Drug combination of an antibody that binds to TIM-3 and an antibody that binds to PD-1

Abstract

A drug combination of an antibody that binds to TIM-3 and an antibody that binds to PD-1 is provided, which includes an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof; optionally, a chemotherapeutic drug is also included. A kit for treating a tumor is also provided, which includes the drug combination. In addition, the use of the drug combination in the preparation of a drug for treating a tumor and a method for treating a tumor with the drug combination are also provided.

Description

Drug combinations of antibodies that bind to TIM-3 and antibodies that bind to PD-1

[0001] This disclosure claims priority to Chinese patent application No. 202211081252.2, filed with the Patent Office of the State Intellectual Property Office of China on September 6, 2022, entitled “Drug combination of an antibody that binds to TIM-3 and an antibody that binds to PD-1,” the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present disclosure relates to the field of biopharmaceuticals, and specifically relates to a drug combination of an antibody that binds to TIM-3 and an antibody that binds to PD-1. Background Art

[0003] In recent years, the incidence of cancer has been on the rise. Treatments for malignant tumors are ineffective, with high rates of late-stage metastasis. Conventional treatments currently used in clinical practice, such as radiotherapy, chemotherapy, and surgery, can alleviate pain and prolong survival, but they all have limitations. Therefore, immunotherapy, which inhibits immune checkpoints, reactivates immune cells, prevents immune escape, and ultimately kills tumor cells, has become a hot topic in the field of cancer treatment.

[0004] T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), also known as hepatitis A virus cellular receptor 2 (HAVCR2), is a member of the TIM family of 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, dendritic cells, natural killer (NK) cells, macrophages, and various tumor cells. TIM-3 has multiple 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 negatively regulates the body's immune response, preventing damage from excessive immune or autoimmune responses. Increasing evidence indicates 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.

[0005] PD-1 (Programmed death-1) is a key immune checkpoint receptor expressed by activated T and B lymphocytes and mediates immunosuppression. Its ligands include PD-L1 and PD-L2. Chinese patent document CN106977602A discloses an anti-PD-1 monoclonal antibody, 14C12H1L1, which effectively blocks the binding of PD-1 to PD-L1 and exhibits significant anti-tumor activity.

[0006] Combining anti-TIM-3 antibodies with anti-PD-1 antibodies can jointly block the signaling pathways of TIM-3 and PD-1 and improve the anti-tumor effect.

[0007] SUMMARY OF THE INVENTION

[0008] In one aspect, the present disclosure provides a drug combination comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof; optionally, further comprising a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a platinum-based anti-tumor agent and / or an antimetabolite-based anti-tumor agent. In some embodiments, the chemotherapeutic agent is a platinum-based anti-tumor agent and / or a cytosine-based anti-tumor agent. In some embodiments, the chemotherapeutic agent is cisplatin and gemcitabine.

[0009] In some embodiments, the drug combination comprises a unit dose of 60-1800 mg of an anti-TIM-3 antibody or its antigen-binding fragment and a unit dose of 10-500 mg of an anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the drug combination comprises a unit dose of 60-1800 mg of an anti-TIM-3 antibody or its antigen-binding fragment, a unit dose of 10-500 mg of an anti-PD-1 antibody or its antigen-binding fragment and a chemotherapy drug. In some embodiments, the drug combination comprises a unit dose of 60-1800 mg of an anti-TIM-3 antibody or its antigen-binding fragment, a unit dose of 10-500 mg of an anti-PD-1 antibody or its antigen-binding fragment, and a unit dose of 2.5-100 mg of cisplatin and a unit dose of 0.2-1.0 g of gemcitabine.

[0010] In some embodiments, the drug combination comprises 100-1800 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof and 10-800 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination comprises 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 a chemotherapy drug. In some embodiments, the drug combination comprises 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, 40-80 mg / m 2 Cisplatin and 0.5-1.0g / m 2 of gemcitabine.

[0011] In some embodiments, the drug combination is suitable for administration within a single treatment cycle, comprising 100-1800 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof and 10-800 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration within a single treatment cycle, comprising 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 a chemotherapy drug. In some embodiments, the drug combination is suitable for administration within a single treatment cycle, comprising 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, 40-80 mg / m 2 Cisplatin and 1.0-2.0g / m 2 of gemcitabine.

[0012] In some embodiments, the drug combination is used to treat a tumor.

[0013] On the other hand, the present disclosure also provides a method for treating a tumor in a subject, comprising administering an effective amount of a drug combination of the present disclosure to the subject. In addition, the present disclosure also provides the use of the drug combination of the present disclosure in the preparation of a medicament for treating a tumor in a subject. In addition, the present disclosure also provides the use of the drug combination of the present disclosure in the preparation of a medicament for first-line treatment of a tumor in a subject. In addition, the present disclosure also provides the use of the drug combination of the present disclosure for treating a tumor in a subject. In addition, the present disclosure also provides the use of the drug combination of the present disclosure for first-line treatment of a tumor in a subject. In some embodiments, in the method or use, it comprises administering an effective amount of a drug combination of the present disclosure to the subject. In some embodiments, in the method or use, comprising administering an effective amount of a drug combination of the present disclosure to the subject in a first treatment phase, and administering an effective amount of a drug combination of the present disclosure to the subject in a second treatment phase.

[0014] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof can be administered simultaneously, sequentially and / or alternately.

[0015] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent can be administered simultaneously, sequentially, and / or alternately. In some embodiments, the chemotherapeutic agent is a platinum-based anti-tumor drug and / or an antimetabolite-based anti-tumor drug. In some embodiments, the chemotherapeutic agent is a platinum-based anti-tumor drug and / or a cytosine-based anti-tumor drug. In some embodiments, the chemotherapeutic agent is cisplatin and gemcitabine.

[0016] 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 each time.

[0017] 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 each time.

[0018] In some embodiments, the cisplatin is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the cisplatin is administered at a dose of 40-80 mg / m 2 Dosage administration.

[0019] In some embodiments, the gemcitabine is administered twice every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the gemcitabine is administered at a dose of 0.5-1.0 g / m 2 Dosage administration.

[0020] In another aspect, the present disclosure provides a kit for treating tumors, comprising the drug combination of the present disclosure. In some embodiments, the kit comprises an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof; optionally, a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a platinum-based anti-tumor drug and / or an antimetabolite-based anti-tumor drug. In some embodiments, the chemotherapeutic agent is a platinum-based anti-tumor drug and / or a cytosine-based anti-tumor drug. In some embodiments, the chemotherapeutic agent is cisplatin and gemcitabine.

[0021] In addition, the present disclosure also provides an anti-TIM-3 antibody or antigen-binding fragment thereof for treating tumors. The present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an effective amount of the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure. The present disclosure also provides the use of the anti-TIM-3 antibody or antigen-binding fragment thereof in the preparation of a medicament for treating a tumor in a subject. The present disclosure also provides the use of the anti-TIM-3 antibody or antigen-binding fragment thereof for treating tumors.

[0022] In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is nasopharyngeal carcinoma.

[0023] Detailed Description of the Invention

[0024] Drug combinations

[0025] In one aspect, the present disclosure provides a drug combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof; optionally, further comprising a chemotherapeutic drug.

[0026] In some embodiments, the chemotherapy drugs include, but are not limited to, one or more of platinum-based antitumor drugs, taxane-based antitumor drugs, antimetabolite-based antitumor drugs, camptothecin-based antitumor drugs, nitrogen mustard-based antitumor drugs, anthracycline-based antitumor drugs, vinca alkaloid-based antitumor drugs, podophylloalkaloid-based antitumor drugs, and hormonal antitumor drugs. In some embodiments, the chemotherapy drugs are platinum-based antitumor drugs and / or antimetabolite-based antitumor drugs. In some embodiments, the chemotherapy drugs are platinum-based antitumor drugs and / or cytosine-based antitumor drugs. In some specific embodiments, the chemotherapy drugs are cisplatin and gemcitabine.

[0027] In some embodiments, the drug combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and a chemotherapy drug. In some embodiments, the drug combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, a platinum-based anti-tumor drug, and an antimetabolite-based anti-tumor drug. In some embodiments, the drug combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, a platinum-based anti-tumor drug, and a cytosine-based anti-tumor drug. In some embodiments, the drug combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, cisplatin, and gemcitabine.

[0028] In addition, the present disclosure also provides a combined drug combination comprising:

[0029] (a) a pharmaceutical combination of the present disclosure, prepared so as to be suitable for administration to a subject during a first treatment phase; and

[0030] (b) A pharmaceutical combination of the present disclosure, formulated to be suitable for administration to a subject during the second treatment phase.

[0031] In some embodiments, the combination drug comprises:

[0032] (a) a pharmaceutical 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 a chemotherapeutic drug, which is prepared to be suitable for administration to a subject in a first treatment phase; and

[0033] (b) a pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, which is prepared and suitable for administration to the subject in the second treatment phase.

[0034] In some embodiments, the combination drug comprises:

[0035] (a) 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, a platinum-based anti-tumor drug, and an antimetabolite-based anti-tumor drug, which is prepared to be suitable for administration to a subject in a first treatment phase; and

[0036] (b) a pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, which is prepared and suitable for administration to the subject in the second treatment phase.

[0037] In some embodiments, the combination drug comprises:

[0038] (a) 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, a platinum-based anti-tumor drug, and a cytosine-based anti-tumor drug, which is prepared to be suitable for administration to a subject in a first treatment phase; and

[0039] (b) a pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, which is prepared and suitable for administration to the subject in the second treatment phase.

[0040] In some embodiments, the combination drug comprises:

[0041] (a) a pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, cisplatin, and gemcitabine, which is prepared and suitable for administration to a subject in a first treatment phase; and

[0042] (b) a pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, which is prepared and suitable for administration to the subject in the second treatment phase.

[0043] In some embodiments, the treatment cycles of the first treatment phase include 1-14 treatment cycles, preferably 2-12 treatment cycles, 2-10 treatment cycles, more preferably 2-8 treatment cycles, for example: 2-8 treatment cycles, 3-8 treatment cycles, 4-8 treatment cycles, 2-7 treatment cycles, 3-7 treatment cycles, 4-7 treatment cycles, 2-6 treatment cycles, 3-6 treatment cycles, or 4-6 treatment cycles; most preferably 4-6 treatment cycles, for example: 4 treatment cycles, 5 treatment cycles, and / or 6 treatment cycles.

[0044] In some embodiments, one treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, one treatment cycle is every 3 weeks.

[0045] In some embodiments, the second treatment period is after the first treatment period. In some embodiments, the second treatment period continues from the end of the first treatment period until the patient loses clinical benefit, has unacceptable toxicity, is evaluated as disease progression (PD), and / or the investigator deems it inappropriate to continue the medication.

[0046] In some embodiments, the drug combination is packaged in the same kit, which further includes instructions for using the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment in combination to treat tumors. In other embodiments, the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment in the drug combination are separately packaged in separate kits, which further include instructions for using the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment in combination to treat tumors.

[0047] In some embodiments, the drug combination is packaged in the same kit, which further includes instructions for using the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment, and a chemotherapy drug (e.g., cisplatin and gemcitabine) in combination to treat tumors. In other embodiments, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment, and the chemotherapy drug (e.g., cisplatin and gemcitabine) in the drug combination are packaged separately in their own medicine boxes, which further include instructions for using the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment, and the chemotherapy drug (e.g., cisplatin and gemcitabine) in combination to treat tumors.

[0048] In some embodiments, the pharmaceutical combination is a fixed combination.In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or in the form of a liquid pharmaceutical composition.

[0049] In some embodiments, the drug combination is a non-fixed combination. In some embodiments, the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment in the non-fixed combination are each in the form of a pharmaceutical composition. In some embodiments, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and the chemotherapy drug (e.g., cisplatin and gemcitabine) in the non-fixed combination are each in the form of a pharmaceutical composition.

[0050] In some embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof in the non-fixed combination is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof is an injectable solution. In some embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof is a lyophilized formulation.

[0051] In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof in the non-fixed combination is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof is an injectable solution. In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized formulation.

[0052] In some embodiments, in the non-fixed combination, 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. In some embodiments, in the non-fixed combination, the pharmaceutical composition comprising the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition comprising the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof is an injectable solution. In some embodiments, the pharmaceutical composition comprising the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized formulation.

[0053] In some specific embodiments, in the non-fixed combination, the pharmaceutical composition containing the chemotherapeutic drug is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some specific embodiments, the pharmaceutical composition containing cisplatin is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some specific embodiments, the pharmaceutical composition containing gemcitabine is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some specific embodiments, the pharmaceutical composition containing cisplatin is an injection. In some specific embodiments, the pharmaceutical composition containing gemcitabine is an injection. The present disclosure also aims to provide 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 the second container includes a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof; optionally, it further comprises one or more other containers, and the other containers include a pharmaceutical composition containing a chemotherapeutic drug (e.g., cisplatin and gemcitabine).

[0054] In some embodiments, the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg. In some embodiments, the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 60 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320 mg, about 360 mg, about 400 mg, about 420 mg, about 440 mg, about 480 mg, about 520 mg, about 540 mg, about 560 mg, about 600 mg, about 640 mg, about 660 mg, about 680 mg, about 720 mg, about 760 mg, about 780 mg, about 800 mg, about 840 mg, about 880 mg, about 900 mg, about 920 mg, about 960 mg, about 980 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg 1500 mg, about 1520 mg, about 1560 mg, about 1600 mg, about 1620 mg, about 1640 mg, about 1680 mg, about 1720 mg, about 1740 mg, about 1760 mg, and / or about 1800 mg, or a range formed by any of the foregoing values. In some embodiments, the unit dose of the anti-TIM-3 antibody or its antigen-binding fragment in the pharmaceutical combination is about 240 mg, about 300 mg, about 360 mg and / or about 600 mg. In some embodiments, the unit dose of the anti-TIM-3 antibody or its antigen-binding fragment in the pharmaceutical combination is about 240 mg and / or about 600 mg.

[0055] 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 about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg In some embodiments, the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 100 mg and / or about 200 mg. In some embodiments, the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is about 100 mg.

[0056] In some embodiments, the drug combination further comprises a chemotherapeutic agent. In some embodiments, the chemotherapeutic agents are cisplatin and gemcitabine. In some embodiments, the unit dose of cisplatin in the drug combination is 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg, and / or 100 mg. In some embodiments, the unit dose of gemcitabine in the drug combination is 0.2 g and / or 1.0 g.

[0057] 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, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg and 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.In some embodiments, the pharmaceutical combination comprises a unit dose of about 60 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320 mg, about 360 mg, about 400 mg, about 420 mg, about 440 mg, about 480 mg, about 520 mg, about 540 mg, about 560 mg, about 600 mg, about 640 mg, about 660 mg, about 680 mg, about 720 mg, about 760 mg, about 780 mg, about 800 mg, about 840 mg, about 880 mg, about 900 mg. , about 920mg, about 960mg, about 1000mg, about 1020mg, about 1040mg, about 1080mg, about 1120mg, about 1140mg, about 1160mg, about 1200mg, about 1240mg, about 1260mg, about 1280mg, about 1320mg, about 1360mg, about 1380mg, about 1400mg, about 1440mg, about 1480mg, about 1500mg, about 1520mg, about 1560mg, about 1600mg, about 1620mg, about 1640mg, about 1680mg, about 1720mg, about 1 The present invention relates to an anti-TIM-3 antibody or antigen-binding fragment thereof of about 740 mg, about 1760 mg, and / or about 1800 mg, or a range formed by any of the foregoing values, and a unit dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg.

[0015] In some embodiments, the present invention relates to an anti-PD-1 antibody or antigen-binding fragment thereof comprising at least one antibody and at least one antibody-binding fragment thereof. The anti-PD-1 antibody or antigen-binding fragment thereof comprises at least one antibody and at least one antibody-binding fragment thereof. The anti-PD-1 antibody or antigen-binding fragment thereof comprises at least one antibody and at least one antibody-binding fragment thereof. In some embodiments, the drug combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof at a unit dose of about 240 mg, about 300 mg, about 360 mg and / or about 600 mg and an anti-PD-1 antibody or an antigen-binding fragment thereof at a unit dose of about 100 mg and / or about 200 mg.In some embodiments, the pharmaceutical combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof at a unit dose of about 240 mg and / or about 600 mg and an anti-PD-1 antibody or an antigen-binding fragment thereof at a unit dose of about 100 mg.

[0058] In some embodiments, the pharmaceutical combination further comprises cisplatin at a unit dose of 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg and / or 100 mg and gemcitabine at a unit dose of 0.2 g and / or 1.0 g. In some embodiments, the pharmaceutical combination further comprises cisplatin at a unit dose of 20 mg, 30 mg and / or 100 mg and gemcitabine at a unit dose of 0.2 g and / or 1.0 g. In some embodiments, the pharmaceutical combination further comprises cisplatin at a unit dose of 30 mg and gemcitabine at a unit dose of 0.2 g and / or 1.0 g.

[0059] 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, cisplatin, and gemcitabine. In some specific embodiments, the drug combination includes an anti-TIM-3 antibody or an antigen-binding fragment thereof at a unit dose of about 240 mg, about 300 mg, about 360 mg, and / or about 600 mg, an anti-PD-1 antibody or an antigen-binding fragment thereof at a unit dose of about 100 mg and / or about 200 mg, cisplatin at a unit dose of 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg, and / or 100 mg, and gemcitabine at a unit dose of 0.2 g and / or 1.0 g. In some specific embodiments, the drug combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof at a unit dose of about 240 mg and / or about 600 mg, an anti-PD-1 antibody or an antigen-binding fragment thereof at a unit dose of about 100 mg, cisplatin at a unit dose of 20 mg, 30 mg and / or 100 mg, and gemcitabine at a unit dose of 0.2 g and / or 1.0 g. In some specific embodiments, the drug combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof at a unit dose of about 240 mg and / or about 600 mg, an anti-PD-1 antibody or an antigen-binding fragment thereof at a unit dose of about 100 mg, cisplatin at a unit dose of 30 mg, and gemcitabine at a unit dose of 0.2 g and / or 1.0 g.

[0060] In some embodiments, the pharmaceutical composition comprises 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or a range formed by any of the foregoing values ​​of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises about 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof.

[0061] In some embodiments, the pharmaceutical composition comprises 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 pharmaceutical composition comprises about 10 mg, about 50 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg, or a range formed by any of the above values ​​of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0062] In some embodiments, the drug combination further comprises a chemotherapy drug. In some embodiments, the chemotherapy drug is cisplatin and gemcitabine. In some embodiments, the drug combination further comprises 40-80 mg / m 2 , or 40-75 mg / m 2 In some embodiments, the drug combination further comprises 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 , 80mg / m 2 , or cisplatin in the range formed by any of the above values. In some embodiments, the drug combination further comprises 40 mg / m 2 , 60mg / m 2or 75 mg / m 2 In some embodiments, the drug combination further comprises 75 mg / m 2 In some embodiments, the drug combination further comprises 80 mg / m 2 In some embodiments, the drug combination further comprises 0.5-1.0 g / m 2 In some embodiments, the drug combination further comprises 0.5 g / m 2 , 0.75g / m 2 , 1.0g / m 2 , or gemcitabine in the range formed by any of the above values. In some embodiments, the drug combination further comprises 0.5 g / m 2 , 0.75g / m 2 or 1.0g / m 2 In some embodiments, the drug combination further comprises 1.0 g / m 2 of gemcitabine.

[0063] In some embodiments, the drug combination comprises 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, and 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the drug combination comprises about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or a range formed by any of the foregoing values, and about 1 0mg, about 50mg, about 100mg, about 120mg, about 140mg, about 160mg, about 180mg, about 200mg, about 220mg, about 240mg, about 260mg, about 280mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, or about 800mg, or a range formed by any of the above values. In some embodiments, the drug combination comprises about 1200mg or about 1500mg of anti-TIM-3 antibody or its antigen-binding fragment and about 200mg of anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the drug combination comprises about 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof and about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0064] In some embodiments, the drug combination further comprises 40-80 mg / m 2 , or 40-75 mg / m 2 Cisplatin, and 0.5-1.0 g / m 2 In some embodiments, the drug combination further comprises 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 , 80mg / m 2 , or cisplatin in the range of any of the above values, and 0.5 g / m 2 , 0.75g / m 2 , 1.0g / m 2 , or gemcitabine in the range formed by any of the above values. In some embodiments, the drug combination further comprises 75 mg / m 2 Cisplatin, and 1.0 g / m2 In some embodiments, the drug combination further comprises 80 mg / m 2 Cisplatin, and 1.0 g / m 2 of gemcitabine.

[0065] In some embodiments, the drug combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, cisplatin, and gemcitabine. In some specific embodiments, the drug combination comprises about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 or 80 mg / m 2 Cisplatin, and 0.5 g / m 2 , 0.75g / m 2 or 1.0g / m 2 In some specific embodiments, the drug combination includes about 1200 mg or about 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment, about 200 mg of anti-PD-1 antibody or its antigen-binding fragment, 75 mg / m 2 of cisplatin, and 1.0 g / m 2 In other specific embodiments, the drug combination comprises about 1200 mg or about 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment, about 200 mg of anti-PD-1 antibody or its antigen-binding fragment, 80 mg / m 2 of cisplatin, and 1.0 g / m 2 In some specific embodiments, the drug combination includes about 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment, about 200 mg of anti-PD-1 antibody or its antigen-binding fragment, 75 mg / m 2 of cisplatin, and 1.0 g / m 2 of gemcitabine.

[0066] In some embodiments, the amount of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a daily dose. In some embodiments, the amount of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a once-daily dose.

[0067] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is present in a uniform dose.

[0068] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof in the drug combination is contained in a dosage for one treatment cycle, and each treatment cycle is 3 weeks.

[0069] In some embodiments, the amount of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a daily dose. In some embodiments, the amount of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a once-daily dose.

[0070] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is present in a uniform dose.

[0071] In some embodiments, the amount of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a dosage for one treatment cycle, and each treatment cycle is 3 weeks. In some embodiments, the amount of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a dosage for one treatment cycle, and each treatment cycle is 2 weeks.

[0072] In some embodiments, the amount of cisplatin in the pharmaceutical combination is a daily dose. In some embodiments, the amount of cisplatin in the pharmaceutical combination is a once-a-day dose.

[0073] In some embodiments, the amount of gemcitabine in the pharmaceutical combination is a daily dose. In some embodiments, the amount of gemcitabine in the pharmaceutical combination is a once-a-day dose.

[0074] In some embodiments, the drug combination is suitable for administration within 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 antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and includes about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or a range formed by any of the above values ​​of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof.

[0075] 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 antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle and includes about 10 mg, about 50 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg, or a range formed by any of the above values ​​of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 200 mg of the anti-PD-1 antibody or antigen-binding fragment thereof.

[0076] In some embodiments, the drug combination is suitable for administration in a single treatment cycle and further comprises a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is cisplatin and gemcitabine. In some embodiments, the drug combination is suitable for administration in a single treatment cycle and further comprises 40-80 mg / m 2 , or 40-75 mg / m 2 In some embodiments, the drug combination is suitable for administration in a single treatment cycle and further comprises 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 , 80mg / m 2 , or cisplatin 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 further comprises 40 mg / m 2 , 60mg / m 2 or 75 mg / m 2 In some embodiments, the drug combination is suitable for administration in a single treatment cycle and further comprises 75 mg / m 2 In some embodiments, the drug combination is suitable for administration in a single treatment cycle and further comprises 80 mg / m 2 In some embodiments, the drug combination is suitable for administration in a single treatment cycle and further comprises 1.0-2.0 g / m 2 In some embodiments, the drug combination is suitable for administration in a single treatment cycle and further comprises 1.0 g / m 2 , 1.25g / m 2, 1.5g / m 2 , 1.75g / m 2 , 2.0g / m 2 , or gemcitabine 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 further comprises 1.0 g / m 2 , 1.25g / m 2 , 1.5g / m 2 , 1.75g / m 2 , 2.0g / m 2 In some embodiments, the drug combination is suitable for administration in a single treatment cycle and further comprises 2.0 g / m 2 of gemcitabine.

[0077] In some embodiments, the drug combination is suitable for administration in a single treatment cycle and includes an anti-TIM-3 antibody or an antigen-binding fragment thereof and 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 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 and 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 pharmaceutical combination is suitable for administration in a single treatment cycle and comprises about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or a range of any of the foregoing values, of an anti-TIM-3 antibody or its antigen binding site. In some embodiments, the drug combination comprises about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and about 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof, or a range thereof, and about 10 mg, about 50 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg, or a range thereof formed by any of the above values. In some embodiments, the drug combination is suitable for administration in a single treatment cycle and comprises about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof and about 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle and includes about 1200 mg of the anti-TIM-3 antibody or antigen-binding fragment thereof and about 200 mg of the anti-PD-1 antibody or antigen-binding fragment thereof.

[0078] In some embodiments, the drug combination is suitable for administration in a single treatment cycle and further comprises 40-80 mg / m 2 , or 40-75 mg / m 2 Cisplatin, and 1.0-2.0 g / m 2 In some embodiments, the drug combination is suitable for administration in a single treatment cycle and further comprises 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 , 80mg / m2 , or cisplatin in the range of any of the above values, and 1.0 g / m 2 , 1.25g / m 2 , 1.5g / m 2 , 1.75g / m 2 , 2.0g / m 2 , or gemcitabine 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 further comprises 75 mg / m 2 Cisplatin, and 2.0g / m 2 In some embodiments, the drug combination is suitable for administration in a single treatment cycle and further comprises 80 mg / m 2 Cisplatin, and 2.0g / m 2 of gemcitabine.

[0079] 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, cisplatin, and gemcitabine. In some specific embodiments, the drug combination is suitable for administration in a single treatment cycle, comprising about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 or 80 mg / m 2 of cisplatin, and 1.0 g / m 2 , 1.25g / m 2 , 1.5g / m 2 , 1.75g / m 2 or 2.0g / m 2 In some specific embodiments, the drug combination is suitable for administration in a single treatment cycle, which includes about 1200 mg or about 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment, about 200 mg of anti-PD-1 antibody or its antigen-binding fragment, 75 mg / m 2 Cisplatin, and 2.0 g / m 2 In other specific embodiments, the drug combination is suitable for administration in a single treatment cycle, which includes about 1200 mg or about 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment, about 200 mg of anti-PD-1 antibody or its antigen-binding fragment, 80 mg / m 2 Cisplatin, and 2.0 g / m 2In some specific embodiments, the drug combination is suitable for administration in a single treatment cycle, which includes about 1200 mg of anti-TIM-3 antibody or antigen-binding fragment thereof, about 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof, 75 mg / m 2 Cisplatin, and 2.0 g / m 2 of gemcitabine.

[0080] In some embodiments, the present disclosure provides a combination drug combination comprising:

[0081] (a) 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, 40-80 mg / m 2 , 40mg / m 2 , 60mg / m 2 , 75mg / m 2 or 80 mg / m 2 Cisplatin, and 1.0-2.0 g / m 2 , 1.0g / m 2 , 1.25g / m 2 , 1.5g / m 2 , 1.75g / m 2 or 2.0g / m 2 a drug combination of gemcitabine and acetaminophen, which is prepared to be administered to the subject in a single treatment cycle in the first treatment phase; and

[0082] (b) a pharmaceutical combination 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 and 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, prepared for administration to the subject in a single treatment cycle during the second treatment phase.

[0083] In some embodiments, the present disclosure provides a combination drug combination comprising:

[0084] (a) comprising about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 or 80 mg / m 2 of cisplatin, and 1.0 g / m2 , 1.25g / m 2 , 1.5g / m 2 , 1.75g / m 2 or 2.0g / m 2 a drug combination of gemcitabine and acetaminophen, which is prepared to be administered to the subject in a single treatment cycle in the first treatment phase; and

[0085] (b) a pharmaceutical combination comprising about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof and about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, prepared for administration to the subject in a single treatment cycle during the second treatment phase.

[0086] In some embodiments, the present disclosure provides a combination drug combination comprising:

[0087] (a) comprising about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 75 mg / m 2 Cisplatin, and 2.0 g / m 2 a drug combination of gemcitabine and acetaminophen, which is prepared to be administered to the subject in a single treatment cycle in the first treatment phase; and

[0088] (b) a pharmaceutical combination comprising about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof and about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, prepared for administration to the subject in a single treatment cycle during the second treatment phase.

[0089] In some embodiments, the present disclosure provides a combination drug combination comprising:

[0090] (a) comprising about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 80 mg / m 2 Cisplatin, and 2.0 g / m 2 a drug combination of gemcitabine and acetaminophen, which is prepared to be administered to the subject in a single treatment cycle in the first treatment phase; and

[0091] (b) a pharmaceutical combination comprising about 1200 mg or about 1500 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof and about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, prepared for administration to the subject in a single treatment cycle during the second treatment phase.

[0092] In some embodiments, the present disclosure provides a combination drug combination comprising:

[0093] (a) comprising approximately 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof, approximately 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 75 mg / m 2 Cisplatin, and 2.0 g / m 2 a drug combination of gemcitabine and acetaminophen, which is prepared to be administered to the subject in a single treatment cycle in the first treatment phase; and

[0094] (b) a pharmaceutical combination comprising about 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof and about 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, prepared for administration to the subject in a single treatment cycle during the second treatment phase.

[0095] In some embodiments, the treatment cycles of the first treatment phase include 1-14 treatment cycles, preferably 2-12 treatment cycles, 2-10 treatment cycles, more preferably 2-8 treatment cycles, for example: 2-8 treatment cycles, 3-8 treatment cycles, 4-8 treatment cycles, 2-7 treatment cycles, 3-7 treatment cycles, 4-7 treatment cycles, 2-6 treatment cycles, 3-6 treatment cycles, or 4-6 treatment cycles; most preferably 4-6 treatment cycles, for example: 4 treatment cycles, 5 treatment cycles, and / or 6 treatment cycles.

[0096] In some embodiments, the second treatment period is after the first treatment period. In some embodiments, the second treatment period continues from the end of the first treatment period until the patient loses clinical benefit, has unacceptable toxicity, is evaluated as PD, and / or the investigator deems it inappropriate to continue the medication.

[0097] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof may be a pharmaceutical composition comprising the anti-TIM-3 antibody or antigen-binding fragment thereof. The pharmaceutical composition comprising the anti-TIM-3 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 approximately 240 mg, approximately 300 mg, approximately 360 mg, and / or approximately 600 mg of the anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing approximately 240 mg and / or approximately 600 mg of the anti-TIM-3 antibody or antigen-binding fragment thereof.

[0098] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof may be a pharmaceutical composition comprising the anti-PD-1 antibody or antigen-binding fragment thereof. The pharmaceutical composition comprising 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 about 100 mg and / or about 200 mg of the 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 about 100 mg of the anti-PD-1 antibody or antigen-binding fragment thereof.

[0099] In some embodiments, the chemotherapeutic agent may be a pharmaceutical composition containing the chemotherapeutic agent. The pharmaceutical composition containing the chemotherapeutic agent is administered in a single dose or multiple doses, preferably multiple doses. In some embodiments, the chemotherapeutic agents are cisplatin and gemcitabine. In some embodiments, the cisplatin may be a pharmaceutical composition containing cisplatin. The pharmaceutical composition containing cisplatin is administered in 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 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg, and / or 100 mg of cisplatin. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing 30 mg of cisplatin. In some embodiments, the gemcitabine may be a pharmaceutical composition containing gemcitabine. The pharmaceutical composition containing gemcitabine is administered in 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 0.2 g and / or 1.0 g of gemcitabine.

[0100] In some embodiments, in the pharmaceutical combination, the mass ratio of the anti-TIM-3 antibody or antigen-binding fragment thereof: the anti-PD-1 antibody or antigen-binding fragment thereof 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 antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof can be packaged separately or together. Furthermore, the anti-TIM-3 antibody or antigen-binding fragment thereof can be packaged in a single portion or in multiple portions, and the anti-PD-1 antibody or antigen-binding fragment thereof can be packaged in a single portion or in multiple portions. In some embodiments, the anti-TIM-3 antibody or its antigen-binding fragment can be packaged in a single portion or multiple aliquots (e.g., 2 aliquots, 3 aliquots, 4 aliquots, 5 aliquots, 6 aliquots, 7 aliquots, 8 aliquots or more), and the anti-PD-1 antibody or its antigen-binding fragment can be packaged in a single portion or multiple aliquots (e.g., 2 aliquots or other aliquots).

[0101] In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprising the anti-TIM-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to a patient 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of the anti-TIM-3 antibody or an antigen-binding fragment thereof, and the pharmaceutical composition comprising the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to a patient 10-800 mg, 50-500 mg, or 100-200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprising the anti-TIM-3 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering to a patient about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg of anti-TIM-3, or a range formed by any of the foregoing values. A single dose or multiple doses of the M-3 antibody or its antigen-binding fragment, and a pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment are prepared to be suitable for administering to a patient a single dose or multiple doses of about 10 mg, about 50 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg, or a range formed by any of the foregoing values, of the anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprising the anti-TIM-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to a patient about 1200 mg or about 1500 mg of the anti-TIM-3 antibody or an antigen-binding fragment thereof, and the pharmaceutical composition comprising the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to a patient about 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof.In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprising the anti-TIM-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to a patient approximately 1200 mg of the anti-TIM-3 antibody or an antigen-binding fragment thereof, and the pharmaceutical composition comprising the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to a patient approximately 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof.

[0102] In some embodiments, the drug combination further comprises a chemotherapeutic drug. In some embodiments, the chemotherapeutic drugs are cisplatin and gemcitabine. In some embodiments, the drug combination further comprises a pharmaceutical composition containing cisplatin and a pharmaceutical composition containing gemcitabine, wherein the pharmaceutical composition containing cisplatin is prepared to be suitable for administration to a patient at a dose of 40-80 mg / m 2 , or 40-75 mg / m 2 Single or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be suitable for administering to a patient 0.5-1.0 g / m 2 In some embodiments, the pharmaceutical combination further comprises a pharmaceutical composition containing cisplatin and a pharmaceutical composition containing gemcitabine, wherein the pharmaceutical composition containing cisplatin is prepared to be suitable for administering 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 , 80mg / m 2 , or a single dose or multiple doses of cisplatin in a range of any of the above values, the pharmaceutical composition containing gemcitabine is prepared to be suitable for administering 0.5 g / m 2 , 0.75g / m 2 , 1.0g / m 2 , or a single dose or multiple doses of gemcitabine in a range of any of the above values. In some embodiments, the pharmaceutical combination further comprises a pharmaceutical composition containing cisplatin and a pharmaceutical composition containing gemcitabine, wherein the pharmaceutical composition containing cisplatin is prepared to be suitable for administering 75 mg / m 2 Single or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be suitable for administering 1.0 g / m 2 In some embodiments, the pharmaceutical combination further comprises a pharmaceutical composition containing cisplatin and a pharmaceutical composition containing gemcitabine, wherein the pharmaceutical composition containing cisplatin is prepared to be suitable for administering 80 mg / m2 to a patient. 2 Single or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be suitable for administering 1.0 g / m 2Single or multiple doses of gemcitabine.

[0103] In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof, a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, a pharmaceutical composition comprising cisplatin, and a pharmaceutical composition comprising gemcitabine. In some specific embodiments, in the pharmaceutical combination, the pharmaceutical composition comprising the anti-TIM-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to a patient about 1200 mg or about 1500 mg of the anti-TIM-3 antibody or an antigen-binding fragment thereof, the pharmaceutical composition comprising the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to a patient about 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof, and the pharmaceutical composition comprising cisplatin is prepared as a single dose or multiple doses suitable for administering to a patient 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 or 80 mg / m 2 Single or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be suitable for administering 0.5 g / m 2 , 0.75g / m 2 or 1.0g / m 2 In some specific embodiments, the pharmaceutical composition comprising the anti-TIM-3 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering to a patient about 1200 mg or about 1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment, the pharmaceutical composition comprising the anti-PD-1 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering to a patient about 200 mg of the anti-PD-1 antibody or its antigen-binding fragment, and the pharmaceutical composition comprising cisplatin is prepared as a single dose or multiple doses suitable for administering to a patient 75 mg / m 2 Single or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be suitable for administering 1.0 g / m 2 In some specific embodiments, the pharmaceutical composition comprising the anti-TIM-3 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering to a patient about 1200 mg or about 1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment, the pharmaceutical composition comprising the anti-PD-1 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses suitable for administering to a patient about 200 mg of the anti-PD-1 antibody or its antigen-binding fragment, and the pharmaceutical composition comprising cisplatin is prepared as a single dose or multiple doses suitable for administering to a patient 80 mg / m 2 Single or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be suitable for administering 1.0 g / m 2In some specific embodiments, 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 to the patient about 1200 mg of the anti-TIM-3 antibody or its antigen-binding fragment, 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 to the patient about 200 mg of the anti-PD-1 antibody or its antigen-binding fragment, and the pharmaceutical composition containing cisplatin is prepared as a single dose or multiple doses suitable for administering to the patient 75 mg / m 2 Single or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be suitable for administering 1.0 g / m 2 Single or multiple doses of gemcitabine.

[0104] In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprising the anti-TIM-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to the patient 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of the anti-TIM-3 antibody or an antigen-binding fragment thereof as the first administration, and the pharmaceutical composition comprising the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to the patient 10-800 mg, 50-500 mg, or 100-200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof as the first administration. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprising the anti-TIM-3 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering to a patient about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg of anti-TIM-3 antibody, or a range formed by any of the foregoing values, when administered for the first time. A single dose or multiple doses of M-3 antibody or its antigen-binding fragment, and a pharmaceutical composition containing an anti-PD-1 antibody or its antigen-binding fragment are prepared so as to be suitable for administering to a patient a single dose or multiple doses of about 10 mg, about 50 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg, or a range formed by any of the foregoing values, of an anti-PD-1 antibody or its antigen-binding fragment, when administered for the first time. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprising the anti-TIM-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to the patient about 1200 mg or about 1500 mg of the anti-TIM-3 antibody or an antigen-binding fragment thereof when the first administration is performed, and the pharmaceutical composition comprising the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to the patient about 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof when the first administration is performed.In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprising the anti-TIM-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to the patient about 1200 mg of the anti-TIM-3 antibody or an antigen-binding fragment thereof when the first administration is performed, and the pharmaceutical composition comprising the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering to the patient about 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof when the first administration is performed.

[0105] In some embodiments, the drug combination further comprises a chemotherapeutic drug. In some embodiments, the chemotherapeutic drugs are cisplatin and gemcitabine. In some embodiments, the drug combination further comprises a pharmaceutical composition containing cisplatin and a pharmaceutical composition containing gemcitabine, wherein the pharmaceutical composition containing cisplatin is prepared to be suitable for administering 40-80 mg / m2 to the patient in the first administration. 2 , or 40-75 mg / m 2 A single dose or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be administered to a patient at a dose of 0.5-1.0 g / m2 per week for two consecutive weeks. 2 In some embodiments, the pharmaceutical combination further comprises a pharmaceutical composition containing cisplatin and a pharmaceutical composition containing gemcitabine, wherein the pharmaceutical composition containing cisplatin is prepared to be suitable for administering 40 mg / m2 to the patient in the first administration. 2 , 60mg / m 2 , 75mg / m 2 , 80mg / m 2 , or a single dose or multiple doses of cisplatin in a range of any of the above values, the pharmaceutical composition containing gemcitabine is prepared to be suitable for administering 0.5 g / m2 to the patient weekly for two consecutive weeks. 2 , 0.75g / m 2 , 1.0g / m 2 , or a single dose or multiple doses of gemcitabine in a range of any of the above values. In some embodiments, the pharmaceutical combination further comprises a pharmaceutical composition containing cisplatin and a pharmaceutical composition containing gemcitabine, wherein the pharmaceutical composition containing cisplatin is prepared to be suitable for administering 75 mg / m2 to the patient in the first administration. 2 Single or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be administered to a patient at a dose of 1.0 g / m2 per week for two consecutive weeks. 2 In some embodiments, the pharmaceutical combination further comprises a pharmaceutical composition containing cisplatin and a pharmaceutical composition containing gemcitabine, wherein the pharmaceutical composition containing cisplatin is prepared to be suitable for administering 80 mg / m2 to the patient in the first administration. 2Single or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be administered to a patient at a dose of 1.0 g / m2 per week for two consecutive weeks. 2 Single or multiple doses of gemcitabine.

[0106] In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof, a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, a pharmaceutical composition comprising cisplatin, and a pharmaceutical composition comprising gemcitabine. In some specific embodiments, in the pharmaceutical combination, the pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses of about 1200 mg or about 1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment to the patient for the first administration, the pharmaceutical composition comprising an anti-PD-1 antibody or its antigen-binding fragment is prepared as a single dose or multiple doses of about 200 mg of the anti-PD-1 antibody or its antigen-binding fragment to the patient for the first administration, and the pharmaceutical composition comprising cisplatin is prepared as a single dose or multiple doses of 40 mg / m2 to the patient for the first administration. 2 , 60mg / m 2 , 75mg / m 2 or 80 mg / m 2 A single dose or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be administered to a patient at a dose of 0.5 g / m2 per week for two consecutive weeks. 2 , 0.75g / m 2 or 1.0g / m 2 In some specific embodiments, in the pharmaceutical combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is prepared to be suitable for administering to the patient a single dose or multiple doses of about 1200 mg or about 1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment when the first administration is performed, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is prepared to be suitable for administering to the patient a single dose or multiple doses of about 200 mg of the anti-PD-1 antibody or its antigen-binding fragment when the first administration is performed, and the pharmaceutical composition containing cisplatin is prepared to be suitable for administering to the patient 75 mg / m 2 Single or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be administered to a patient at a dose of 1.0 g / m2 per week for two consecutive weeks. 2In some specific embodiments, in the pharmaceutical combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is prepared to be suitable for administering to the patient a single dose or multiple doses of about 1200 mg or about 1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment when the first administration is performed, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is prepared to be suitable for administering to the patient a single dose or multiple doses of about 200 mg of the anti-PD-1 antibody or its antigen-binding fragment when the first administration is performed, and the pharmaceutical composition containing cisplatin is prepared to be suitable for administering to the patient 80 mg / m2 when the first administration is performed. 2 Single or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be administered to a patient at a dose of 1.0 g / m2 per week for two consecutive weeks. 2 In some specific embodiments, in the pharmaceutical combination, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is prepared to be suitable for administering to the patient a single dose or multiple doses of about 1200 mg of the anti-TIM-3 antibody or its antigen-binding fragment when the first administration is performed, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is prepared to be suitable for administering to the patient a single dose or multiple doses of about 200 mg of the anti-PD-1 antibody or its antigen-binding fragment when the first administration is performed, and the pharmaceutical composition containing cisplatin is prepared to be suitable for administering to the patient 75 mg / m 2 Single or multiple doses of cisplatin, a pharmaceutical composition containing gemcitabine is prepared to be administered to a patient at a dose of 1.0 g / m2 per week for two consecutive weeks. 2 Single or multiple doses of gemcitabine.

[0107] In another aspect, the present disclosure provides a kit for treating a tumor, comprising a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, and instructions for using the pharmaceutical composition comprising the anti-TIM-3 antibody or an antigen-binding fragment thereof and the pharmaceutical composition comprising the anti-PD-1 antibody or an antigen-binding fragment thereof in combination to treat the tumor.

[0108] In other embodiments, the kit includes a pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof, a pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, and a pharmaceutical composition comprising a chemotherapeutic agent, as well as instructions for using the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof, a pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, and a pharmaceutical composition comprising a chemotherapeutic agent in combination to treat a tumor. In some embodiments, the chemotherapeutic agent is a platinum-based anti-tumor agent and / or an antimetabolite-based anti-tumor agent. In some embodiments, the chemotherapeutic agent is a platinum-based anti-tumor agent and / or a cytosine-based anti-tumor agent. In some embodiments, the chemotherapeutic agent is cisplatin and gemcitabine. In some specific embodiments, the kit includes a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof, a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, a pharmaceutical composition comprising cisplatin, and a pharmaceutical composition comprising gemcitabine, as well as instructions for using the pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof, the pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, the pharmaceutical composition comprising cisplatin, and the pharmaceutical composition comprising gemcitabine in combination to treat a tumor.

[0109] In another aspect, the present disclosure provides a kit for treating a tumor, comprising a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, and instructions for using the pharmaceutical composition comprising the anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof to treat a tumor.

[0110] In other embodiments, the kit includes a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, a pharmaceutical composition comprising a chemotherapeutic agent, and instructions for using the pharmaceutical composition comprising the 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 comprising a chemotherapeutic agent in combination to treat tumors. In some embodiments, the chemotherapeutic agent is a platinum-based anti-tumor drug and / or an antimetabolite-based anti-tumor drug. In some embodiments, the chemotherapeutic agent is a platinum-based anti-tumor drug and / or a cytosine-based anti-tumor drug. In some embodiments, the chemotherapeutic agent is cisplatin and gemcitabine. In some specific embodiments, the kit includes a pharmaceutical composition comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, a pharmaceutical composition comprising cisplatin, and a pharmaceutical composition comprising gemcitabine, and instructions for using the pharmaceutical composition comprising the anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, a pharmaceutical composition comprising cisplatin, and a pharmaceutical composition comprising gemcitabine in combination to treat tumors.

[0111] In another aspect, the present disclosure further provides a drug package for treating tumors, which contains individually packaged pharmaceutical compositions in separate containers, wherein the first container contains a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof, and the second container contains a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof; optionally, the package further comprises one or more other containers, each containing a pharmaceutical composition containing a chemotherapeutic drug. In some embodiments, the chemotherapeutic drug is a platinum-based anti-tumor drug and / or an antimetabolite-based anti-tumor drug. In some embodiments, the chemotherapeutic drug is a platinum-based anti-tumor drug and / or a cytosine-based anti-tumor drug. In some embodiments, the chemotherapeutic drug is cisplatin and gemcitabine. In some specific embodiments, the drug package contains individually packaged pharmaceutical compositions in separate containers, wherein the first container contains a pharmaceutical composition containing an anti-TIM-3 antibody or an antigen-binding fragment thereof, and the second container contains a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof. In some specific embodiments, the drug pack 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, the third container includes a pharmaceutical composition containing cisplatin, and the fourth container includes a pharmaceutical composition containing gemcitabine.

[0112] In another aspect, the present disclosure further provides a drug package for treating tumors, which contains individually packaged pharmaceutical compositions in separate containers, wherein the first container contains 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; optionally, the package further comprises one or more other containers, each containing a pharmaceutical composition containing a chemotherapeutic drug. In some embodiments, the chemotherapeutic drug is a platinum-based anti-tumor drug and / or an antimetabolite anti-tumor drug. In some embodiments, the chemotherapeutic drug is a platinum-based anti-tumor drug and / or a cytosine-based anti-tumor drug. In some embodiments, the chemotherapeutic drug is cisplatin and gemcitabine. In some specific embodiments, the drug package contains individually packaged pharmaceutical compositions in separate containers, wherein the first container contains 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. In some specific embodiments, the drug pack 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, the second container includes a pharmaceutical composition containing cisplatin, and the third container includes a pharmaceutical composition containing gemcitabine.

[0113] In some embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof in the kit or pharmaceutical pack is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof is an injectable solution. In some embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof is a lyophilized formulation.

[0114] In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof in the kit or pharmaceutical pack is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof is an injection. In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized formulation.

[0115] In some embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof in the kit or pharmaceutical pack is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof is an injectable solution. In some embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized formulation. In some embodiments, the pharmaceutical composition containing the chemotherapeutic drug in the kit or pharmaceutical pack is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition containing cisplatin in the kit or pharmaceutical pack is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition containing gemcitabine in the kit or pharmaceutical pack is a liquid pharmaceutical composition or a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition containing cisplatin is an injectable solution. In some embodiments, the pharmaceutical composition containing gemcitabine is an injectable solution. In some embodiments, the pharmaceutical composition containing cisplatin is a powder. In some embodiments, the pharmaceutical composition containing gemcitabine is a powder.

[0116] In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is nasopharyngeal carcinoma.

[0117] Uses of drug combinations

[0118] The present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an effective amount of the pharmaceutical combination of the present disclosure. In addition, the present disclosure also provides a use of the pharmaceutical combination of the present disclosure as a first-line treatment for a tumor in a subject.

[0119] In another aspect, the present disclosure further provides the use of the pharmaceutical combination of the present disclosure in preparing a medicament for treating a tumor in a subject. In addition, the present disclosure further provides the use of the pharmaceutical combination of the present disclosure in preparing a medicament for first-line treatment of a tumor in a subject.

[0120] In some embodiments, in the method or use, the pharmaceutical combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0121] In some embodiments, in the methods or uses, the drug combination comprises an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and a chemotherapy drug. In some embodiments, the chemotherapy drug includes, but is not limited to, one or more of a platinum-based anti-tumor drug, a taxane-based anti-tumor drug, an antimetabolite-based anti-tumor drug, a camptothecin-based anti-tumor drug, a nitrogen mustard-based anti-tumor drug, an anthracycline-based anti-tumor drug, a vinblastine-based anti-tumor drug, a podophylloalkaloid-based anti-tumor drug, and a hormonal anti-tumor drug. In some embodiments, the chemotherapy drug is a platinum-based anti-tumor drug and / or an antimetabolite-based anti-tumor drug. In some embodiments, the chemotherapy drug is a platinum-based anti-tumor drug and / or a cytosine-based anti-tumor drug. In some specific embodiments, the chemotherapy drug is cisplatin and gemcitabine. In some embodiments, in the methods or uses, the drug combination comprises an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, a platinum-based anti-tumor drug, and an antimetabolite-based anti-tumor drug. In some embodiments, in the methods or uses, the drug combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, a platinum-based anti-tumor drug, and a cytosine-based anti-tumor drug. In some embodiments, in the methods or uses, the drug combination comprises an anti-TIM-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, cisplatin, and gemcitabine.

[0122] The present disclosure also provides use of an anti-TIM-3 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is used in combination with the anti-PD-1 antibody antigen-binding fragment of the present disclosure.

[0123] The present disclosure also provides the use of an anti-TIM-3 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is used in combination with the anti-PD-1 antibody antigen-binding fragment of the present disclosure and a chemotherapeutic drug.

[0124] The present disclosure also provides uses of an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody antigen-binding fragment in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is used in combination with a chemotherapeutic drug.

[0125] In some embodiments, the chemotherapy drugs include but are not limited to one or more of platinum anti-tumor drugs, taxane anti-tumor drugs, antimetabolite anti-tumor drugs, camptothecin anti-tumor drugs, nitrogen mustard anti-tumor drugs, anthracycline anti-tumor drugs, vinca alkaloid anti-tumor drugs, podophylloalkaloid anti-tumor drugs, and hormone anti-tumor drugs. In some embodiments, the chemotherapy drugs are platinum anti-tumor drugs and / or antimetabolite anti-tumor drugs. In some embodiments, the chemotherapy drugs are platinum anti-tumor drugs and / or cytosine anti-tumor drugs. In some specific embodiments, the chemotherapy drugs are cisplatin and gemcitabine. In some embodiments, the present disclosure provides the use of an anti-TIM-3 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is used in combination with the anti-PD-1 antibody antigen-binding fragment of the present disclosure, cisplatin and gemcitabine. In some embodiments, the present disclosure provides a use of an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody antigen-binding fragment in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is for use in combination with cisplatin and gemcitabine.

[0126] In some embodiments, the method or use comprises administering to the subject an effective amount of the pharmaceutical combination of the present disclosure in a first treatment phase, and administering to the subject an effective amount of the pharmaceutical combination of the present disclosure in a second treatment phase.

[0127] In some embodiments, the method or use comprises administering to the subject an effective amount of 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 a chemotherapeutic drug in a first treatment phase; and

[0128] In the second treatment phase, the subject is administered an effective amount of a drug combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0129] In some embodiments, the method or use comprises administering to the subject in a first treatment phase an effective amount of 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, a platinum anti-tumor drug, and an antimetabolite anti-tumor drug; and

[0130] In the second treatment phase, the subject is administered an effective amount of a drug combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0131] In some embodiments, the method or use comprises administering to the subject in a first treatment phase an effective amount of 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, a platinum-based anti-tumor drug, and a cytosine-based anti-tumor drug; and

[0132] In the second treatment phase, the subject is administered an effective amount of a drug combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0133] In some embodiments, the method or use comprises administering to the subject an effective amount of 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, cisplatin, and gemcitabine in a first treatment phase; and

[0134] In the second treatment phase, the subject is administered an effective amount of a drug combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0135] In some embodiments, the treatment cycles of the first treatment phase include 1-14 treatment cycles, preferably 2-12 treatment cycles, 2-10 treatment cycles, more preferably 2-8 treatment cycles, for example: 2-8 treatment cycles, 3-8 treatment cycles, 4-8 treatment cycles, 2-7 treatment cycles, 3-7 treatment cycles, 4-7 treatment cycles, 2-6 treatment cycles, 3-6 treatment cycles, or 4-6 treatment cycles; most preferably 4-6 treatment cycles, for example: 4 treatment cycles, 5 treatment cycles, and / or 6 treatment cycles.

[0136] In some embodiments, the second treatment phase is after the first treatment phase. In some embodiments, the second treatment phase continues from the end of the first treatment phase until the patient loses clinical benefit, has unacceptable toxicity, is evaluated as PD, or the investigator deems it inappropriate to continue the medication.

[0137] In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered sequentially. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered simultaneously. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition and can be administered sequentially. In some embodiments, in the methods or uses, the anti-PD-1 antibody or antigen-binding fragment thereof is administered first, followed by the anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition, and the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof is administered first, followed by the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, in the methods or uses, 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 and administered simultaneously.

[0138] In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic drug can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic drug are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, 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, and the single formulation and the chemotherapeutic drug can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, 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, and the single formulation, cisplatin, and gemcitabine can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, 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, and the single formulation and a pharmaceutical composition containing a chemotherapeutic drug can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, 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, and the single formulation, a pharmaceutical composition containing cisplatin, and a pharmaceutical composition containing gemcitabine can be administered simultaneously, sequentially, and / or alternately.

[0139] In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered using the same or different dosing regimens. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered using different dosing regimens.

[0140] In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent are administered in the same or different dosing regimens. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine are administered in the same or different dosing regimens. In some specific embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin, and gemcitabine are administered in different dosing regimens.

[0141] In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once a week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In a specific embodiment, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks. In a specific embodiment, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once 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. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, or a range thereof. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of about 1200 mg or about 1500 mg. 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, at a dose of 1200-1500 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 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of about 1200 mg or about 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 about 1200 mg or about 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 about 1200 mg of the anti-TIM-3 antibody or antigen-binding fragment thereof.

[0142] In some embodiments, in the methods or uses, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once a week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In a specific embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 2 weeks. In a specific embodiment, 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 about 10 mg, about 50 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg, or a range formed by any of the above values. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg. 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, each time at a dose of about 200 mg of the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 2 weeks at a dose of about 200 mg of the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of about 200 mg of the anti-PD-1 antibody or antigen-binding fragment thereof.

[0143] In some embodiments, in the methods or uses, the cisplatin is administered once a week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In some embodiments, in the methods or uses, the cisplatin is administered once every 3 weeks (q3w). In some embodiments, the cisplatin is administered at a dose of 40-80 mg / m 2 , or 40-75 mg / m 2 In some embodiments, the cisplatin is administered at a dose of 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 , 80mg / m 2 , or a dose within the range formed by any of the above values. In some embodiments, the cisplatin is administered once every 3 weeks at a dose of 40 mg / m2 , 60mg / m 2 , 75mg / m 2 , 80mg / m 2 In some embodiments, the cisplatin is administered once every 3 weeks at a dose of 75 mg / m 2 In some embodiments, the cisplatin is administered once every 3 weeks at a dose of 80 mg / m 2 Dosage administration of cisplatin.

[0144] In some embodiments, in the method or use, the gemcitabine is administered once a week. In some embodiments, the gemcitabine is administered at a dose of 0.5-1.0 g / m 2 In some embodiments, the gemcitabine is administered at a dose of 0.5 g / m 2 , 0.75g / m 2 or 1.0g / m 2 In some embodiments, the gemcitabine is administered at a dose of 0.5-1.0 g / m once a week. 2 In some embodiments, the gemcitabine is administered at a dose of 0.5 g / m2 once a week. 2 , 0.75g / m 2 or 1.0g / m 2 In some embodiments, the gemcitabine is administered at a dose of 1.0 g / m once a week. 2 The dose of gemcitabine was administered in a 2-week on-and-1-week dosing schedule.

[0145] In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof have the same or different treatment cycles. In some specific embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof 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 antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof have the same treatment cycle, for example, every 3 weeks is a treatment cycle.

[0146] In some embodiments, in the methods or uses, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment, and the chemotherapy drug have the same or different treatment cycles. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment, cisplatin, and gemcitabine 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, cisplatin, and gemcitabine 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, cisplatin, and gemcitabine have the same treatment cycle, for example, every 3 weeks is a treatment cycle.

[0147] In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are administered in each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are administered once in each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the anti-TIM-3 antibody or its antigen-binding fragment is administered on day 1 of each treatment cycle, and the anti-PD-1 antibody or its antigen-binding fragment is administered on day 1 of each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the anti-TIM-3 antibody or its antigen-binding fragment is administered once on day 1 of each treatment cycle, and the anti-PD-1 antibody or its antigen-binding fragment is administered once on day 1 of each treatment cycle.

[0148] In some embodiments, in the methods or uses, 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. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the single formulation is administered in each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the single formulation is administered once in each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the single formulation is administered on day 1 of each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the single formulation is administered once on day 1 of each treatment cycle.

[0149] In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and about 1200 mg or about 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered in each treatment cycle, and about 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle. In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and about 1200 mg or about 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on day 1 of each treatment cycle, and about 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on day 1 of each treatment cycle. In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and about 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on day 1 of each treatment cycle, and about 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on day 1 of each treatment cycle.

[0150] In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and anti-TIM-3 antibodies or antigen-binding fragments thereof, anti-PD-1 antibodies or antigen-binding fragments thereof, and chemotherapy drugs are administered in each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and anti-TIM-3 antibodies or antigen-binding fragments thereof, anti-PD-1 antibodies or antigen-binding fragments thereof, cisplatin and gemcitabine are administered in each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and anti-TIM-3 antibodies or antigen-binding fragments thereof, anti-PD-1 antibodies or antigen-binding fragments thereof, and cisplatin are administered once and gemcitabine is administered twice in each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and anti-TIM-3 antibodies or antigen-binding fragments thereof, anti-PD-1 antibodies or antigen-binding fragments thereof, and cisplatin are administered on day 1 of each treatment cycle, anti-PD-1 antibodies or antigen-binding fragments thereof are administered on day 1 of each treatment cycle, cisplatin is administered on day 1 of each treatment cycle, and gemcitabine is administered on days 1 and 8 of each treatment cycle. In some embodiments, in the methods or uses, 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, cisplatin is administered once on day 1 of each treatment cycle, and gemcitabine is administered once on day 1 and day 8 of each treatment cycle, respectively.

[0151] In some embodiments, in the methods or uses, 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. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the single formulation and chemotherapy drug are administered in each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the single formulation, cisplatin, and gemcitabine are administered in each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the single formulation, cisplatin, and gemcitabine are administered in each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the single formulation is administered once, cisplatin is administered once, and gemcitabine is administered twice in each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the single formulation is administered on day 1 of each treatment cycle, cisplatin is administered on day 1 of each treatment cycle, and gemcitabine is administered on days 1 and 8 of each treatment cycle. In some embodiments, in the method or use, one treatment cycle is every 3 weeks, the single formulation is administered once on day 1 of each treatment cycle, cisplatin is administered once on day 1 of each treatment cycle, and gemcitabine is administered once on day 1 and day 8 of each treatment cycle.

[0152] In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and about 1200 mg or about 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered in each treatment cycle, about 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle, and 75 mg / m2 is administered in each treatment cycle. 2 Cisplatin, 2.0 g / m2 per treatment cycle 2 In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and about 1200 mg or about 1500 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, about 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 75 mg / m2 is administered on the first day of each treatment cycle. 2 Cisplatin, 1.0 g / m2 on day 1 and day 8 of each treatment cycle 2 In some specific embodiments, in the methods or uses, one treatment cycle is 3 weeks, and about 1200 mg of anti-TIM-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, about 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 75 mg / m2 is administered on the first day of each treatment cycle. 2 Cisplatin, 1.0 g / m2 on day 1 and day 8 of each treatment cycle 2 of gemcitabine.

[0153] 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 (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 of the anti-TIM-3 antibody or its antigen-binding fragment: the anti-PD-1 antibody or its antigen-binding fragment; optionally, the subject is further administered a chemotherapy drug. In some embodiments, the chemotherapy drug is a platinum-based anti-tumor drug and / or an antimetabolite anti-tumor drug. In some embodiments, the chemotherapy drug is a platinum-based anti-tumor drug and / or a cytosine-based anti-tumor drug. In some specific embodiments, the chemotherapy drugs are cisplatin and gemcitabine. 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; optionally, the subject is further administered cisplatin and gemcitabine.

[0154] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered in multiple doses or a single dose in each treatment cycle. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are both administered in multiple doses in each treatment cycle. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof and the chemotherapeutic drug are administered in multiple doses or a single dose in each treatment cycle. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin and gemcitabine are administered in multiple doses or a single dose in each treatment cycle. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin and gemcitabine are both administered in multiple doses in each treatment cycle.

[0155] 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 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 3 mg / kg, 3 to 40 mg / kg, 3 to 35 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, 10 to 40 mg / kg, 10 to 30 mg / kg. kg, 10 to 25 mg / kg, or 20 to 25 mg / 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, 1200-16 A uniform dose of 100 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, 600 mg, 900 mg, 1200 mg, 1500 mg or 1800 mg is administered to the subject.

[0156] 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.

[0157] In some embodiments, in the methods or uses, the dosing regimen (e.g., dosing cycle, dosage, and dose adjustment) of the anti-TIM-3 antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof, and chemotherapy drug (e.g., cisplatin or gemcitabine) can be adjusted according to the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health status of the patient. For example, a treatment cycle of the anti-TIM-3 antibody or antigen-binding fragment thereof and / or anti-PD-1 antibody or antigen-binding fragment thereof 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.

[0158] For example, in some embodiments, a single dose of cisplatin may be 40-80 mg / m 2 , or 40-75 mg / m 2 In some embodiments, a single dose of cisplatin can be 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 or 80 mg / m 2In some embodiments, the single dose of cisplatin may be 50-200 mg. In some embodiments, the dose of cisplatin in a single treatment cycle may be 40-80 mg / m 2 , or 40-75 mg / m 2 In some embodiments, the dosage of cisplatin in a single treatment cycle can be 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 , or 80 mg / m 2 In some embodiments, the dosage of cisplatin administered in a single treatment cycle may be 50-200 mg.

[0159] For example, in some embodiments, the single dose of gemcitabine can be 0.5-1.0 g / m 2 In some embodiments, the single dose of gemcitabine can be 0.5 g / m 2 , 0.75g / m 2 or 1.0g / m 2 In some embodiments, the single dose of gemcitabine can be 0.5-2.5 g. In some embodiments, the dose of gemcitabine in a single treatment cycle can be 1.0-2.0 g / m 2 In some embodiments, the dosage of gemcitabine in a single treatment cycle can be 1.0 g / m 2 , 1.25g / m 2 , 1.5g / m 2 , 1.75g / m 2 or 2.0g / m 2 In some embodiments, the dosage of gemcitabine administered in a single treatment cycle may be 1.0-5.0 g.

[0160] Anti-TIM-3 antibodies or antigen-binding fragments thereof

[0161] In some embodiments, the anti-TIM-3 antibodies or antigen-binding fragments thereof described herein comprise: a heavy chain CDR1 (HCDR1) of the amino acid sequence set forth in SEQ ID NO: 1 or 21, a HCDR2 of the amino acid sequence set forth in SEQ ID NO: 2 or 22, a HCDR3 of the amino acid sequence set forth in SEQ ID NO: 3 or 23, a light chain CDR1 (LCDR1) of the amino acid sequence set forth in SEQ ID NO: 4 or 24, a LCDR2 of the amino acid sequence set forth in SEQ ID NO: 5 or 25, and a LCDR3 of the amino acid sequence set forth in SEQ ID NO: 6 or 26. In some embodiments, the anti-TIM-3 antibodies or antigen-binding fragments thereof described herein comprise: a HCDR1 of the amino acid sequence set forth in SEQ ID NO: 1, a HCDR2 of the amino acid sequence set forth in SEQ ID NO: 2, a HCDR3 of the amino acid sequence set forth in SEQ ID NO: 3, a LCDR1 of the amino acid sequence set forth in SEQ ID NO: 4, a LCDR2 of the amino acid sequence set forth in SEQ ID NO: 5, and a LCDR3 of the amino acid sequence set forth in SEQ ID NO: 6. In some embodiments, the anti-TIM-3 antibodies or antigen-binding fragments thereof described herein comprise: a HCDR1 having an amino acid sequence as set forth in SEQ ID NO: 21, a HCDR2 having an amino acid sequence as set forth in SEQ ID NO: 22, a HCDR3 having an amino acid sequence as set forth in SEQ ID NO: 23, a LCDR1 having an amino acid sequence as set forth in SEQ ID NO: 24, a LCDR2 having an amino acid sequence as set forth in SEQ ID NO: 25, and a LCDR3 having an amino acid sequence as set forth in SEQ ID NO: 26. The CDR sequences of the anti-TIM-3 antibodies or antigen-binding fragments thereof are shown in Table 1.

[0162] Table 1. CDR sequences of anti-TIM-3 antibodies or antigen-binding fragments thereof

[0163] 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 shows CDR sequences (wherein the CDR regions shown in SEQ ID NOs: 1-6 are defined by the AbM numbering system), when referring to antibodies defined by specific CDR sequences disclosed herein, the scope of the antibodies also encompasses antibodies defined by CDR sequences converted to any other numbering system (e.g., one or more combinations of the definitions of Kabat, Chothia, CCG, IMGT, or Contact, which are well known in the art). For example, an anti-TIM-3 antibody or antigen-binding fragment thereof comprising the following amino acid sequence: HCDR1 of the amino acid sequence set forth in SEQ ID NO: 1, HCDR2 of the amino acid sequence set forth in SEQ ID NO: 2, HCDR3 of the amino acid sequence set forth in ARRYYGYDAMDY (SEQ ID NO: 31), LCDR1 of the amino acid sequence set forth in SEQ ID NO: 4, LCDR2 of the amino acid sequence set forth in SEQ ID NO: 5, and LCDR3 of the amino acid sequence set forth in SEQ ID NO: 6 is also encompassed within the scope of the anti-TIM-3 antibodies or antigen-binding fragments thereof of the present disclosure.

[0164] 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 having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 27 and a light chain variable region having the amino acid sequence of 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 set forth in SEQ ID NO: 7, and the amino acid sequence of the light chain variable region is as set forth 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 set forth in SEQ ID NO: 27, and the amino acid sequence of the light chain variable region is as set forth in SEQ ID NO: 28.

[0165] In some embodiments, the anti-TIM-3 antibodies or antigen-binding fragments thereof described herein comprise 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.

[0166] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof may further comprise an immunoglobulin constant region, or a fragment, analog, variant, or derivative of the constant region. 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 derived 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 derived from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any modification described herein, such as insertion, deletion, substitution, or chemical modification of amino acids. In some embodiments, the constant region comprises a mutation that alters effector function. In some embodiments, any amino acid residue in the constant region may be substituted with an amino acid residue of any allotype.

[0167] In some embodiments, the anti-TIM-3 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% identical to the amino acid sequence of SEQ ID NO: 9 or 29, and 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% 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 having the amino acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain having the amino acid sequence of SEQ ID NO: 29 and a light chain having the amino acid sequence of 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 set forth in SEQ ID NO: 9, and the amino acid sequence of the light chain is as set forth 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 set forth in SEQ ID NO: 29, and the amino acid sequence of the light chain is as set forth in SEQ ID NO: 30.

[0168] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure is mAb 50B5 or an antigen-binding fragment thereof described in the patent application document with publication number WO2020041520 or CN112566936A, 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.

[0169] In other embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof disclosed herein is mAb 15B4 or an antigen-binding fragment thereof described in patent application publication No. WO2020041520 or CN112566936A, 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.

[0170] In other embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure is selected from Sabatolimab, Cobolimab, Surzebiclimab, Lomvastomig, SHR-1702 of Hengrui Medicine, INCAGN-2390 of Agenus, BC-3402 of WuXi Biologics, LBL-003 of Weilizhibo, LNL-005 of Jianxin Bio, or BMS-986258 of BMS.

[0171] Anti-PD-1 antibodies or antigen-binding fragments thereof

[0172] In some embodiments, the anti-PD-1 antibodies or antigen-binding fragments thereof described herein comprise: a HCDR1 having an amino acid sequence as set forth in SEQ ID NO: 11, a HCDR2 having an amino acid sequence as set forth in SEQ ID NO: 12, a HCDR3 having an amino acid sequence as set forth in SEQ ID NO: 13, a LCDR1 having an amino acid sequence as set forth in SEQ ID NO: 14, a LCDR2 having an amino acid sequence as set forth in SEQ ID NO: 15, and a LCDR3 having an amino acid sequence as set forth in SEQ ID NO: 16. The CDR sequences of the anti-PD-1 antibodies or antigen-binding fragments thereof are shown in Table 2.

[0173] Table 2. CDR sequences of anti-PD-1 antibodies or antigen-binding fragments thereof

[0174] 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 are shown in Table 2, when referring to antibodies defined by specific CDR sequences, 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 AbM, Kabat, CCG, Chothia, IMGT, or Contact definitions known in the art).

[0175] 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 the amino acid sequence of SEQ ID NO: 17, and a light chain variable region having the amino acid sequence of 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.

[0176] In some embodiments, the anti-PD-1 antibodies or antigen-binding fragments thereof described in the present disclosure comprise 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.

[0177] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment may further comprise an immunoglobulin constant region, 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 IgG1, IgG2, IgG3 and IgG4 or other classes of immunoglobulin heavy chains, preferably IgG1 heavy chains. In some embodiments, the light chain constant region is from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin. 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 alters effector function. In some embodiments, any amino acid residue in the constant region may be substituted with an amino acid residue of any allotype.

[0178] 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% identical to the amino acid sequence of SEQ ID NO: 19, and 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% 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.

[0179] In other embodiments, the anti-PD-1 antibodies or antigen-binding fragments thereof disclosed herein are selected from nivolumab, pembrolizumab, toripalimab, sintilimab, camrelizumab, tislelizumab, zimberelimab, balstilimab, geptanolimab, Livzon Pharmaceuticals L ZM009, Cemiplimab, Serplulimab, Prolgolimab, Pucotenlimab (HX008), Nofazinlimab, Finotonlimab, Dostarlimab, Cetrelimab, Qilu Pharmaceutical QL1604, Spartalizumab, Retifanlimab, Sasanlimab, Rulonilimab (F520), or Shangjian Biotechnology SG001.

[0180] Pharmaceutical compositions containing antibodies or antigen-binding fragments thereof

[0181] In some embodiments, the unit dose of the pharmaceutical composition comprising the anti-TIM-3 antibody or antigen-binding fragment thereof is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg of the anti-TIM-3 antibody or antigen-binding fragment thereof, for example, about 60 mg, about 120 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 300 mg, about 320 mg, about 360 mg, about 400 mg, about 420 mg, about 440 mg, about 480 mg, about 520 mg, about 540 mg, about 560 mg, about 600 mg, about 640 mg, about 660 mg, about 680 mg, about 720 mg, about 760 mg, about 780 mg, about 800 mg, about or an anti-TIM-3 antibody or antigen-binding fragment thereof, or a range thereof, of about 840 mg, about 880 mg, about 900 mg, about 920 mg, about 960 mg, about 1000 mg, about 1020 mg, about 1040 mg, about 1080 mg, about 1120 mg, about 1140 mg, about 1160 mg, about 1200 mg, about 1240 mg, about 1260 mg, about 1280 mg, about 1320 mg, about 1360 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1520 mg, about 1560 mg, about 1600 mg, about 1620 mg, about 1640 mg, about 1680 mg, about 1720 mg, about 1740 mg, about 1760 mg, or about 1800 mg, or a range thereof.

[0182] 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 anti-TIM-3 antibody or its antigen-binding fragment, for example, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg , about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, or a range formed by any of the foregoing values.

[0183] In some embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or antigen-binding fragment thereof may further comprise one or more pharmaceutically acceptable excipients to prepare a suitable formulation. In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof may further comprise one or more pharmaceutically acceptable excipients to prepare a suitable formulation. The formulations include, but are not limited to, tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (i.e., formulations suitable for injection, such as formulations suitable for intramuscular, intravenous, intraperitoneal, or subcutaneous injection), granules, emulsions, suspensions, solutions, dispersions, and sustained-release formulations for oral or parenteral administration.

[0184] In some embodiments, the anti-TIM-3 antibody or its antigen-binding fragment and / or the anti-PD-1 antibody or its antigen-binding fragment are formulated as a formulation for parenteral 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 are formulated as a formulation for intravenous, intramuscular, subcutaneous or other parenteral 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 are formulated as a formulation 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 are formulated as a formulation for intravenous injection or infusion.

[0185] In some embodiments, 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. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated together with one or more pharmaceutically acceptable excipients to form a suitable pharmaceutical composition.

[0186] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated separately (i.e., each in the form of a pharmaceutical composition). In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is formulated together with one or more pharmaceutically acceptable excipients to form a suitable pharmaceutical composition. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is formulated together with one or more pharmaceutically acceptable excipients to form a suitable pharmaceutical composition.

[0187] As used herein, "excipient" is used to describe any ingredient other than the compounds of the present disclosure. The choice of excipient will depend, to a large extent, on factors such as the specific mode of administration, the efficacy of the excipient on solubility and stability, and the nature of the dosage form. As used herein, "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. that are physiologically compatible. Some examples of pharmaceutically acceptable excipients are water, saline, dextrose, glycerol, ethanol, etc., and combinations thereof. In many cases, an isotonic agent is included in the pharmaceutical composition. Other examples of pharmaceutically acceptable excipients are wetting agents or small amounts of auxiliary substances, such as wetting agents or emulsifiers, preservatives or buffers, which increase the shelf life or effectiveness of the antibody.

[0188] In one embodiment, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof is a water-soluble injection. In one embodiment, the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is a water-soluble injection. In one embodiment, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof is a water-soluble injection. Such water-soluble injections include, but are not limited to, unlyophilized water-soluble formulations or water-soluble formulations reconstituted from lyophilized powders.

[0189] In other embodiments, the pharmaceutical composition containing the anti-TIM-3 antibody or its antigen-binding fragment is a lyophilized preparation. In other embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is a lyophilized preparation. In a specific embodiment, 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. 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 disclosure can also be dried by other methods known in the art, such as spray drying and bubble drying.

[0190] In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical composition comprising the anti-PD-1 antibody or antigen-binding fragment thereof 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 antigen-binding fragment thereof is about 0.8 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 15 mg / mL, or about 20 mg / mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is about 1 mg / mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is about 2 mg / mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is about 5 mg / mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is about 10 mg / mL.

[0191] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is in the form of a pharmaceutical composition comprising the 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 pharmaceutical composition (e.g., an injection) comprising the anti-PD-1 antibody or antigen-binding fragment thereof, sodium acetate trihydrate, glacial acetic acid, sorbitol, and polysorbate 80.

[0192] chemotherapy drugs

[0193] In some embodiments of the present disclosure, the chemotherapy drugs include but are not limited to platinum anti-tumor drugs (including but not limited to oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, miplatin, lobaplatin, picoplatin, lebaplatin, triplatin tetranitrate, phenanthreneplatin, satraplatin), camptothecin anti-tumor drugs (including but not limited to camptothecin, hydroxycamptothecin, aminocamptothecin, irinotecan, topotecan, exitecan, rubitecan, lurtotecan, gimatecan, karenitecin, 7-ethylcamptothecin) , taxane anti-tumor drugs (including but not limited to paclitaxel, liposome paclitaxel, albumin-bound paclitaxel and docetaxel), nitrogen mustard anti-tumor drugs (including but not limited to cyclophosphamide, ifosfamide, chlorambucil, carmustine, melphalan, bendamustine), antimetabolite anti-tumor drugs (including but not limited to fluorouracil anti-tumor drugs (including but not limited to carmofur, 5-fluorouracil, tegafur, capecitabine, tegafur, bifurcated pyrimidine, doxorubicin, trifluridine), cytosine anti-tumor drugs (including but not limited to cytarabine, gemcitabine, azacitidine, Anxiidine antitumor drugs), purine antitumor drugs (including but not limited to mercaptopurine and fludarabine), antifolate antitumor drugs (including but not limited to methotrexate and pemetrexed), anthracycline antitumor drugs (including but not limited to doxorubicin, epirubicin, pirarubicin, amrubicin, aclarubicin, idarubicin, daunorubicin, mitoxantrone, idarubicin, valrubicin, daunorubicin, pixantrone, liposomal doxorubicin), vinca alkaloid antitumor drugs (including but not limited to vinblastine, vincristine, vindesine, vinflunine and vinorelbine), podophyllotoxin antitumor drugs One or more of tumor drugs (including but not limited to etoposide and teniposide), hormonal anti-tumor drugs (including but not limited to prednisone, prednisolone, dexamethasone, methylprednisolone sodium succinate), procarbazine, hexamethasone, dacarbazine, mitomycin, actinomycin D (dactinomycin), bleomycin, bleomycin, temozolomide, decamidine, peplomycin, eribulin, plinabulin, sapacitabine, treosulfan, 153Sm-EDTMP, and encequidar.

[0194] In some embodiments, the chemotherapy drug is selected from one or more of a platinum-based anti-tumor drug, a taxane-based anti-tumor drug, and an antimetabolite-based anti-tumor drug. In some embodiments, the chemotherapy drug is a platinum-based anti-tumor drug and / or an antimetabolite-based anti-tumor drug. In some embodiments, the chemotherapy drug is a platinum-based anti-tumor drug and / or a cytosine-based anti-tumor drug.

[0195] Furthermore, the platinum anti-tumor drug is selected from one or more of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miplatin, lobaplatin, levoplatin, triplatin tetranitrate, phenaplatin or satraplatin, preferably carboplatin and / or cisplatin, more preferably cisplatin.

[0196] In some embodiments, the antimetabolite anti-tumor drug is selected from one or more of cytarabine, gemcitabine, azacitidine, or ancitabine, preferably gemcitabine. In some embodiments, the cytosine anti-tumor drug is selected from one or more of cytarabine, gemcitabine, azacitidine, or ancitabine, preferably gemcitabine.

[0197] In some embodiments, the chemotherapy drug is a platinum-based anti-tumor drug and an antimetabolite-based anti-tumor drug. In some embodiments, the chemotherapy drug is a platinum-based anti-tumor drug and a cytosine-based anti-tumor drug. In some specific embodiments, the chemotherapy drug is cisplatin and gemcitabine.

[0198] In some embodiments, the chemotherapy drug is administered according to a known administration regimen (including administration cycle, administration dosage and dosage adjustment, and administration route).

[0199] Gemcitabine

[0200] As used in this disclosure, the chemical name of gemcitabine is 2'-deoxy-2',2'-difluorocytidine (β-isomer), which has the structural formula (I):

[0201] As used in the present disclosure, gemcitabine includes its free base form, also includes pharmaceutically acceptable salts, and the non-salt form or salt are all included in the protection scope of the present disclosure. Gemcitabine can be administered in its free base form, or in the form of its pharmaceutically acceptable salt. For example, the pharmaceutically acceptable salt of gemcitabine is within the scope of the present disclosure, and can be produced by different organic acids and inorganic acids according to methods well 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 gemcitabine can be the hydrochloride of gemcitabine.

[0202] In some embodiments of the present disclosure, gemcitabine is administered in the form of its hydrochloride salt. In some embodiments, gemcitabine is administered in the form of its monohydrochloride salt.

[0203] The dosages of gemcitabine referred to in this disclosure, unless otherwise stated, are based on the molecular weight of the compound of formula (I).

[0204] Pharmaceutical compositions containing chemotherapy drugs

[0205] In some embodiments of the present disclosure, the unit dose of the pharmaceutical composition containing cisplatin is 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg and / or 100 mg of cisplatin. In some embodiments, the unit dose of the pharmaceutical composition containing cisplatin is 20 mg, 30 mg and / or 100 mg of cisplatin. In some embodiments, the unit dose of the pharmaceutical composition containing cisplatin is 30 mg of cisplatin.

[0206] In some embodiments of the present disclosure, the unit dose of the gemcitabine-containing pharmaceutical composition is 0.2 mg or 1.0 mg of gemcitabine.

[0207] In some embodiments, the pharmaceutical composition containing cisplatin is a formulation suitable for injection. In some embodiments, the pharmaceutical composition containing cisplatin is a liquid formulation. In some embodiments, the pharmaceutical composition containing cisplatin is a liquid formulation suitable for injection. In some embodiments, the pharmaceutical composition containing cisplatin is a liquid formulation suitable for intravenous injection. In some embodiments, the pharmaceutical composition containing cisplatin is a lyophilized formulation. In some embodiments, the pharmaceutical composition containing cisplatin is a powder.

[0208] In some embodiments, the pharmaceutical composition containing gemcitabine is a formulation suitable for injection. In some embodiments, the pharmaceutical composition containing gemcitabine is a liquid formulation. In some embodiments, the pharmaceutical composition containing gemcitabine is a liquid formulation suitable for injection. In some embodiments, the pharmaceutical composition containing gemcitabine is a liquid formulation suitable for intravenous injection. In some embodiments, the pharmaceutical composition containing gemcitabine is a lyophilized formulation. In some embodiments, the pharmaceutical composition containing gemcitabine is a powder.

[0209] The liquid preparation suitable for injection can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc. In a specific embodiment, the pharmaceutically acceptable carrier of the liquid preparation suitable for injection containing cisplatin includes polyethylene glycol 400 and sodium chloride. In a specific embodiment, the pharmaceutically acceptable carrier of the liquid preparation suitable for injection containing gemcitabine includes mannitol, sodium acetate, hydrochloric acid and sodium hydroxide.

[0210] Administration

[0211] The following does not limit the mode of administration of the pharmaceutical combination of the present disclosure.

[0212] The components of the pharmaceutical combination of the present disclosure can be administered independently or partially or all thereof together in various suitable routes, including but not limited to oral or parenteral routes (e.g., intravenously, intramuscularly, topically or subcutaneously). In some embodiments, the components of the pharmaceutical combination of the present disclosure can be administered independently or partially or all thereof together orally or by injection, for example, by intravenous or subcutaneous injection.

[0213] The components in the pharmaceutical combination of the present disclosure can be each independently, or part or all of them can be formulated into a suitable dosage form together, including but not limited to, tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal, subcutaneous), granules, powders, emulsions, suspensions, solutions, dispersants and dosage forms of sustained-release preparations for oral or parenteral administration. In some embodiments, the components of the pharmaceutical combination of the present disclosure can each independently, or part or all of them can be formulated into an injection together.

[0214] The components in the pharmaceutical combination of the present disclosure may each independently, or some or all of them may contain a pharmaceutically acceptable carrier and / or excipient.

[0215] The pharmaceutical combination of the present disclosure may further comprise an additional therapeutic agent. In one embodiment, the additional therapeutic agent may be a tumor therapeutic agent known in the art.

[0216] tumor

[0217] In certain aspects, the tumors disclosed herein are malignant tumors (i.e., cancers); malignant tumors refer to any malignant and / or invasive growth caused by abnormal cell growth. In some embodiments, the tumors are solid tumors. In some embodiments, the tumors are treatment-naive, refractory, recurrent, metastatic, and / or advanced solid tumors. In some embodiments, the tumors are recurrent and / or metastatic solid tumors.

[0218] In some embodiments, the tumor is nasopharyngeal carcinoma. In some embodiments, the tumor is treatment-naive, refractory, recurrent, metastatic, and / or advanced nasopharyngeal carcinoma. In some embodiments, the tumor is treatment-naive nasopharyngeal carcinoma. In some embodiments, the tumor is advanced nasopharyngeal carcinoma. In some embodiments, the tumor is advanced treatment-naive nasopharyngeal carcinoma. In some embodiments, the tumor is recurrent nasopharyngeal carcinoma. In some embodiments, the tumor is metastatic nasopharyngeal carcinoma. In some embodiments, the tumor is recurrent and / or metastatic nasopharyngeal carcinoma.

[0219] In some embodiments, the nasopharyngeal carcinoma is differentiated or undifferentiated nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is keratinizing or non-keratinizing nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is undifferentiated non-keratinizing nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is undifferentiated non-keratinizing advanced nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is undifferentiated non-keratinizing recurrent and / or metastatic nasopharyngeal carcinoma.

[0220] In some embodiments, the nasopharyngeal carcinoma is stage IV nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is stage IVb nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is nasopharyngeal carcinoma that is not suitable for local treatment. In some embodiments, the nasopharyngeal carcinoma is stage IVb or recurrent nasopharyngeal carcinoma that is not suitable for local treatment.

[0221] In some embodiments, the subject with nasopharyngeal carcinoma has not been previously treated for nasopharyngeal carcinoma (e.g., lacks an effective treatment regimen). In some embodiments, the subject with nasopharyngeal carcinoma has not previously received systemic therapy to treat nasopharyngeal carcinoma (e.g., has not previously received systemic therapy to treat advanced, previously untreated nasopharyngeal carcinoma). In some embodiments, the subject with nasopharyngeal carcinoma has not previously received radiation therapy, chemotherapy, and / or immunotherapy to treat nasopharyngeal carcinoma.

[0222] In some embodiments, the nasopharyngeal carcinoma is an advanced stage nasopharyngeal carcinoma, and the subject of the advanced stage nasopharyngeal carcinoma has not previously received systemic treatment for nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is an advanced stage nasopharyngeal carcinoma, and the subject of the advanced stage nasopharyngeal carcinoma has not previously received radiotherapy, chemotherapy, and / or immunotherapy for nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is an advanced stage nasopharyngeal carcinoma, and the subject of the advanced stage nasopharyngeal carcinoma has not previously received immune checkpoint (e.g., PD-1 or PD-L1) inhibitors for nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is an advanced stage nasopharyngeal carcinoma, and the subject of the advanced stage nasopharyngeal carcinoma has not previously received systemic treatment and immune checkpoint (e.g., PD-1 or PD-L1) inhibitors for nasopharyngeal carcinoma.

[0223] In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma, and the subject of the recurrent and / or metastatic nasopharyngeal carcinoma has not previously received systemic treatment for the treatment of nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma, and the subject of the recurrent and / or metastatic nasopharyngeal carcinoma has not previously received radiotherapy, chemotherapy, and / or immunotherapy for the treatment of nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma, and the subject of the recurrent and / or metastatic nasopharyngeal carcinoma has not previously received immune checkpoint (e.g., PD-1 or PD-L1) inhibitors for the treatment of nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma, and the subject of the recurrent and / or metastatic nasopharyngeal carcinoma has not previously received systemic treatment and immune checkpoint (e.g., PD-1 or PD-L1) inhibitors for the treatment of nasopharyngeal carcinoma.

[0224] In some embodiments, the subject with nasopharyngeal carcinoma has not previously received systemic therapy for nasopharyngeal carcinoma. In some embodiments, the subject with recurrent and / or metastatic nasopharyngeal carcinoma has not previously received systemic therapy for recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, the subject with advanced nasopharyngeal carcinoma has not previously received systemic therapy for advanced nasopharyngeal carcinoma.

[0225] In some embodiments, the subject with nasopharyngeal carcinoma has not previously received treatment with an immune checkpoint inhibitor for nasopharyngeal carcinoma. In some embodiments, the subject with recurrent and / or metastatic nasopharyngeal carcinoma has not previously received treatment with an immune checkpoint inhibitor for recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, the subject with advanced nasopharyngeal carcinoma has not previously received treatment with an immune checkpoint inhibitor for advanced nasopharyngeal carcinoma.

[0226] In some embodiments, the subject of nasopharyngeal carcinoma has previously been treated for nasopharyngeal carcinoma with one or more different anti-tumor treatments (e.g., treatment failure or intolerance). In some embodiments, the subject of nasopharyngeal carcinoma has previously received a systemic systemic treatment regimen for nasopharyngeal carcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject of nasopharyngeal carcinoma has previously received at least one first-line systemic systemic treatment regimen for nasopharyngeal carcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject of nasopharyngeal carcinoma has previously received neoadjuvant therapy or adjuvant therapy, and radical synchronous chemoradiotherapy to treat nasopharyngeal carcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject of nasopharyngeal carcinoma has previously received immune checkpoint inhibitors to treat nasopharyngeal carcinoma (e.g., treatment failure or intolerance) in the locally advanced stage.

[0227] In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma, and the subject of the recurrent and / or metastatic nasopharyngeal carcinoma has previously received systemic systemic treatment for nasopharyngeal carcinoma (for example, treatment failure or intolerance). In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma, and the subject of the recurrent and / or metastatic nasopharyngeal carcinoma has previously received at least one first-line systemic systemic treatment for nasopharyngeal carcinoma (for example, treatment failure or intolerance). In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma, and the subject of the recurrent and metastatic nasopharyngeal carcinoma has previously received neoadjuvant therapy or adjuvant therapy and radical synchronous chemoradiotherapy to treat nasopharyngeal carcinoma (for example, treatment failure or intolerance). In some specific embodiments, the subject of the recurrent and / or metastatic nasopharyngeal carcinoma has previously received neoadjuvant therapy or adjuvant therapy and radical synchronous chemoradiotherapy to treat nasopharyngeal carcinoma, and during treatment or within 6 months (for example 2,3,4,5 or 6 months) disease progression after stopping treatment. In some embodiments, the subject with recurrent and / or metastatic NPC has received prior immune checkpoint inhibitor treatment for NPC at a locally advanced stage (e.g., treatment failure or intolerance).

[0228] In some embodiments, the nasopharyngeal carcinoma is advanced nasopharyngeal carcinoma, and the subject of the advanced nasopharyngeal carcinoma has previously received a systemic systemic treatment regimen for nasopharyngeal carcinoma (for example, treatment failure or intolerance). In some embodiments, the nasopharyngeal carcinoma is advanced nasopharyngeal carcinoma, and the subject of the advanced nasopharyngeal carcinoma has previously received at least one first-line systemic systemic treatment regimen for nasopharyngeal carcinoma (for example, treatment failure or intolerance). In some embodiments, the nasopharyngeal carcinoma is advanced nasopharyngeal carcinoma, and the subject of the advanced nasopharyngeal carcinoma has previously received neoadjuvant therapy or adjuvant therapy and radical synchronous chemoradiotherapy to treat nasopharyngeal carcinoma (for example, treatment failure or intolerance). In some specific embodiments, the subject of the advanced nasopharyngeal carcinoma has previously received neoadjuvant therapy or adjuvant therapy and radical synchronous chemoradiotherapy to treat nasopharyngeal carcinoma, and the disease progresses within 6 months (for example 2, 3, 4, 5 or 6 months) during treatment or after stopping treatment.

[0229] In some embodiments, the subject of nasopharyngeal carcinoma has previously been treated with one or more of radiotherapy, chemotherapy, and immunotherapy for nasopharyngeal carcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject of nasopharyngeal carcinoma has previously received a platinum-based anti-tumor drug to treat nasopharyngeal carcinoma (e.g., treatment failure). In some embodiments, the subject of nasopharyngeal carcinoma has previously received an immune checkpoint (e.g., PD-1 or PD-L1) inhibitor to treat nasopharyngeal carcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject of nasopharyngeal carcinoma has previously received a platinum-based anti-tumor drug and an immune checkpoint (e.g., PD-1 or PD-L1) inhibitor to treat nasopharyngeal carcinoma (e.g., treatment failure or intolerance).

[0230] In some embodiments, the nasopharyngeal carcinoma is nasopharyngeal carcinoma that has failed immune checkpoint inhibitor treatment. In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma that has failed immune checkpoint inhibitor treatment. In some embodiments, the nasopharyngeal carcinoma is advanced nasopharyngeal carcinoma that has failed immune checkpoint inhibitor treatment.

[0231] In some specific embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma, and the subject of the recurrent and / or metastatic nasopharyngeal carcinoma has previously received a platinum-based anti-tumor drug and an immune checkpoint (e.g., PD-1 or PD-L1) inhibitor to treat nasopharyngeal carcinoma (e.g., treatment failure or intolerance). In some specific embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma, and the subject of the recurrent and / or metastatic nasopharyngeal carcinoma has previously received a platinum-based anti-tumor drug and an immune checkpoint (e.g., PD-1 or PD-L1) inhibitor to treat nasopharyngeal carcinoma, and the disease progresses during treatment or within 6 months (e.g., 2, 3, 4, 5, or 6 months) after stopping treatment.

[0232] In some specific embodiments, the nasopharyngeal carcinoma is advanced nasopharyngeal carcinoma, and the subject of the advanced nasopharyngeal carcinoma has previously received a platinum anti-tumor drug and an immune checkpoint (e.g., PD-1 or PD-L1) inhibitor to treat nasopharyngeal carcinoma (e.g., treatment failure or intolerance). In some specific embodiments, the nasopharyngeal carcinoma is advanced nasopharyngeal carcinoma, and the subject of the advanced nasopharyngeal carcinoma has previously received a platinum anti-tumor drug and an immune checkpoint (e.g., PD-1 or PD-L1) inhibitor to treat nasopharyngeal carcinoma, and the disease progresses during treatment or within 6 months (e.g., 2, 3, 4, 5 or 6 months) after stopping treatment.

[0233] In some embodiments, the immune checkpoint (e.g., PD-1 or PD-L1) inhibitor is an antibody or antigen-binding fragment thereof against an immune checkpoint (e.g., PD-1 or PD-L1), such as Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Balstilimab, Zimberelimab, Atezolizumab, Durvalumab, Avelumab, Envafolimab, or Sugemalimab.

[0234] In some embodiments, the platinum anti-tumor drug includes but is not limited to one or more of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miplatin, lobaplatin, levoplatin, triplatin tetranitrate, phenaplatin, or satraplatin.

[0235] Technical Effects

[0236] In general, use of the above-described pharmaceutical combinations of the present disclosure will help:

[0237] (1) Produce a better therapeutic effect in reducing tumor growth or even eliminating tumors compared to administering either drug alone;

[0238] (2) provide for administration of a smaller amount of the drug than would be possible with either drug alone;

[0239] (3) provide a treatment that is well tolerated by patients and has fewer adverse effects and / or complications than either drug given alone;

[0240] (4) provide better disease control rates among treated patients;

[0241] (5) provide longer survival (e.g., median survival, progression-free survival, or overall survival) in treated patients;

[0242] (6) provide longer survival (e.g., median survival, progression-free survival, or overall survival) for treated patients compared to standard chemotherapy;

[0243] (7) provide a longer duration of disease remission (DOR); and / or

[0244] (8) Compared with the administration of any drug in the combination alone, it has good anti-tumor activity and shows a more excellent anti-tumor synergistic effect.

[0245] The drug combination and treatment regimen disclosed herein have good efficacy in treating nasopharyngeal carcinoma, especially recurrent and / or metastatic nasopharyngeal carcinoma, and have beneficial effects on at least one of ORR, DCR, DOR, PFS, OS, tolerability, and side effects.

[0246] Definition and Description

[0247] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this disclosure, it is intended to refer to the corresponding commercial product or its active ingredient.

[0248] 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 own pharmaceutically acceptable salt or ester derivatives, prodrugs or compositions) administered simultaneously or sequentially. The active ingredients 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.

[0249] 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.

[0250] The term "non-fixed combination" refers to two or more active ingredients administered to a subject as independent entities (e.g., pharmaceutical compositions, formulations) 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, e.g., 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.

[0251] As used herein, the term "antibody" refers to an antigen-binding protein having at least one antigen-binding domain. The antibodies and fragments thereof disclosed herein may be whole antibodies or any fragment thereof. Therefore, the antibodies and fragments thereof disclosed herein include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof. Examples of antibodies and antigen-binding fragments thereof include monospecific antibodies, bispecific antibodies, multispecific antibodies, Fab fragments, Fab' fragments, F(ab)'2 fragments, Fv fragments, isolated CDR regions, single-chain Fv molecules (scFv) and other antibody fragments known in the art. The anti-TIM-3 antibodies and anti-PD-1 antibodies and antigen-binding fragments thereof disclosed herein may be IgG1, IgG2, IgG3 or IgG4 isotypes. The term "isotype" refers to the class of antibodies encoded by the heavy chain constant region gene. The anti-TIM-3 antibodies and antigen-binding fragments thereof and anti-PD-1 antibodies and antigen-binding fragments thereof disclosed herein may be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans. The anti-TIM-3 antibodies and antigen-binding fragments thereof, as well as the anti-PD-1 antibodies and antigen-binding fragments thereof disclosed herein can be murine antibodies, chimeric antibodies, humanized antibodies, or fully human antibodies. Unless otherwise indicated, the "antibodies" disclosed herein include whole antibodies and any antigen-binding fragments (or "antigen-binding portions") or single chains thereof. Conventional "whole antibodies" are glycoproteins comprising two heavy (H) chains and two light (L) chains, the heavy chains and light chains being linked by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region consists of three domains, namely CH1, CH2, and CH3. Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region consists of one domain, CL. The VH and VL regions can also be divided into hypervariable regions, namely complementarity determining regions (CDRs), and framework regions (FRs) whose sequences are relatively conserved. 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 regions of the heavy and light chains contain binding domains that interact with antigens. 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 will be appreciated by those skilled in the art, special "whole antibodies," such as nanobodies, have only heavy (H) chains and no light (L) chains.

[0252] An "antigen-binding fragment" or "antibody binding portion" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen (e.g., TIM-3 or PD-1). It has been demonstrated that the antigen-binding function of an antibody can be performed by fragments of the entire antibody. Examples encompassed by the term "antigen-binding portion / fragment" of an antibody include: (i) Fab fragment: a fragment consisting of V L 、V H The invention relates to a monovalent fragment consisting of a single variable domain (VL), a monovalent fragment consisting of a CL and a 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) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment consisting of a 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 pair 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 by the term antigen-binding portion / fragment. In addition, recombinant polypeptides, fusion proteins, and immunoconjugates comprising the antigen-binding portion / fragment are also encompassed by the term antigen-binding portion / fragment.

[0253] 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.

[0254] "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 contain CDRs derived from one or more murine antibodies and human framework regions and human constant regions. Exemplary humanized antibodies are provided herein. Additional anti-TIM-3 antibodies or variants thereof comprising the HCDRs and LCDRs provided herein can be produced using any human framework sequence and are also included in the present disclosure. Additional anti-PD-1 antibodies or variants thereof comprising the HCDRs and LCDRs provided herein can be produced using any human framework sequence and are also included in the present disclosure. In one embodiment, framework sequences suitable for use in the present disclosure include those 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 reverting mutations 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.

[0255] 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 aligned that are identical to the amino acid residues in the specific amino acid sequence shown in this article, after comparing the sequence to be aligned and, if necessary, introducing gaps to achieve maximum sequence identity, and not considering any conservative substitutions as part of sequence identity. The alignment of amino acid sequences for identity can be performed 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 aligning sequences, including any algorithm needed to obtain maximum alignment over the full length of the comparison sequence.

[0256] The term "treatment" refers to an attempt to change the natural course of a disease in a treated individual, and can be for the purpose of preventing, improving or eliminating a disease or one or more symptoms associated with the disease, including but not limited to preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the disease state, and remission or improved prognosis. The term "effective amount" means (i) treating a specific disease, condition or disorder, (ii) alleviating, improving or eliminating one or more symptoms of a specific disease, condition or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a specific disease, condition or disorder described herein. The amount of the active substance (e.g., an antibody or antigen-binding fragment thereof) constituting a "therapeutically effective amount" can vary according to factors such as the disease state, age, sex and weight of the individual, and the ability of the therapeutic agent or therapeutic agent combination to induce a desired response in the individual. The effective amount can also be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0257] As used herein, the "first treatment phase" refers to the initial treatment phase, which may be an induction treatment phase, and the "second treatment phase" refers to the treatment phase following the initial treatment phase, which may be a maintenance treatment phase.

[0258] The terms "administering" or "administering" refer to the physical introduction of a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0259] The administration routes 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) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral administration routes, such as by injection or infusion. As used herein, the phrase "parenteral administration" refers to a mode of administration that is not enteral, usually 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 over one or more extended time periods.

[0260] The term "flat dose" is used to refer to a dose administered to a patient regardless of the patient's weight or body surface area (BSA). Therefore, a flat dose is specified as an absolute amount of an agent (e.g., an anti-TIM-3 antibody or antigen-binding fragment thereof or an anti-PD-1 antibody or antigen-binding fragment thereof) rather than as a mg / kg dose. For example, a 60 kg person and a 100 kg person would receive the same dose of antibody (e.g., 1200 mg or 1500 mg of an anti-TIM-3 antibody or antigen-binding fragment thereof; or, for example, 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof).

[0261] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, 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.

[0262] As used herein, the terms "subject," "patient," or "subject" are used interchangeably. In some embodiments, the subject, patient, or subject is a mammal. In some embodiments, the subject, patient, or subject is a mouse. In some embodiments, the subject, patient, or subject is a human.

[0263] 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" can mean within 1 or more than 1 standard deviation as practiced in the art. Alternatively, "about" can mean a range of up to ±5%, such as fluctuations within ±2%, within ±1%, or within ±0.5% of the specific numerical range given. When a specific value is given in the present disclosure or claims, unless otherwise indicated, the meaning of "about" should be considered to be within the acceptable error range for that specific value. In this document, unless otherwise indicated, all values ​​for drug doses, times, step parameters, or conditions are modified by "about" by default.

[0264] 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 substances are formulated in a single formulation and administered to a subject simultaneously. Alternatively, part of the active substances are formulated in a single formulation, and the other parts of the active substances are each administered to a subject simultaneously as a single formulation, or sequentially in any order.

[0265] 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 tablets, then one tablet is a single dose; or if a bottle of injection is a single dose. The term "multiple dose" refers to a combination of multiple single doses.

[0266] The term "unit dose" refers to the dose of the active ingredient contained in the smallest packaging unit containing a certain amount of medicine. For example, the dose of antibody contained in a bottle of antibody injection is a unit dose.

[0267] Herein, the terms "pharmaceutical composition" and "formulation" have the same meaning and are used interchangeably.

[0268] The term "recurrent" cancer is a cancer that has regrown at the original site or at a distant site after responding to initial treatment (eg, surgery).

[0269] The term "metastatic" cancer refers to cancer that has spread from one part of the body (such as the nasopharynx) to another part of the body.

[0270] As used herein, "treatment failure" is defined as disease progression or recurrence during or after the last treatment.

[0271] As used herein, a "line of treatment" refers to a position in the sequence of different drugs or other treatments a patient receives. The term "first-line treatment" refers to the drug that can be selected first or the standard treatment based on the patient's condition.

[0272] The words “comprise,” “comprise,” or “comprises,” and variations thereof such as comprises or comprising, should be construed in an open, non-exclusive sense, ie, “including but not limited to.”

[0273] Herein, singular terms encompass plural referents and vice versa unless the context clearly dictates otherwise.

[0274] For the purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present disclosure. All statements regarding the dates of these documents or 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 citation of these publications herein does not constitute an admission that such publications are part of the common general knowledge in the art in any country.

[0275] The present disclosure also provides the following specific implementation schemes, but the protection scope of the present disclosure is not limited thereto:

[0276] Embodiment 1. A pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-TIM-3 antibody or the antigen-binding fragment thereof comprises:

[0277] (1) HCDR1 of the amino acid sequence set forth in SEQ ID NO: 1, HCDR2 of the amino acid sequence set forth in SEQ ID NO: 2, HCDR3 of the amino acid sequence set forth in SEQ ID NO: 3, LCDR1 of the amino acid sequence set forth in SEQ ID NO: 4, LCDR2 of the amino acid sequence set forth in SEQ ID NO: 5, and LCDR3 of the amino acid sequence set forth in SEQ ID NO: 6; or

[0278] (2) 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.

[0279] Embodiment 2. The pharmaceutical combination according to embodiment 1, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises:

[0280] (1) 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

[0281] (2) a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 27, and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 28.

[0282] Embodiment 3. The pharmaceutical combination according to embodiment 1 or 2, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises:

[0283] (1) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 9, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 10; or

[0284] (2) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 29, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 30.

[0285] Embodiment 4. The pharmaceutical combination according to any one of Embodiments 1-3, wherein the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg; preferably, the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof is 240 mg, 300 mg, 360 mg and / or 600 mg.

[0286] Embodiment 5. The drug combination according to any one of Embodiments 1-4, 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.

[0287] Embodiment 6. The drug combination according to any one of Embodiments 1-5, 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.

[0288] Embodiment 7. The drug combination according to any one of Embodiments 1-6, wherein the drug combination is suitable for administration in a single treatment cycle, and comprises 100-1800 mg, 600-1800 mg, 600-1500 mg, or 1200-1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment; preferably, the drug combination is suitable for administration in a single treatment cycle, and comprises 1200 mg or 1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment; more preferably, the drug combination is suitable for administration in a single treatment cycle, and comprises 1200 mg of the anti-TIM-3 antibody or its antigen-binding fragment.

[0289] Embodiment 8. The drug combination according to Embodiment 7, wherein the drug combination further comprises 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof; preferably, the drug combination further comprises 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0290] Embodiment 9. The drug combination according to any one of Embodiments 1-8, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a HCDR1 of the amino acid sequence shown in SEQ ID NO: 11, a HCDR2 of the amino acid sequence shown in SEQ ID NO: 12, a HCDR3 of the amino acid sequence shown in SEQ ID NO: 13, a LCDR1 of the amino acid sequence shown in SEQ ID NO: 14, a LCDR2 of the amino acid sequence shown in SEQ ID NO: 15, and a LCDR3 of the amino acid sequence shown in SEQ ID NO: 16.

[0291] Embodiment 10. The drug combination according to any one of Embodiments 1-9, 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 of 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 of SEQ ID NO: 18.

[0292] Embodiment 11. The drug combination of any one of Embodiments 1-10, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 19, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 20.

[0293] Embodiment 12. The pharmaceutical combination according to any one of Embodiments 1-11, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and / or the anti-PD-1 antibody or antigen-binding fragment thereof is formulated as a preparation for parenteral administration, preferably, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody and / or antigen-binding fragment thereof are formulated as a preparation for intravenous, intramuscular or subcutaneous administration.

[0294] Embodiment 13. The pharmaceutical combination according to any one of Embodiments 1-12, 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.

[0295] Embodiment 14. The pharmaceutical combination according to any one of Embodiments 1-13, 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.

[0296] Embodiment 15. A drug combination comprising the drug combination of any one of embodiments 1-14 and a chemotherapeutic drug.

[0297] Embodiment 16. The pharmaceutical combination according to embodiment 15, wherein the chemotherapy drug is a platinum-based anti-tumor drug and / or an antimetabolite anti-tumor drug;

[0298] Optionally, the platinum anti-tumor drug is selected from one or more of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miplatin, lobaplatin, levoplatin, triplatin tetranitrate, phenanthreneplatin or satraplatin;

[0299] Optionally, the antimetabolite anti-tumor drug is selected from one or more of cytarabine, gemcitabine, azacitidine, and ancitabine.

[0300] Embodiment 17. The drug combination according to embodiment 16, wherein the chemotherapy drugs are cisplatin and gemcitabine.

[0301] Embodiment 18. The pharmaceutical combination according to embodiment 17, wherein the unit dose of gemcitabine is 0.2 g and / or 1.0 g, and the unit dose of cisplatin is 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg and / or 100 mg.

[0302] Embodiment 19. The pharmaceutical combination according to embodiment 17 or 18, wherein the pharmaceutical combination is suitable for administration in a single treatment cycle and the dose of gemcitabine is 1.0-2.0 g / m 2 The dose of cisplatin is 40-80 mg / m 2 or 40-75 mg / m 2 .

[0303] Embodiment 20. Use of the pharmaceutical combination of any one of Embodiments 1-14 for the preparation of a medicament for treating a tumor in a subject.

[0304] Embodiment 21. The use according to Embodiment 20, wherein the tumor is a solid tumor; optionally, the solid tumor is nasopharyngeal carcinoma.

[0305] Embodiment 22. The use according to embodiment 20 or 21, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof can be administered simultaneously, sequentially and / or alternately.

[0306] Embodiment 23. The use according to embodiment 22, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered sequentially.

[0307] Embodiment 24. The use according to any one of Embodiments 20-23, 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; 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 or 1500 mg each time; more preferably, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg each time.

[0308] Embodiment 25. The use according to any one of Embodiments 20-24, 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; 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.

[0309] Embodiment 26. Use of the pharmaceutical combination of any one of Embodiments 15-19 for the preparation of a medicament for treating a tumor in a subject.

[0310] Embodiment 27. The use according to Embodiment 26, wherein the tumor is a solid tumor; optionally, the solid tumor is nasopharyngeal carcinoma.

[0311] Embodiment 28. The use according to embodiment 26 or 27, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof, cisplatin and gemcitabine can be administered simultaneously, sequentially and / or alternately.

[0312] Embodiment 29. The use according to any one of Embodiments 26-28, 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; 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 or 1500 mg each time; more preferably, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg each time.

[0313] Embodiment 30. The use according to any one of Embodiments 26-29, 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; 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.

[0314] Embodiment 31. The use according to any one of embodiments 26-30, wherein the cisplatin is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; optionally, the cisplatin is administered at a dose of 40-80 mg / m 2 , or 40-75 mg / m 2 Preferably, the cisplatin is administered at a dose of 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 , 80mg / m 2 Dosage administration.

[0315] Embodiment 32. The use according to any one of embodiments 26-31, wherein the gemcitabine is administered twice every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; optionally, the gemcitabine is administered at a dose of 0.5-1.0 g / m 2 Preferably, the gemcitabine is administered at a dose of 0.5 g / m 2 , 0.75g / m 2 or 1.0g / m 2 Dosage administration.

[0316] Embodiment 33. A method of treating a tumor in a subject, wherein the method comprises administering to the subject an effective amount of the pharmaceutical combination of any one of embodiments 1-19.

[0317] Embodiment 34. A method of treating a tumor in a subject, wherein the method comprises administering to the subject an effective amount of the drug combination of any one of embodiments 15-19 in a first treatment phase, and administering to the subject an effective amount of the drug combination of any one of embodiments 1-14 in a second treatment phase.

[0318] Embodiment 35. The method according to embodiment 34, wherein the treatment cycles of the first treatment phase include 1-14 treatment cycles, 2-12 treatment cycles or 2-10 treatment cycles, preferably 2-8 treatment cycles, and more preferably 4-6 treatment cycles.

[0319] Embodiment 36. The method of any one of Embodiments 33-35, wherein the tumor is a solid tumor; optionally, the solid tumor is nasopharyngeal carcinoma.

[0320] Embodiment 37. A kit for treating tumors, comprising the drug combination of any one of Embodiments 1-19; optionally, the tumor is a solid tumor; optionally, the solid tumor is nasopharyngeal carcinoma.

[0321] Embodiment 38. A combination drug comprising:

[0322] a) The pharmaceutical combination according to any one of embodiments 15-19, which is formulated to be suitable for administration during the first treatment phase; and

[0323] b) The pharmaceutical combination according to any one of embodiments 1 to 14, which is formulated to be suitable for administration during the second treatment phase.

[0324] Embodiment 39. The combination drug combination according to embodiment 38, wherein the treatment cycles of the first treatment phase include 1-14 treatment cycles, 2-12 treatment cycles or 2-10 treatment cycles, preferably 2-8 treatment cycles, and more preferably 4-6 treatment cycles.

[0325] Embodiment 40. Use of the combination drug described in Embodiment 39 in the preparation of a medicament for treating a tumor in a subject.

[0326] Embodiment 41. The use according to Embodiment 40, wherein the tumor is a solid tumor; optionally, the solid tumor is nasopharyngeal carcinoma. Example

[0327] For the sake of clarity, the present disclosure is further illustrated with examples, but the examples do not limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0328] The entire contents of WO2020041520 or CN112566936A patent application documents are incorporated herein. The heavy chain amino acid sequence of the anti-TIM-3 antibody in the following examples is shown in SEQ ID NO: 9 of the present disclosure, and the light chain amino acid sequence is shown in SEQ ID NO: 10 of the present disclosure.

[0329] The entire contents of the CN106977602A patent application are incorporated herein by reference. 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 disclosure, and the light chain amino acid sequence is shown in SEQ ID NO: 20 of the present disclosure.

[0330] Example 1: Clinical trial of nasopharyngeal carcinoma

[0331] 1. Inclusion Criteria

[0332] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0333] (1) The subjects voluntarily participated in this study and signed the informed consent form (ICF);

[0334] (2) Age: Subjects enrolled in cohort 1: 18-75 years old (at the time of signing the ICF); subjects enrolled in cohort 2: 18-70 years old (at the time of signing the ICF); ECOG PS score: 0-1 points; expected survival time is more than 3 months;

[0335] (3) Enrolled patients meet the following criteria: histologically or cytologically confirmed nasopharyngeal carcinoma, stage IVb according to the 2017 8th edition of the AJCC TNM staging system for nasopharyngeal carcinoma, or recurrent nasopharyngeal carcinoma that is not suitable for local treatment (for neoadjuvant / adjuvant therapy, radical concurrent chemoradiotherapy, if the disease progresses during treatment or within 6 months after stopping treatment, it should be counted as a failure of the original first-line treatment. If it exceeds 6 months, it cannot be counted as a failure of the first-line treatment. All changes in treatment regimen due to drug intolerance are not counted as treatment failures):

[0336] Patients enrolled in Cohort 1 must also meet the following requirements:

[0337] 1) Patients should have received at least first-line treatment for recurrent / metastatic lesions, and the last anti-tumor treatment before enrollment should have evidence of radiographic progression in accordance with RECIST 1.1 standards;

[0338] 2) Patients who have previously failed at least one treatment with platinum-containing chemotherapy and immune checkpoint inhibitors (anti-PD-1 monoclonal antibody / anti-PD-L1 monoclonal antibody, etc.) and have evidence of radiographic progression that meets RECIST 1.1 criteria. Platinum-containing chemotherapy and immunotherapy can be administered during palliative treatment for recurrent / metastatic lesions or during radical treatment for locally advanced disease;

[0339] 3) No more than two lines of immunotherapy for recurrent / metastatic lesions. (For neoadjuvant / adjuvant therapy and radical concurrent chemoradiotherapy, if the disease progresses during treatment or within 6 months after stopping treatment, it should be counted as a failure of the original first-line treatment. If it exceeds 6 months, it is not counted as a failure of the first-line treatment. All changes in treatment regimen due to drug intolerance are not counted as treatment failures);

[0340] 4) The most recent immunotherapy before enrollment, if for recurrence / metastasis, the best efficacy is at least SD (≥6 weeks) or confirmed PR or immunotherapy duration ≥12 weeks.

[0341] Patients enrolled in cohort 2 must also meet the following requirements:

[0342] 1) Patients who have not received systemic anti-tumor treatment for recurrent / metastatic nasopharyngeal carcinoma;

[0343] 2) Patients who have not received treatment with immune checkpoint inhibitors (anti-PD-1 monoclonal antibodies / anti-PD-L1 monoclonal antibodies, etc.) in the local advanced radical treatment stage and have used no more than one immune checkpoint inhibitor (limited to anti-CTLA-4 / PD-1 / PD-L1 monoclonal antibodies) may be included if they meet the following criteria:

[0344] a) If used in the induction phase (with or without other drug treatment), the best efficacy in the induction phase was at least PR;

[0345] b) If used during radical chemoradiotherapy / radiotherapy or the subsequent maintenance phase, there is no imaging or obvious clinical progression during treatment and within 6 months after stopping treatment, and the time of disease progression is more than one year after the completion of radical chemoradiotherapy.

[0346] (4) confirmed to have at least one measurable lesion according to RECIST 1.1 criteria;

[0347] (5) The major organs function normally, that is, they meet the following criteria:

[0348] 1) Routine blood test standards (no blood transfusion and no use of hematopoietic stimulating factor drugs within 14 days before the test):

[0349] a. Hemoglobin (HGB) ≥ 90 g / L;

[0350] b. Neutrophil absolute count (NEUT) ≥ 1.5 × 10 9 / L;

[0351] c. Platelet count (PLT) ≥100×10 9 / L;

[0352] 2) Biochemical examination must meet the following standards:

[0353] a. Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN) (for patients with Gilbert syndrome: TBIL ≤ 3 × ULN);

[0354] b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (for primary hepatobiliary tumors or liver metastases: ALT and AST ≤ 5 × ULN);

[0355] c. Serum creatinine (CR) ≤ 1.5 × ULN or creatinine clearance (CCR) ≥ 60 mL / min;

[0356] 3) Coagulation function must meet the following standards:

[0357] activated partial thromboplastin time (APTT), international normalized ratio (INR), and prothrombin time (PT) ≤ 1.5 × ULN (not receiving anticoagulant therapy);

[0358] 4) Thyroid function tests must meet the following criteria:

[0359] Thyroid-stimulating hormone (TSH) ≤ ULN; if abnormal, T3 and T4 levels should be examined. Patients can be selected if triiodothyronine (T3) and tetraiodothyronine (T4) levels are normal.

[0360] 5) Echocardiogram assessment: left ventricular ejection fraction (LVEF) ≥ 50%.

[0361] (6) 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 / urine pregnancy test should be negative within 7 days before study enrollment, 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.

[0362] 2. Experimental Drugs

[0363] Anti-PD-1 antibody injection is infused first, followed by anti-TIM-3 antibody injection.

[0364] 2.1 Anti-PD-1 Antibody Injection (Specification: 100 mg / 10 mL / bottle): One treatment cycle is 3 weeks (dosing time window: ±3 days). Administer via intravenous infusion at a dose of 200 mg of anti-PD-1 antibody once on the first day of each treatment cycle (i.e., 200 mg, d1 / Q3W).

[0365] 2.2 Anti-TIM-3 Antibody Injection (Specifications: 240 mg / 4 mL / bottle, or 600 mg / 10 mL / bottle): Administer 1200 mg or 1500 mg of anti-TIM-3 antibody once on day 1 of each treatment cycle (i.e., 1200 mg or 1500 mg, d1 / Q3W) via intravenous infusion, with one treatment cycle consisting of 3 weeks (dosing window: ±3 days).

[0366] 2.3 Gemcitabine hydrochloride injection: starting dose 1g / m 2 , administered on days 1 and 8 of each treatment cycle.

[0367] 2.4 Cisplatin injection: starting dose 75 mg / m 2 , administered on day 1 of each treatment cycle.

[0368] 3. Treatment options

[0369] 3.1 Cohort 1: anti-TIM-3 antibody injection (1200 mg or 1500 mg, d1 / Q3W) + anti-PD-1 antibody injection (200 mg, d1 / Q3W).

[0370] 3.2 Cohort 2: After 4-6 cycles of induction treatment with anti-TIM-3 antibody injection (1200 mg, d1 / Q3W) + anti-PD-1 antibody injection (200 mg, d1 / Q3W) + GP chemotherapy regimen (gemcitabine + cisplatin), maintenance treatment was performed with anti-TIM-3 antibody injection (1200 mg, d1 / Q3W) + anti-PD-1 antibody injection (200 mg, d1 / Q3W).

[0371] 4. Evaluation Criteria

[0372] The efficacy evaluation criteria were based on RECIST 1.1, and the iRECIST criteria were used to confirm the efficacy.

[0373] 5. Endpoint indicators

[0374] Objective response rate (ORR), complete response rate (CRR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), etc.;

[0375] Adverse event rate: the occurrence of all adverse events (AEs), serious adverse events (SAEs), and treatment-related adverse events (TRAEs), as well as abnormal laboratory test indicators.

[0376] 6. Results

[0377] Preliminary studies have shown that the drug combination disclosed herein can safely and effectively treat nasopharyngeal carcinoma, especially advanced, recurrent and / or metastatic nasopharyngeal carcinoma.

[0378] In cohort 1, patients with advanced nasopharyngeal carcinoma who had failed immune checkpoint inhibitor treatment had their condition effectively alleviated and controlled after treatment with regimen 3.1.

[0379] In Cohort 2, patients with recurrent / metastatic nasopharyngeal carcinoma achieved effective disease remission and control after treatment with regimen 3.2. As of the data collection date, 13 evaluable patients were enrolled, of whom 9 had partial responses (PRs) and 4 had stable disease (SDs), resulting in an ORR of 69.2% and a DCR of 100%. Details of exemplary patients from Cohort 2 are shown below.

[0380] (1) Patient 001

[0381] The patient was diagnosed with undifferentiated, non-keratinizing nasopharyngeal carcinoma with bone metastasis. He had not received any previous treatment for nasopharyngeal carcinoma.

[0382] The patient received 6 cycles of induction therapy with anti-TIM-3 antibody injection, anti-PD-1 antibody injection, and GP chemotherapy, followed by maintenance therapy with anti-TIM-3 antibody injection and anti-PD-1 antibody injection. The target lesion size and assessment results are shown below:

[0383] During the screening period, target lesion: 34 mm;

[0384] After the second treatment cycle, the target lesion was 28 mm;

[0385] After the fourth treatment cycle, target lesion: 25 mm;

[0386] After the sixth treatment cycle, target lesion: 21 mm;

[0387] After the 8th treatment cycle, the target lesion was 22 mm.

[0388] According to the efficacy evaluation criteria, the best efficacy of the patient was PR.

[0389] (2) Patient 002

[0390] The patient was diagnosed with a newly diagnosed non-keratinizing nasopharyngeal carcinoma with liver and bone metastases. He had not received any previous treatment for nasopharyngeal carcinoma.

[0391] The patient received 6 cycles of induction therapy with anti-TIM-3 antibody injection, anti-PD-1 antibody injection, and GP chemotherapy, followed by maintenance therapy with anti-TIM-3 antibody injection and anti-PD-1 antibody injection. The target lesion size and assessment results are shown below:

[0392] During the screening period, target lesion: 41 mm;

[0393] After the second treatment cycle, the target lesion was 28 mm;

[0394] After the fourth treatment cycle, target lesion: 19 mm;

[0395] After the sixth treatment cycle, target lesion: 17 mm;

[0396] After the 8th treatment cycle, the target lesion was 18 mm.

[0397] According to the efficacy evaluation criteria, the best efficacy of the patient was PR.

[0398] (3) Patient 003

[0399] The patient was diagnosed with undifferentiated, non-keratinizing nasopharyngeal carcinoma, a treatment-naive disease. He had not received any previous treatment for nasopharyngeal carcinoma.

[0400] The patient received 4 cycles of induction therapy with anti-TIM-3 antibody injection, anti-PD-1 antibody injection, and GP chemotherapy, followed by maintenance therapy with anti-TIM-3 antibody injection and anti-PD-1 antibody injection. The target lesion size and assessment results are shown below:

[0401] During the screening period, target lesion: 30.5 mm;

[0402] After the second treatment cycle, the target lesion was 20.3 mm;

[0403] After the fourth treatment cycle, the target lesion was 19.4 mm;

[0404] After the sixth treatment cycle, the target lesion was 19.2 mm;

[0405] After the 8th treatment cycle, the target lesion was 15.3 mm.

[0406] According to the efficacy evaluation criteria, the best efficacy of the patient was PR.

[0407] (4) Patient 004

[0408] The patient was diagnosed with undifferentiated, non-keratinizing nasopharyngeal carcinoma with lung metastasis. He received combined radiotherapy and nimotuzumab at the locally advanced stage.

[0409] Four cycles of induction therapy with anti-TIM-3 antibody injection, anti-PD-1 antibody injection, and GP chemotherapy were performed. The target lesion size and assessment results are shown below:

[0410] During the screening period, target lesion: 35 mm;

[0411] After the second treatment cycle, target lesion: 15 mm;

[0412] After the fourth treatment cycle, the target lesion was 14 mm.

[0413] According to the efficacy evaluation criteria, the best efficacy of the patient was PR.

[0414] (5) Patient 005

[0415] The patient was diagnosed with a newly diagnosed non-keratinizing squamous cell carcinoma of the nasopharynx (T2N3M1, stage IVb) with liver and bone metastases. He had not received prior treatment for nasopharyngeal carcinoma.

[0416] The patient received 6 cycles of induction therapy with anti-TIM-3 antibody injection, anti-PD-1 antibody injection, and GP chemotherapy, followed by maintenance therapy with anti-TIM-3 antibody injection and anti-PD-1 antibody injection. The target lesion size and assessment results are shown below:

[0417] During the screening period, target lesion: 112.36 mm;

[0418] After the second treatment cycle, the target lesion was 77.2 mm;

[0419] After the fourth treatment cycle, the target lesion was 66.4 mm;

[0420] After the sixth treatment cycle, the target lesion was 65.2 mm.

[0421] According to the efficacy evaluation criteria, the best efficacy of the patient was PR.

[0422] (6) Patient 006

[0423] The patient was diagnosed with undifferentiated, non-keratinizing nasopharyngeal carcinoma with multiple cervical and axillary lymph node metastases. He had not received prior treatment for nasopharyngeal carcinoma.

[0424] The patient received 5 cycles of induction therapy with anti-TIM-3 antibody injection, anti-PD-1 antibody injection, and GP chemotherapy. The target lesion size and assessment results are shown below:

[0425] During the screening period, target lesion: 39 mm;

[0426] After the second treatment cycle, the target lesion was 19 mm;

[0427] After the fourth treatment cycle, the target lesion was 13.5 mm.

[0428] According to the efficacy evaluation criteria, the best efficacy of the patient was PR.

[0429] (7) Patient 007

[0430] The patient was diagnosed with undifferentiated, non-keratinizing nasopharyngeal carcinoma with multiple lymph node metastases in the mediastinum and bilateral hilar regions. He had previously received GP chemotherapy with induction chemotherapy, radiotherapy, anti-PD-1 antibody (sintilimab), and cisplatin.

[0431] Four cycles of induction therapy with anti-TIM-3 antibody injection, anti-PD-1 antibody injection, and GP chemotherapy were performed. The target lesion size and assessment results are shown below:

[0432] During the screening period, target lesion: 17 mm;

[0433] After the second treatment cycle, the target lesion was 11 mm.

[0434] According to the efficacy evaluation criteria, the best efficacy of the patient was PR.

[0435] (8) Patient 008

[0436] The patient was diagnosed with undifferentiated, non-keratinizing nasopharyngeal carcinoma with liver metastasis. He had not received any previous treatment for nasopharyngeal carcinoma.

[0437] Four cycles of induction therapy with anti-TIM-3 antibody injection, anti-PD-1 antibody injection, and GP chemotherapy were performed. The target lesion size and assessment results are shown below:

[0438] During the screening period, target lesion: 84 mm;

[0439] After the second treatment cycle, the target lesion was 34 mm.

[0440] According to the efficacy evaluation criteria, the best efficacy of the patient was PR.

[0441] (9) Patient 009

[0442] The patient was diagnosed with undifferentiated, non-keratinizing nasopharyngeal carcinoma with bone metastasis. He had not received any previous treatment for nasopharyngeal carcinoma.

[0443] Treatment plan: Anti-TIM-3 antibody injection + anti-PD-1 antibody injection + GP chemotherapy regimen induction treatment for 3 cycles. The target lesion size and evaluation results are as follows:

[0444] During the screening period, target lesion: 53.4 mm;

[0445] After the second treatment cycle, the target lesion was 19.7 mm.

[0446] According to the efficacy evaluation criteria, the best efficacy of the patient was PR.

Claims

1. A pharmaceutical combination comprising an anti-TIM-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein: The anti-TIM-3 antibody or antigen-binding fragment thereof comprises: (1) HCDR1 of the amino acid sequence set forth in SEQ ID NO: 1, HCDR2 of the amino acid sequence set forth in SEQ ID NO: 2, HCDR3 of the amino acid sequence set forth in SEQ ID NO: 3, LCDR1 of the amino acid sequence set forth in SEQ ID NO: 4, LCDR2 of the amino acid sequence set forth in SEQ ID NO: 5, and LCDR3 of the amino acid sequence set forth in SEQ ID NO: 6; (2) HCDR1 of the amino acid sequence set forth in SEQ ID NO:21, HCDR2 of the amino acid sequence set forth in SEQ ID NO:22, HCDR3 of the amino acid sequence set forth in SEQ ID NO:23, LCDR1 of the amino acid sequence set forth in SEQ ID NO:24, LCDR2 of the amino acid sequence set forth in SEQ ID NO:25, and LCDR3 of the amino acid sequence set forth in SEQ ID NO:26; (3) 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: 7, 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: 8; (4) a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 27, and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 28; (5) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 9, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 10; or (6) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 29, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:

30.

2. The pharmaceutical combination according to claim 1, wherein The unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof is 60-1800 mg, 100-1600 mg, 120-1600 mg, 180-1200 mg, or 240-600 mg; preferably, the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof is 240 mg, 300 mg, 360 mg and / or 600 mg; Optionally, 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.

3. The pharmaceutical combination according to claim 1 or 2, 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.

4. The pharmaceutical combination according to any one of claims 1 to 3, 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 the anti-TIM-3 antibody or its antigen-binding fragment; preferably, the drug combination is suitable for administration in a single treatment cycle, comprising 1200 mg or 1500 mg of the anti-TIM-3 antibody or its antigen-binding fragment; Optionally, the drug combination further comprises 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof; preferably, the drug combination further comprises 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

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: (1) HCDR1 of the amino acid sequence set forth in SEQ ID NO:11, HCDR2 of the amino acid sequence set forth in SEQ ID NO:12, HCDR3 of the amino acid sequence set forth in SEQ ID NO:13, LCDR1 of the amino acid sequence set forth in SEQ ID NO:14, LCDR2 of the amino acid sequence set forth in SEQ ID NO:15, and LCDR3 of the amino acid sequence set forth in SEQ ID NO:16; (2) a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 17, and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 18; or (3) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 19, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:

20.

6. The pharmaceutical combination according to any one of claims 1 to 5, 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 or in a single formulation.

7. A drug combination comprising the drug combination according to any one of claims 1 to 6 and a chemotherapy drug; preferably, the chemotherapy drug is a platinum-based antitumor drug and / or an antimetabolite antitumor drug; Optionally, the platinum anti-tumor drug is selected from one or more of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miplatin, lobaplatin, levoplatin, triplatin tetranitrate, phenanthreneplatin or satraplatin; Optionally, the antimetabolite anti-tumor drug is selected from one or more of cytarabine, gemcitabine, azacitidine, and ancitabine; Optionally, the chemotherapy drugs are cisplatin and gemcitabine.

8. The pharmaceutical combination according to claim 7, wherein the unit dose of gemcitabine is 0.2 g and / or 1.0 g, and the unit dose of cisplatin is 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg and / or 100 mg.

9. Use of the pharmaceutical combination according to any one of claims 1 to 6 in the preparation of a medicament for treating a tumor in a subject; preferably, the tumor is a solid tumor; more preferably, the solid tumor is nasopharyngeal carcinoma.

10. The use according to claim 9, wherein The anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment can be administered simultaneously, sequentially and / or alternately; preferably, the anti-TIM-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are administered sequentially.

11. Use of the pharmaceutical combination according to any one of claims 7-8 in the preparation of a medicament for treating a tumor in a subject; preferably, the tumor is a solid tumor; more preferably, the solid tumor is nasopharyngeal carcinoma.

12. The use according to claim 11, wherein The anti-TIM-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment, cisplatin and gemcitabine can be administered simultaneously, sequentially and / or alternately.

13. The use according to any one of claims 9 to 12, 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; 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 per administration; preferably, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 1200 mg or 1500 mg per administration; Optionally, 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; 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.

14. The use according to any one of claims 11 to 13, wherein The cisplatin is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; Optionally, the cisplatin is administered at a dose of 40-80 mg / m 2 or 40–75 mg / m 2 Preferably, the cisplatin is administered at a dose of 40 mg / m 2 , 60mg / m 2 , 75mg / m 2 , 80mg / m 2 Dosage administration of cisplatin; Optionally, the gemcitabine is administered twice every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; Optionally, the gemcitabine is administered at a dose of 0.5-1.0 g / m 2 Preferably, the gemcitabine is administered at a dose of 0.5 g / m 2 , 0.75g / m 2 or 1.0g / m 2 Dosage administration.

15. A method of treating a tumor in a subject, wherein: The method comprises administering to the subject an effective amount of the drug combination of any one of claims 1 to 8; or, the method comprises administering to the subject an effective amount of the drug combination of any one of claims 7 to 8 in a first treatment phase, and administering to the subject an effective amount of the drug combination of any one of claims 1 to 6 in a second treatment phase; Optionally, the treatment cycle of the first treatment stage is 1-14 treatment cycles, 2-12 treatment cycles or 2-10 treatment cycles, preferably 2-8 treatment cycles, more preferably 4-6 treatment cycles; Optionally, the tumor is a solid tumor; preferably, the solid tumor is nasopharyngeal carcinoma.

16. A combined drug combination comprising: (a) The pharmaceutical combination according to any one of claims 7 to 8, which is prepared for administration in a first treatment phase; and (b) the pharmaceutical combination of any one of claims 1 to 6, which is prepared for administration in the second treatment phase; Optionally, the treatment cycle of the first treatment stage is 1-14 treatment cycles, 2-12 treatment cycles or 2-10 treatment cycles, preferably 2-8 treatment cycles, and more preferably 4-6 treatment cycles.

17. Use of the combined drug combination of claim 16 in the preparation of a medicament for treating a tumor in a subject; preferably, the tumor is a solid tumor; more preferably, the solid tumor is nasopharyngeal carcinoma.