Application of anti-LAG-3 antibody and anti-PD-1 antibody

Abstract

The invention belongs to the field of biological medicines, and particularly relates to application of an anti-LAG-3 antibody and an anti-PD-1 antibody, for example, application in preparation of medicines for treating tumors.

Description

Technical Field

[0001] The present application belongs to the field of biomedicine, and specifically relates to a drug combination of an antibody binding to LAG-3 and an antibody binding to PD-1 and uses thereof. Background Art

[0002] Lymphocyte activation gene-3 (LAG-3) belongs to the immunoglobulin superfamily and is mainly expressed on the surface of activated T cells, NK cells, B cells, plasmacytoid dendritic cells and other cells. LAG-3 has a variety of different ligands, including major histocompatibility complex-II molecule (MHC-II), fibronectin protein 1 (FGL1), galectin-3 and liver sinusoidal endothelial cell lectin (LSECtin). As an immune checkpoint, LAG-3 can negatively regulate T cells and play an important role in maintaining the homeostasis of the body's immune system. However, increasing evidence shows that tumor cells express LAG-3 ligands, which bind to LAG-3 highly expressed on tumor infiltrating lymphocytes (TILs), resulting in T cell dysfunction or even exhaustion, leading to tumor cell immune escape and promoting tumor development.

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

[0004] Lung cancer is one of the malignant tumors with the highest morbidity and mortality rates worldwide. The two main types of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Its prognosis is usually poor. Liver cancer is the seventh most common malignant tumor in the world. However, due to the highly proliferative characteristics of liver cancer cells, the vast majority of liver cancer patients have reached the middle and late stages of the disease when they are first diagnosed. About 70% of patients lose the opportunity for surgery, resulting in short survival and poor prognosis. Nasopharyngeal carcinoma is a malignant tumor derived from the nasopharyngeal epithelium and is a complex disease affected by multiple factors. Nasopharyngeal carcinoma has abundant lymphatic drainage pathways and is prone to recurrence or distant metastasis. Studies have shown that the median survival of nasopharyngeal carcinoma patients with distant metastasis is only 12-15 months. Currently, there are few treatment options for these advanced tumors, and the overall efficacy is limited. This field urgently needs to develop other therapeutic drugs. SUMMARY OF THE INVENTION

[0006] In one aspect, the present application provides a drug combination, which includes an anti-LAG-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 further includes a chemotherapeutic drug. In some embodiments, the drug combination is used to treat a tumor.

[0007] In another aspect, the present application also provides a method for treating a tumor in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical combination of the present application.

[0008] On the other hand, the application also provides the use of the drug combination of the application in the preparation of a drug for treating a tumor in a subject. In some specific embodiments, the application also provides the use of the drug combination of the application in the preparation of a drug for treating a tumor in a subject in a third line or more front line (e.g., second line or first line). In addition, the application also provides the use of the drug combination of the application for treating a tumor in a subject. In some embodiments, the use includes administering a therapeutically effective amount of the drug combination of the application to the subject.

[0009] In another aspect, the present application also provides a method for treating a tumor in a subject, comprising administering to the subject a therapeutically effective amount of the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof of the present application.

[0010] On the other hand, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for treating a tumor in a subject. In some specific embodiments, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for third-line or more front-line (e.g., second-line or first-line) treatment of a tumor in a subject. In addition, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application in the treatment of a tumor in a subject. In some embodiments, the use includes administering to the subject a therapeutically effective amount of the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application.

[0011] On the other hand, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment of the present application 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 or its antigen-binding fragment of the present application. In some specific embodiments, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for third-line or more front-line (e.g., second-line or first-line) treatment of a tumor in a subject, wherein the medicament is used in combination with the anti-PD-1 antibody or its antigen-binding fragment of the present application. On the other hand, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for treating a tumor in combination with the anti-PD-1 antibody or its antigen-binding fragment of the present application.

[0012] On the other hand, the present application also provides the use of an anti-PD-1 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-LAG-3 antibody or its antigen-binding fragment of the present application. In some specific embodiments, the present application also provides the use of the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for third-line or more front-line (e.g., second-line or first-line) treatment of a tumor in a subject, wherein the medicament is used in combination with the anti-LAG-3 antibody or its antigen-binding fragment of the present application. On the other hand, the present application also provides the use of the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for treating a tumor in combination with the anti-LAG-3 antibody or its antigen-binding fragment of the present application.

[0013] In another aspect, the present application also provides a method for treating a tumor in a subject, comprising administering to the subject a therapeutically effective amount of the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and a chemotherapeutic drug of the present application.

[0014] On the other hand, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and the chemotherapeutic drug of the present application in the preparation of a drug for treating a tumor in a subject. In some specific embodiments, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and the chemotherapeutic drug of the present application in the preparation of a drug for the third-line or more front-line (e.g., second-line or first-line) treatment of a tumor in a subject. In addition, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and the chemotherapeutic drug of the present application for treating a tumor in a subject. In some embodiments, the use includes administering a therapeutically effective amount of the anti-LAG-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and the chemotherapeutic drug of the present application to the subject.

[0015] On the other hand, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment of the present application 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 or its antigen-binding fragment of the present application and a chemotherapeutic drug. In some specific embodiments, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for third-line or more front-line (e.g., second-line or first-line) treatment of a tumor in a subject, wherein the medicament is used in combination with the anti-PD-1 antibody or its antigen-binding fragment of the present application and a chemotherapeutic drug. On the other hand, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for treating a tumor in combination with the anti-PD-1 antibody or its antigen-binding fragment of the present application and a chemotherapeutic drug.

[0016] On the other hand, the present application also provides the use of an anti-PD-1 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-LAG-3 antibody or its antigen-binding fragment of the present application and a chemotherapeutic drug. In some specific embodiments, the present application also provides the use of the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for third-line or more front-line (e.g., second-line or first-line) treatment of a tumor in a subject, wherein the medicament is used in combination with the anti-LAG-3 antibody or its antigen-binding fragment of the present application and a chemotherapeutic drug. On the other hand, the present application also provides the use of the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for treating a tumor in combination with the anti-LAG-3 antibody or its antigen-binding fragment of the present application and a chemotherapeutic drug.

[0017] In some embodiments, in the methods and uses, the anti-LAG-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 and uses, the anti-LAG-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 and uses, the anti-LAG-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 and uses, the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof and the chemotherapeutic drug are administered sequentially.

[0018] In some embodiments, in the methods and uses, the anti-LAG-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, in the methods and uses, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks. In some embodiments, in the methods and uses, 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, in the methods and uses, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks.

[0019] In some embodiments, in the methods and uses, the chemotherapeutic drug is administered according to known methods.

[0020] On the other hand, the present application also provides a kit for treating a tumor, which includes the drug combination of the present application. In some specific embodiments, the kit includes an anti-LAG-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, and instructions for combining the anti-LAG-3 antibody or an antigen-binding fragment thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof to treat a tumor. In some specific embodiments, the kit includes an anti-LAG-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and a chemotherapeutic drug, and instructions for combining the anti-LAG-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and a chemotherapeutic drug to treat a tumor.

[0021] In some embodiments, the tumor is a solid tumor. In some specific embodiments, the tumor is hepatocellular carcinoma. In some specific embodiments, the tumor is advanced hepatocellular carcinoma. In some specific embodiments, the tumor is non-small cell lung cancer. In some specific embodiments, the tumor is locally advanced non-small cell lung cancer. In some specific embodiments, the tumor is recurrent or metastatic non-small cell lung cancer. In some specific embodiments, the tumor is nasopharyngeal carcinoma. In some specific embodiments, the tumor is advanced nasopharyngeal carcinoma. In some specific embodiments, the tumor is recurrent or metastatic nasopharyngeal carcinoma. DETAILED DESCRIPTION OF THE INVENTION

[0023] Drug combinations

[0024] In one aspect, the present application provides a pharmaceutical combination comprising an anti-LAG-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0025] In some embodiments, the drug combination further comprises a chemotherapeutic drug. In some embodiments, the chemotherapeutic drug comprises one or more of a platinum anti-tumor drug, a taxane anti-tumor drug, an antimetabolite anti-tumor drug, a camptothecin anti-tumor drug, a nitrogen mustard anti-tumor drug, an anthracycline anti-tumor drug, a vinca alkaloid anti-tumor drug, a podophyllotoxin alkaloid anti-tumor drug, and a hormone anti-tumor drug. In some embodiments, the chemotherapeutic drug comprises a platinum anti-tumor drug and / or an antimetabolite anti-tumor drug. In some embodiments, the chemotherapeutic drug comprises a platinum anti-tumor drug and gemcitabine. In some specific embodiments, the chemotherapeutic drug comprises cisplatin and gemcitabine.

[0026] In some embodiments, the drug combination is packaged in the same kit, and the kit further includes instructions for using the anti-LAG-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-LAG-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 their own medicine boxes, and the medicine box further includes instructions for using the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment in combination to treat tumors.

[0027] In some embodiments, the drug combination is packaged in the same kit, and the kit further includes instructions for using the anti-LAG-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment, and the chemotherapeutic drug in combination to treat tumors. In other embodiments, the anti-LAG-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment, and the chemotherapeutic drug in the drug combination are separately packaged in respective medicine boxes, and the medicine box further includes instructions for using the anti-LAG-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment, and the chemotherapeutic drug in combination to treat tumors.

[0028] In some embodiments, the anti-LAG-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. In some embodiments, the anti-LAG-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. In some embodiments, the pharmaceutical composition containing the anti-LAG-3 antibody or antigen-binding fragment thereof is a liquid preparation or a solid preparation. In some embodiments, the pharmaceutical composition containing the anti-LAG-3 antibody or antigen-binding fragment thereof is an injection. In some embodiments, the pharmaceutical composition containing the anti-LAG-3 antibody or antigen-binding fragment thereof is a lyophilized preparation. In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof is a liquid preparation or a solid preparation. 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 preparation. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single preparation. In some embodiments, the single formulation is a liquid formulation or a solid formulation. In some embodiments, the single formulation is an injection. In some embodiments, the single formulation is a lyophilized formulation.

[0029] In some embodiments, the pharmaceutical composition comprises 80-1800 mg, 120-1200 mg, 140-1000 mg, 160-800 mg, or 400-800 mg of an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, In some embodiments, the pharmaceutical composition comprises 160-800 mg or 400-800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 160 mg, 200 mg, 300 mg, 400 mg, 600 mg or 800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination includes 600 mg of an anti-LAG-3 antibody or antigen-binding fragment thereof.

[0030] In some embodiments, the drug combination includes 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination includes 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof in a range formed by any of the above values. In some embodiments, the drug combination includes 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination includes 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0031] In some embodiments, the drug combination comprises 80-1800 mg, 120-1200 mg, 140-1000 mg, 160-800 mg, or 400-800 mg of an anti-LAG-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 drug combination comprises 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, 800 mg, 820 mg, 840 mg, 860 mg, 880 mg, 900 mg, 920 mg, 940 mg, 960 mg, 980 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, or an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof, or a range formed by any value thereof. In some embodiments, the drug combination includes 160-800 mg or 400-800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination includes 160 mg, 200 mg, 300 mg, 400 mg, 600 mg or 800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination includes 600 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0032] In some embodiments, the drug combination further comprises 1000-1250 mg / m 2Gemcitabine and 80-100 mg / m 2 Cisplatin. In some embodiments, the drug combination further comprises 1000 mg / m 2 Gemcitabine and 80 mg / m 2 Cisplatin.

[0033] In some embodiments, the amount of the anti-LAG-3 antibody or its antigen-binding fragment in the pharmaceutical combination is a daily dose. In some embodiments, the amount of the anti-LAG-3 antibody or its antigen-binding fragment in the pharmaceutical combination is a once-a-day dose. In some embodiments, the amount of the anti-LAG-3 antibody or its antigen-binding fragment in the pharmaceutical combination is a uniform dose. In some embodiments, the amount of the anti-LAG-3 antibody or its antigen-binding fragment in the pharmaceutical combination is a dose for one treatment cycle, and each treatment cycle is 3 weeks.

[0034] In some embodiments, the content of the anti-PD-1 antibody or its antigen-binding fragment in the drug combination is a daily dose. In some embodiments, the content of the anti-PD-1 antibody or its antigen-binding fragment in the drug combination is a once-a-day dose. In some embodiments, the content of the anti-PD-1 antibody or its antigen-binding fragment in the drug combination is a uniform dose. In some embodiments, the content of the anti-PD-1 antibody or its antigen-binding fragment in the drug combination is a dose for one treatment cycle, and each treatment cycle is 3 weeks.

[0035] In some embodiments, the content of gemcitabine in the pharmaceutical combination is a daily dose. In some embodiments, the content of gemcitabine in the pharmaceutical combination is a once-a-day dose.

[0036] In some embodiments, the content of cisplatin in the pharmaceutical combination is a daily dose. In some embodiments, the content of cisplatin in the pharmaceutical combination is a once-a-day dose.

[0037] In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 80-1800 mg, 120-1200 mg, 140-1000 mg, 160-800 mg, or 400-800 mg of an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and comprises 160-800 mg or 400-800 mg of an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 160 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg of an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 600 mg of an anti-LAG-3 antibody or antigen-binding fragment thereof.

[0038] In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof in a range formed by any of the above values. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 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, which includes 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0039] In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes an anti-LAG-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 80-1800 mg, 120-1200 mg, 140-1000 mg, 160-800 mg, or 400-800 mg of an anti-LAG-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 drug combination is suitable for administration in a single treatment cycle and includes 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, 800 mg, 820 mg, 840 mg, 860 mg, 880 mg, 900 mg , 920 mg, 940 mg, 960 mg, 980 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, or an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof, or a range formed by any value thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 160-800 mg or 400-800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 160 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 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 includes 600 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof, and 200 mg of the anti-PD-1 antibody or antigen-binding fragment thereof.

[0040] In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and the drug combination further comprises 1000-3000 mg / m 2 Gemcitabine and 80-100 mg / m 2 Cisplatin. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and the drug combination further comprises 2000 mg / m 2 Gemcitabine and 80 mg / m 2 Cisplatin.

[0041] In some embodiments, in the drug combination, the mass ratio of the anti-LAG-3 antibody or its antigen-binding fragment: the anti-PD-1 antibody or its antigen-binding fragment is (0.1-20):1, (0.5-10):1, (1-10):1, (1-5):1 or 3:1.

[0042] In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-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-LAG-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering 80-1800 mg, 120-1200 mg, 140-1000 mg, 160-800 mg, or 400-800 mg of the anti-LAG-3 antibody or an antigen-binding fragment thereof to a patient, 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 10-800 mg, 50-500 mg, or 100-200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-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-LAG-3 antibody or an antigen-binding fragment thereof is prepared to be suitable for administration to a patient at 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg , 320mg, 340mg, 360mg, 380mg, 400mg, 420mg, 440mg, 460mg, 480mg, 500mg, 520mg, 540mg, 560mg, 580mg, 600mg, 620mg, 640mg, 660mg, 680mg, 700mg, 720mg, 740mg, 760mg, 780mg, 800mg, 820mg, 840mg, 860mg, 8 A single dose or multiple doses of an anti-LAG-3 antibody or an antigen-binding fragment thereof of 80 mg, 900 mg, 920 mg, 940 mg, 960 mg, 980 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, or a range formed by any of the above values, and a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering to a patient for 10 A single dose or multiple doses of an anti-PD-1 antibody or antigen-binding fragment thereof of 1 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, or a range formed by any of the above values.In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-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-LAG-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering 160-800 mg or 400-800 mg of the anti-LAG-3 antibody or an antigen-binding fragment thereof to a patient, 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 100-200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-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-LAG-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering 160 mg, 200 mg, 300 mg, 400 mg, 600 mg or 800 mg of the anti-LAG-3 antibody or an antigen-binding fragment thereof to a patient, 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 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-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-LAG-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering 600 mg of the anti-LAG-3 antibody or an antigen-binding fragment thereof to a patient, 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 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient.

[0043] In some embodiments, the pharmaceutical combination further comprises a pharmaceutical composition comprising gemcitabine and a pharmaceutical composition comprising cisplatin, wherein the pharmaceutical composition comprising gemcitabine is prepared to be suitable for administration to a patient at a dose of 1000-1250 mg / m 2 A single dose or multiple doses of gemcitabine, wherein the pharmaceutical composition containing cisplatin is prepared to be suitable for administering 80-100 mg / m 2 In some embodiments, the pharmaceutical composition containing gemcitabine is prepared to be suitable for administering 1000 mg / m 2 A single dose or multiple doses of gemcitabine, wherein the pharmaceutical composition containing cisplatin is prepared to be suitable for administering 80 mg / m 2 Single or multiple doses of cisplatin.

[0044] On the other hand, the present application provides a kit for treating tumors, the kit comprising a pharmaceutical composition containing an anti-LAG-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, and instructions for combining the pharmaceutical composition containing an anti-LAG-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof to treat tumors. On the other hand, the present application provides a kit for treating tumors, the kit comprising a pharmaceutical composition containing an anti-LAG-3 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, and a chemotherapeutic drug, and instructions for combining the pharmaceutical composition containing an anti-LAG-3 antibody or an antigen-binding fragment thereof, a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof, and a chemotherapeutic drug to treat tumors. In some embodiments, the pharmaceutical composition containing an anti-LAG-3 antibody or an antigen-binding fragment thereof is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing an anti-LAG-3 antibody or an antigen-binding fragment thereof is an injection. In some specific embodiments, the pharmaceutical composition containing an anti-LAG-3 antibody or an antigen-binding fragment thereof is a lyophilized preparation. In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is an injection. In some specific embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is a lyophilized preparation.

[0045] In some specific embodiments, the tumor is a solid tumor. In some specific embodiments, the tumor is hepatocellular carcinoma. In some specific embodiments, the tumor is advanced hepatocellular carcinoma. In some specific embodiments, the tumor is non-small cell lung cancer. In some specific embodiments, the tumor is locally advanced non-small cell lung cancer. In some specific embodiments, the tumor is recurrent or metastatic non-small cell lung cancer. In some specific embodiments, the tumor is nasopharyngeal carcinoma. In some specific embodiments, the tumor is advanced nasopharyngeal carcinoma. In some specific embodiments, the tumor is recurrent or metastatic nasopharyngeal carcinoma.

[0046] use

[0047] In one aspect, the present application also provides a method for treating a tumor in a subject, comprising administering the drug combination of the present application to the subject. In addition, the present application also provides a method for treating a tumor in a subject, comprising administering the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application to the subject. In addition, the present application also provides a method for treating a tumor in a subject, comprising administering the anti-LAG-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and a chemotherapeutic drug to the subject. In addition, the present application also provides a method for treating a tumor in a subject, comprising administering a therapeutically effective amount of the drug combination of the present application to the subject. In addition, the present application also provides a method for treating a tumor in a subject, comprising administering a therapeutically effective amount of the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application to the subject. In addition, the present application also provides a method for treating a tumor in a subject, comprising administering a therapeutically effective amount of the anti-LAG-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and a chemotherapeutic drug to the subject.

[0048] On the other hand, the present application also provides the use of the drug combination of the present application in the preparation of a drug for treating a tumor in a subject. In some specific embodiments, the present application also provides the use of the drug combination of the present application in the preparation of a drug for third-line or more front-line (e.g., second-line or first-line) treatment of a tumor in a subject. In addition, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a drug for treating a tumor in a subject. In some specific embodiments, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a drug for third-line or more front-line (e.g., second-line or first-line) treatment of a tumor in a subject. In addition, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and the chemotherapeutic drug of the present application in the preparation of a drug for treating a tumor in a subject. In some specific embodiments, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and the chemotherapeutic drug of the present application in the preparation of a medicament for the third-line or higher-line (e.g., second-line or first-line) treatment of a tumor in a subject.

[0049] On the other hand, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment of the present application 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 or its antigen-binding fragment of the present application. In some specific embodiments, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for treating a tumor in a subject in the third line or more front line (e.g., second line or first line), wherein the medicament is used in combination with the anti-PD-1 antibody or its antigen-binding fragment of the present application. In addition, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment of the present application 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 or its antigen-binding fragment of the present application and a chemotherapeutic drug. In some specific embodiments, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for treating a tumor in a subject in the third line or more front line (e.g., second line or first line), wherein the medicament is used in combination with the anti-PD-1 antibody or its antigen-binding fragment of the present application and a chemotherapeutic drug. In addition, the present application also provides the use of an anti-PD-1 antibody or an antigen-binding fragment thereof in the preparation of a drug for treating a tumor in a subject, wherein the drug is used in combination with the anti-LAG-3 antibody or its antigen-binding fragment of the present application. In some specific embodiments, the present application also provides the use of an anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a drug for treating a tumor in a subject in the third line or more front line (e.g., second line or first line), wherein the drug is used in combination with the anti-LAG-3 antibody or its antigen-binding fragment of the present application. In addition, the present application also provides the use of an anti-PD-1 antibody or its antigen-binding fragment in the preparation of a drug for treating a tumor in a subject, wherein the drug is used in combination with the anti-LAG-3 antibody or its antigen-binding fragment of the present application and a chemotherapeutic drug. In some specific embodiments, the present application also provides the use of an anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a drug for treating a tumor in a subject in the third line or more front line (e.g., second line or first line), wherein the drug is used in combination with the anti-LAG-3 antibody or its antigen-binding fragment of the present application and a chemotherapeutic drug.

[0050] On the other hand, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment of the present application in the preparation of a drug for treating tumors in combination with the anti-PD-1 antibody or its antigen-binding fragment of the present application. In addition, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment of the present application in the preparation of a drug for treating tumors in combination with the anti-PD-1 antibody or its antigen-binding fragment of the present application and chemotherapeutic drugs. In addition, the present application also provides the use of the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a drug for treating tumors in combination with the anti-LAG-3 antibody or its antigen-binding fragment of the present application. In addition, the present application also provides the use of the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a drug for treating tumors in combination with the anti-LAG-3 antibody or its antigen-binding fragment of the present application and chemotherapeutic drugs.

[0051] In some embodiments, in the method or use, the anti-LAG-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 method or use, the anti-LAG-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 method or use, the anti-PD-1 antibody or antigen-binding fragment thereof is administered first, and then the anti-LAG-3 antibody or antigen-binding fragment thereof is administered. In some embodiments, in the method or use, the anti-LAG-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 method or use, the anti-LAG-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 administered sequentially. In some embodiments, in the methods or uses, the anti-LAG-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-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single preparation.

[0052] In some embodiments, in the methods and uses, the anti-LAG-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 and uses, the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic drug are administered sequentially. In some embodiments, in the methods or uses, the anti-PD-1 antibody or antigen-binding fragment thereof is administered first, then the anti-LAG-3 antibody or antigen-binding fragment thereof is administered, and then the chemotherapeutic drug is administered. In some embodiments, in the methods or uses, the anti-LAG-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-LAG-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 administered sequentially. In some embodiments, in the methods or uses, the anti-LAG-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 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-LAG-3 antibody or antigen-binding fragment thereof, and then the pharmaceutical composition containing the chemotherapeutic drug. In some embodiments, in the methods or uses, the anti-LAG-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 is administered first, followed by the pharmaceutical composition containing the chemotherapeutic drug.

[0053] In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered in the same or different dosing regimens. In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered in different dosing regimens. In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic drug are administered in the same or different dosing regimens. In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic drug are administered in different dosing regimens.

[0054] In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 4 weeks. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 80-1800 mg, 120-1200 mg, 140-1000 mg, 160-800 mg, or 400-800 mg each time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 160-800 mg or 400-800 mg per administration. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 160 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg each time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 600 mg each time. In some embodiments, the anti-LAG-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 80-1800 mg, 120-1200 mg, 140-1000 mg, 160-800 mg, or 400-800 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof.In some embodiments, the anti-LAG-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 160-800 mg or 400-800 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-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 160 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 160-800 mg or 400-800 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of 160 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of 600 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof.

[0055] In some embodiments, in the method or use, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In some specific embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 3 weeks. In some specific embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 4 weeks. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 10-800 mg, 50-500 mg, or 100-200 mg each time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 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 100-200 mg each time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 200 mg each time. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 10-800 mg, 50-500 mg, or 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 200 mg of anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 3 weeks, each time at a dose of 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 200 mg of the anti-PD-1 antibody or antigen-binding fragment thereof.

[0056] In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 0.1-50 mg / kg, 0.1-40 mg / kg, 0.1-30 mg / kg, 0.1-20 mg / kg, 0.1-10 mg / kg, 1-50 mg / kg, 1-40 mg / kg, 1-30 mg / kg, 1-20 mg / kg, 1-10 mg / kg, 3-50 mg / kg, 3-40 mg / kg, 3-30 mg / kg, 3-20 mg / kg, 3-10 mg / kg, 1-5 mg / kg, or 3-5 mg / kg per administration. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 0.1 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, or a range formed by any of the above values. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 1-10 mg / kg each time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 3 mg / kg, 5 mg / kg or 10 mg / kg each time. In some embodiments, the anti-LAG-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 0.1-50 mg / kg, 0.1-40 mg / kg, 0.1-30 mg / kg, 0.1-20 mg / kg, 0.1-10 mg / kg, 1-50 mg / kg, 1-40 mg / kg, 1-30 mg / kg, 1-20 mg / kg, 1-10 mg / kg, 3-50 mg / kg, 3-40 mg / kg, 3-30 mg / kg, 3-20 mg / kg, 3-10 mg / kg, 1-5 mg / kg, or 3-5 mg / kg. In some embodiments, the anti-LAG-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 1-10 mg / kg. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of 1-10 mg / kg each time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of 3 mg / kg, 5 mg / kg or 10 mg / kg each time.

[0057] In some embodiments, in the method or use, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 0.1-50 mg / kg, 0.1-40 mg / kg, 0.1-30 mg / kg, 0.1-20 mg / kg, 0.1-10 mg / kg, 1-50 mg / kg, 1-40 mg / kg, 1-30 mg / kg, 1-20 mg / kg, 1-10 mg / kg, 3-50 mg / kg, 3-40 mg / kg, 3-30 mg / kg, 3-20 mg / kg, 3-10 mg / kg, 1-5 mg / kg, or 3-5 mg / kg each time. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 0.1 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, or a range formed by any of the above values. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 1-5 mg / kg each time. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 2 mg / kg, 3 mg / kg or 5 mg / kg each time. 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 0.1-50 mg / kg, 0.1-40 mg / kg, 0.1-30 mg / kg, 0.1-20 mg / kg, 0.1-10 mg / kg, 1-50 mg / kg, 1-40 mg / kg, 1-30 mg / kg, 1-20 mg / kg, 1-10 mg / kg, 3-50 mg / kg, 3-40 mg / kg, 3-30 mg / kg, 3-20 mg / kg, 3-10 mg / kg, 1-5 mg / kg, or 3-5 mg / kg. 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 1-5 mg / kg. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of 1-5 mg / kg each time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of 2 mg / kg, 3 mg / kg or 5 mg / kg each time.

[0058] In some embodiments, in the methods and uses, the chemotherapeutic drug is administered according to known methods. For example, gemcitabine is administered twice every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In some specific embodiments, gemcitabine is administered twice every 3 weeks. In some embodiments, gemcitabine is administered at 1000-1250 mg / m 2 In some embodiments, gemcitabine is administered at a dose of 1000 mg / m 2 In some embodiments, gemcitabine is administered twice every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at 1000-1250 mg / m 2 In some embodiments, gemcitabine is administered twice every 3 weeks at 1000-1250 mg / m 2 In some embodiments, gemcitabine is administered twice every 3 weeks at 1000 mg / m 2 For example, cisplatin is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In some specific embodiments, cisplatin is administered once every 3 weeks. In some embodiments, cisplatin is administered at 80-100 mg / m 2 In some embodiments, cisplatin is administered at a dose of 80 mg / m 2 In some embodiments, cisplatin is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at 80-100 mg / m 2 In some embodiments, cisplatin is administered once every 3 weeks at a dose of 80-100 mg / m 2 In some embodiments, cisplatin is administered once every 3 weeks at 80 mg / m 2 dosage administration.

[0059] In some embodiments, in the methods or uses, the anti-LAG-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, respectively. In some specific embodiments, the anti-LAG-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, one treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some specific embodiments, the anti-LAG-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, one treatment cycle is every 3 weeks.

[0060] In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic drug have the same or different treatment cycles, respectively. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic drug have the same treatment cycle, for example, one treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic drug have the same treatment cycle, for example, one treatment cycle is every 3 weeks.

[0061] In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and anti-LAG-3 antibodies or antigen-binding fragments thereof and anti-PD-1 antibodies or antigen-binding fragments thereof are administered in each treatment cycle. In some specific embodiments, every 3 weeks is a treatment cycle, and anti-LAG-3 antibodies or antigen-binding fragments thereof and anti-PD-1 antibodies or antigen-binding fragments thereof are administered once in each treatment cycle. In some specific embodiments, every 3 weeks is a treatment cycle, and anti-LAG-3 antibodies or antigen-binding fragments thereof are administered on day 1 of each treatment cycle, and anti-PD-1 antibodies or antigen-binding fragments thereof are administered on day 1 of each treatment cycle. In some specific embodiments, every 3 weeks is a treatment cycle, and anti-LAG-3 antibodies or antigen-binding fragments thereof are administered once on day 1 of each treatment cycle, and anti-PD-1 antibodies or antigen-binding fragments thereof are administered once on day 1 of each treatment cycle.

[0062] In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, and 80-1800 mg, 120-1200 mg, 140-1000 mg, 160-800 mg, or 400-800 mg of anti-LAG-3 antibody or its antigen-binding fragment is administered in each treatment cycle, and 10-800 mg, 50-500 mg, or 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, and 160-800 mg or 400-800 mg of anti-LAG-3 antibody or its antigen-binding fragment is administered in each treatment cycle, and 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, and 160-800 mg or 400-800 mg of anti-LAG-3 antibody or antigen-binding fragment thereof is administered on the first day of each treatment cycle, and 100-200 mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered on the first day of each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, and 160 mg, 200 mg, 300 mg, 400 mg, 600 mg or 800 mg of anti-LAG-3 antibody or antigen-binding fragment thereof is administered on the first day of each treatment cycle, and 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered on the first day of each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, and 600 mg of anti-LAG-3 antibody or antigen-binding fragment thereof is administered on the first day of each treatment cycle, and 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered on the first day of each treatment cycle.

[0063] In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and anti-LAG-3 antibody or its antigen-binding fragment, anti-PD-1 antibody or its antigen-binding fragment and chemotherapeutic drugs are administered in each treatment cycle. In some specific embodiments, every 3 weeks is a treatment cycle, anti-LAG-3 antibody or its antigen-binding fragment is administered on day 1 of each treatment cycle, anti-PD-1 antibody or its antigen-binding fragment is administered on day 1 of each treatment cycle, gemcitabine is administered on day 1 and day 8 of each treatment cycle, and cisplatin 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, 160-800 mg or 400-800 mg of anti-LAG-3 antibody or its antigen-binding fragment is administered in each treatment cycle, 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle, and 1000-3000 mg / m2 Gemcitabine, 80–100 mg / m2 per treatment cycle 2 Cisplatin. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 160-800 mg or 400-800 mg of anti-LAG-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 1000 mg / m2 is administered on the first and eighth days of each treatment cycle. 2 Gemcitabine, 80 mg / m2 on day 1 of each treatment cycle 2 Cisplatin. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 600 mg of anti-LAG-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 1000 mg / m2 is administered on the first and eighth days of each treatment cycle. 2 Gemcitabine, 80 mg / m2 on day 1 of each treatment cycle 2 Cisplatin.

[0064] In some embodiments, in each treatment cycle, the anti-LAG-3 antibody or antigen binding fragment thereof and the anti-PD-1 antibody or antigen binding fragment thereof are administered to the subject at a mass ratio of (0.1-20): 1, (0.5-10): 1, (1-10): 1, (1-5): 1 or 3: 1 of anti-LAG-3 antibody or antigen binding fragment thereof: anti-PD-1 antibody or antigen binding fragment thereof. In some embodiments, in each treatment cycle, the anti-LAG-3 antibody or antigen binding fragment thereof and the anti-PD-1 antibody or antigen binding fragment thereof are administered to the subject at a mass ratio of (0.1-20): 1, (0.5-10): 1, (1-10): 1, (1-5): 1 or 3: 1 of anti-LAG-3 antibody or antigen binding fragment thereof: anti-PD-1 antibody or antigen binding fragment thereof, and the chemotherapeutic drug is further administered.

[0065] In some embodiments, in the methods or uses, the dosing regimen (e.g., dosing cycle, dosing dose, and dose adjustment) of the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof can be adjusted according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. For example, one treatment cycle of the anti-LAG-3 antibody or antigen-binding fragment thereof and / or the 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.

[0066] In some embodiments, in the method or use, the dosing regimen of the chemotherapeutic drug (e.g., dosing cycle, dosing dose, and dose adjustment) can be adjusted according to the severity of the disease, the response of the disease, any treatment-related toxicity, and the age and health status of the patient.

[0067] Anti-LAG-3 antibodies or antigen-binding fragments thereof

[0068] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof described herein comprises: a heavy chain CDR1 (HCDR1) of the amino acid sequence of SEQ ID NO: 1 or 21, a HCDR2 of the amino acid sequence of SEQ ID NO: 2 or 22, a HCDR3 of the amino acid sequence of SEQ ID NO: 3 or 23, a light chain CDR1 (LCDR1) of the amino acid sequence of SEQ ID NO: 4 or 24, a LCDR2 of the amino acid sequence of SEQ ID NO: 5 or 25, and a LCDR3 of the amino acid sequence of SEQ ID NO: 6 or 26. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof described herein comprises: a HCDR1 of the amino acid sequence of SEQ ID NO: 1, a HCDR2 of the amino acid sequence of SEQ ID NO: 2, a HCDR3 of the amino acid sequence of SEQ ID NO: 3, a LCDR1 of the amino acid sequence of SEQ ID NO: 4, a LCDR2 of the amino acid sequence of SEQ ID NO: 5, and a LCDR3 of the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof described herein comprises: HCDR1 of the amino acid sequence shown in SEQ ID NO: 21, HCDR2 of the amino acid sequence shown in SEQ ID NO: 22, HCDR3 of the amino acid sequence shown in SEQ ID NO: 23, LCDR1 of the amino acid sequence shown in SEQ ID NO: 24, LCDR2 of the amino acid sequence shown in SEQ ID NO: 25, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 26. The CDR sequences of the anti-LAG-3 antibody or antigen-binding fragment thereof are shown in Table 1.

[0069] Table 1. CDR sequences of anti-LAG-3 antibodies or antigen-binding fragments thereof

[0070]

[0071] It will be understood by those skilled in the art that, unless otherwise specified, the term "CDR" or "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass complementarity determining regions defined by any known scheme. Although Table 1 has shown CDR sequences, however, when referring to anti-LAG-3 antibodies or antigen-binding fragments thereof defined by specific CDR sequences, the scope of the anti-LAG-3 antibodies or antigen-binding fragments thereof encompasses anti-LAG-3 antibodies or antigen-binding fragments thereof defined by any numbering system (e.g., a combination of one or more of the AbM, Kabat, Chothia, CCG, IMGT or Contact definitions known in the art).

[0072] In some embodiments, the anti-LAG-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 set forth in SEQ ID NO: 7 or 27. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8 or 28. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO: 7. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a light chain variable region set forth in SEQ ID NO: 8. In some embodiments, the anti-LAG-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.

[0073] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO:1, a HCDR2 comprising the amino acid sequence of SEQ ID NO:2, a HCDR3 comprising the amino acid sequence of SEQ ID NO:3, a LCDR1 comprising the amino acid sequence of SEQ ID NO:4, a LCDR2 comprising the amino acid sequence of SEQ ID NO:5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:6; and the anti-LAG-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, and 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. The amino acid sequence shown in NO:8 has a light chain variable region 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.

[0074] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region of the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO: 27, and a light chain variable region of the amino acid sequence set forth in SEQ ID NO: 28. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-LAG-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-LAG-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.

[0075] QVQLQQWGAGLLRPSETLSLTCAVYGESFSGYYWNWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISSVDTSKTQFSLKLSSVTAADTAVYYCARGWDLLDWNDYWNEYWGQGTLVTVSS(SEQ ID NO:7);

[0076] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK(SEQ ID NO:8);

[0077] EVQLLESGGGLVQPGGSLRLSCAASGFDFRSYAMMWVRQAPGKGLEWVGGINGEVGGSNTYYAPA VKGRATISRDNSKNTLYLQMNSLRAEDTAVYYCVKGAGACGICNDIDIDAWGQGTLVTVSS (SEQ ID NO: 27);

[0078] SYELTQDPAVSVALGQTVRITCSGAGSYAGSYYYGWHQQKPGQAPVTVIYDNDKRPSNIPDRFSGSSSGNTASLTITGAQAEDEADYYCGSTNDNDDGGLFGSGTKVTVL (SEQ ID NO: 28).

[0079] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof may further comprise a constant region of an immunoglobulin, or a fragment, analog, variant or derivative of the constant region. In some embodiments, the constant region comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is from a human immunoglobulin heavy chain, such as a heavy chain of IgG1, IgG2, IgG3 and IgG4 or other classes of immunoglobulins, preferably a heavy chain of IgG1. In some embodiments, the light chain constant region is from a human immunoglobulin light chain, such as a κ light chain or a λ light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any modification described in the text, such as insertion, deletion, substitution and / 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.

[0080] In some embodiments, the anti-LAG-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. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10 or 30. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the heavy chain set forth in SEQ ID NO: 9. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the light chain set forth in SEQ ID NO: 10. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:9 or 29, and a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:10 or 30. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO: 9, and a light chain having an amino acid sequence as shown in SEQ ID NO: 10. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO: 29, and a light chain having an amino acid sequence as shown in SEQ ID NO: 30. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-LAG-3 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 9, and the amino acid sequence of the light chain is as shown in SEQ ID NO: 10. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-LAG-3 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 29, and the amino acid sequence of the light chain is as shown in SEQ ID NO: 30.Among them, the terminal amino acid K of SEQ ID NO:9 and 29 may or may not be present.

[0081] QVQLQQWGAGLLRPSETLSLTCAVYGESFSGYYWNWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKTQFSLKLSSVTAADTAVYYCARGWDLLDWNDYWNEYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:9);

[0082] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:10);

[0083] EVQLLESGGGLVQPGGSLRLSCAASGFDFRSYAMMWVRQAPGKGLEWVGGINGEVGGSNTYYAPAVKGRATISRDNSKNTLYLQMNSLRAEDTAVYYCVKGAGACGICNDDIDAWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:29);

[0084] SYELTQDPAVSVALGQTVRITCSGAGSYAGSYYYGWHQQKPGQAPVTVIYDNDKRPSNIPDRFSGSSSGNTASLTITGAQAEDEADYYCGSTNDNDDGGLFGSGTKVTVLRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:30)。

[0085] Anti-PD-1 antibody or antigen-binding fragment thereof

[0086] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof described herein comprises: HCDR1 of the amino acid sequence shown in SEQ ID NO: 11, HCDR2 of the amino acid sequence shown in SEQ ID NO: 12, HCDR3 of the amino acid sequence shown in SEQ ID NO: 13, LCDR1 of the amino acid sequence shown in SEQ ID NO: 14, LCDR2 of the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 16. The CDR sequences of the anti-PD-1 antibody or antigen-binding fragment thereof are shown in Table 2.

[0087] Table 2. CDR sequences of anti-PD-1 antibodies or antigen-binding fragments thereof

[0088] HCDR1 GFAFSSYD SEQ ID NO:11 HCDR2 ISGGGRYT SEQ ID NO:12 HCDR3 ANRYGEAWFAY SEQ ID NO:13 LCDR1 QDINTY SEQ ID NO:14 LCDR2 RAN SEQ ID NO:15 LCDR3 LQYDEFPLT SEQ ID NO:16

[0089] 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, however, when it comes to defining anti-PD-1 antibodies or antigen-binding fragments thereof with specific CDR sequences, the scope of the anti-PD-1 antibodies or antigen-binding fragments thereof encompasses anti-PD-1 antibodies or antigen-binding fragments thereof defined by any numbering system (e.g., a combination of one or more of the definitions of AbM, Kabat, Chothia, CCG, IMGT or Contact, etc., which are well known in the art).

[0090] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region as shown in SEQ ID NO: 17. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region as shown in SEQ ID NO:18. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18.

[0091] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 11, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 12, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 13, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 14, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 15, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; and 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 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: 18. The amino acid sequence shown in NO:18 has a light chain variable region 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.

[0092] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 18. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 17, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 18.

[0093] EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKG RFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSS(SEQ ID NO:17);

[0094] DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELK (SEQ ID NO: 18).

[0095] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment may further comprise a constant region of an immunoglobulin, or a fragment, analog, variant or derivative of the constant region. In some embodiments, the constant region comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is from a human immunoglobulin heavy chain, such as a heavy chain of IgG1, IgG2, IgG3 and IgG4 or other classes of immunoglobulins, preferably a heavy chain of IgG1. In some embodiments, the light chain constant region is from a human immunoglobulin light chain, such as a κ light chain or a λ light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any modification described in the text, such as insertion, deletion, substitution and / or chemical modification of amino acids. In some embodiments, the constant region comprises a mutation that changes effector function. In some embodiments, any amino acid residue in the constant region may be substituted with an amino acid residue of any allotype.

[0096] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 19. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain as set forth in SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19, and a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO: 19, and a light chain having an amino acid sequence as shown in SEQ ID NO: 20. In some specific embodiments, the heavy chain amino acid sequence of the anti-PD-1 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 19, and the light chain amino acid sequence is as shown in SEQ ID NO: 20. The terminal amino acid K of SEQ ID NO: 19 may be present or absent.

[0097] EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPSCDKTHT CPPCPAPEAAGAPSVFLPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLPG(SEQ ID NO:19);

[0098] DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:20).

[0099] In some other embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the present application is selected from: Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Zimberelimab, Balstilimab, geptanolimab, Lipustobar t(LZM-009), Cemiplimab, Serplulimab, Prolgolimab, Putlimab (HX008), Nofazinlimab, Finotonlimab, Dostarlimab, Cetrelimab, Qilu Pharmaceutical's QL1604, Spartalizumab, Retifanlimab, Sasanlimab, Shandong New Times Pharmaceutical's Rulonilimab (F520), or Shangjian Bio's Enlonstobart (SG001).

[0100] Pharmaceutical composition containing antibody or antigen-binding fragment thereof

[0101] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated as a formulation for parenteral administration. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated as a formulation for intravenous, intramuscular, subcutaneous or other parenteral administration, such as for injection or infusion. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated as a formulation for intravenous, intramuscular or subcutaneous administration. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated as a formulation for intravenous injection or infusion.

[0102] The anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated into a suitable dosage form, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (i.e., preparations suitable for injection, such as preparations suitable for intramuscular, intravenous, intraperitoneal, subcutaneous injections), granules, emulsions, suspensions, solutions, dispersions, and sustained-release preparations for oral or parenteral administration. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated into an injection (e.g., an injection solution or a lyophilized preparation for injection). In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated into an injection solution suitable for intravenous injection.

[0103] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is formulated with one or more pharmaceutically acceptable carriers to prepare a suitable pharmaceutical composition.

[0104] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof can be formulated as a formulation for parenteral administration. In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof can be formulated as a formulation for intravenous, intramuscular, subcutaneous or other parenteral administration, such as for injection or infusion. In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof can be formulated as a formulation for intravenous, intramuscular or subcutaneous administration. In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof can be formulated as a formulation for intravenous injection or infusion.

[0105] The anti-PD-1 antibody or its antigen-binding fragment can be formulated into a suitable dosage form, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (i.e., preparations suitable for injection, such as preparations suitable for intramuscular, intravenous, intraperitoneal, subcutaneous injection), granules, emulsions, suspensions, solutions, dispersions, and sustained-release preparations for oral or parenteral administration. In some specific embodiments, the anti-PD-1 antibody or its antigen-binding fragment can be formulated into an injection (e.g., an injection solution or a lyophilized preparation for injection). In some specific embodiments, the anti-PD-1 antibody or its antigen-binding fragment can be formulated into an injection solution suitable for intravenous injection.

[0106] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is formulated with one or more pharmaceutically acceptable carriers to prepare a suitable pharmaceutical composition.

[0107] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated separately.

[0108] In some embodiments, the anti-LAG-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-LAG-3 body or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof are formulated together with one or more pharmaceutically acceptable carriers to prepare a suitable pharmaceutical composition.

[0109] Pharmaceutically acceptable carriers include, for example, excipients, diluents, encapsulating materials, fillers, buffers or other agents.

[0110] In some embodiments, the pharmaceutical composition containing the anti-LAG-3 antibody or antigen-binding fragment thereof is an aqueous injection. In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof is an aqueous injection. In some embodiments, a single formulation containing the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof is an aqueous injection. The aqueous injection includes but is not limited to an aqueous formulation that has not been lyophilized or an aqueous formulation reconstituted with a lyophilized powder.

[0111] In other embodiments, the pharmaceutical composition containing anti-LAG-3 antibodies or antigen-binding fragments thereof is a lyophilized preparation for injection. In other embodiments, the pharmaceutical composition containing anti-PD-1 antibodies or antigen-binding fragments thereof is a lyophilized preparation for injection. In other embodiments, a single formulation containing anti-LAG-3 antibodies or antigen-binding fragments thereof and anti-PD-1 antibodies or antigen-binding fragments thereof is a lyophilized preparation for injection. The lyophilized preparation for injection refers to a preparation prepared by a freeze-drying process of an aqueous solution, in which the substance is first frozen, and then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (secondary drying process) until the amount of solvent is a value that no longer supports biological activity or chemical reaction. The lyophilized preparation of the present application can also be dried by other methods known in the art, such as spray drying and bubbling drying (bubbledrying).

[0112] In some embodiments, the unit dose of the pharmaceutical composition comprising the anti-LAG-3 antibody or antigen-binding fragment thereof is 10-1000 mg, 20-800 mg, 40-600 mg, 80-400 mg, or 100-300 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof, for example, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, or a range formed by any of the foregoing values ​​of the anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the unit dose of the pharmaceutical composition comprising the anti-LAG-3 antibody or antigen-binding fragment thereof is 100 mg, 160 mg, 200 mg and / or 300 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the unit dose of the pharmaceutical composition comprising the anti-LAG-3 antibody or antigen-binding fragment thereof is 160 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof.

[0113] In some embodiments, the unit dose of the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is 10-500 mg, 50-500 mg, 50-200 mg, or 100-200 mg of the anti-PD-1 antibody or its antigen-binding fragment, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 In some embodiments, the unit dose of the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is 100 mg and / or 200 mg of the anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the unit dose of the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is 100 mg and / or 200 mg of the anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the unit dose of the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is 100 mg of the anti-PD-1 antibody or its antigen-binding fragment.

[0114] Chemotherapy drugs

[0115] The chemotherapeutic drugs of the present application include but are not limited to platinum anti-tumor drugs (including but not limited to oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, miplatin, lobaplatin, picoplatin, triplatin tetranitrate, phenanthridine, 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. Drugs (including but not limited to 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, bifurouracil, doxifluridine, trifluridine), cytosine anti-tumor drugs (including but not limited to cytarabine, gemcitabine, azacitidine, ancitabine), purine anti-tumor drugs Anti-cancer drugs (including but not limited to mercaptopurine, fludarabine), anti-folate anti-cancer drugs (including but not limited to methotrexate, pemetrexed)), anthracycline anti-cancer drugs (including but not limited to doxorubicin, epirubicin, pirarubicin, amrubicin, aclarubicin, idarubicin, daunorubicin, mitoxantrone, idarubicin, valrubicin, zorubicin, pixantrone, liposomal doxorubicin), vinca alkaloid anti-cancer drugs (including but not limited to vinblastine, vincristine, vindesine, vinflunine and vinorelbine), One or more of podophyllotoxin alkaloid anti-tumor drugs (including but not limited to etoposide and teniposide), hormone anti-tumor drugs (including but not limited to prednisone, prednisolone, dexamethasone, methylprednisolone sodium succinate), procarbazine, hexamethonium, dacarbazine, mitomycin, actinomycin D (dactinomycin), bleomycin, bleomycin, temozolomide, decarbazine, peplomycin, eribulin, plinabulin, sapacitabine, and treosulfan.

[0116] In some embodiments, the chemotherapy drugs include platinum anti-tumor drugs, taxane anti-tumor drugs and / or anti-metabolite anti-tumor drugs. In some embodiments, the chemotherapy drugs include platinum anti-tumor drugs and / or anti-metabolite anti-tumor drugs.

[0117] Furthermore, the platinum anti-tumor drug is selected from one or more of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miplatin, lobaplatin, triplatin tetranitrate, phenaplatin and satraplatin, for example, carboplatin or cisplatin.

[0118] In some embodiments, the antimetabolite anti-tumor drug is selected from one or more of 5-fluorouracil, capecitabine, cytarabine, gemcitabine, azacitidine, fludarabine, methotrexate, and pemetrexed, for example, gemcitabine.

[0119] In some specific embodiments, the chemotherapeutic drugs include cisplatin and gemcitabine.

[0120] 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).

[0121] Pharmaceutical composition containing chemotherapeutic drugs

[0122] In some embodiments, 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 10 mg, 20 mg, 30 mg, 50 mg and / or 100 mg of cisplatin.

[0123] In some embodiments, the unit dose of the gemcitabine-containing pharmaceutical composition is 200 mg and / or 1000 mg of gemcitabine.

[0124] Mode of administration

[0125] The following content does not limit the administration mode of the drug combination of the present application.

[0126] Each component in the drug combination of the present application can be administered independently or partly or all thereof in various suitable routes, including but not limited to parenteral (e.g., by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, each component in the drug combination of the present application can be administered independently or partly or all thereof in injection, such as intravenous or subcutaneous injection.

[0127] The pharmaceutical combination of the present application may further comprise an additional therapeutic agent. In some embodiments, the additional therapeutic agent may be a tumor therapeutic agent known in the art.

[0128] Tumor

[0129] The tumor described in the present application is a malignant tumor (ie, cancer); the malignant tumor refers to any malignant and / or invasive growth caused by abnormal cell growth.

[0130] In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is a treatment-naive, unresectable, refractory, advanced, recurrent and / or metastatic solid tumor.

[0131] In some embodiments, the solid tumor is liver cancer. In some embodiments, the tumor is liver cancer. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the liver cancer is hepatocellular carcinoma that is newly treated, unresectable, refractory, advanced, recurrent and / or metastatic. In some embodiments, the liver cancer is unresectable hepatocellular carcinoma. In some embodiments, the liver cancer is refractory hepatocellular carcinoma. In some embodiments, the liver cancer is advanced hepatocellular carcinoma. In some embodiments, the liver cancer is locally advanced hepatocellular carcinoma. In some embodiments, the liver cancer is recurrent hepatocellular carcinoma. In some embodiments, the liver cancer is metastatic hepatocellular carcinoma. In some embodiments, the liver cancer is refractory, metastatic and / or recurrent hepatocellular carcinoma. In some embodiments, the liver cancer is refractory and / or recurrent hepatocellular carcinoma. In some embodiments, the liver cancer is metastatic and / or recurrent hepatocellular carcinoma.

[0132] In some embodiments, the liver cancer is untreated hepatocellular carcinoma (e.g., lack of an effective treatment regimen). In some embodiments, the liver cancer is hepatocellular carcinoma that has not been treated with surgery, radiotherapy, chemotherapy, and / or immunotherapy. In some embodiments, the liver cancer is hepatocellular carcinoma that has not been treated with systemic therapy. In some embodiments, the liver cancer is hepatocellular carcinoma that has not been treated with immunotherapy. In some embodiments, the liver cancer is advanced hepatocellular carcinoma that has not been treated with systemic therapy. In some embodiments, the liver cancer is advanced hepatocellular carcinoma that has not been treated with immunotherapy.

[0133] In some embodiments, the subject of hepatocellular carcinoma has not been previously treated for hepatocellular carcinoma (e.g., lack of an effective treatment regimen). In some embodiments, the subject of hepatocellular carcinoma has not previously received surgery, radiotherapy, chemotherapy, and / or immunotherapy to treat hepatocellular carcinoma. In some embodiments, the subject of hepatocellular carcinoma has not previously received systemic treatment to treat hepatocellular carcinoma. In some embodiments, the subject of hepatocellular carcinoma has not previously received immunotherapy to treat hepatocellular carcinoma. In some embodiments, the subject of hepatocellular carcinoma has not previously received systemic treatment to treat advanced hepatocellular carcinoma. In some embodiments, the subject of hepatocellular carcinoma has not previously received immunotherapy to treat advanced hepatocellular carcinoma.

[0134] In some embodiments, the subject of hepatocellular carcinoma has previously been treated for hepatocellular carcinoma with one or more different anti-tumor therapies (e.g., treatment failed or is not applicable). In some embodiments, the subject of hepatocellular carcinoma has previously been treated for hepatocellular carcinoma with no more than two anti-tumor therapies (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of hepatocellular carcinoma has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and / or adjuvant chemotherapy to treat hepatocellular carcinoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of hepatocellular carcinoma has previously received systemic treatment to treat hepatocellular carcinoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of hepatocellular carcinoma has previously received first-line or second-line treatment to treat hepatocellular carcinoma (e.g., treatment failed or is not applicable).

[0135] In some embodiments, the liver cancer is hepatocellular carcinoma with a CNLC stage of III or a BCLC stage of C. In some embodiments, the liver cancer is hepatocellular carcinoma with a CNLC stage of II or a BCLC stage of B. In some embodiments, the liver cancer is hepatocellular carcinoma that is not suitable for local treatment or is refractory to local treatment. In some embodiments, the liver cancer is hepatocellular carcinoma with a CNLC stage of II that is not suitable for local treatment or is refractory to local treatment. In some embodiments, the liver cancer is hepatocellular carcinoma with a BCLC stage of B that is not suitable for local treatment or is refractory to local treatment. In some embodiments, the subject of the liver cancer has not previously received immunotherapy to treat hepatocellular carcinoma. In some embodiments, the local treatment includes but is not limited to surgery, transarterial chemoembolization (TACE), hepatic artery embolization (TAI), radiofrequency or microwave ablation, anhydrous alcohol injection, and radiotherapy.

[0136] In some embodiments, the hepatocellular carcinoma is Child-Pugh grade A or B hepatocellular carcinoma.

[0137] In some embodiments, the solid tumor is non-small cell lung cancer. In some embodiments, the tumor is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is treatment-naive, unresectable, refractory, advanced, recurrent and / or metastatic non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is unresectable non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is refractory non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is locally advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is recurrent non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is metastatic non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is refractory, metastatic and / or recurrent non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is refractory and / or recurrent non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is metastatic and / or recurrent non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is stage IIIB, stage IIIC, or stage IV non-small cell lung cancer.

[0138] In some embodiments, the non-small cell lung cancer is a squamous non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is a non-squamous non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is an adenocarcinoma (also known as adenocarcinoma of the lung). In some embodiments, the non-small cell lung cancer is a large cell carcinoma (also known as large cell carcinoma of the lung). In some embodiments, the non-small cell lung cancer is an adenosquamous carcinoma (also known as adenosquamous carcinoma of the lung).

[0139] In some embodiments, the non-small cell lung cancer does not have a driver gene mutation, and the driver gene includes but is not limited to: EGFR, ALK, ROS1, BRAF, NTRK, MET and / or KRAS. In some embodiments, the non-small cell lung cancer does not have an EGFR mutation. In some embodiments, the non-small cell lung cancer does not have an ALK fusion. In some embodiments, the non-small cell lung cancer does not have a ROS1 mutation.

[0140] In some embodiments, the non-small cell lung cancer is PD-L1 positive non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is PD-L1 positive advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is PD-L1 positive locally advanced, metastatic and / or recurrent non-small cell lung cancer.

[0141] In some embodiments, the non-small cell lung cancer is untreated non-small cell lung cancer (e.g., lack of an effective treatment regimen). In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that has not been treated with surgery, radiotherapy, chemotherapy, and / or immunotherapy. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that has not been treated systemically. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer that has not been treated systemically. In some embodiments, the non-small cell lung cancer is locally advanced, metastatic, and / or recurrent non-small cell lung cancer that has not been treated systemically. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer that has not been treated systemically and is positive for PD-L1 expression. In some embodiments, the non-small cell lung cancer is locally advanced, metastatic, and / or recurrent non-small cell lung cancer that has not been treated systemically and is positive for PD-L1 expression.

[0142] In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer that is not suitable for surgery and radical concurrent chemoradiotherapy. In some embodiments, the non-small cell lung cancer is an advanced non-small cell lung cancer that is not suitable for surgery and radical concurrent chemoradiotherapy. In some embodiments, the non-small cell lung cancer is a locally advanced, metastatic and / or recurrent non-small cell lung cancer that is not suitable for surgery and radical concurrent chemoradiotherapy. In some embodiments, the non-small cell lung cancer is an advanced non-small cell lung cancer that has not been systemically treated and is not suitable for surgery and radical concurrent chemoradiotherapy. In some embodiments, the non-small cell lung cancer is a locally advanced, metastatic and / or recurrent non-small cell lung cancer that has not been systemically treated and is not suitable for surgery and radical concurrent chemoradiotherapy. In some embodiments, the non-small cell lung cancer is a PD-L1-positive advanced non-small cell lung cancer that has not been systemically treated and is not suitable for surgery and radical concurrent chemoradiotherapy. In some embodiments, the non-small cell lung cancer is a PD-L1-positive locally advanced, metastatic and / or recurrent non-small cell lung cancer that has not been systemically treated and is not suitable for surgery and radical concurrent chemoradiotherapy.

[0143] In some embodiments, the non-small cell lung cancer is unresectable advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is unresectable locally advanced, metastatic and / or recurrent non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is unresectable advanced non-small cell lung cancer without systemic treatment. In some embodiments, the non-small cell lung cancer is unresectable locally advanced, metastatic and / or recurrent non-small cell lung cancer without systemic treatment. In some embodiments, the non-small cell lung cancer is PD-L1 positive, unresectable advanced non-small cell lung cancer without systemic treatment. In some embodiments, the non-small cell lung cancer is PD-L1 positive, unresectable locally advanced, metastatic and / or recurrent non-small cell lung cancer without systemic treatment.

[0144] In some embodiments, the subject of non-small cell lung cancer has previously been treated with one or more different anti-tumor therapies for non-small cell lung cancer (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of non-small cell lung cancer has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and / or adjuvant chemotherapy to treat non-small cell lung cancer (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of non-small cell lung cancer has previously received neoadjuvant or adjuvant therapy (e.g., chemotherapy or radiotherapy) to treat non-small cell lung cancer (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of non-small cell lung cancer has previously received systemic therapy to treat non-small cell lung cancer (e.g., treatment failed or is not applicable).

[0145] In some embodiments, the solid tumor is nasopharyngeal carcinoma. In some embodiments, the tumor is nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is a newly treated, unresectable, refractory, advanced, recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is an unresectable nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is a refractory nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is an advanced nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is a locally advanced nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is a recurrent nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is a metastatic nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is a refractory, metastatic and / or recurrent nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is a refractory and / or recurrent nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is a metastatic and / or recurrent nasopharyngeal carcinoma.

[0146] In some embodiments, the nasopharyngeal carcinoma is an untreated nasopharyngeal carcinoma (e.g., lacking an effective treatment regimen). In some embodiments, the nasopharyngeal carcinoma is a nasopharyngeal carcinoma that has not been treated with surgery, radiotherapy, chemotherapy, and / or immunotherapy. In some embodiments, the nasopharyngeal carcinoma is a nasopharyngeal carcinoma that has not been treated with systemic therapy. In some embodiments, the nasopharyngeal carcinoma is an advanced nasopharyngeal carcinoma that has not been treated with systemic therapy. In some embodiments, the nasopharyngeal carcinoma is a metastatic and / or recurrent nasopharyngeal carcinoma that has not been treated with systemic therapy. In some embodiments, the nasopharyngeal carcinoma is an advanced nasopharyngeal carcinoma that has not been treated with immunotherapy. In some embodiments, the nasopharyngeal carcinoma is a metastatic and / or recurrent nasopharyngeal carcinoma that has not been treated with immunotherapy.

[0147] In some embodiments, the nasopharyngeal carcinoma is not suitable for local treatment and radical synchronous chemoradiotherapy. In some embodiments, the nasopharyngeal carcinoma is not suitable for local treatment and radical synchronous chemoradiotherapy for advanced nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is not suitable for local treatment and radical synchronous chemoradiotherapy for metastatic and / or recurrent nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is not suitable for systemic treatment and local treatment and radical synchronous chemoradiotherapy for advanced nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is not suitable for systemic treatment and local treatment and radical synchronous chemoradiotherapy for metastatic and / or recurrent nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is not suitable for systemic treatment and local treatment and radical synchronous chemoradiotherapy for metastatic and / or recurrent nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is not suitable for immunotherapy treatment and local treatment and radical synchronous chemoradiotherapy for advanced nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is not suitable for immunotherapy treatment and local treatment and radical synchronous chemoradiotherapy for metastatic and / or recurrent nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is an advanced nasopharyngeal carcinoma that has not been treated with immunotherapy and systemic treatment, and is not suitable for local treatment and radical synchronous chemoradiotherapy. In some embodiments, the nasopharyngeal carcinoma is a metastatic and / or recurrent nasopharyngeal carcinoma that has not been treated with immunotherapy and systemic treatment, and is not suitable for local treatment and radical synchronous chemoradiotherapy.

[0148] In some embodiments, the nasopharyngeal carcinoma is an unresectable advanced nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is an unresectable metastatic and / or recurrent nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is an unresectable advanced nasopharyngeal carcinoma without systemic treatment. In some embodiments, the nasopharyngeal carcinoma is an unresectable metastatic and / or recurrent nasopharyngeal carcinoma without systemic treatment. In some embodiments, the nasopharyngeal carcinoma is an unresectable advanced nasopharyngeal carcinoma without immunotherapy. In some embodiments, the nasopharyngeal carcinoma is an unresectable metastatic and / or recurrent nasopharyngeal carcinoma without immunotherapy. In some embodiments, the nasopharyngeal carcinoma is an unresectable metastatic and / or recurrent nasopharyngeal carcinoma without immunotherapy. In some embodiments, the nasopharyngeal carcinoma is an unresectable advanced nasopharyngeal carcinoma without immunotherapy and systemic treatment. In some embodiments, the nasopharyngeal carcinoma is an unresectable metastatic and / or recurrent nasopharyngeal carcinoma without immunotherapy and systemic treatment.

[0149] In some embodiments, the subject of nasopharyngeal carcinoma has previously been treated with one or more different anti-tumor therapies for nasopharyngeal carcinoma (e.g., treatment failed or is not applicable). In some embodiments, the subject of nasopharyngeal carcinoma has previously received surgery, radiotherapy, induction chemotherapy, concurrent chemotherapy and / or adjuvant chemotherapy to treat nasopharyngeal carcinoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of nasopharyngeal carcinoma has previously received neoadjuvant or adjuvant therapy (e.g., chemotherapy or radiotherapy) to treat nasopharyngeal carcinoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of nasopharyngeal carcinoma has previously received systemic treatment to treat nasopharyngeal carcinoma (e.g., treatment failed or is not applicable).

[0150] In some embodiments, the immunotherapy includes but is not limited to immune cell therapy, immune checkpoint inhibitor therapy, cytokine therapy, cancer vaccine therapy, or any combination thereof. In some embodiments, the immune checkpoints include PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 and / or CD160. In some embodiments, the immune checkpoint inhibitor is an antibody or antigen-binding fragment thereof for immune checkpoints (e.g., PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 and / or CD160), such as: Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab umab, tislelizumab, balstilimab, zimberelimab, atezolizumab, durvalumab, avelumab, envfolimab, sugemalimab, ipilimumab, or tremelimumab.

[0151] Technical Effects

[0152] Generally, the use of the drug combination of the present application, or the combined use of the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof of the present application will help:

[0153] (1) Producing a better therapeutic effect in reducing tumor growth or eliminating tumors compared to administering any of the drugs in the combination alone;

[0154] (2) provide for administration of a smaller amount of the drug in the combination than when either drug is administered alone;

[0155] (3) provide a treatment that is well tolerated in patients and has fewer adverse effects and / or complications than either drug given alone;

[0156] (4) provide better disease control rates among treated patients;

[0157] (5) Providing a longer survival (e.g., median survival, progression-free survival, or overall survival) in the patients treated;

[0158] (6) Providing a longer survival (e.g., median survival, progression-free survival, or overall survival) for the treated patients compared to standard chemotherapy;

[0159] (7) provide a longer duration of disease remission (DOR); and / or

[0160] (8) Compared with the administration of any drug in the combination alone, the combination has good anti-tumor activity and exhibits a more excellent anti-tumor synergistic effect.

[0161] The drug combination and treatment regimen of the present application have good efficacy in treating solid tumors (including hepatocellular carcinoma, non-small cell lung cancer, and nasopharyngeal carcinoma), and have beneficial effects in at least one of ORR, DCR, DOR, PFS, OS, tolerance, and side effects.

[0162] Definition and Description

[0163] Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this application, it is intended to refer to the corresponding commodity or its active ingredient.

[0164] As used herein, the term "pharmaceutical combination" refers to a combination of two or more active ingredients (including administration in the form of each active ingredient itself, or in the form of its respective pharmaceutically acceptable salt or ester derivatives, prodrugs or compositions) administered in any order. The active ingredients can be administered to a subject each simultaneously as a single formulation, or each sequentially in any order as a single formulation, or simultaneously as a single formulation.

[0165] As used herein, the term "antibody" refers to an antigen binding protein having at least one antigen binding domain. The antibody and its fragment of the present application may be a whole antibody or any fragment thereof. Therefore, the antibody and its fragment of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof. Examples of antibody and its antigen binding fragment fragments include monospecific antibodies, bispecific antibodies, multispecific antibodies, single domain 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-LAG-3 antibodies and antigen binding fragments thereof 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 antibody species encoded by the heavy chain constant region gene. The anti-LAG-3 antibodies and antigen binding fragments thereof and anti-PD-1 antibodies and antigen binding fragments thereof of the present application may be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans. The anti-LAG-3 antibody and its antigen-binding fragment and the anti-PD-1 antibody and its antigen-binding fragment of the present application can be a murine antibody, a chimeric antibody, a humanized antibody or a fully human antibody. Unless otherwise specified, the "antibody" of the present application includes the whole antibody and any antigen-binding fragment or single chain thereof. The conventional "whole antibody" is a glycoprotein comprising two heavy (H) chains and two light (L) chains, and the heavy chain and the light chain are connected by a disulfide bond. 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) with relatively conservative sequences. Each VH and VL is composed of three CDRs and four FRs, respectively, from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable 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 immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. At the same time, as those skilled in the art will appreciate, special "whole antibodies", such as nanobodies, have only heavy (H) chains and no light (L) chains.

[0166] An "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen (e.g., LAG-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 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 and a heavy chain variable region comprising a single variable domain and two constant domains. The invention relates to a monovalent fragment consisting of a single variable domain and a single constant domain comprising a Fab fragment; a monovalent fragment consisting of a CL and CH1 domain; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment consisting of the VH domain (see Ward et al., Nature. 341:544-546 (1989)); (vi) an isolated complementarity determining region (CDR); and (vii) a nanobody, a heavy chain variable region comprising a single variable domain and two constant domains. In addition, although the two domains VL and VH of the Fv fragment are encoded by different genes, VH and VL can be connected into a single protein chain by a recombinant method through a synthetic linker, wherein VL and VH are paired to form a monovalent molecule (called single-chain Fv (scFv); see, for example, Bird et al., Science. 242: 423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85: 5879-5883 (1988)). These single-chain antibodies are also encompassed in the term antigen-binding fragment. In addition, recombinant polypeptides, fusion proteins, small modular immunopharmaceuticals (SMIPs) and immunoconjugates comprising the antigen-binding fragment are also encompassed in the term antigen-binding fragment.

[0167] 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.

[0168] "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-LAG-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-LAG-3 antibodies or variants thereof comprising the HCDRs and LCDRs provided herein may be produced using any human framework sequence and are also included in the present application. Additional anti-PD-1 antibodies or variants thereof comprising the HCDRs and LCDRs provided herein may be produced using any human framework sequence and are also included in the present application. In one embodiment, framework sequences suitable for use in the present application include those framework sequences that are structurally similar to the framework sequences provided herein. Additional modifications may be made in the framework region to improve the properties of the antibodies provided herein. Such additional framework modifications may include chemical modifications; point mutations to reduce immunogenicity or remove T cell epitopes; or reverting mutations to residues in the original germline sequence.

[0169] The term "identity" is also known as consistency. The "percentage (%) identity" of an amino acid sequence refers to the percentage of amino acid residues in the sequence to be compared that are identical to the amino acid residues in the specific amino acid sequence shown in this article, after comparing the sequence to be compared with the specific amino acid sequence shown in this article and introducing spaces if necessary to achieve the maximum sequence identity percentage, and not considering any conservative substitutions as part of the sequence identity. The amino acid sequence alignment of identity can be carried out in a variety of ways within the scope of the art, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for comparing sequences, including any algorithm required to obtain the maximum alignment in the full length of the comparison sequence.

[0170] The term "treatment" generally refers to an operation to obtain a desired pharmacological and / or physiological effect. The effect may be preventive, in terms of completely or partially preventing a disease or its symptoms; and / or therapeutic, in terms of partially or completely stabilizing or curing a disease and / or side effects produced by the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including but not limited to preventing the occurrence or recurrence of a disease, alleviating symptoms of a disease, reducing any direct or indirect pathological consequences of a disease, preventing the metastasis of a disease, slowing the progression of a disease, improving or alleviating the state of a disease, extending the frequency and duration of symptom-free periods, and resolving or improving the prognosis of a disease.

[0171] A "therapeutically effective amount" or "therapeutically effective dose" is any amount of a drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of disease or promotes disease regression, as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or the prevention of impairment or disability resulting from disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by measuring the activity of the agent in in vitro assays.

[0172]

[00136] The terms "administering" or "administering" refer to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0173] Administration routes for antibodies or antigen-binding fragments thereof (e.g., anti-LAG-3 antibodies or antigen-binding fragments thereof or anti-PD-1 antibodies or antigen-binding fragments thereof) 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 modes of administration other than enteral administration, which is typically performed by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. Administration can also be performed, for example, once, multiple times, and / or over one or more extended time periods.

[0174] The term "flat dose" is used to refer to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). The flat dose is thus specified as an absolute amount of an agent (e.g., 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 will receive the same dose of antibody (e.g., 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof).

[0175] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0176] The term "pharmaceutical composition" refers to a mixture of the compound of the present application and a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration of the compound of the present application to a subject. In this article, the terms "pharmaceutical composition" and "preparation" have the same meaning and can be used interchangeably.

[0177] As used herein, the terms "subject," "patient," or "subject" are used interchangeably. "Subject," "patient," or "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the terms "subject," "patient," or "subject" are mammals. In some embodiments, the subject, patient, or subject is a mouse. In some embodiments, the subject, patient, or subject is a human.

[0178] As used herein, "combination", "combination use" or "combined use" means that two or more compounds 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.

[0179] 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 a bottle of injection is a single dose. The term "multiple doses" consists of multiple single doses. The term "unit dose" refers to the dose of active ingredient contained in the smallest packaging unit containing a certain amount of medicine, for example, the dose of antibody contained in a bottle of antibody injection is a unit dose.

[0180] The words “comprise”, “comprise” or “comprises” and their English variations such as comprises or comprising should be construed in an open, non-exclusive sense, ie, “including but not limited to”.

[0181] The term "PD-L1 positive" or "PD-L1 expression positive" related to cell surface PD-L1 expression refers to the proportion of cells in a test tissue sample containing tumor cells and tumor-infiltrating immune cells, above which the sample is assessed to express cell surface PD-L1. For cell surface expression determined by immunohistochemistry (IHC), PD-L1 positive tumors or PD-L1 expression positive tumors mean that at least about 0.01%, at least about 0.5%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, or at least about 30% of the total number of cells express PD-L1. PD-L1 positive tumors or PD-L1 expression positive tumors can also be described herein as tumors expressing PD-L1. In other embodiments, a PD-L1 positive tumor or a PD-L1 expression positive tumor means that at least about 0.1%-20%, at least about 0.1%-10%, at least about 1%, at least about 5%, at least about 1% or 1%-5% of the total number of cells express PD-L1 on the cell surface. In some embodiments, a PD-L1 positive tumor or a PD-L1 expression positive tumor means that at least about 1% of the total number of cells express PD-L1 on the cell surface. In some embodiments, a PD-L1 positive tumor or a PD-L1 expression positive tumor means that at least about 1% of the total number of tumor cells or tumor infiltrating immune cells express PD-L1 on the cell surface.

[0182] Herein, singular terms include plural referents and vice versa unless the context clearly dictates otherwise.

[0183] For the purpose of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements about the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Moreover, any reference to these publications in this document does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

[0184] The present application also provides the following specific implementation schemes, but is not limited thereto:

[0185] 1. A drug combination comprising an anti-LAG-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein:

[0186] The anti-LAG-3 antibody or antigen-binding fragment thereof comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO:1, a HCDR2 comprising the amino acid sequence of SEQ ID NO:2, a HCDR3 comprising the amino acid sequence of SEQ ID NO:3, a LCDR1 comprising the amino acid sequence of SEQ ID NO:4, a LCDR2 comprising the amino acid sequence of SEQ ID NO:5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:6; or a HCDR1 comprising the amino acid sequence of SEQ ID NO:21, a HCDR2 comprising the amino acid sequence of SEQ ID NO:22, a HCDR3 comprising the amino acid sequence of SEQ ID NO:23, a LCDR1 comprising the amino acid sequence of SEQ ID NO:24, a LCDR2 comprising the amino acid sequence of SEQ ID NO:25, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:26;

[0187] The anti-PD-1 antibody or antigen-binding fragment thereof comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 11, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 12, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 13, LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 14, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 16.

[0188] 2. The drug combination according to embodiment 1, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence shown 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 shown in SEQ ID NO:8; or a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:27, and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:28.

[0189] 3. The pharmaceutical combination according to embodiment 1 or 2, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:9, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:10; or a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:29, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:30.

[0190] 4. The drug combination according to any one of Embodiments 1 to 3, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region whose amino acid sequence is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 17, and a light chain variable region whose amino acid sequence is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 18.

[0191] 5. The drug combination according to any one of embodiments 1 to 4, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises: a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 19, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 20.

[0192] 6. The drug combination according to any one of embodiments 1-5, wherein the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated as a preparation for parenteral administration; preferably, the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated as a preparation for intravenous, intramuscular or subcutaneous administration.

[0193] 7. The pharmaceutical combination according to any one of embodiments 1-6, wherein the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated separately, or the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated in a single preparation.

[0194] 8. The drug combination according to any one of embodiments 1-7, wherein the drug combination further comprises a chemotherapy drug; preferably, the chemotherapy drug comprises a platinum-based anti-tumor drug and / or an anti-metabolic anti-tumor drug.

[0195] 9. Use of the drug combination described in any one of Embodiments 1-8 in the preparation of a medicament for treating tumors.

[0196] 10. The use according to embodiment 9, wherein the tumor is a solid tumor; preferably, the solid tumor is liver cancer, non-small cell lung cancer or nasopharyngeal carcinoma.

[0197] 11. The use according to embodiment 10, wherein the liver cancer is hepatocellular carcinoma; optionally, the liver cancer is advanced hepatocellular carcinoma; optionally, the liver cancer is hepatocellular carcinoma that has not been treated with immunotherapy; optionally, the liver cancer is advanced hepatocellular carcinoma that has not been treated with immunotherapy.

[0198] 12. The use according to embodiment 10, wherein the non-small cell lung cancer is advanced non-small cell lung cancer; optionally, the non-small cell lung cancer is locally advanced, metastatic and / or recurrent non-small cell lung cancer; optionally, the non-small cell lung cancer is PD-L1 positive non-small cell lung cancer; optionally, the non-small cell lung cancer is non-small cell lung cancer that has not been systemically treated; optionally, the non-small cell lung cancer is locally advanced, metastatic and / or recurrent non-small cell lung cancer that has not been systemically treated.

[0199] 13. The use according to embodiment 10, wherein the nasopharyngeal carcinoma is advanced nasopharyngeal carcinoma; optionally, the nasopharyngeal carcinoma is metastatic and / or recurrent nasopharyngeal carcinoma; optionally, the nasopharyngeal carcinoma is nasopharyngeal carcinoma that has not been treated systemically; optionally, the nasopharyngeal carcinoma is metastatic and / or recurrent nasopharyngeal carcinoma that has not been treated systemically.

[0200] 14. The use according to any one of embodiments 9 to 13, wherein the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment can be administered simultaneously, sequentially or alternately; or the anti-LAG-3 antibody or its antigen-binding fragment, the anti-PD-1 antibody or its antigen-binding fragment and the chemotherapeutic drug can be administered simultaneously, sequentially or alternately.

[0201] 15. The use according to any one of embodiments 9-14, wherein the anti-LAG-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 80-1800 mg, 120-1200 mg, 140-1000 mg, 160-800 mg, or 400-800 mg.

[0202] 16. The use according to any one of embodiments 9-15, 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; each time at a dose of 10-800 mg, 50-500 mg, or 100-200 mg.

[0203] 17. Use of an anti-LAG-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating a tumor, wherein:

[0204] The anti-LAG-3 antibody or antigen-binding fragment thereof comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO:1, a HCDR2 comprising the amino acid sequence of SEQ ID NO:2, a HCDR3 comprising the amino acid sequence of SEQ ID NO:3, a LCDR1 comprising the amino acid sequence of SEQ ID NO:4, a LCDR2 comprising the amino acid sequence of SEQ ID NO:5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:6; or a HCDR1 comprising the amino acid sequence of SEQ ID NO:21, a HCDR2 comprising the amino acid sequence of SEQ ID NO:22, a HCDR3 comprising the amino acid sequence of SEQ ID NO:23, a LCDR1 comprising the amino acid sequence of SEQ ID NO:24, a LCDR2 comprising the amino acid sequence of SEQ ID NO:25, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:26;

[0205] The anti-PD-1 antibody or antigen-binding fragment thereof comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 11, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 12, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 13, LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 14, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 16.

[0206] 18. Use of an anti-LAG-3 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating tumors in combination with an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein:

[0207] The anti-LAG-3 antibody or antigen-binding fragment thereof comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO:1, a HCDR2 comprising the amino acid sequence of SEQ ID NO:2, a HCDR3 comprising the amino acid sequence of SEQ ID NO:3, a LCDR1 comprising the amino acid sequence of SEQ ID NO:4, a LCDR2 comprising the amino acid sequence of SEQ ID NO:5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:6; or a HCDR1 comprising the amino acid sequence of SEQ ID NO:21, a HCDR2 comprising the amino acid sequence of SEQ ID NO:22, a HCDR3 comprising the amino acid sequence of SEQ ID NO:23, a LCDR1 comprising the amino acid sequence of SEQ ID NO:24, a LCDR2 comprising the amino acid sequence of SEQ ID NO:25, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:26;

[0208] The anti-PD-1 antibody or antigen-binding fragment thereof comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 11, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 12, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 13, LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 14, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 16.

[0209] 19. The use according to embodiment 17 or 18, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:8; or a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence 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.

[0210] 20. The use according to any one of embodiments 17-19, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:9, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:10; or a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:29, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:30.

[0211] 21. The use according to any one of embodiments 17 to 20, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 17, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 18.

[0212] 22. The use according to any one of embodiments 17 to 21, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 19, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 20.

[0213] 23. The use according to any one of embodiments 17-22, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated as a preparation for parenteral administration; preferably, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated as a preparation for intravenous, intramuscular or subcutaneous administration.

[0214] 24. The use according to any one of embodiments 17-23, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated separately, or the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation.

[0215] 25. The use according to any one of embodiments 17-24, wherein the tumor is a solid tumor; preferably, the solid tumor is liver cancer, non-small cell lung cancer or nasopharyngeal carcinoma.

[0216] 26. The use according to embodiment 25, wherein the liver cancer is hepatocellular carcinoma; optionally, the liver cancer is advanced hepatocellular carcinoma; optionally, the liver cancer is hepatocellular carcinoma that has not been treated with immunotherapy; optionally, the liver cancer is advanced hepatocellular carcinoma that has not been treated with immunotherapy.

[0217] 27. The use according to embodiment 25, wherein the non-small cell lung cancer is advanced non-small cell lung cancer; optionally, the non-small cell lung cancer is locally advanced, metastatic and / or recurrent non-small cell lung cancer; optionally, the non-small cell lung cancer is PD-L1 positive non-small cell lung cancer; optionally, the non-small cell lung cancer is non-small cell lung cancer that has not been systemically treated; optionally, the non-small cell lung cancer is locally advanced, metastatic and / or recurrent non-small cell lung cancer that has not been systemically treated.

[0218] 28. The use according to embodiment 25, wherein the nasopharyngeal carcinoma is advanced nasopharyngeal carcinoma; optionally, the nasopharyngeal carcinoma is metastatic and / or recurrent nasopharyngeal carcinoma; optionally, the nasopharyngeal carcinoma is nasopharyngeal carcinoma that has not been treated systemically; optionally, the nasopharyngeal carcinoma is metastatic and / or recurrent nasopharyngeal carcinoma that has not been treated systemically.

[0219] 29. The use according to any one of embodiments 17-28, wherein the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment can be administered simultaneously, sequentially or alternately.

[0220] 30. The use according to any one of embodiments 17-29, wherein the anti-LAG-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 80-1800 mg, 120-1200 mg, 140-1000 mg, 160-800 mg, or 400-800 mg.

[0221] 31. The use according to any one of embodiments 17-30, 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; each time at a dose of 10-800 mg, 50-500 mg, or 100-200 mg.

[0222] 32. Use of an anti-LAG-3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and a chemotherapeutic drug in the preparation of a drug for treating a tumor, wherein:

[0223] The anti-LAG-3 antibody or antigen-binding fragment thereof comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO:1, a HCDR2 comprising the amino acid sequence of SEQ ID NO:2, a HCDR3 comprising the amino acid sequence of SEQ ID NO:3, a LCDR1 comprising the amino acid sequence of SEQ ID NO:4, a LCDR2 comprising the amino acid sequence of SEQ ID NO:5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:6; or a HCDR1 comprising the amino acid sequence of SEQ ID NO:21, a HCDR2 comprising the amino acid sequence of SEQ ID NO:22, a HCDR3 comprising the amino acid sequence of SEQ ID NO:23, a LCDR1 comprising the amino acid sequence of SEQ ID NO:24, a LCDR2 comprising the amino acid sequence of SEQ ID NO:25, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:26;

[0224] The anti-PD-1 antibody or antigen-binding fragment thereof comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 11, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 12, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 13, LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 14, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 16.

[0225] 33. Use of an anti-LAG-3 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating tumors in combination with an anti-PD-1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug, wherein:

[0226] The anti-LAG-3 antibody or antigen-binding fragment thereof comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO:1, a HCDR2 comprising the amino acid sequence of SEQ ID NO:2, a HCDR3 comprising the amino acid sequence of SEQ ID NO:3, a LCDR1 comprising the amino acid sequence of SEQ ID NO:4, a LCDR2 comprising the amino acid sequence of SEQ ID NO:5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:6; or a HCDR1 comprising the amino acid sequence of SEQ ID NO:21, a HCDR2 comprising the amino acid sequence of SEQ ID NO:22, a HCDR3 comprising the amino acid sequence of SEQ ID NO:23, a LCDR1 comprising the amino acid sequence of SEQ ID NO:24, a LCDR2 comprising the amino acid sequence of SEQ ID NO:25, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:26;

[0227] The anti-PD-1 antibody or antigen-binding fragment thereof comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 11, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 12, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 13, LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 14, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 16.

[0228] 34. The use according to embodiment 32 or 33, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:8; or a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence 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.

[0229] 35. The use according to any one of embodiments 32-34, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:9, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:10; or a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:29, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:30.

[0230] 36. The use according to any one of embodiments 32-35, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 17, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 18.

[0231] 37. The use according to any one of embodiments 32-36, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 19, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 20.

[0232] 38. The use according to any one of embodiments 32-37, wherein the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated as a preparation for parenteral administration; preferably, the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are formulated as a preparation for intravenous, intramuscular or subcutaneous administration.

[0233] 39. The use according to any one of embodiments 32-38, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated separately, or the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation.

[0234] 40. The use according to any one of embodiments 32-39, wherein the chemotherapy drug comprises a platinum anti-tumor drug and / or an anti-metabolic anti-tumor drug.

[0235] 41. The use according to any one of embodiments 32-40, wherein the tumor is a solid tumor; preferably, the solid tumor is liver cancer, non-small cell lung cancer or nasopharyngeal carcinoma.

[0236] 42. The use according to embodiment 41, wherein the liver cancer is hepatocellular carcinoma; optionally, the liver cancer is advanced hepatocellular carcinoma; optionally, the liver cancer is hepatocellular carcinoma that has not been treated with immunotherapy; optionally, the liver cancer is advanced hepatocellular carcinoma that has not been treated with immunotherapy.

[0237] 43. The use according to embodiment 41, wherein the non-small cell lung cancer is advanced non-small cell lung cancer; optionally, the non-small cell lung cancer is locally advanced, metastatic and / or recurrent non-small cell lung cancer; optionally, the non-small cell lung cancer is PD-L1 positive non-small cell lung cancer; optionally, the non-small cell lung cancer is non-small cell lung cancer that has not been systemically treated; optionally, the non-small cell lung cancer is locally advanced, metastatic and / or recurrent non-small cell lung cancer that has not been systemically treated.

[0238] 44. The use according to embodiment 41, wherein the nasopharyngeal carcinoma is advanced nasopharyngeal carcinoma; optionally, the nasopharyngeal carcinoma is metastatic and / or recurrent nasopharyngeal carcinoma; optionally, the nasopharyngeal carcinoma is nasopharyngeal carcinoma that has not been treated systemically; optionally, the nasopharyngeal carcinoma is metastatic and / or recurrent nasopharyngeal carcinoma that has not been treated systemically.

[0239] 45. The use according to any one of embodiments 32-44, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof and chemotherapeutic drug can be administered simultaneously, sequentially or alternately.

[0240] 46. ​​The use according to any one of embodiments 32-45, wherein the anti-LAG-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 80-1800 mg, 120-1200 mg, 140-1000 mg, 160-800 mg, or 400-800 mg.

[0241] 47. The use according to any one of embodiments 32-46, 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; each time at a dose of 10-800 mg, 50-500 mg, or 100-200 mg. Example

[0242] For the sake of clarity, the present application is further described with examples, but the examples do not limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification.

[0243] The entire contents of the WO2018069500A patent application document are incorporated herein. The heavy chain amino acid sequence of the anti-LAG-3 antibody in the following examples is shown in SEQ ID NO: 9 of the present application, and the light chain amino acid sequence is shown in SEQ ID NO: 10 of the present application.

[0244] The entire contents of the patent application document of CN106977602A are incorporated into this application. The heavy chain amino acid sequence of penpulimab in the following examples is shown in SEQ ID NO: 19 of this application, and the light chain amino acid sequence is shown in SEQ ID NO: 20 of this application.

[0245] Example 1 Clinical trial for the treatment of liver cancer

[0246] 1. Selection criteria

[0247] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0248] (1) The subjects voluntarily participated in this study, signed the informed consent form (ICF), and had good compliance;

[0249] (2) Age: 18-75 years old (at the time of signing the ICF); ECOGPS score: 0-1 points; expected survival time is more than 3 months;

[0250] (3) The subjects met the following criteria:

[0251] 1) Subjects with hepatocellular carcinoma confirmed by histopathological or cytological examination or meeting the clinical diagnostic criteria for hepatocellular carcinoma of the American Association for the Study of Liver Diseases (AASLD) or the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition);

[0252] 2) Have not received any immunotherapy for advanced hepatocellular carcinoma (including immune checkpoint inhibitors, immune cell therapy, etc.) (≤

[0253] 2 lines);

[0254] 3) Subjects with Chinese Clinical Stage III Liver Cancer (CNLC) or Barcelona Clinical Stage C Liver Cancer (BCLC), or subjects with CNLC-II or BCLC-B who are not suitable for local treatment (such as transarterial chemoembolization) and surgical treatment or who are judged by the investigator to be unable to benefit from local treatment and surgical treatment;

[0255] 4) Child-Pugh liver function grade: A or B (≤7 points);

[0256] 5) HBsAg-positive subjects must meet the requirement of HBV DNA quantification <1×10 4 IU / mL (or 5×10 4HBV infection (HCV Ab or HCV RNA positive): The investigator judges that the patient is in a stable state. If the patient is receiving antiviral treatment at the time of enrollment, the investigator shall continue to receive approved antiviral treatment;

[0257] 6) Subjects who have undergone local treatment (including but not limited to surgery, transarterial chemoembolization (TACE), hepatic artery embolization (TAI), radiofrequency or microwave ablation, anhydrous alcohol injection, radiotherapy, etc.) should be enrolled at least 4 weeks after the end of local treatment and have fully recovered from treatment toxicity and / or complications;

[0258] 7) Radiotherapy for bone metastases with clinical symptoms must be completed at least 2 weeks before the start of the study;

[0259] (4) confirmed to have at least one measurable lesion according to RECIST 1.1 criteria;

[0260] (5) The major organs function normally, that is, they meet the following criteria:

[0261] 1) Routine blood test standards (no blood transfusion or blood products, no use of granulocyte colony-stimulating factor, no use of medication correction within 7 days before screening):

[0262] a. Hemoglobin (HGB) ≥ 90 g / L;

[0263] b. Neutrophil absolute count (NEUT) ≥ 1.5 × 10 9 / L;

[0264] c. Platelet count (PLT) ≥ 75 × 10 9 / L;

[0265] 2) Biochemical examination must meet the following standards:

[0266] a. Albumin ≥ 30 g / L (no albumin or blood products transfused within 14 days);

[0267] b. Total bilirubin ≤ 3 times the upper limit of normal (ULN);

[0268] c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <5.0×ULN;

[0269] d. Serum creatinine (CR) ≤ 1.5 × ULN or creatinine clearance (Ccr) > 50 mL / min (Cockcroft Gault formula: Ccr = (140-age) × body weight (kg) / 72 × Scr (mg / dL) or Ccr = (140-age) × body weight (kg) / 0.818 × Scr (umol / L), for women, the calculated result × 0.85);

[0270] 3) Prothrombin time (PT) is prolonged by ≤6 seconds compared to the upper limit of normal value;

[0271] (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.

[0272] 2. Experimental drugs

[0273] Penpulimab injection (Specification: 100 mg / 10 mL / bottle): 3 weeks as one treatment cycle, administered by intravenous infusion, with 200 mg of penpulimab administered once on the first day of each treatment cycle;

[0274] Anti-LAG-3 antibody injection (specification: 160 mg / 8 mL / bottle): One treatment cycle is 3 weeks, administered by intravenous infusion, with 600 mg of anti-LAG-3 antibody administered once on the first day of each treatment cycle.

[0275] 3. Treatment options

[0276] The infusion of penpulimab injection was performed first, and the anti-LAG-3 antibody injection was given at least 30 minutes later.

[0277] 4. Adjustment of dosing regimen

[0278] Penpulimab injection: delayed medication is allowed, but the longest delay should not exceed 12 weeks;

[0279] Anti-LAG-3 antibody injection: Delayed medication is allowed, but the longest delay should not exceed 12 weeks.

[0280] 5. Evaluation Criteria

[0281] The efficacy evaluation criteria were based on RECIST 1.1, and the iRECIST criteria were used to confirm the efficacy;

[0282] The NCI-CTC AE 5.0 standard was used to judge the severity of adverse events.

[0283] 6. End point indicators

[0284] Objective response rate (ORR = CR + PR) and disease control rate (DCR = CR + PR + SD) were mainly analyzed descriptively, and the exact binomial method based on the F distribution was used to calculate ORR and DCR and 95% Clopper-Pearson confidence intervals;

[0285] Progression-free survival (PFS), overall survival (OS), and duration of response (DOR) will be estimated using the Kaplan-Meier method with the median and its two-sided 95% confidence interval;

[0286] 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;

[0287] Pharmacokinetic / pharmacodynamic related indicators: pharmacokinetic (PK) parameters, immunogenicity (ADA) incidence, receptor occupancy (RO), etc.

[0288] Detection of treatment-related biomarkers: such as the expression of PD-L1 and LAG-3 in tumor tissues.

[0289] 7. Results

[0290] The anti-LAG-3 antibody combined with penpulimab in this application can safely and effectively treat advanced hepatocellular carcinoma, significantly improve the clinical efficacy and survival benefits of hepatocellular carcinoma patients, alleviate and control the patient's condition, slow down the progression of the disease, prolong the patient's progression-free survival and overall survival, and the incidence and severity of adverse events are low. As of the date of data statistics, a total of 5 patients achieved PR.

[0291] Among them, the specific results of exemplary patients are as follows:

[0292] (1) Patient 1

[0293] Treatment effect and evaluation:

[0294] Screening period: target lesion 149 mm;

[0295] After 2 cycles of treatment: target lesion 113 mm;

[0296] Treatment for 4 cycles: target lesion 40 mm;

[0297] Treatment for 6 cycles: target lesion 37 mm;

[0298] 8 cycles of treatment: target lesion 34 mm;

[0299] According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

[0300] (2) Patient 2

[0301] Treatment effect and evaluation:

[0302] Screening period: target lesion 122 mm;

[0303] After 2 cycles of treatment: target lesion 59 mm;

[0304] After 4 cycles of treatment: target lesion 59 mm;

[0305] According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

[0306] (3) Patient 3

[0307] Treatment effect and evaluation:

[0308] Screening period: target lesion 149 mm;

[0309] Treatment for 2 cycles: target lesion 25 mm;

[0310] Treatment for 4 cycles: target lesion 22 mm;

[0311] Treatment for 6 cycles: target lesion 14 mm;

[0312] According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

[0313] Example 2 Clinical trial for the treatment of non-small cell lung cancer

[0314] 1. Selection criteria

[0315] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0316] (1) The subjects voluntarily participated in this study, signed the informed consent form (ICF), and had good compliance;

[0317] (2) Age: 18-75 years old (at the time of signing the ICF); ECOGPS score: 0-1 points; expected survival time is more than 3 months;

[0318] (3) The subjects met the following criteria:

[0319] 1) Patients with locally advanced (stage IIIB / IIIC), recurrent or metastatic (stage IV) non-small cell lung cancer (NSCLC) who are not suitable for surgical treatment and radical concurrent chemoradiotherapy as confirmed by histological or cytological examination;

[0320] 2) Positive PD-L1 expression (TPS ≥ 1%);

[0321] 3) Subjects have not received systemic anti-tumor treatment for advanced disease. Subjects who have received neoadjuvant / adjuvant chemotherapy or radiotherapy or concurrent chemoradiotherapy are allowed to have received the disease before, but the interval between disease recurrence and / or metastasis and the completion of the last treatment must be at least 6 months;

[0322] 4) For non-squamous NSCLC, testing demonstrated the absence of EGFR mutation, ALK fusion, or ROS1 mutation (for squamous NSCLC, patients with known mutations in the above genes were excluded, and testing was not mandatory for those with unknown status);

[0323] (4) confirmed to have at least one measurable lesion according to RECIST 1.1 criteria;

[0324] (5) The major organs function normally, that is, they meet the following criteria:

[0325] 1) Routine blood test standards (no blood transfusion or blood products within 7 days before screening, no use of hematopoietic stimulating factor drugs for correction):

[0326] a. Hemoglobin (HGB) ≥ 90 g / L;

[0327] b. Neutrophil absolute count (NEUT) ≥ 1.5 × 10 9 / L;

[0328] c. Platelet count (PLT) ≥ 100 × 10 9 / L;

[0329] 2) Biochemical examination must meet the following standards:

[0330] a. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN);

[0331] b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; if accompanied by liver metastasis, ALT and AST ≤ 5 × ULN;

[0332] c. Creatinine clearance (Ccr) ≥ 60 mL / min (Cockcroft Gault formula: Ccr = (140-age) × body weight (kg) / 72 × Scr

[0333] (mg / dL) or Ccr = (140-age) × body weight (kg) / 0.818 × Scr (umol / L), for women, the calculated result × 0.85);

[0334] 3) Coagulation function must meet the following standards:

[0335] a. International normalized ratio (INR) ≤ 1.5 × ULN (not receiving anticoagulant therapy);

[0336] 4) Thyroid function tests must meet the following criteria:

[0337] a. Thyroid stimulating hormone (TSH) ≤ ULN; if abnormal, FT3 and FT4 levels should be examined; if FT3 and FT4 levels are normal, the patient can be selected (if FT3 and FT4 cannot be detected, T3 and T4 shall prevail);

[0338] 5) Cardiac ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ 50%;

[0339] (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.

[0340] 2. Experimental drugs

[0341] Penpulimab injection (Specification: 100 mg / 10 mL / bottle): 3 weeks as one treatment cycle, administered by intravenous infusion, with 200 mg of penpulimab administered once on the first day of each treatment cycle;

[0342] Anti-LAG-3 antibody injection (specification: 160 mg / 8 mL / bottle): One treatment cycle is 3 weeks, administered by intravenous infusion, with 600 mg of anti-LAG-3 antibody administered once on the first day of each treatment cycle.

[0343] 3. Treatment options

[0344] The infusion of penpulimab injection was performed first, and the anti-LAG-3 antibody injection was given at least 30 minutes later.

[0345] 4. Adjustment of dosing regimen

[0346] Penpulimab injection: delayed medication is allowed, but the longest delay should not exceed 12 weeks;

[0347] Anti-LAG-3 antibody injection: Delayed medication is allowed, but the longest delay should not exceed 12 weeks.

[0348] 5. Evaluation Criteria

[0349] The efficacy evaluation criteria were based on RECIST 1.1, and the iRECIST criteria were used to confirm the efficacy;

[0350] The NCI-CTC AE 5.0 standard was used to judge the severity of adverse events.

[0351] 6. End point indicators

[0352] Objective response rate (ORR = CR + PR) and disease control rate (DCR = CR + PR + SD) were mainly analyzed by descriptive analysis, and the exact binomial method based on the F distribution was used to calculate ORR and DCR and 95% Clopper-Pearson confidence intervals;

[0353] Progression-free survival (PFS), overall survival (OS), and duration of response (DOR) will be estimated using the Kaplan-Meier method with the median and its two-sided 95% confidence interval;

[0354] 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;

[0355] Pharmacokinetic / pharmacodynamic related indicators: pharmacokinetic (PK) parameters, immunogenicity (ADA) incidence, receptor occupancy (RO), etc.

[0356] Detection of treatment-related biomarkers: such as the expression of PD-L1 and LAG-3 in tumor tissues.

[0357] 7. Results

[0358] The anti-LAG-3 antibody combined with penpulimab in this application can safely and effectively treat locally advanced, recurrent or metastatic non-small cell lung cancer, significantly improve the clinical efficacy and survival benefits of patients with non-small cell lung cancer, alleviate and control the patient's condition, slow down the progression of the disease, prolong the patient's progression-free survival and overall survival, and the incidence and severity of adverse events are low. As of the date of data statistics, a total of 14 patients achieved PR.

[0359] Among them, the specific results of exemplary patients are as follows:

[0360] (1) Patient 1

[0361] Diagnosis: Diagnosed with squamous cell lung carcinoma, with a TPS score of 3%.

[0362] Treatment effect and evaluation:

[0363] Screening period: target lesion 90.04 mm;

[0364] After 2 cycles of treatment: target lesion 63.81 mm;

[0365] After 4 cycles of treatment: target lesion 42.14 mm;

[0366] After 6 cycles of treatment: target lesion 36.38 mm;

[0367] 8 cycles of treatment: target lesion 31.73 mm;

[0368] According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

[0369] (2) Patient 2

[0370] Diagnosis: Diagnosed with squamous cell lung carcinoma, with a TPS score of 55%.

[0371] Treatment effect and evaluation:

[0372] Screening period: target lesion 74 mm;

[0373] Treatment for 2 cycles: target lesion 45 mm;

[0374] Treatment for 4 cycles: target lesion 33 mm;

[0375] Treatment for 6 cycles: target lesion 30 mm;

[0376] Treatment for 8 cycles: target lesion 25 mm;

[0377] According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

[0378] (3) Patient 3

[0379] Diagnosis: Diagnosed with lung squamous cell carcinoma, with a TPS score of 90%.

[0380] Treatment effect and evaluation:

[0381] Screening period: target lesion 70 mm;

[0382] Treatment for 2 cycles: target lesion 26 mm;

[0383] Treatment for 4 cycles: target lesion 26 mm;

[0384] Treatment for 6 cycles: target lesion 22 mm;

[0385] Treatment for 8 cycles: target lesion 18 mm;

[0386] According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

[0387] (4) Patient 4

[0388] Diagnosis: Diagnosed with lung adenocarcinoma, with a TPS score of 1%.

[0389] Treatment effect and evaluation:

[0390] Screening period: target lesion 65 mm;

[0391] Treatment for 2 cycles: target lesion 56 mm;

[0392] 4 cycles of treatment: target lesion 52 mm;

[0393] After 6 cycles of treatment: target lesion 41 mm;

[0394] Treatment for 8 cycles: target lesion 35 mm;

[0395] According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

[0396] (5) Patient 5

[0397] Diagnosis: Diagnosed with lung adenocarcinoma, with a TPS score of 60%.

[0398] Treatment effect and evaluation:

[0399] Screening period: target lesion 21 mm;

[0400] Treatment for 2 cycles: target lesion 12 mm;

[0401] According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

[0402] (6) Patient 6

[0403] Diagnosis: Diagnosed with lung adenocarcinoma, with a TPS score of 90%.

[0404] Treatment effect and evaluation:

[0405] Screening period: target lesion 139 mm;

[0406] After 2 cycles of treatment: target lesion 92.22 mm;

[0407] After 4 cycles of treatment: target lesion 87.29 mm;

[0408] According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

[0409] (7) Patient 7

[0410] Diagnosis: Diagnosed with pulmonary lymphoepithelioma-like carcinoma, with a TPS score of 10%.

[0411] Treatment effect and evaluation:

[0412] Screening period: target lesion 35 mm;

[0413] Treatment for 2 cycles: target lesion 21 mm;

[0414] Treatment for 4 cycles: target lesion 18 mm;

[0415] Treatment for 6 cycles: target lesion 18 mm;

[0416] Treatment for 8 cycles: target lesion 18 mm;

[0417] 10 cycles of treatment: target lesion 17 mm;

[0418] Treatment for 12 cycles: target lesion 15 mm;

[0419] According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

[0420] Example 3 Clinical trial for the treatment of nasopharyngeal carcinoma

[0421] 1. Selection criteria

[0422] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0423] (1) The subjects voluntarily participated in this study, signed the informed consent form (ICF), and had good compliance;

[0424] (2) Age: 18-70 years old (at the time of signing the ICF); ECOGPS score: 0-1 points; expected survival time is more than 3 months;

[0425] (3) The subjects met the following criteria:

[0426] 1) Patients with recurrent or metastatic nasopharyngeal carcinoma who are not suitable for local treatment or radical treatment;

[0427] 2) The recurrent or metastatic lesions must have not been treated systematically or have previously received neoadjuvant / adjuvant chemotherapy or radiotherapy or concurrent chemoradiotherapy for the purpose of cure, but the time between disease recurrence and / or metastasis and the completion of the last treatment must be at least 6 months apart;

[0428] 3) Patients have not received immune checkpoint inhibitor treatment;

[0429] (4) confirmed to have at least one measurable lesion according to RECIST 1.1 criteria;

[0430] (5) The major organs function normally, that is, they meet the following criteria:

[0431] 1) Routine blood test standards (no blood transfusion or blood products within 7 days before screening, no use of hematopoietic stimulating factor drugs for correction):

[0432] a. Hemoglobin (HGB) ≥ 90 g / L;

[0433] b. Neutrophil absolute count (NEUT) ≥ 1.5 × 10 9 / L;

[0434] c. Platelet count (PLT) ≥ 100 × 10 9 / L;

[0435] 2) Biochemical examination must meet the following standards:

[0436] a. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN);

[0437] b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; if accompanied by liver metastasis, ALT and AST ≤ 5 × ULN;

[0438] c. Creatinine clearance (Ccr) ≥ 60 mL / min (Cockcroft Gault formula: Ccr = (140-age) × body weight (kg) / 72 × Scr

[0439] (mg / dL) or Ccr = (140-age) × body weight (kg) / 0.818 × Scr (umol / L), for women, the calculated result × 0.85);

[0440] 3) Coagulation function must meet the following standards:

[0441] a. International normalized ratio (INR) ≤ 1.5 × ULN (not receiving anticoagulant therapy);

[0442] 4) Thyroid function tests must meet the following criteria:

[0443] a. Thyroid stimulating hormone (TSH) ≤ ULN; if abnormal, FT3 and FT4 levels should be examined; if FT3 and FT4 levels are normal, the patient can be selected (if FT3 and FT4 cannot be detected, T3 and T4 shall prevail);

[0444] 5) Cardiac ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ 50%;

[0445] (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.

[0446] 2. Experimental drugs

[0447] Penpulimab injection (Specification: 100 mg / 10 mL / bottle): 3 weeks as one treatment cycle, administered by intravenous infusion, with 200 mg of penpulimab administered once on the first day of each treatment cycle;

[0448] Anti-LAG-3 antibody injection (Specification: 160 mg / 8 mL / bottle): 3 weeks as one treatment cycle, administered by intravenous infusion, with 600 mg of anti-LAG-3 antibody administered once on the first day of each treatment cycle;

[0449] Gemcitabine: 1000 mg / m2 on the first and eighth days of each treatment cycle, with 3 weeks as one treatment cycle. 2 Dosage administration, a total of 4-6 treatment cycles;

[0450] Cisplatin: 3 weeks per treatment cycle, by intravenous infusion, 80 mg / m on the first day of each treatment cycle 2 The dosage is administered for a total of 4-6 treatment cycles.

[0451] 3. Treatment options

[0452] The infusion of penpulimab injection was performed first, followed by the anti-LAG-3 antibody injection at least 30 minutes later, and gemcitabine and cisplatin at least 10 minutes later.

[0453] 4. Adjustment of dosing regimen

[0454] Penpulimab injection: delayed medication is allowed, but the longest delay should not exceed 12 weeks;

[0455] Anti-LAG-3 antibody injection: delayed medication is allowed, but the longest delay should not exceed 12 weeks;

[0456] Refer to the instructions for dosage adjustments of chemotherapy drugs.

[0457] 5. Evaluation Criteria

[0458] The efficacy evaluation criteria were based on RECIST 1.1, and the iRECIST criteria were used to confirm the efficacy;

[0459] The NCI-CTC AE 5.0 standard was used to judge the severity of adverse events.

[0460] 6. End point indicators

[0461] Objective response rate (ORR = CR + PR) and disease control rate (DCR = CR + PR + SD) were mainly analyzed by descriptive analysis, and the exact binomial method based on the F distribution was used to calculate ORR and DCR and 95% Clopper-Pearson confidence intervals;

[0462] Progression-free survival (PFS), overall survival (OS), and duration of response (DOR) will be estimated using the Kaplan-Meier method with the median and its two-sided 95% confidence interval;

[0463] 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;

[0464] Pharmacokinetic / pharmacodynamic related indicators: pharmacokinetic (PK) parameters, immunogenicity (ADA) incidence, receptor occupancy (RO), etc.

[0465] Detection of treatment-related biomarkers: such as the expression of PD-L1 and LAG-3 in tumor tissues.

[0466] 7. Results

[0467] The anti-LAG-3 antibody of this application combined with penpulimab and chemotherapy (gemcitabine + cisplatin) can safely and effectively treat recurrent or metastatic nasopharyngeal carcinoma, significantly improve the clinical efficacy and survival benefits of nasopharyngeal carcinoma patients, relieve and control the patient's condition, slow down the progression of the disease, prolong the patient's progression-free survival and overall survival, and the incidence and severity of adverse events are low. As of the date of data statistics, a total of 14 patients achieved PR.

[0468] Among them, the specific results of exemplary patients are as follows:

[0469] (1) Patient 1

[0470] Treatment effect and evaluation:

[0471] Screening period: target lesion 114 mm;

[0472] Treatment for 2 cycles: target lesion 58 mm;

[0473] Treatment for 4 cycles: target lesion 48 mm;

[0474] According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

[0475] (2) Patient 2

[0476] Treatment effect and evaluation:

[0477] Screening period: target lesion 57 mm;

[0478] Treatment for 2 cycles: target lesion 40 mm;

[0479] 4 cycles of treatment: target lesion 31 mm;

[0480] Treatment for 6 cycles: target lesion 25 mm;

[0481] According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

[0482] (3) Patient 3

[0483] Treatment effect and evaluation:

[0484] Screening period: target lesion 17 mm;

[0485] Treatment for 2 cycles: target lesion 10 mm;

[0486] Treatment for 4 cycles: target lesion 8 mm;

[0487] Treatment for 6 cycles: target lesion 7 mm;

[0488] According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

Claims

1. A drug combination comprising an anti-LAG-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein: The anti-LAG-3 antibody or antigen-binding fragment thereof comprises: HCDR1 comprising the amino acid sequence of SEQ ID NO:1, HCDR2 comprising the amino acid sequence of SEQ ID NO:2, HCDR3 comprising the amino acid sequence of SEQ ID NO:3, LCDR1 comprising the amino acid sequence of SEQ ID NO:4, LCDR2 comprising the amino acid sequence of SEQ ID NO:5, and LCDR3 comprising the amino acid sequence of SEQ ID NO:6; or A HCDR1 comprising the amino acid sequence of SEQ ID NO:21, a HCDR2 comprising the amino acid sequence of SEQ ID NO:22, a HCDR3 comprising the amino acid sequence of SEQ ID NO:23, a LCDR1 comprising the amino acid sequence of SEQ ID NO:24, a LCDR2 comprising the amino acid sequence of SEQ ID NO:25, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:26; The anti-PD-1 antibody or antigen-binding fragment thereof comprises: A HCDR1 comprising the amino acid sequence shown in SEQ ID NO:11, a HCDR2 comprising the amino acid sequence shown in SEQ ID NO:12, a HCDR3 comprising the amino acid sequence shown in SEQ ID NO:13, a LCDR1 comprising the amino acid sequence shown in SEQ ID NO:14, a LCDR2 comprising the amino acid sequence shown in SEQ ID NO:15, and a LCDR3 comprising the amino acid sequence shown in SEQ ID NO:

16.

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

28.

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

30.

4. The pharmaceutical combination according to any one of claims 1 to 3, wherein The anti-PD-1 antibody or antigen-binding fragment thereof comprises: A heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: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.

5. The pharmaceutical combination according to any one of claims 1 to 4, wherein The anti-PD-1 antibody or antigen-binding fragment thereof comprises: A heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:19, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO:

20.

6. The pharmaceutical combination according to any one of claims 1 to 5, wherein The anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated as preparations for parenteral administration; preferably, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated as preparations for intravenous, intramuscular or subcutaneous administration.

7. The pharmaceutical combination according to any one of claims 1 to 6, wherein The anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated separately, or the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation.

8. The pharmaceutical combination according to any one of claims 1 to 7, wherein The drug combination further comprises a chemotherapeutic drug; preferably, the chemotherapeutic drug comprises a platinum-based anti-tumor drug and / or an antimetabolite-based anti-tumor drug.

9. Use of the drug combination according to any one of claims 1 to 8 in the preparation of a drug for treating tumors.

10. The use according to claim 9, wherein The tumor is a solid tumor; preferably, the solid tumor is liver cancer, non-small cell lung cancer or nasopharyngeal carcinoma.

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