRAF inhibitors to treat colorectal cancer (e.g., treatment failure or intolerance).

[0179] In some embodiments, the subject of colorectal cancer has previously received at least one first-line treatment drug for colorectal cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of colorectal cancer has previously received at least two-line treatment drugs for colorectal cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of colorectal cancer has previously received at least three-line treatment drugs for colorectal cancer (e.g., treatment failure or intolerance). In some specific embodiments, the subject of colorectal cancer has previously received at least three-line standard treatment drugs for colorectal cancer (e.g., treatment failure or intolerance). In some embodiments, the colorectal cancer is recurrent and / or metastatic colorectal cancer. In some embodiments, the colorectal cancer is advanced colorectal cancer. In some embodiments, the colorectal cancer is recurrent and / or metastatic advanced colorectal cancer. In some embodiments, the subject of recurrent and / or metastatic colorectal cancer has previously received at least three-line treatment drugs for colorectal cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the advanced colorectal cancer has previously received at least three lines of treatment for colorectal cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the recurrent and / or metastatic advanced colorectal cancer has previously received at least three lines of treatment for colorectal cancer (e.g., treatment failure or intolerance).

[0180] In some embodiments, the colorectal cancer is a recurrent and / or metastatic colorectal cancer that has failed or is intolerant to third-line treatment drugs. In some embodiments, the colorectal cancer is an advanced colorectal cancer that has failed or is intolerant to third-line treatment drugs. In some embodiments, the colorectal cancer is a recurrent and / or metastatic advanced colorectal cancer that has failed or is intolerant to third-line treatment drugs.

[0181] In some embodiments, the therapeutic drug includes one or more combinations of fluorouracils, irinotecan, oxaliplatin, folinic acid, capecitabine, drugs targeting VEGF (e.g., bevacizumab), drugs targeting EGFR (e.g., cetuximab), regorafenib, furiquintinib, and / or TAS-102. In some embodiments, the therapeutic drug includes fluorouracils, irinotecan, and oxaliplatin; optionally, bevacizumab is also included. In some embodiments, the therapeutic drug includes fluorouracils, irinotecan, and oxaliplatin; optionally, cetuximab is also included. In some embodiments, the therapeutic drug includes regorafenib, furiquintinib, and / or TAS-102. In some embodiments, the therapeutic drug includes fluorouracils, folinic acid, and irinotecan; optionally, cetuximab is also included. In some embodiments, the therapeutic drug includes fluorouracils, folinic acid, and oxaliplatin; optionally, cetuximab is also included. In some embodiments, the therapeutic drugs include fluorouracils, folinic acid, and irinotecan; optionally, bevacizumab. In some embodiments, the therapeutic drugs include capecitabine and oxaliplatin; optionally, bevacizumab. In some embodiments, the therapeutic drugs include fluorouracils, folinic acid, and oxaliplatin; optionally, bevacizumab. In some embodiments, the therapeutic drugs include fluorouracils, folinic acid, oxaliplatin, and irinotecan; optionally, bevacizumab.

[0182] In some embodiments, the colorectal cancer is a colorectal cancer of the mismatch repair complete (pMMR) type. In some embodiments, the colorectal cancer is a recurrent and / or metastatic colorectal cancer of the pMMR type. In some embodiments, the colorectal cancer is a pMMR type of advanced colorectal cancer. In some embodiments, the colorectal cancer is a pMMR type of recurrent and / or metastatic advanced colorectal cancer. In some embodiments, the colorectal cancer is a microsatellite stable (MSS) or low microsatellite instability (MSI-L) type of colorectal cancer. In some embodiments, the colorectal cancer is a recurrent and / or metastatic colorectal cancer of the MSS or MSI-L type. In some embodiments, the colorectal cancer is a MSS or MSI-L type of advanced colorectal cancer. In some embodiments, the colorectal cancer is a MSS or MSI-L type of recurrent and / or metastatic advanced colorectal cancer.

[0183] In some embodiments, the colorectal cancer is a colorectal cancer with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H type). In some embodiments, the colorectal cancer is a recurrent or / and metastatic colorectal cancer of dMMR / MSI-H type. In some embodiments, the colorectal cancer is an advanced colorectal cancer of dMMR / MSI-H type. In some embodiments, the colorectal cancer is a recurrent and / or metastatic advanced colorectal cancer of dMMR / MSI-H type. In some embodiments, the subject of the dMMR / MSI-H type colorectal cancer has received immune checkpoint inhibitors to treat colorectal cancer (e.g., treatment failure or inapplicability). In some embodiments, the subject of the dMMR / MSI-H type recurrent and / or metastatic colorectal cancer has received immune checkpoint inhibitors to treat colorectal cancer (e.g., treatment failure or inapplicability). In some embodiments, the subject of the dMMR / MSI-H type of advanced colorectal cancer has received immune checkpoint inhibitors to treat colorectal cancer (e.g., treatment failure or inapplicability). In some embodiments, the subject of the dMMR / MSI-H type of recurrent and / or metastatic advanced colorectal cancer has received immune checkpoint inhibitors to treat colorectal cancer (e.g., treatment failure or inapplicability).

[0184] In some embodiments, the colorectal cancer is RAS / BRAF wild-type colorectal cancer. In some embodiments, the colorectal cancer is RAS / BRAF wild-type recurrent and / or metastatic colorectal cancer. In some embodiments, the colorectal cancer is RAS / BRAF wild-type advanced colorectal cancer. In some embodiments, the colorectal cancer is RAS / BRAF wild-type recurrent and / or metastatic advanced colorectal cancer. In some embodiments, the subject of colorectal cancer with RAS / BRAF wild type has received EGFR-targeted drug treatment for colorectal cancer (e.g., treatment failure or inapplicability). In some embodiments, the subject of recurrent and / or metastatic colorectal cancer with RAS / BRAF wild type has received EGFR-targeted drug treatment for colorectal cancer (e.g., treatment failure or inapplicability). In some embodiments, the subject of advanced colorectal cancer with RAS / BRAF wild type has received EGFR-targeted drug treatment for colorectal cancer (e.g., treatment failure or inapplicability). In some embodiments, the subject with RAS / BRAF wild-type recurrent and / or metastatic advanced colorectal cancer has received treatment with a drug targeting EGFR for colorectal cancer (eg, treatment has failed or is not suitable).

[0185] In some embodiments, the colorectal cancer is a BRAF V600E mutant colorectal cancer. In some embodiments, the colorectal cancer is a recurrent and / or metastatic colorectal cancer of the BRAF V600E mutant type. In some embodiments, the colorectal cancer is an advanced colorectal cancer of the BRAF V600E mutant type. In some embodiments, the colorectal cancer is a recurrent and / or metastatic advanced colorectal cancer of the BRAF V600E mutant type. In some embodiments, the subject of the BRAFV600E mutant colorectal cancer has received BRAF inhibitors for colorectal cancer (e.g., treatment failure or inapplicability). In some embodiments, the subject of the BRAF V600E mutant recurrent and / or metastatic colorectal cancer has received BRAF inhibitors for colorectal cancer (e.g., treatment failure or inapplicability). In some embodiments, the subject of the BRAFV600E mutant advanced colorectal cancer has received BRAF inhibitors for colorectal cancer (e.g., treatment failure or inapplicability). In some embodiments, the subject with recurrent and / or metastatic advanced colorectal cancer with the BRAF V600E mutation has received prior treatment for colorectal cancer with a BRAF inhibitor (eg, treatment failure or inappropriateness).

[0186] In some specific embodiments, the colorectal cancer is a pMMR type colorectal cancer of RAS / BRAF wild type. In some specific embodiments, the colorectal cancer is a pMMR type colorectal cancer of BRAF V600E mutant type. In some specific embodiments, the colorectal cancer is a MSS or MSI-L type colorectal cancer of RAS / BRAF wild type. In some specific embodiments, the colorectal cancer is a MSS or MSI-L type colorectal cancer of BRAF V600E mutant type. In some specific embodiments, the colorectal cancer is a dMMR / MSI-H type colorectal cancer of RAS / BRAF wild type. In some specific embodiments, the colorectal cancer is a dMMR / MSI-H type colorectal cancer of BRAF V600E mutant type. In some embodiments, the colorectal cancer is recurrent and / or metastatic colorectal cancer. In some embodiments, the colorectal cancer is advanced colorectal cancer. In some embodiments, the colorectal cancer is recurrent and / or metastatic advanced colorectal cancer.

[0187] In some embodiments, the immune checkpoint inhibitor includes antibodies or antigen-binding fragments thereof against immune checkpoints, such as anti-PD-1 antibodies or antigen-binding fragments thereof, anti-PD-L1 antibodies or antigen-binding fragments thereof, and anti-CTLA-4 antibodies or antigen-binding fragments thereof.

[0188] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof includes nivolumab, pembrolizumab, toripalimab, sintilimab, camrelizumab, tislelizumab, zimberelimab, balstilimab, geptanolimab, lipustobart (LZM009), Cemiplimab, Serplulimab, Pucotenlimab, Prolgolimab, Nofazinlimab, Finotonlimab, Dostarlimab, Cetrelimab, Qilu Pharmaceutical QL1604, Spartalizumab, Retifanlimab, Sasanlimab, Shandong New Era Pharmaceutical Rulonilimab or Shangjian Biotechnology Enlonstobart (SG001).

[0189] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof includes Atezolizumab, Durvalumab, Avelumab, Envafolimab, Sugemalimab, Adebrelimab, Socazolimab, Sudubrilimab, Betifisolimab, Lepu Biotech LP002, Junshi Biosciences JS003, or Sichuan Kelun KL-A167.

[0190] In some embodiments, the anti-CTLA-4 antibodies or antigen-binding fragments thereof include Ipilimumab and Tremelimumab.

[0191] In some embodiments, the drug targeting VEGF includes anti-VEGF antibodies or antigen-binding fragments thereof and VEGF small molecule inhibitors, such as bevacizumab.

[0192] In some embodiments, the drugs targeting EGFR include anti-EGFR antibodies or antigen-binding fragments thereof and EGFR small molecule inhibitors, such as cetuximab and panitumumab.

[0193] In some embodiments, the BRAF inhibitor refers to a substance that can inhibit (e.g., block, destroy or inactivate) the activity of BRAF kinase or mutant BRAF kinase (one or more mutant forms of the serine-threonine protein kinase B-RAF (BRAF)) or its downstream signal transduction, such as Vemurafenib, Regorafenib, Dasatinib, Dabrafenib and Encorafenib.

[0194] The present disclosure also provides the following specific implementation schemes, but the protection scope of the present disclosure is not limited thereto:

[0195] Embodiment 1. A drug combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and anlotinib or a pharmaceutically acceptable salt thereof, wherein the anti-TIM-3 antibody or an antigen-binding fragment thereof comprises:

[0196] HCDR1 of the amino acid sequence shown in SEQ ID NO:1, HCDR2 of the amino acid sequence shown in SEQ ID NO:2, HCDR3 of the amino acid sequence shown in SEQ ID NO:3, LCDR1 of the amino acid sequence shown in SEQ ID NO:4, LCDR2 of the amino acid sequence shown in SEQ ID NO:5, and LCDR3 of the amino acid sequence shown in SEQ ID NO:6; or

[0197] HCDR1 of the amino acid sequence shown in SEQ ID NO:21, HCDR2 of the amino acid sequence shown in SEQ ID NO:22, HCDR3 of the amino acid sequence shown in SEQ ID NO:23, LCDR1 of the amino acid sequence shown in SEQ ID NO:24, LCDR2 of the amino acid sequence shown in SEQ ID NO:25, and LCDR3 of the amino acid sequence shown in SEQ ID NO:26.

[0198] Embodiment 2. The drug combination according to Embodiment 1, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 7, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 8; or a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 27, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 28.

[0199] Embodiment 3. The pharmaceutical combination according to embodiment 1 or 2, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises:

[0200] A heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO:9, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO:10; or a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO:29, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO:30.

[0201] Embodiment 4. A drug combination according to any one of Embodiments 1 to 3, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: HCDR1 of the amino acid sequence shown in SEQ ID NO: 11, HCDR2 of the amino acid sequence shown in SEQ ID NO: 12, HCDR3 of the amino acid sequence shown in SEQ ID NO: 13, LCDR1 of the amino acid sequence shown in SEQ ID NO: 14, LCDR2 of the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 16.

[0202] Embodiment 5. A drug combination according to any one of Embodiments 1-4, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises: a heavy chain variable region whose amino acid sequence is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 17, 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: 18.

[0203] Embodiment 6. A drug combination according to any one of Embodiments 1-5, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises: a heavy chain whose amino acid sequence is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 19, and a light chain whose amino acid sequence is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 20.

[0204] Embodiment 7. A drug combination according to any one of Embodiments 1 to 6, wherein the anti-TIM-3 antibody or its antigen-binding fragment and / or the anti-PD-1 antibody or its antigen-binding fragment is formulated as a preparation for parenteral administration, preferably, the anti-TIM-3 antibody or its antigen-binding fragment and / or the anti-PD-1 antibody or its antigen-binding fragment is formulated as a preparation for intravenous, intramuscular or subcutaneous administration.

[0205] Embodiment 8. A pharmaceutical combination according to any one of Embodiments 1-7, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation.

[0206] Embodiment 9. A pharmaceutical combination according to any one of Embodiments 1-7, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated separately.

[0207] Embodiment 10. A drug combination according to any one of Embodiments 1-9, wherein the unit dose of the anti-TIM-3 antibody or its antigen-binding fragment is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg; preferably, the unit dose of the anti-TIM-3 antibody or its antigen-binding fragment is 240 mg, 300 mg, 360 mg and / or 600 mg.

[0208] Embodiment 11. A drug combination according to any one of Embodiments 1-10, wherein the unit dose of the anti-PD-1 antibody or its antigen-binding fragment is 10-500 mg, 50-500 mg, 50-200 mg, or 100-200 mg; preferably, the unit dose of the anti-PD-1 antibody or its antigen-binding fragment is 100 mg and / or 200 mg.

[0209] Embodiment 12. The pharmaceutical combination according to any one of Embodiments 1-11, wherein the unit dose of anlotinib or a pharmaceutically acceptable salt thereof is 6 mg, 8 mg, 10 mg and / or 12 mg.

[0210] Embodiment 13. A drug combination according to any one of Embodiments 1-12, wherein the mass ratio of the anti-TIM-3 antibody or its antigen-binding fragment: the anti-PD-1 antibody or its antigen-binding fragment is (0.1-180):1, (0.2-50):1, (0.5-9):1, (3-7.5):1, (4-7.5):1 or (6-7.5):1.

[0211] Embodiment 14. A drug combination according to any one of Embodiments 1-13, wherein the mass ratio of the anti-TIM-3 antibody or its antigen-binding fragment: anlotinib or its pharmaceutically acceptable salt is (0.1-50):1, (1-30):1, (3-20):1, (6-18):1, (7-15):1, (8-12):1, (7-11):1, (7-8):1 or (8-9):1.

[0212] Embodiment 15. A drug combination according to any one of Embodiments 1-14, wherein the mass ratio of the anti-PD-1 antibody or its antigen-binding fragment: anlotinib or its pharmaceutically acceptable salt is (0.01-10):1, (0.1-10):1, (0.1-5):1, (0.2-4):1, (0.5-2):1 or (1-2):1.

[0213] Embodiment 16. A drug combination according to any one of Embodiments 1-15, wherein the drug combination is suitable for administration in a single treatment cycle, comprising 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 84-168 mg, or 84-140 mg or 112-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.

[0214] Embodiment 17. Use of the pharmaceutical combination of any one of Embodiments 1-16 for the preparation of a medicament for treating a tumor in a subject.

[0215] Embodiment 18. The use according to Embodiment 17, wherein the tumor is a solid tumor; preferably, the solid tumor is liver cancer or colorectal cancer; more preferably, the solid tumor is hepatocellular carcinoma.

[0216] Embodiment 19. The use according to Embodiment 18, wherein the hepatocellular carcinoma is advanced hepatocellular carcinoma.

[0217] Embodiment 20. The use according to Embodiment 18 or 19, wherein the subject with hepatocellular carcinoma has not been previously treated for hepatocellular carcinoma; preferably, the subject with hepatocellular carcinoma has not previously received systemic treatment for hepatocellular carcinoma.

[0218] Embodiment 21. The use according to Embodiment 18, wherein the colorectal cancer is advanced colorectal cancer or metastatic colorectal cancer.

[0219] Embodiment 22. The use according to any one of Embodiments 17-21, wherein the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or a pharmaceutically acceptable salt thereof can be administered simultaneously, sequentially and / or alternately.

[0220] Embodiment 23. The use according to any one of Embodiments 17-22, wherein 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, preferably once every 3 weeks; optionally, 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, preferably, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg each time.

[0221] Embodiment 24. The use according to any one of Embodiments 17-23, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, preferably, once every 3 weeks; optionally, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10-800 mg, 50-500 mg, or 100-200 mg each time, preferably, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 200 mg each time.

[0222] Embodiment 25. The use according to any one of Embodiments 17-24, wherein the anlotinib or a pharmaceutically acceptable salt thereof is administered in a regimen of continuous medication for 2 weeks and rest for 1 week; optionally, the anlotinib or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 6 mg, 8 mg, 10 mg or 12 mg each time, preferably, the anlotinib or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 10 mg or 12 mg each time.

[0223] Embodiment 26. A kit for treating a tumor, comprising the pharmaceutical combination according to any one of Embodiments 1-25.

[0224] Embodiment 27. Use of an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and anlotinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a tumor, wherein the anti-TIM-3 antibody or an antigen-binding fragment thereof comprises:

[0225] HCDR1 of the amino acid sequence shown in SEQ ID NO:1, HCDR2 of the amino acid sequence shown in SEQ ID NO:2, HCDR3 of the amino acid sequence shown in SEQ ID NO:3, LCDR1 of the amino acid sequence shown in SEQ ID NO:4, LCDR2 of the amino acid sequence shown in SEQ ID NO:5, and LCDR3 of the amino acid sequence shown in SEQ ID NO:6; or

[0226] HCDR1 of the amino acid sequence shown in SEQ ID NO:21, HCDR2 of the amino acid sequence shown in SEQ ID NO:22, HCDR3 of the amino acid sequence shown in SEQ ID NO:23, LCDR1 of the amino acid sequence shown in SEQ ID NO:24, LCDR2 of the amino acid sequence shown in SEQ ID NO:25, and LCDR3 of the amino acid sequence shown in SEQ ID NO:26.

[0227] Embodiment 28. The use according to Embodiment 27, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 7, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 8; or a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 27, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 28.

[0228] Embodiment 29. The use according to Embodiment 27 or 28, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 9, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 10; or a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 29, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 30.

[0229] Embodiment 30. The use according to any one of Embodiments 27-29, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: HCDR1 of the amino acid sequence shown in SEQ ID NO:11, HCDR2 of the amino acid sequence shown in SEQ ID NO:12, HCDR3 of the amino acid sequence shown in SEQ ID NO:13, LCDR1 of the amino acid sequence shown in SEQ ID NO:14, LCDR2 of the amino acid sequence shown in SEQ ID NO:15, and LCDR3 of the amino acid sequence shown in SEQ ID NO:16.

[0230] Embodiment 31. The use according to any one of Embodiments 27-30, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 17, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 18.

[0231] Embodiment 32. The use according to any one of Embodiments 27-31, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 19, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 20.

[0232] Embodiment 33. The use according to any one of Embodiments 27-32, wherein the anti-TIM-3 antibody or its antigen-binding fragment and / or the anti-PD-1 antibody or its antigen-binding fragment is formulated as a preparation for parenteral administration, preferably, the anti-TIM-3 antibody or its antigen-binding fragment and / or the anti-PD-1 antibody or its antigen-binding fragment is formulated as a preparation for intravenous, intramuscular or subcutaneous administration.

[0233] Embodiment 34. The use according to any one of Embodiments 27-33, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation.

[0234] Embodiment 35. The use according to any one of Embodiments 27-33, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated separately.

[0235] Embodiment 36. The use according to any one of Embodiments 27-35, wherein the unit dose of the anti-TIM-3 antibody or its antigen-binding fragment is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg; preferably, the unit dose of the anti-TIM-3 antibody or its antigen-binding fragment is 240 mg, 300 mg, 360 mg and / or 600 mg.

[0236] Embodiment 37. The use according to any one of Embodiments 27-36, wherein the unit dose of the anti-PD-1 antibody or its antigen-binding fragment is 10-500 mg, 50-500 mg, 50-200 mg, or 100-200 mg; preferably, the unit dose of the anti-PD-1 antibody or its antigen-binding fragment is 100 mg and / or 200 mg.

[0237] Embodiment 38. The use according to any one of Embodiments 27-37, wherein the unit dose of anlotinib or a pharmaceutically acceptable salt thereof is 6 mg, 8 mg, 10 mg and / or 12 mg.

[0238] Embodiment 39. The use according to any one of Embodiments 27-38, wherein the tumor is a solid tumor; preferably, the solid tumor is liver cancer or colorectal cancer; more preferably, the solid tumor is hepatocellular carcinoma.

[0239] Embodiment 40. The use according to Embodiment 39, wherein the hepatocellular carcinoma is advanced hepatocellular carcinoma.

[0240] Embodiment 41. The use according to Embodiment 39 or 40, wherein the subject with hepatocellular carcinoma has not been previously treated for hepatocellular carcinoma; preferably, the subject with hepatocellular carcinoma has not previously received systemic treatment for hepatocellular carcinoma.

[0241] Embodiment 42. The use according to claim 39, wherein the colorectal cancer is advanced colorectal cancer or metastatic colorectal cancer.

[0242] Embodiment 43. The use according to any one of Embodiments 27-42, wherein the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and anlotinib or a pharmaceutically acceptable salt thereof can be administered simultaneously, sequentially and / or alternately.

[0243] Embodiment 44. The use according to any one of Embodiments 27-43, wherein 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, preferably, once every 3 weeks; optionally, 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, preferably, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg each time.

[0244] Embodiment 45. The use according to any one of Embodiments 27-44, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, preferably, once every 3 weeks; optionally, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10-800 mg, 50-500 mg, or 100-200 mg each time, preferably, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 200 mg each time.

[0245] Embodiment 46. The use according to any one of Embodiments 27-45, wherein the anlotinib or a pharmaceutically acceptable salt thereof is administered in a regimen of continuous medication for 2 weeks and rest for 1 week; optionally, the anlotinib or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 6 mg, 8 mg, 10 mg or 12 mg each time, preferably, the anlotinib or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 10 mg or 12 mg each time.

[0246] Technical Effects

[0247] In general, using the drug combination of this application will help:

[0248] (1) Producing a better therapeutic effect in reducing tumor growth or eliminating tumors compared to administering any of the drugs in the combination alone;

[0249] (2) provide for administration of a smaller amount of the drug in the combination than when either drug is administered alone;

[0250] (3) provide a treatment that is well tolerated in patients and has fewer adverse effects and / or complications than either drug given alone;

[0251] (4) provide better disease control rate (DCR) among treated patients;

[0252] (5) provide a longer survival (e.g., median survival, progression-free survival (PFS), or overall survival (OS)) in treated patients;

[0253] (6) Providing a longer survival (e.g., median survival, progression-free survival, or overall survival) for the treated patients compared to standard chemotherapy;

[0254] (7) provide a longer duration of disease remission (DOR); and / or

[0255] (8) Compared with the administration of any drug in the combination alone, the combination has good anti-tumor activity and exhibits a more excellent anti-tumor synergistic effect.

[0256] The drug combination and treatment regimen of the present application have good efficacy in treating liver cancer, especially hepatocellular carcinoma. The drug combination and treatment regimen of the present application have good efficacy in treating colorectal cancer, especially recurrent and / or metastatic advanced colorectal cancer. At least one of objective response rate (ORR), DCR, DOR, PFS, OS, tolerance and side effects has a beneficial effect.

[0257] Definition and Description

[0258] Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this application, it is intended to refer to the corresponding commodity or its active ingredient.

[0259] As used herein, the term "drug combination" refers to a combination of two or more active ingredients (including administration in the form of each active ingredient itself, or in the form of its respective pharmaceutically acceptable salt or ester derivatives, prodrugs or compositions) administered simultaneously or sequentially. The active ingredients can be administered to the subject simultaneously as a single formulation, or sequentially in any order as a single formulation. Alternatively, all of the active ingredients are formulated in a single formulation and administered to the subject simultaneously. Alternatively, part of the active ingredients are formulated in a single formulation and the other parts of the active ingredients are each administered to the subject simultaneously or sequentially in any order as a single formulation.

[0260] The term "fixed combination" means that the active ingredients are administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.

[0261] The term "non-fixed combination" refers to two or more active ingredients administered to a subject as independent entities (e.g., pharmaceutical compositions, preparations) simultaneously, concurrently or sequentially, wherein the active ingredients administered to the subject reach a therapeutically effective level. An example of a non-fixed combination is cocktail therapy, such as the administration of three or more active ingredients. In a non-fixed combination, the individual active ingredients may be packaged, sold or administered as completely independent pharmaceutical compositions. The "non-fixed combination" also includes the combined use of "fixed combinations" or "fixed combinations" with any one or more independent entities of the active ingredients.

[0262] As used herein, the term "antibody" refers to an antigen binding protein having at least one antigen binding domain. The antibody and its fragment of the present application may be a whole antibody or any fragment thereof. Therefore, the antibody and its fragment of the present application include a monoclonal antibody or its fragment and an antibody variant or its fragment. Examples of antibody and its antigen binding fragment fragment 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-1 antibodies and their antigen binding fragments disclosed herein may be IgG1, IgG2, IgG3 or IgG4 isotypes. The term "isotype" refers to the antibody species encoded by the heavy chain constant region gene. The anti-TIM-3 antibodies and their antigen binding fragments and anti-PD-1 antibodies and their antigen binding fragments of the present application may be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans. The anti-TIM-3 antibody and its antigen-binding fragment and the anti-PD-1 antibody and its antigen-binding fragment of the present application can be a murine antibody, a chimeric antibody, a humanized antibody or a fully human antibody. Unless otherwise specified, the "antibody" of the present application includes a whole antibody and any antigen-binding fragment or single chain thereof. Conventional "whole antibodies" are glycoproteins comprising two heavy (H) chains and two light (L) chains, and the heavy chains and light chains are connected 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 a domain CL. The VH and VL regions can also be divided into hypervariable regions, i.e., complementary determining regions (CDRs), and framework regions (FRs) with relatively conservative sequences. Each VH and VL is composed of three CDRs and four FRs, respectively, from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable region of the antibody contains a binding domain that interacts with the antigen. The constant region of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. At the same time, as those skilled in the art understand, special "whole antibodies", such as nanobodies, have only heavy (H) chains and no light (L) chains.

[0263] An "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen. It has been demonstrated that the antigen-binding function of an antibody can be performed by fragments of the entire antibody. Examples of the term "antigen-binding fragment" of an antibody include: (i) Fab fragment: a fragment consisting of V L 、V HThe invention relates to a monovalent fragment consisting of a single variable domain and a heavy chain variable region comprising a single variable domain and two constant domains. The invention relates to a monovalent fragment consisting of a single variable domain and a single constant domain comprising a Fab fragment; a monovalent fragment consisting of a CL and CH1 domain; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment consisting of the VH domain (see Ward et al., Nature. 341:544-546 (1989)); (vi) an isolated complementarity determining region (CDR); and (vii) a nanobody, a heavy chain variable region comprising a single variable domain and two constant domains. In addition, although the two domains VL and VH of the Fv fragment are encoded by different genes, VH and VL can be connected into a single protein chain by a recombinant method through a synthetic linker, wherein VL and VH are paired to form a monovalent molecule (called 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)). These single-chain antibodies are also encompassed in the term antigen-binding fragment. In addition, recombinant polypeptides, fusion proteins and immunoconjugates comprising the antigen-binding fragment are also encompassed in the term antigen-binding fragment.

[0264] A "chimeric antibody" is an antibody having at least a portion of a heavy chain variable region and at least a portion of a light chain variable region derived from one species; and at least a portion of a constant region derived from another species. For example, in one embodiment, a chimeric antibody may comprise a murine variable region and a human constant region.

[0265] "Humanized antibodies" are antibodies that contain complementary determining regions (CDRs) derived from non-human antibodies, and framework regions and constant regions derived from human antibodies. For example, anti-TIM-3 antibodies and anti-PD-1 antibodies may include CDRs derived from one or more murine antibodies, as well as human framework regions and human constant regions. Additional anti-TIM-3 antibodies or variants thereof comprising HCDRs and LCDRs provided herein may be produced using any human framework sequence, and are also included in the present application. Additional anti-PD-1 antibodies or variants thereof comprising HCDRs and LCDRs provided herein may be produced using any human framework sequence, and are also included in the present application. In one embodiment, framework sequences suitable for use in the present application include those framework sequences that are structurally similar to the framework sequences provided herein. Additional modifications may be made in the framework region 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 may be returned to residues in the original germline sequence. In some embodiments, such modifications include those corresponding to the mutations exemplified herein, including back mutations to the germline sequence. 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.

[0266] The term "identity" is also known as consistency. The "percentage (%) identity" of an amino acid sequence refers to the percentage of amino acid residues in the sequence to be compared that are identical to the amino acid residues in the specific amino acid sequence shown in this article, after comparing the sequence to be compared with the specific amino acid sequence shown in this article and introducing spaces if necessary to achieve the maximum sequence identity percentage, and not considering any conservative substitutions as part of the sequence identity. The amino acid sequence alignment of identity can be carried out in a variety of ways within the scope of the art, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for comparing sequences, including any algorithm required to obtain the maximum alignment in the full length of the comparison sequence.

[0267] The term "treatment" generally refers to an operation to obtain a desired pharmacological and / or physiological effect. The effect may be preventive, in terms of completely or partially preventing a disease or its symptoms; and / or therapeutic, in terms of partially or completely stabilizing or curing a disease and / or side effects produced by the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including but not limited to preventing the occurrence or recurrence of a disease, alleviating symptoms of a disease, reducing any direct or indirect pathological consequences of a disease, preventing the metastasis of a disease, slowing the progression of a disease, improving or alleviating the state of a disease, extending the frequency and duration of symptom-free periods, and resolving or improving the prognosis of a disease.

[0268] A "therapeutically effective amount" or "therapeutically effective dose" is any amount of a drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of disease or promotes disease regression, as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or the prevention of impairment or disability resulting from disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by measuring the activity of the agent in in vitro assays.

[0269] The terms "administering," "dosing," or "administering" refer to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0270] The administration route of the antibody or its antigen-binding fragment (e.g., anti-TIM-3 antibody or its antigen-binding fragment or anti-PD-1 antibody or its antigen-binding fragment) includes intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral administration routes, such as by injection or infusion. The term "parenteral administration" as used herein refers to a mode of administration other than enteral administration, which is usually performed by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. Administration can also be performed, for example, once, multiple times, and / or in one or more extended time periods.

[0271] Anlotinib or a pharmaceutically acceptable salt thereof can be administered by a variety of routes, including but not limited to oral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, vaginal, intraocular, subcutaneous, intrafatty, intraarticular, intraperitoneal and intrathecal administration. In some specific embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered orally.

[0272] The term "flat dose" is used to refer to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). A flat dose is thus specified as an absolute amount of an agent (e.g., an antibody or antigen-binding fragment thereof) rather than as a mg / kg dose. For example, a 60 kg person and a 100 kg person will receive the same dose of an antibody.

[0273] The term "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 the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0274] The term "pharmaceutically acceptable salt" includes salts formed by alkaline ions and free acids, or salts formed by acidic ions and free bases, including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formates, acetates, trifluoroacetates, fumarates, oxalates, maleates, citrates, succinates, methanesulfonates, benzoates, benzenesulfonates or p-toluenesulfonates, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-toluenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, etc.

[0275] The term "excipient" refers to any ingredient other than the active ingredient. The choice of excipient will depend, to a large extent, on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. As used herein, "pharmaceutically acceptable excipients" include, but are not limited to, excipients, diluents, fillers, binders, disintegrants, solubilizers, stabilizers, colorants, flavoring agents, surfactants, emulsifiers, buffers, or encapsulating materials. The amount of each excipient can vary within the conventional range in the art.

[0276] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present application and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the active ingredients of the present application to a subject. In this article, the terms "pharmaceutical composition" and "preparation" have the same meaning and can be used interchangeably.

[0277] As used herein, the terms "subject," "patient," or "subject" are used interchangeably. "Subject," "patient," or "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the terms "subject," "patient," or "subject" are mammals. In some embodiments, the subject, patient, or subject is a mouse. In some embodiments, the subject, patient, or subject is a human.

[0278] As used herein, "combination" or "combined use" means that two or more active substances can be administered to a subject simultaneously as a single formulation, or sequentially in any order as a single formulation. Alternatively, all of the active ingredients are formulated in a single formulation and administered to a subject simultaneously. Alternatively, part of the active ingredients are formulated in a single formulation and the other parts of the active ingredients are each administered to a subject simultaneously or sequentially in any order as a single formulation.

[0279] The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine, for example, if a box of medicine contains seven capsules, then one capsule is a single dose; or a bottle of injection is a single dose. The term "multiple doses" consists of multiple single doses.

[0280] The term "unit dose" refers to the dose of an active ingredient contained in the smallest packaging unit containing a certain amount of a drug. For example, the dose of an antibody contained in a bottle of antibody injection is a unit dose.

[0281] The term "recurrent" cancer is a cancer that has regrown in the original site or at a distant site after responding to initial treatment (eg, surgery). The term "metastatic" cancer refers to cancer that has spread from one part of the body (eg, the liver) to another part of the body.

[0282] The term "refractory" refers to a condition in which a subject or mammal has residual cancer cells in its body even after intensive treatment.

[0283] The term "first-line treatment" refers to the drug that can be selected first or standardly based on the patient's condition.

[0284] The words “comprise”, “comprise” or “comprises” and their English variations such as comprises or comprising should be construed in an open, non-exclusive sense, ie, “including but not limited to”.

[0285] Herein, singular terms include plural referents and vice versa unless the context clearly dictates otherwise.

[0286] As used herein, "about" means within the acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" may mean within 1 or more than 1 standard deviation as practiced in the art. Alternatively, "about" may mean a range of up to ±5%, such as fluctuations within ±2%, ±1%, or ±0.5% of a given specific numerical range. When a specific value is given in the present application or claims, unless otherwise stated, the meaning of "about" should be considered to be within the acceptable error range for that specific value. In this document, unless otherwise stated, all values ​​of drug doses, times, step parameters, or conditions are modified by "about" by default.

[0287] For the purpose of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements regarding the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any reference to these publications herein does not constitute an admission that the publications are part of the common general knowledge in the art in any country. Example

[0288] For the sake of clarity, the present application is further described with examples, but the examples do not limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification.

[0289] The entire contents of WO2020041520 or CN112566936 patent application documents are incorporated into this application. The heavy chain amino acid sequence of the anti-TIM-3 antibody in the following examples is shown in SEQ ID NO: 9 of this application, and the light chain amino acid sequence is shown in SEQ ID NO: 10 of this application.

[0290] The entire contents of the CN106977602A patent application document are incorporated herein. The heavy chain amino acid sequence of the anti-PD-1 antibody in the following examples is shown in SEQ ID NO: 19 of the present application, and the light chain amino acid sequence is shown in SEQ ID NO: 20 of the present application.

[0291] Example 1: Clinical trial of hepatocellular carcinoma (HCC)

[0292] 1. Selection criteria

[0293] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0294] (1) Age 18-75 years old; ECOGPS score: 0-1 points; expected survival time more than 3 months;

[0295] (2) HCC patients diagnosed by histopathological or cytological examination or meeting the clinical diagnostic criteria for hepatocellular carcinoma of the American Association for the Study of Liver Diseases (AASLD) or the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition);

[0296] (3) had not received any systemic treatment for advanced HCC;

[0297] (4) Subjects with Chinese Clinical Liver Cancer (CNLC) stage III (or BCLC stage C) or subjects with stage II (BCLC stage B) who are not suitable for local treatment (such as TACE) and surgical treatment or who are judged by the investigator to be unable to benefit from local treatment and surgical treatment;

[0298] (5) Child-Pugh liver function grade: A or B (≤7 points), and MELD score ≤18 points;

[0299] (6) HBsAg-positive patients must meet the requirement of HBV DNA quantification <1×10 4 IU / mL (or 5×10 4 HBV infection (HCV Ab or HCV RNA positive): patients who are in a stable state as determined by the investigator and are receiving antiviral treatment at the time of enrollment should continue to receive approved antiviral treatment during the study;

[0300] (7) Patients who have undergone local treatment (including but not limited to surgery, transarterial chemoembolization (TACE), hepatic arterial chemotherapy (HAIC), transcatheter arterial chemotherapy (TAI), radiofrequency or microwave ablation, and anhydrous alcohol injection) should be treated at least 4 weeks after the completion of local treatment.

[0301] Patients can be enrolled only if they have fully recovered from treatment toxicity and / or complications;

[0302] (8) Radiotherapy for bone metastases with clinical symptoms must be completed at least 2 weeks before the start of the study;

[0303] (9) at least one measurable lesion (RECIST 1.1);

[0304] (10) The major organs function normally, that is, they meet the following criteria:

[0305] 1) The blood routine examination standards must meet the following requirements: a) hemoglobin ≥ 90 g / L; b) absolute neutrophil count ≥ 1.5 × 10 9 / L; c) Platelet count ≥75×10 9 / L; (no blood transfusion or blood products, no use of granulocyte colony-stimulating factor, and no use of medication for correction within 7 days);

[0306] 2) Biochemical examinations must meet the following criteria: a) albumin ≥ 30 g / L (no albumin or blood product transfusion within 14 days); b) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5.0 × upper limit of normal range (ULN); total bilirubin ≤ 3 × ULN;

[0307] c) Serum creatinine ≤1.5×ULN or creatinine clearance (Ccr)>50mL / min (calculated using the Cockcroft-Gault formula:

[0308] or or );

[0310] 3) Prothrombin time (PT) is prolonged by ≤6 seconds compared with the upper limit of normal value;

[0311] (11) Women of childbearing age must agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study and within 6 months after the end of the study; their serum HCG test must be negative within 7 days before enrollment in the study, and they must not be breastfeeding. Men must agree to use contraceptive measures during the study.

[0312] Contraceptive measures must be used within 6 months after the end of the study period;

[0313] (12) The patients voluntarily participated in this study, signed the informed consent, and had good compliance.

[0314] 2. Experimental drugs

[0315] 2.1 Anti-PD-1 antibody injection, specification is 100 mg / 10 mL / bottle, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.;

[0316] 2.2 Anti-TIM-3 antibody injection, with specifications of 240 mg / 4 mL / bottle or 600 mg / 10 mL / bottle, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[0317] 2.3 Anlotinib hydrochloride capsules (active ingredient is anlotinib dihydrochloride), specifications are 12mg / capsule, 10mg / capsule, 8mg / capsule, or 6mg / capsule

[0318] Tablets were provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[0319] 3. Treatment options

[0320] Anti-PD-1 antibody injection: 3 weeks as one treatment cycle, administered by intravenous infusion, with 200 mg of anti-PD-1 antibody administered once on the first day of each treatment cycle (dosing time window: ±3 days);

[0321] Anti-TIM-3 antibody injection: 1 treatment cycle is 3 weeks, administered by intravenous infusion, with 1200 mg of anti-TIM-3 antibody administered once on the first day of each treatment cycle (administration time window: ±3 days);

[0322] Anlotinib Hydrochloride Capsules: One treatment cycle is 3 weeks (2 weeks of continuous medication and 1 week of rest). During the medication period, anlotinib is administered orally once a day at a dose of 10 mg each time.

[0323] Dosage order: Anlotinib hydrochloride capsules → anti-PD-1 antibody injection → anti-TIM-3 antibody injection

[0324] 4. Adjustment of dosing regimen

[0325] 4.1 Anti-PD-1 Antibody Injection: Delayed medication is allowed, but the longest delay should not exceed 12 weeks.

[0326] 4.2 Anti-TIM-3 Antibody Injection: Delayed medication is allowed, but the longest delay should not exceed 12 weeks.

[0327] 4.3 Anlotinib Hydrochloride Capsules: In each treatment cycle, Anlotinib Hydrochloride Capsules are allowed to be delayed during the administration period (i.e., Days 1-14), and the longest delay time shall not exceed 5 days; until the next treatment cycle, the medication is allowed to be delayed, and the longest delay time shall not exceed 4 weeks. The dose can be reduced by 10mg→8mg→6mg; after a period of dose reduction, the dose can be increased once starting from the next cycle.

[0328] 5. Evaluation Criteria

[0329] The efficacy evaluation criteria were based on RECIST 1.1, and the iRECIST criteria were used to confirm the efficacy. The severity of adverse events was determined using the NCI-CTC AE 5.0 criteria.

[0330] 6. End point indicators

[0331] Objective response rate (ORR), overall survival (OS), progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), etc.

[0332] The occurrence of anti-drug antibodies (ADA) and neutralizing antibodies (NAb);

[0333] The incidence and severity of adverse events (AEs) and serious adverse events (SAEs).

[0334] 7. Results

[0335] Preliminary research results show that the combination of anti-TIM-3 antibodies, anti-PD-1 antibodies and anlotinib hydrochloride can safely and effectively treat advanced hepatocellular carcinoma. After combined treatment with anti-TIM-3 antibodies, anti-PD-1 antibodies and anlotinib hydrochloride, the clinical efficacy and survival benefits of patients with advanced hepatocellular carcinoma were significantly improved, the patients' condition was alleviated and controlled, the patients' progression-free survival and overall survival were prolonged, and some patients achieved complete remission (CR) or partial remission (PR). The exemplary results are shown in Table 3 below:

[0336] Table 3. Efficacy information

[0337]

[0338] Example 2: Clinical trial of colorectal cancer

[0339] 1. Selection criteria

[0340] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0341] (1) Age: 18-75 years old (calculated based on the date of signing the informed consent form); ECOGPS score: 0-1 points; expected survival period is more than 3 months; (2) Metastatic colorectal cancer confirmed by histology / cytology and clear RAS / BRAF status.

[0342] (3) Subjects must provide fresh or archived tumor tissue (formalin-fixed, paraffin-embedded (FFPE) tissue blocks or unstained FFPE slides) that meets the requirements for mismatch repair (MMR) protein testing, and the test results must be intact mismatch repair function (pMMR). Patients with previous MSI / MMR test results that meet the requirements are acceptable, and the previous test results must be pMMR / MSI-L / MSS.

[0343] dMMR / MSI-H type, the patient must have progressed after previous treatment with PD-1 / PD-L1 inhibitors.

[0344] (4) The subject can provide tumor tissue that meets the requirements for PD-L1 expression level detection (tumor tissue specimen requirements are the same as those in Inclusion Criteria 3). The subject’s previous PD-L1 expression level detection report that meets the requirements will be recognized.

[0345] (5) Advanced colorectal cancer with progression or intolerance after ≥3 lines of standard treatment, with standard treatment being chemotherapy based on fluorouracil, irinotecan and oxaliplatin and bevacizumab. Patients with RAS / BRAF wild-type on the left colon must have received anti-EGFR treatment; patients with BRAF V600E mutation must have received RAF inhibitor treatment. Patients who received oxaliplatin in adjuvant therapy and developed metastasis within 6 months of completing adjuvant therapy were considered to have received first-line oxaliplatin treatment. Patients who received oxaliplatin in adjuvant therapy and developed metastasis within 6 months of completing adjuvant therapy were considered to have received first-line oxaliplatin treatment.

[0346] Patients with metastatic disease at 6 months had to have received oxaliplatin-containing therapy for metastatic disease to be eligible.

[0347] (6) Patients who have failed at least one of the following treatments (TAS-102, regorafenib, or furiquintinib).

[0348] (7) Patients were confirmed to have at least one measurable lesion according to RECIST 1.1 criteria; measurable lesions should not have received local treatment such as radiotherapy (lesions located within the previous radiotherapy target area can also be selected as target lesions if they are confirmed to have progressed).

[0349] (8) Weight ≥ 40 kg and BMI ≥ 18.5 kg / m 2 .

[0350] (9) The major organs function well, that is, they meet the following criteria:

[0351] 1) The blood routine examination standards must meet (no blood transfusion and no use of hematopoietic stimulating factor drugs within 14 days before the examination):

[0352] a) Hemoglobin content (HB) ≥ 90 g / L;

[0353] b) Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L;

[0354] c) Platelet count (PLT) ≥100×10 9 / L.

[0355] 2) Biochemical examination must meet the following standards:

[0356] a) Serum total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN) (≤ 3 × ULN for patients with Gilbert syndrome);

[0357] b) ALT and AST ≤ 2.5 × ULN; if accompanied by liver metastasis, ALT and AST ≤ 5 × ULN;

[0358] c) serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance (CCr) ≥ 50 mL / min (calculated using the Cockcroft-Gault formula);

[0359] d) Urinalysis examination standard: Urinalysis indicates urine protein <++; if urine protein ≥++, it is necessary to confirm that the 24-hour urine protein quantity is ≤1.0g.

[0360] 3) Adequate coagulation function, defined as prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) ≤ 1.5 × ULN (without anticoagulant therapy).

[0361] 4) Thyroid function tests must meet the following criteria: thyroid stimulating hormone (TSH) ≤ ULN; if abnormal, triiodothyronine (T3) and tetraiodothyronine (T4) levels should be examined. Patients can be selected if T3 and T4 levels are normal.

[0362] 5) Cardiac ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ 50%.

[0363] (10) Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study and within 6 months after the end of the study; the serum pregnancy test should be negative within 7 days before study entry, and the subjects must be non-breastfeeding; male subjects should agree to use contraceptive measures during the study and within 6 months after the end of the study.

[0364] (11) The subjects voluntarily participated in this study, signed the informed consent, and had good compliance.

[0365] 2. Experimental drugs

[0366] 2.1 Anti-PD-1 antibody injection, with a specification of 100 mg / 10 mL / bottle, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.; one treatment cycle is 3 weeks, and it is administered once on the first day of each treatment cycle (dosing time window: ±3 days) by intravenous infusion at a dose of 200 mg of anti-PD-1 antibody.

[0367] 2.2 Anti-TIM-3 antibody injection, with specifications of 240 mg / 4 mL / bottle or 600 mg / 10 mL / bottle, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.; 3 weeks as a treatment cycle, through intravenous infusion, on the first day of each treatment cycle (dosing time window: ±3 days) at a dose of 1200 mg anti-TIM-3 antibody.

[0368] 2.3 Anlotinib hydrochloride capsules (active ingredient is anlotinib dihydrochloride), specifications are 12mg / capsule, 10mg / capsule, 8mg / capsule, or 6mg / capsule

[0369] Tablets were provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.; 3 weeks constituted a treatment cycle (2 weeks of continuous medication and 1 week of drug withdrawal), and anlotinib was orally administered once a day at a dose of 12 mg each time.

[0370] 3. Treatment options

[0371] Experimental group A: anti-TIM-3 antibody injection + anti-PD-1 antibody injection + anlotinib hydrochloride capsules;

[0372] Experimental group B: anti-TIM-3 antibody injection + anti-PD-1 antibody injection;

[0373] Trial C: anti-TIM-3 antibody injection;

[0374] Among them, in experimental group A and experimental group B, anti-PD-1 antibody injection was administered first, and then anti-TIM-3 antibody injection was administered.

[0375] 4. Adjustment of dosing regimen

[0376] 4.1 Anti-PD-1 Antibody Injection: Delayed medication is allowed, but the longest delay should not exceed 12 weeks.

[0377] 4.2 Anti-TIM-3 Antibody Injection: Delayed medication is allowed, but the longest delay should not exceed 12 weeks.

[0378] 4.3 Anlotinib Hydrochloride Capsules: In each treatment cycle, Anlotinib Hydrochloride Capsules are allowed to be delayed during the administration period (i.e., Days 1-14), and the longest delay time shall not exceed 5 days; until the next treatment cycle, the medication is allowed to be delayed, and the longest delay time shall not exceed 4 weeks. It is allowed to reduce the dose from 12mg→10mg→8mg; after reducing the dose for a period of time, it is allowed to increase the dose once starting from the next cycle.

[0379] 5. Evaluation Criteria

[0380] The efficacy evaluation criteria were based on RECIST 1.1, and the iRECIST criteria were used to confirm the efficacy. The severity of adverse events was determined using the NCI-CTC AE 5.0 criteria.

[0381] 6. End point indicators

[0382] Objective response rate (ORR), overall survival (OS), progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), etc.

[0383] The occurrence of anti-drug antibodies (ADA) and neutralizing antibodies (NAb);

[0384] The incidence and severity of adverse events (AEs) and serious adverse events (SAEs).

[0385] 7. Results

[0386] Preliminary research results show that the combined use of anti-TIM-3 antibodies and anti-PD-1 antibodies, or the combined use of anti-TIM-3 antibodies, anti-PD-1 antibodies and anlotinib hydrochloride can safely and effectively treat advanced colorectal cancer.

Claims

1. A drug combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and anlotinib or a pharmaceutically acceptable salt thereof, wherein: The anti-TIM-3 antibody or antigen-binding fragment thereof comprises: HCDR1 of the amino acid sequence shown in SEQ ID NO:1, HCDR2 of the amino acid sequence shown in SEQ ID NO:2, HCDR3 of the amino acid sequence shown in SEQ ID NO:3, LCDR1 of the amino acid sequence shown in SEQ ID NO:4, LCDR2 of the amino acid sequence shown in SEQ ID NO:5, and LCDR3 of the amino acid sequence shown in SEQ ID NO:6; or HCDR1 of the amino acid sequence shown in SEQ ID NO:21, HCDR2 of the amino acid sequence shown in SEQ ID NO:22, HCDR3 of the amino acid sequence shown in SEQ ID NO:23, LCDR1 of the amino acid sequence shown in SEQ ID NO:24, LCDR2 of the amino acid sequence shown in SEQ ID NO:25, and LCDR3 of the amino acid sequence shown in SEQ ID NO:

26.

2. The pharmaceutical combination according to claim 1, wherein The anti-TIM-3 antibody or antigen-binding fragment thereof comprises: A heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:8; or A heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:27, and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:

28.

3. The pharmaceutical combination according to claim 1 or 2, wherein: The anti-TIM-3 antibody or antigen-binding fragment thereof comprises: A heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:9, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:10; or A heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:29, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:

30.

4. The pharmaceutical combination according to any one of claims 1 to 3, wherein The anti-PD-1 antibody or its antigen-binding fragment comprises: HCDR1 of the amino acid sequence shown in SEQ ID NO: 11, HCDR2 of the amino acid sequence shown in SEQ ID NO: 12, HCDR3 of the amino acid sequence shown in SEQ ID NO: 13, LCDR1 of the amino acid sequence shown in SEQ ID NO: 14, LCDR2 of the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 of the amino acid sequence shown in SEQ ID NO:

16.

5. The pharmaceutical combination according to any one of claims 1 to 4, wherein The anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region whose amino acid sequence is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 17, 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:

18.

6. The pharmaceutical combination according to any one of claims 1 to 5, wherein The anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain whose amino acid sequence is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 19, and a light chain whose amino acid sequence is at least 95% identical to the amino acid sequence shown in SEQ ID NO:

20.

7. The pharmaceutical combination according to any one of claims 1 to 6, wherein The anti-TIM-3 antibody or its antigen-binding fragment and / or the anti-PD-1 antibody or its antigen-binding fragment is formulated as a preparation for parenteral administration. Preferably, the anti-TIM-3 antibody or its antigen-binding fragment and / or the anti-PD-1 antibody or its antigen-binding fragment is formulated as a preparation for intravenous, intramuscular or subcutaneous administration.

8. The pharmaceutical combination according to any one of claims 1 to 7, wherein The anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation.

9. The pharmaceutical combination according to any one of claims 1 to 7, wherein The anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated separately.

10. The pharmaceutical combination according to any one of claims 1 to 9, wherein The unit dose of the anti-TIM-3 antibody or its antigen-binding fragment is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg; preferably, the unit dose of the anti-TIM-3 antibody or its antigen-binding fragment is 240 mg, 300 mg, 360 mg and / or 600 mg.

Images