CN119607196A - Application of anti-LAG-3 antibodies and anti-PD-1 antibodies - Google Patents

Abstract

The application belongs to the field of biological medicine, and in particular relates to application of an anti-LAG-3 antibody and an anti-PD-1 antibody, such as application in preparation of a medicine for treating tumors.

Description

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

Technical Field

The application belongs to the field of biological medicine, and in particular relates to a pharmaceutical combination of an antibody binding to LAG-3 and an antibody binding to PD-1 and application thereof.

Background

Lymphocyte activating 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 number of different ligands including major histocompatibility complex-class II molecules (MHC-II), cellulose protein 1 (FGL 1), galectin-3 (Galectin-3), and liver sinus endothelial cell lectin (lseclin), among others. LAG-3 acts as an immune checkpoint that negatively regulates T cells and plays an important role in maintaining homeostasis of the immune system of the body. However, there is growing evidence that tumor cells promote tumor development by expressing LAG-3 ligands that bind to LAG-3 that is highly expressed on Tumor Infiltrating Lymphocytes (TILs), resulting in reduced T cell function and even depletion, thereby causing immune escape of tumor cells.

PD-1 (Programmed death receptor 1) is a key immune checkpoint receptor expressed by activated T-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 combination of PD-1 and PD-L1 and shows better anti-tumor activity.

Lung cancer is one of the most frequently occurring malignant tumors worldwide, and the two major types of lung cancer are Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC). Its prognosis is often poor. Liver cancer is the seventh most common malignant tumor worldwide, however, most liver cancer patients have reached middle and late stages at the time of initial diagnosis due to the characteristic of high proliferation of liver cancer cells, about 70% of patients lose surgical opportunities, and the survival time of the patients is short and the prognosis is poor. Nasopharyngeal carcinoma is a malignant tumor of nasopharyngeal epithelium origin, a complex disease affected by multiple factors. Nasopharyngeal carcinoma has abundant lymphatic return paths, recurrence or distant metastasis easily occurs, and researches show that the median survival time of nasopharyngeal carcinoma patients with distant metastasis is only 12-15 months. Current treatment regimens for these advanced tumors are few and have limited overall efficacy, and there is an urgent need in the art to develop additional therapeutic agents.

Summary of The Invention

In one aspect, the application provides a pharmaceutical combination comprising an anti-LAG-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination further comprises a chemotherapeutic agent. In some embodiments, the pharmaceutical combination is for treating a tumor.

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

In another aspect, the application also provides the use of a pharmaceutical combination of the application in the manufacture of a medicament for treating a tumor in a subject. In some specific embodiments, the application also provides the use of a pharmaceutical combination of the application in the manufacture of a medicament for treating a tumor in a subject with a triple or more anterior line (e.g., a double or first line). In addition, the application also provides the use of the pharmaceutical combination of the application for treating tumors in a subject. In some embodiments, the use comprises administering to the subject a therapeutically effective amount of a pharmaceutical combination of the application.

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

In another aspect, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for treating a tumor in a subject. In some specific embodiments, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for treating a tumor in a subject with a three-wire or more anterior (e.g., two-wire or first-wire) therapy. In addition, the application also provides the use of the anti-LAG-3 antibodies or antigen-binding fragments thereof and anti-PD-1 antibodies or antigen-binding fragments thereof of the application to treat a tumor in a subject. In some embodiments, the use comprises administering to the subject a therapeutically effective amount of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application and an anti-PD-1 antibody or antigen-binding fragment thereof.

In another aspect, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for treating a tumor in a subject, wherein the medicament is for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof of the application. In some specific embodiments, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for treating a tumor in a subject three-wire or more (e.g., two-wire or one-wire), wherein the medicament is for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof of the application. In another aspect, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof of the application in the treatment of a tumor.

In another aspect, the application also provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating a tumor in a subject, wherein the medicament is for use in combination with an anti-LAG-3 antibody or antigen-binding fragment thereof of the application. In some specific embodiments, the application also provides the use of an anti-PD-1 antibody of the application, or an antigen-binding fragment thereof, in the manufacture of a medicament for treating a tumor in a subject three-wire or more (e.g., two-wire or one-wire), wherein the medicament is for use in combination with an anti-LAG-3 antibody of the application, or an antigen-binding fragment thereof. In another aspect, the application also provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for use in combination with an anti-LAG-3 antibody or antigen-binding fragment thereof of the application in the treatment of a tumor.

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

In another aspect, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent of the application in the manufacture of a medicament for treating a tumor in a subject. In some specific embodiments, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof of the application, and a chemotherapeutic agent in the manufacture of a medicament for treating a tumor in a subject in a three-wire or more anterior (e.g., two-wire or first-wire) manner. In addition, the application also provides the use of the anti-LAG-3 antibodies or antigen-binding fragments thereof, anti-PD-1 antibodies or antigen-binding fragments thereof, and chemotherapeutic agents of the application to treat a tumor in a subject. In some embodiments, the use comprises administering to the subject a therapeutically effective amount of an anti-LAG-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent of the application.

In another aspect, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for treating a tumor in a subject, wherein the medicament is for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof of the application and a chemotherapeutic agent. In some specific embodiments, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for treating a tumor in a subject three-wire or more (e.g., two-wire or one-wire), wherein the medicament is for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof of the application and a chemotherapeutic agent. In another aspect, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for use in the treatment of a tumor in combination with an anti-PD-1 antibody or antigen-binding fragment thereof of the application and a chemotherapeutic agent.

In another aspect, the application also provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating a tumor in a subject, wherein the medicament is for use in combination with an anti-LAG-3 antibody or antigen-binding fragment thereof of the application and a chemotherapeutic agent. In some specific embodiments, the application also provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for treating a tumor in a subject three-wire or more (e.g., two-wire or one-wire), wherein the medicament is for use in combination with an anti-LAG-3 antibody or antigen-binding fragment thereof of the application and a chemotherapeutic agent. In another aspect, the application also provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for use in the treatment of a tumor in combination with an anti-LAG-3 antibody or antigen-binding fragment thereof of the application and a chemotherapeutic agent.

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof may be administered simultaneously, sequentially and/or alternately in the methods and uses. 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 agent may 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 agent are administered sequentially.

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.

In some embodiments, in the methods and uses, the chemotherapeutic agent is administered according to known methods.

In another aspect, the application also provides a kit for treating a tumor comprising the pharmaceutical combination of the application. In some specific embodiments, the kit comprises an anti-LAG-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof, and instructions for using the anti-LAG-3 antibody or antigen-binding fragment thereof in combination with the anti-PD-1 antibody or antigen-binding fragment thereof to treat a tumor. In some specific embodiments, the kit comprises an anti-LAG-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent, and instructions for using the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent in combination to treat a tumor.

In some embodiments, the tumor is a solid tumor. In some specific embodiments, the tumor is a 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 a 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

Pharmaceutical combination

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

In some embodiments, the pharmaceutical combination further comprises a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent comprises one or more of a platinum-based anti-tumor agent, a taxane-based anti-tumor agent, an antimetabolite-based anti-tumor agent, a camptothecin-based anti-tumor agent, a nitrogen mustard-based anti-tumor agent, an anthracycline-based anti-tumor agent, a vinblastine-based anti-tumor agent, a podophyllum alkaloid-based anti-tumor agent, and a hormonal-based anti-tumor agent. In some embodiments, the chemotherapeutic agent comprises a platinum-based anti-tumor agent and/or an anti-metabolite-based anti-tumor agent. In some embodiments, the chemotherapeutic agent comprises a platinum-based antineoplastic agent and gemcitabine. In some embodiments, the chemotherapeutic agent comprises cisplatin and gemcitabine.

In some embodiments, the pharmaceutical combination is packaged in the same kit, which further comprises instructions for the combined use of an anti-LAG-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof to treat a tumor. In other embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination are packaged separately in separate kits, which further comprise instructions for 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 to treat a tumor.

In some embodiments, the pharmaceutical combination is packaged in the same kit, which further comprises instructions for using the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent in combination to treat the tumor. In other embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent in the pharmaceutical combination are packaged separately in separate kits, which further include instructions for using the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent in combination to treat a tumor.

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, anti-PD-1 antibody or antigen-binding fragment thereof, and chemotherapeutic agent are each in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprising an anti-LAG-3 antibody, or antigen-binding fragment thereof, is a liquid formulation or a solid formulation. In some embodiments, the pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof is an injection. In some embodiments, the pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof is a lyophilized formulation. In some embodiments, the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is a liquid formulation or a solid formulation. In some embodiments, the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is an injection. In some embodiments, the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized formulation. 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 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.

In some embodiments, the pharmaceutical combination comprises 80-1800mg, 120-1200mg, 140-1000mg, 160-800mg, or 400-800mg of an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 80mg、100mg、120mg、140mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、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、880mg、900mg、920mg、940mg、960mg、980mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、 or a range of any of the above values for an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 160-800mg or 400-800mg of an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 160mg, 200mg, 300mg, 400mg, 600mg, or 800mg of an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 600mg of an anti-LAG-3 antibody or antigen-binding fragment thereof.

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

In some embodiments, the pharmaceutical combination comprises 80-1800mg, 120-1200mg, 140-1000mg, 160-800mg, or 400-800mg of an anti-LAG-3 antibody or antigen-binding fragment thereof, and 10-800mg, 50-500mg, or 100-200mg of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 80mg、100mg、120mg、140mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、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、880mg、900mg、920mg、940mg、960mg、980mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、 or a range of any of the above values of the anti-LAG-3 antibody or antigen-binding fragment thereof, and 10mg、50mg、100mg、120mg、140mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、 or a range of any of the above values of the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 160-800mg or 400-800mg of an anti-LAG-3 antibody or antigen-binding fragment thereof, and 100-200mg of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 160mg, 200mg, 300mg, 400mg, 600mg, or 800mg of the anti-LAG-3 antibody or antigen-binding fragment thereof, and 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 600mg of the anti-LAG-3 antibody, or antigen-binding fragment thereof, and 200mg of the anti-PD-1 antibody, or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination further comprises 1000-1250mg/m² gemcitabine and 80-100mg/m² cisplatin. In some embodiments, the pharmaceutical combination further comprises 1000mg/m² gemcitabine and 80mg/m² cisplatin.

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

In some embodiments, the amount of anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is one daily dose. In some embodiments, the amount of anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a once daily dose. In some embodiments, the amount of anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a uniform dose. In some embodiments, the amount of anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a dose for one treatment cycle, each treatment cycle being 3 weeks.

In some embodiments, the amount of gemcitabine in the pharmaceutical combination is one daily dose. In some embodiments, the amount of gemcitabine in the pharmaceutical combination is one daily dose.

In some embodiments, the amount of cisplatin in the pharmaceutical combination is one daily dose. In some embodiments, the amount of cisplatin in the pharmaceutical combination is a once daily dose.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 80-1800mg, 120-1200mg, 140-1000mg, 160-800mg, or 400-800mg of an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 80mg、100mg、120mg、140mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、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、880mg、900mg、920mg、940mg、960mg、980mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、 or a range of any of the above values for an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 160-800mg or 400-800mg of an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 160mg, 200mg, 300mg, 400mg, 600mg, or 800mg of an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 600mg of the anti-LAG-3 antibody or antigen-binding fragment thereof.

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

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising an anti-LAG-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 80-1800mg, 120-1200mg, 140-1000mg, 160-800mg, or 400-800mg of an anti-LAG-3 antibody or antigen-binding fragment thereof, and 10-800mg, 50-500mg, or 100-200mg of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 80mg、100mg、120mg、140mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、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、880mg、900mg、920mg、940mg、960mg、980mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、 or a range of any of the above values of an anti-LAG-3 antibody or antigen-binding fragment thereof, and 10mg、50mg、100mg、120mg、140mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg or 800mg, or a range of any of the above values of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 160-800mg or 400-800mg of an anti-LAG-3 antibody or antigen-binding fragment thereof, and 100-200mg of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 160mg, 200mg, 300mg, 400mg, 600mg, or 800mg of the anti-LAG-3 antibody or antigen-binding fragment thereof, and 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 600mg of the anti-LAG-3 antibody or antigen-binding fragment thereof, and 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, the pharmaceutical combination further comprising 1000-3000mg/m² gemcitabine and 80-100mg/m² cisplatin. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, the pharmaceutical combination further comprising 2000mg/m² gemcitabine and 80mg/m² cisplatin.

In some embodiments, the mass ratio of the anti-LAG-3 antibody or antigen-binding fragment thereof to the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is (0.1-20): 1, (0.5-10): 1, (1-5): 1 or 3:1.

In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, wherein the pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administration to a patient of 80-1800mg, 120-1200mg, 140-1000mg, 160-800mg, or 400-800mg of an anti-LAG-3 antibody or antigen-binding fragment thereof, and the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administration to a patient of 10-800mg, A single dose or multiple doses of 50-500mg, or 100-200mg, of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, wherein the pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administration to a patient of 80mg、100mg、120mg、140mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、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、880mg、900mg、920mg、940mg、960mg、980mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、 or a range of any of the values described above of an anti-LAG-3 antibody or antigen-binding fragment thereof, and the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administration to a patient of 10mg、50mg、100mg、120mg、140mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、 or a range of any of the values described above of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, wherein the pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administration to a patient of 160-800mg or 400-800mg of an anti-LAG-3 antibody or antigen-binding fragment thereof, and the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administration to a patient of 100-200mg of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, wherein the pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administration of 160mg, 200mg, 300mg, 400mg, 600mg, or 800mg of the anti-LAG-3 antibody or antigen-binding fragment thereof to a patient, and the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administration of 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof to a patient. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, wherein the pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administration of 600mg of the anti-LAG-3 antibody or antigen-binding fragment thereof to a patient, and the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administration of 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof to a patient.

In some embodiments, the pharmaceutical combination further comprises a gemcitabine-containing pharmaceutical composition that is prepared to be suitable for being prepared to be suitable for administering a single dose or multiple doses of 1000-1250mg/m² gemcitabine to a patient and a cisplatin-containing pharmaceutical composition that is prepared to be suitable for being prepared to be suitable for administering a single dose or multiple doses of 80-100mg/m² cisplatin to a patient. In some embodiments, the gemcitabine-containing pharmaceutical composition is prepared as a single dose or multiple doses suitable for being prepared as a single dose or multiple doses suitable for administering 1000mg/m² of gemcitabine to a patient, and the cisplatin-containing pharmaceutical composition is prepared as a single dose or multiple doses suitable for being prepared as a single dose or multiple doses suitable for administering 80mg/m² of cisplatin to a patient.

In another aspect, the application provides a kit for treating a tumor, the kit comprising a pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, and instructions for using the pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof in combination with the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof to treat the tumor. In another aspect, the application provides a kit for treating a tumor, the kit comprising a pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof, a pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent, and instructions for using the pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof, the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent in combination to treat a tumor. In some embodiments, the pharmaceutical composition comprising an anti-LAG-3 antibody, or antigen-binding fragment thereof, is a liquid formulation or a solid formulation. In some specific embodiments, the pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof is an injection. In some specific embodiments, the pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof is a lyophilized formulation. In some embodiments, the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is a liquid formulation or a solid formulation. In some specific embodiments, the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is an injection. In some specific embodiments, the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized formulation.

In some specific embodiments, the tumor is a solid tumor. In some specific embodiments, the tumor is a 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 a nasopharyngeal carcinoma. In some specific embodiments, the tumor is advanced nasopharyngeal carcinoma. In some specific embodiments, the tumor is recurrent or metastatic nasopharyngeal carcinoma.

Use of the same

In one aspect, the application also provides a method of treating a tumor in a subject comprising administering to the subject a pharmaceutical combination of the application. In addition, the application also provides a method of treating a tumor in a subject comprising administering to the subject an anti-LAG-3 antibody or antigen-binding fragment thereof of the application and an anti-PD-1 antibody or antigen-binding fragment thereof. In addition, the application also provides a method of treating a tumor in a subject comprising administering to the subject an anti-LAG-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof of the application, and a chemotherapeutic agent. In addition, the present application also provides a method of treating a tumor in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical combination of the application. In addition, the application also provides a method of treating a tumor in a subject comprising administering to the subject a therapeutically effective amount of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application and an anti-PD-1 antibody or antigen-binding fragment thereof. In addition, the application also provides a method of treating a tumor in a subject comprising administering to the subject a therapeutically effective amount of an anti-LAG-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, of the application, and a chemotherapeutic agent.

In another aspect, the application also provides the use of a pharmaceutical combination of the application in the manufacture of a medicament for treating a tumor in a subject. In some specific embodiments, the application also provides the use of a pharmaceutical combination of the application in the manufacture of a medicament for treating a tumor in a subject with a triple or more anterior line (e.g., a double or first line). In addition, the application also provides the use of the anti-LAG-3 antibodies or antigen-binding fragments thereof and anti-PD-1 antibodies or antigen-binding fragments thereof of the application in the manufacture of a medicament for treating a tumor in a subject. In some specific embodiments, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for treating a tumor in a subject with a three-wire or more anterior (e.g., two-wire or first-wire) therapy. In addition, the application also provides the use of the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent of the application in the manufacture of a medicament for treating a tumor in a subject. In some specific embodiments, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof of the application, and a chemotherapeutic agent in the manufacture of a medicament for treating a tumor in a subject in a three-wire or more anterior (e.g., two-wire or first-wire) manner.

In another aspect, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for treating a tumor in a subject, wherein the medicament is for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof of the application. In some specific embodiments, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for treating a tumor in a subject three-wire or more (e.g., two-wire or one-wire), wherein the medicament is for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof of the application. In addition, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for treating a tumor in a subject, wherein the medicament is for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof of the application and a chemotherapeutic agent. In some specific embodiments, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for treating a tumor in a subject three-wire or more (e.g., two-wire or one-wire), wherein the medicament is for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof of the application and a chemotherapeutic agent. In addition, the application also provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating a tumor in a subject, wherein the medicament is for use in combination with an anti-LAG-3 antibody or antigen-binding fragment thereof of the application. In some specific embodiments, the application also provides the use of an anti-PD-1 antibody of the application, or an antigen-binding fragment thereof, in the manufacture of a medicament for treating a tumor in a subject three-wire or more (e.g., two-wire or one-wire), wherein the medicament is for use in combination with an anti-LAG-3 antibody of the application, or an antigen-binding fragment thereof. In addition, the application also provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating a tumor in a subject, wherein the medicament is for use in combination with an anti-LAG-3 antibody or antigen-binding fragment thereof of the application and a chemotherapeutic agent. In some specific embodiments, the application also provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for treating a tumor in a subject three-wire or more (e.g., two-wire or one-wire), wherein the medicament is for use in combination with an anti-LAG-3 antibody or antigen-binding fragment thereof of the application and a chemotherapeutic agent.

In another aspect, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof of the application in the treatment of a tumor. In addition, the application also provides the use of an anti-LAG-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for use in the treatment of a tumor in combination with an anti-PD-1 antibody or antigen-binding fragment thereof of the application and a chemotherapeutic agent. In addition, the application also provides the use of an anti-PD-1 antibody or an antigen-binding fragment thereof of the application in the manufacture of a medicament for use in combination with an anti-LAG-3 antibody or an antigen-binding fragment thereof of the application in the treatment of a tumor. In addition, the application also provides the use of the anti-PD-1 antibodies or antigen-binding fragments thereof of the application in the manufacture of a medicament for use in combination with an anti-LAG-3 antibody or antigen-binding fragment thereof of the application and a chemotherapeutic agent in the treatment of a tumor.

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof may be administered simultaneously, sequentially and/or alternately in the method or use. 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 methods or uses, an anti-PD-1 antibody or antigen-binding fragment thereof is administered prior to administration of an 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 each in the form of a pharmaceutical composition, which may 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 for administration sequentially. 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 the pharmaceutical composition comprising the anti-PD-1 antibody or antigen-binding fragment thereof is administered prior to administration of the pharmaceutical composition comprising 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 formulation.

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 agent may 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 agent are administered sequentially. In some embodiments, in the methods or uses, an anti-PD-1 antibody or antigen-binding fragment thereof is administered prior to an anti-LAG-3 antibody or antigen-binding fragment thereof, followed by administration of a chemotherapeutic agent. 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 agent are each in the form of a pharmaceutical composition, which may 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, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent are each in the form of a pharmaceutical composition for administration sequentially. In some embodiments, in the method or use, the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent are each in the form of a pharmaceutical composition, and the pharmaceutical composition comprising the anti-PD-1 antibody or antigen-binding fragment thereof is administered first, followed by the pharmaceutical composition comprising the anti-LAG-3 antibody or antigen-binding fragment thereof, and then the pharmaceutical composition comprising the chemotherapeutic agent. 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 formulated in a single formulation, which is administered prior to administration of the pharmaceutical composition comprising the chemotherapeutic agent.

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 on the same or different dosing regimen. 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 in different dosing regimens. In some embodiments, in the method or use, the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent are administered on the same or different dosing regimen. In some embodiments, in the method or use, the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent are administered in different dosing schedules.

In some embodiments, in the method or use, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 1 week (q 1 w), every 2 weeks (q 2 w), every 3 weeks (q 3 w), or every 4 weeks (q 4 w). 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 80-1800mg, 120-1200mg, 140-1000mg, 160-800mg, or 400-800mg per time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose ranging from 80mg、100mg、120mg、140mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、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、880mg、900mg、920mg、940mg、960mg、980mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、 or any of the values set forth above each time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 160-800mg or 400-800mg at a time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 160mg, 200mg, 300mg, 400mg, 600mg, or 800mg at a time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 600mg 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, at a dose of 80-1800mg, 120-1200mg, 140-1000mg, 160-800mg, or 400-800mg 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 at a dose of 160-800mg or 400-800mg 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 at a dose of 160mg, 200mg, 300mg, 400mg, 600mg, or 800mg 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 at a dose of 160-800mg or 400-800mg 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 160mg, 200mg, 300mg, 400mg, 600mg, or 800mg 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 at a dose of 600mg of the anti-LAG-3 antibody or antigen-binding fragment thereof.

In some embodiments, in the methods or uses, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 1 week (q 1 w), every 2 weeks (q 2 w), every 3 weeks (q 3 w), or every 4 weeks (q 4 w). In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks. In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 4 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10-800mg, 50-500mg, or 100-200mg per time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose ranging from 10mg、50mg、100mg、120mg、140mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、 or any of the values set forth above each time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 100-200mg per time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 200mg 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 at a dose of 10-800mg, 50-500mg, or 100-200mg of the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each at a dose of 100-200mg of the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each at a dose of 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each at a dose of 100-200mg of the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof.

In some embodiments, in the method or use, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 0.1-50mg/kg、0.1-40mg/kg、0.1-30mg/kg、0.1-20mg/kg、0.1-10mg/kg、1-50mg/kg、1-40mg/kg、1-30mg/kg、1-20mg/kg、1-10mg/kg、3-50mg/kg、3-40mg/kg、3-30mg/kg、3-20mg/kg、3-10mg/kg、1-5mg/kg、 or 3-5mg/kg at a time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose ranging from 0.1mg/kg、1mg/kg、1.5mg/kg、2mg/kg、2.5mg/kg、3mg/kg、3.5mg/kg、4mg/kg、4.5mg/kg、5mg/kg、5.5mg/kg、6mg/kg、6.5mg/kg、7mg/kg、7.5mg/kg、8mg/kg、9mg/kg、10mg/kg、20mg/kg、30mg/kg、40mg/kg、50mg/kg、 or any of the values set forth above each time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 1-10mg/kg at a time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 3mg/kg, 5mg/kg, or 10mg/kg at a 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 at a dose of 0.1-50mg/kg、0.1-40mg/kg、0.1-30mg/kg、0.1-20mg/kg、0.1-10mg/kg、1-50mg/kg、1-40mg/kg、1-30mg/kg、1-20mg/kg、1-10mg/kg、3-50mg/kg、3-40mg/kg、3-30mg/kg、3-20mg/kg、3-10mg/kg、1-5mg/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 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, each 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 3mg/kg, 5mg/kg, or 10mg/kg each time.

In some embodiments, in the method or use, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 0.1-50mg/kg、0.1-40mg/kg、0.1-30mg/kg、0.1-20mg/kg、0.1-10mg/kg、1-50mg/kg、1-40mg/kg、1-30mg/kg、1-20mg/kg、1-10mg/kg、3-50mg/kg、3-40mg/kg、3-30mg/kg、3-20mg/kg、3-10mg/kg、1-5mg/kg、 or 3-5mg/kg at a time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose ranging from 0.1mg/kg、1mg/kg、1.5mg/kg、2mg/kg、2.5mg/kg、3mg/kg、3.5mg/kg、4mg/kg、4.5mg/kg、5mg/kg、5.5mg/kg、6mg/kg、6.5mg/kg、7mg/kg、7.5mg/kg、8mg/kg、9mg/kg、10mg/kg、20mg/kg、30mg/kg、40mg/kg、50mg/kg、 or any of the values set forth above each time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 1-5mg/kg each time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 2mg/kg, 3mg/kg, or 5mg/kg at a 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 at a dose of 0.1-50mg/kg、0.1-40mg/kg、0.1-30mg/kg、0.1-20mg/kg、0.1-10mg/kg、1-50mg/kg、1-40mg/kg、1-30mg/kg、1-20mg/kg、1-10mg/kg、3-50mg/kg、3-40mg/kg、3-30mg/kg、3-20mg/kg、3-10mg/kg、1-5mg/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 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, each 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 2mg/kg, 3mg/kg, or 5mg/kg each time.

In some embodiments, in the methods and uses, the chemotherapeutic agent is administered according to known methods. For example, gemcitabine is administered twice every 1 week (q 1 w), every 2 weeks (q 2 w), every 3 weeks (q 3 w), or every 4 weeks (q 4 w). In some specific embodiments, gemcitabine is administered twice every 3 weeks. In some embodiments, gemcitabine is administered at a dose of 1000-1250mg/m² at a time. In some embodiments, gemcitabine is administered at a dose of 1000mg/m² at a time. In some embodiments, gemcitabine is administered twice every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each at a dose of 1000-1250mg/m². In some embodiments, gemcitabine is administered twice every 3 weeks, each at a dose of 1000-1250mg/m². In some embodiments, gemcitabine is administered twice every 3 weeks, each at a dose of 1000mg/m². For example, cisplatin is administered every 1 week (q 1 w), every 2 weeks (q 2 w), every 3 weeks (q 3 w), or every 4 weeks (q 4 w). In some specific embodiments, cisplatin is administered once every 3 weeks. In some embodiments, cisplatin is administered at a dose of 80-100mg/m² at a time. In some embodiments, cisplatin is administered at a dose of 80mg/m² at a time. In some embodiments, cisplatin is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each at a dose of 80-100mg/m². In some embodiments, cisplatin is administered once every 3 weeks, each at a dose of 80-100mg/m². In some embodiments, cisplatin is administered once every 3 weeks, each at a dose of 80mg/m².

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, respectively, have the same or different treatment cycles. 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, e.g., one treatment cycle 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, e.g., one treatment cycle every 3 weeks.

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 agent 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 agent have the same treatment cycle, e.g., one treatment cycle 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 agent have the same treatment cycle, e.g., one treatment cycle every 3 weeks.

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 every 3 weeks for one treatment cycle. 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 are administered once each treatment cycle, respectively, every 3 weeks. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, on day 1 of each treatment cycle, and the anti-PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks for a treatment cycle, once on day 1 of each treatment cycle, and once on day 1 of each treatment cycle.

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

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 agent are administered every 3 weeks for one treatment cycle. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, the anti-PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, gemcitabine is administered on days 1 and 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, one treatment cycle is administered every 3 weeks, 160-800mg or 400-800mg of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered per treatment cycle, 100-200mg of the anti-PD-1 antibody or antigen-binding fragment thereof is administered per treatment cycle, 1000-3000mg/m² gemcitabine is administered per treatment cycle, and 80-100mg/m² cisplatin is administered per treatment cycle. In some specific embodiments, in the method or use, one treatment cycle is administered every 3 weeks, 160-800mg or 400-800mg of anti-LAG-3 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, 100-200mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, 1000mg/m² gemcitabine is administered on each of day 1 and day 8 of each treatment cycle, and 80mg/m² cisplatin is administered on day 1 of each treatment cycle. In some specific embodiments, in the method or use, 600mg of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for one treatment cycle, 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof is administered every 1 day of each treatment cycle, 1000mg/m² gemcitabine is administered every 1 day and 8 days of each treatment cycle, and 80mg/m² cisplatin is administered every 1 day of each treatment cycle.

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 administered to the subject at a mass ratio of (0.1-20): 1, (0.5-10): 1, (1-5): 1 or 3:1 anti-LAG-3 antibody or antigen-binding fragment thereof per treatment cycle. 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 administered to the subject at a mass ratio of (0.1-20): 1, (0.5-10): 1, (1-5): 1 or 3:1, in each treatment cycle, and the chemotherapeutic agent is further administered.

In some embodiments, in the methods or uses, the dosing regimen (e.g., dosing cycle, dosing, and dosing regimen) of the anti-LAG-3 antibody or antigen-binding fragment thereof and 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 of the patient. For example, one treatment cycle of an anti-LAG-3 antibody or antigen-binding fragment thereof and/or an anti-PD-1 antibody or antigen-binding fragment thereof may 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.

In some embodiments, in the methods or uses, the dosing regimen (e.g., dosing cycle, dosing, and dosing regimen) of the chemotherapeutic agent can be adjusted according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient.

Anti-LAG-3 antibodies or antigen-binding fragments thereof

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

TABLE 1 CDR sequences of anti-LAG-3 antibodies or antigen binding fragments thereof

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) is to be understood as encompassing complementarity determining regions defined by any one of the known schemes. Although the CDR sequences have been shown in table 1, when reference is made to defining an anti-LAG-3 antibody or antigen-binding fragment thereof with a particular CDR sequence, the scope of the anti-LAG-3 antibody or antigen-binding fragment thereof encompasses any numbering system definition (e.g., binding of one or more of the AbM, kabat, chothia, CCG, IMGT or Contact etc. definitions known in the art) of an anti-LAG-3 antibody or antigen-binding fragment thereof.

In some embodiments, the anti-LAG-3 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% 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 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 the heavy chain variable region shown in SEQ ID NO. 7. In some embodiments, the anti-LAG-3 antibody or antigen binding fragment thereof comprises the light chain variable region shown 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 set forth in 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 set forth in SEQ ID No. 8 or 28.

In some embodiments, the anti-LAG-3 antibody or antigen binding fragment thereof comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 6, and the anti-LAG-3 antibody or antigen binding fragment thereof comprises a heavy chain variable region having 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 shown in SEQ ID NO. 7, and a heavy chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 92%, 94%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown 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. 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 shown in SEQ ID NO. 27 and a light chain variable region of the amino acid sequence shown in SEQ ID NO. 28. In some specific embodiments, the anti-LAG-3 antibody or antigen binding fragment thereof has the amino acid sequence of the heavy chain variable region as shown in SEQ ID NO. 7 and the amino acid sequence of the light chain variable region as shown in SEQ ID NO. 8. In some specific embodiments, the heavy chain variable region of the anti-LAG-3 antibody or antigen binding fragment thereof has an amino acid sequence as shown in SEQ ID NO. 27 and the light chain variable region has an amino acid sequence as shown in SEQ ID NO. 28.

QVQLQQWGAGLLRPSETLSLTCAVYGESFSGYYWNWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRV TISVDTSKTQFSLKLSSVTAADTAVYYCARGWDLLDWNDYWNEYWGQGTLVTVSS(SEQ ID NO:7);

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGT DFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK(SEQ ID NO:8);

EVQLLESGGGLVQPGGSLRLSCAASGFDFRSYAMMWVRQAPGKGLEWVGGINGEVGGSNTYYAPA VKGRATISRDNSKNTLYLQMNSLRAEDTAVYYCVKGAGACGICNDDIDAWGQGTLVTVSS(SEQ ID NO:27);

SYELTQDPAVSVALGQTVRITCSGAGSYAGSYYYGWHQQKPGQAPVTVIYDNDKRPSNIPDRFSGSS SGNTASLTITGAQAEDEADYYCGSTNDNDDGGLFGSGTKVTVL(SEQ ID NO:28).

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 the heavy chain of IgG1, igG2, igG3, and IgG4 or other classes of immunoglobulins, preferably the heavy chain of IgG 1. In some embodiments, the light chain constant region is from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any of the modifications described herein, such as amino acid insertions, deletions, substitutions, and/or chemical modifications. In some embodiments, the constant region comprises a mutation that alters effector function. In some embodiments, any amino acid residue of the constant region may be substituted with an amino acid residue of any allotype (allotype).

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 set forth in 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 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. 10 or 30. in some embodiments, the anti-LAG-3 antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO. 9. In some embodiments, the anti-LAG-3 antibody or antigen binding fragment thereof comprises the light chain 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 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. 9 or 29, and 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 light chain. In some embodiments, the anti-LAG-3 antibody or antigen binding fragment thereof comprises a heavy chain of the amino acid sequence shown in SEQ ID NO. 9 and a light chain of the amino acid sequence shown in SEQ ID NO. 10. In some embodiments, the anti-LAG-3 antibody or antigen binding fragment thereof comprises a heavy chain of the amino acid sequence shown in SEQ ID NO. 29 and a light chain of the amino acid sequence shown in SEQ ID NO. 30. In some specific embodiments, the heavy chain of the anti-LAG-3 antibody or antigen binding fragment thereof has an amino acid sequence as shown in SEQ ID NO. 9 and the light chain has an amino acid sequence as shown in SEQ ID NO. 10. in some specific embodiments, the heavy chain of the anti-LAG-3 antibody or antigen binding fragment thereof has an amino acid sequence as shown in SEQ ID NO. 29 and the light chain has an amino acid sequence as shown in SEQ ID NO. 30. Wherein the terminal amino acids K of SEQ ID NOS 9 and 29 may or may not be present.

QVQLQQWGAGLLRPSETLSLTCAVYGESFSGYYWNWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKTQFSLKLSSVTAADTAVYYCARGWDLLDWNDYWNEYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:9);

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:10);

EVQLLESGGGLVQPGGSLRLSCAASGFDFRSYAMMWVRQAPGKGLEWVGGINGEVGGSNTYYAPAVKGRATISRDNSKNTLYLQMNSLRAEDTAVYYCVKGAGACGICNDDIDAWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:29);

SYELTQDPAVSVALGQTVRITCSGAGSYAGSYYYGWHQQKPGQAPVTVIYDNDKRPSNIPDRFSGSSSGNTASLTITGAQAEDEADYYCGSTNDNDDGGLFGSGTKVTVLRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:30).

Anti-PD-1 antibodies or antigen-binding fragments thereof

In some embodiments, an anti-PD-1 antibody or antigen-binding fragment thereof of the application comprises HCDR1 of the amino acid sequence set forth in SEQ ID NO. 11, HCDR2 of the amino acid sequence set forth in SEQ ID NO. 12, HCDR3 of the amino acid sequence set forth in SEQ ID NO. 13, LCDR1 of the amino acid sequence set forth in SEQ ID NO. 14, LCDR2 of the amino acid sequence set forth in SEQ ID NO. 15, and LCDR3 of the amino acid sequence set forth in SEQ ID NO. 16. The CDR sequences of the anti-PD-1 antibodies or antigen-binding fragments thereof are shown in table 2.

TABLE 2 CDR sequences of anti-PD-1 antibodies or antigen binding fragments thereof

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

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) is to be understood as encompassing complementarity determining regions defined by any one of the known schemes. Although CDR regions have been shown in table 2, when reference is made to defining an anti-PD-1 antibody or antigen-binding fragment thereof with a particular CDR sequence, the scope of the anti-PD-1 antibody or antigen-binding fragment thereof encompasses any numbering system definition (e.g., binding of one or more of the AbM, kabat, chothia, CCG, IMGT or Contact etc. definitions as known in the art) of an anti-PD-1 antibody or antigen-binding fragment thereof.

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 set forth in 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 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. 18. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises the heavy chain variable region set forth in SEQ ID NO. 17. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises the light chain variable region set forth 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 set forth in 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 set forth in SEQ ID NO. 18.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises HCDR1 comprising the amino acid sequence set forth in SEQ ID NO. 11, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO. 12, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO. 13, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO. 14, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO. 15, and LCDR3 comprising the amino acid sequence set forth in 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 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 set forth in SEQ ID NO. 17, and an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 90%, 92%, 96%, 98%, 99% or 100% variable chain identity to the amino acid sequence set forth in SEQ ID NO. 18.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO. 17 and a light chain variable region of the amino acid sequence set forth in SEQ ID NO. 18. In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof has the amino acid sequence of the heavy chain variable region shown in SEQ ID NO. 17 and the amino acid sequence of the light chain variable region shown in SEQ ID NO. 18.

EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKG RFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSS(SEQ ID NO:17);

DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSG QDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELK(SEQ ID NO:18).

In some embodiments, the anti-PD-1 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 the heavy chain of IgG1, igG2, igG3, and IgG4 or other classes of immunoglobulins, preferably the heavy chain of IgG 1. In some embodiments, the light chain constant region is from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any of the modifications described herein, such as amino acid insertions, deletions, substitutions, and/or chemical modifications. In some embodiments, the constant region comprises a mutation that alters effector function. In some embodiments, any amino acid residue of the constant region may be substituted with an amino acid residue of any allotype (allotype).

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 set forth in 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 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. 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises the heavy chain shown in SEQ ID NO. 19. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises the light chain shown 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 set forth in 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 set forth in SEQ ID NO. 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence set forth in SEQ ID NO. 19 and a light chain of the amino acid sequence set forth in SEQ ID NO. 20. In some specific embodiments, the heavy chain amino acid sequence of the anti-PD-1 antibody or antigen-binding fragment thereof is shown in SEQ ID NO. 19 and the light chain amino acid sequence is shown in SEQ ID NO. 20. Wherein the terminal amino acid K of SEQ ID NO. 19 may or may not be present.

EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:19);

DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:20).

In other embodiments, the anti-PD-1 antibodies or antigen-binding fragments thereof of the application are selected from the group consisting of Na Wu Liyou mab (Nivolumab), parbolizumab (Pembrolizumab), terlipressin Li Shan mab (Toripalimab), xindi Li Shan mab (Sintilimab), carilizumab (Camrelizumab), tirelizumab (Tislelizumab), cepalizumab (Zimberelimab), batirimumab (Balstilimab), jennuzumab (geptanolimab), lizhuzhi Lipustobart (LZM-009), simipn Li Shan mab (Cemiplimab), st Lu Lishan mab (Serplulimab), prolgolimab, prinsensin (HX 008), nofazinlimab, finotonlimab, dostarlimab, cetrelimab, QL1604, spartalizumab, retifanlimab, sasanlimab of QL, rulonilimab (F520) of New pharmaceutical industry in Shandong, or Shandor's biological Enlonstobart (SG 001).

Pharmaceutical compositions containing antibodies or antigen-binding fragments thereof

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof may be formulated as a formulation for parenteral administration. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof may be formulated for intravenous, intramuscular, subcutaneous, or other parenteral administration, e.g., for injection or infusion. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof may 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 may be formulated as a formulation for intravenous injection or infusion.

The anti-LAG-3 antibodies, or antigen-binding fragments thereof, may be formulated into suitable dosage forms, including, but not limited to, tablets, troches, pills, capsules (e.g., hard capsules, soft capsules, enteric capsules, microcapsules), elixirs, granules, syrups, injections (i.e., formulations suitable for injection, e.g., formulations suitable for intramuscular, intravenous, intraperitoneal, subcutaneous injection), granules, emulsions, suspensions, solutions, dispersions, and sustained release formulations for oral or non-oral administration. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof may be formulated as an injection (e.g., an injection or lyophilized formulation for injection). In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof may be formulated into an injection suitable for intravenous injection.

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

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof may be formulated for parenteral administration. In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof may be formulated for intravenous, intramuscular, subcutaneous, or other parenteral administration, e.g., for injection or infusion. In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof may 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 may be formulated as a formulation for intravenous injection or infusion.

The anti-PD-1 antibodies or antigen-binding fragments thereof may be formulated into suitable dosage forms including, but not limited to, tablets, troches, pills, capsules (e.g., hard capsules, soft capsules, enteric capsules, microcapsules), elixirs, granules, syrups, injections (i.e., formulations suitable for injection, e.g., formulations suitable for intramuscular, intravenous, intraperitoneal, subcutaneous injection), granules, emulsions, suspensions, solutions, dispersions, and sustained release formulations for oral or non-oral administration. In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof may be formulated as an injection (e.g., an injection or lyophilized formulation for injection). In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof may be formulated into an injection suitable for intravenous injection.

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

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.

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, is formulated with one or more pharmaceutically acceptable carriers to make a suitable pharmaceutical composition.

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

In some embodiments, the pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof is an aqueous injection. In some embodiments, the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is an aqueous injection. In some embodiments, the single formulation comprising an anti-LAG-3 antibody or antigen-binding fragment thereof and an 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 that has been reconstituted from a lyophilized powder.

In other embodiments, the pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof is a lyophilized formulation for injection. In other embodiments, the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized formulation for injection. In other embodiments, the single formulation comprising the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized formulation for injection. The lyophilized preparation for injection refers to a preparation prepared by subjecting an aqueous solution to a lyophilization process in which a substance is first frozen, 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 formulation of the present application may also be dried by other methods known in the art, such as spray drying and bubble drying (bubbledrying).

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

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

Chemotherapeutic agents

The chemotherapeutic agents of the present application include, but are not limited to, platinum-based antitumor agents (including, but not limited to, oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, midoproplatin, lobaplatin, picoplatin (picoplatin), triplatin tetranitrate, phenanthreneplatin, satraplatin), camptothecine-based antitumor agents (including, but not limited to, camptothecine, hydroxycamptothecin, aminocamptothecin, irinotecan, topotecan, irinotecan, luratican, luratidine (lurtotecan), ge Ma Tikang, karenitecin, 7-ethylcamptothecin), taxane-based antitumor agents (including, but not limited to, paclitaxel and docetaxel), nitrogen mustard-based antitumor agents (including, but not limited to, cyclophosphamide, ifosfamide, chlorambucil, carmustine, melphalan, bendamustine), and bendamustine antimetabolite antitumor drugs (including but not limited to fluorouracil antitumor drugs (including but not limited to carmofur, 5-fluorouracil, tegafur, capecitabine, tigogens, bififluraciens, doxifluridine, trifluoracetam), cytosine antitumor drugs (including but not limited to cytarabine, gemcitabine, azacytidine, and ancitabine), purine antitumor drugs (including but not limited to mercaptopurine, fludarabine), antitumor drugs (including but not limited to methotrexate, and pemetrexed), anthracycline antitumor drugs (including but not limited to doxorubicin, epirubicin, pirarubicin, amorubicin, idarubicin, daunorubicin, mitoxantrone, idarubicin, pentarubicin, pentazocin, and pinacolin), liposomal doxorubicin, and other antitumor drugs, vinblastine antitumor agents (including but not limited to vinblastine, vincristine, vindesine, vin Funing (vinflunine) and vinorelbine), podophyllotoxin antitumor agents (including but not limited to etoposide, teniposide), hormonal antitumor agents (including but not limited to prednisone, prednisolone, dexamethasone, methylprednisolone sodium succinate), procarbazine, hexamethylenemine, dacarbazine, mitomycin, actinomycin D (dactinomycin), bleomycin, pingyanmycin, temozolomide, amimine, pelomycin, eribulin, plinabulin (plinabulin), sapacitabine, and trastuzumab (treosulfan).

In some embodiments, the chemotherapeutic agent comprises a platinum-based anti-tumor agent, a taxane-based anti-tumor agent, and/or an anti-metabolite-based anti-tumor agent. In some embodiments, the chemotherapeutic agent comprises a platinum-based anti-tumor agent and/or an anti-metabolite-based anti-tumor agent.

Further, the platinum-based antitumor drug is selected from one or more of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miltiplatin, lobaplatin, triplatin tetranitrate, phenanthreneplatin and satraplatin, for example, carboplatin or cisplatin.

In some embodiments, the antimetabolite antineoplastic agent is selected from one or more of 5-fluorouracil, capecitabine, cytarabine, gemcitabine, azacytidine, fludarabine, methotrexate, pemetrexed, e.g., gemcitabine.

In some specific embodiments, the chemotherapeutic agent comprises cisplatin and gemcitabine.

In some embodiments, the chemotherapeutic agent is administered according to known dosing regimens, including dosing cycles, dosing amounts and dosing adjustments, and routes of administration.

Pharmaceutical composition containing chemotherapeutic agent

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

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

Mode of administration

The following is not intended to limit the manner of administration of the pharmaceutical combination of the application.

The components of the pharmaceutical combination of the present application may each be administered independently, or some or all of them together, in a suitable variety of ways, including but not limited to parenteral (e.g., by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combination of the present application may each be administered independently, or some or all of them together, as an injection, such as intravenous injection or subcutaneous injection.

The pharmaceutical combinations of the application may also comprise additional therapeutic agents. In some embodiments, the additional therapeutic agent may be a tumor therapeutic agent known in the art.

Tumor(s)

The tumor according to the present application is a malignant tumor (i.e. cancer), which refers to any malignant and/or invasive growth caused by abnormal cell growth.

In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is a primary, unresectable, refractory, advanced, recurrent, and/or metastatic solid tumor.

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 primary, unresectable, refractory, advanced, recurrent, and/or metastatic hepatocellular carcinoma. 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.

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 by surgery, radiation therapy, chemotherapy, and/or immunotherapy. In some embodiments, the liver cancer is a liver cell cancer that has not been systematically treated. In some embodiments, the liver cancer is hepatocellular carcinoma not treated by immunotherapy. In some embodiments, the liver cancer is advanced hepatocellular carcinoma without systemic treatment. In some embodiments, the liver cancer is advanced hepatocellular carcinoma not treated with immunotherapy.

In some embodiments, the subject of the hepatocellular carcinoma has not previously been treated for hepatocellular carcinoma (e.g., lacks an effective treatment regimen). In some embodiments, the subject of hepatocellular carcinoma has not previously received surgery, radiation therapy, 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.

In some embodiments, the subject of hepatocellular carcinoma has previously been treated with one or more different anti-tumor therapies (e.g., failed or inapplicable). In some embodiments, the subject of hepatocellular carcinoma has previously been treated with no more than two anti-tumor therapies (e.g., failed or inapplicable). In some specific embodiments, the subject of hepatocellular carcinoma has previously received surgical treatment, radiation therapy, induction chemotherapy, contemporaneous chemotherapy, and/or adjuvant chemotherapy to treat hepatocellular carcinoma (e.g., treatment failure or inapplicability). In some specific embodiments, the subject of hepatocellular carcinoma has previously received systemic treatment to treat hepatocellular carcinoma (e.g., failed or inapplicable). In some specific embodiments, the subject of hepatocellular carcinoma has previously been treated with a first-line or second-line treatment to treat hepatocellular carcinoma (e.g., failed or inapplicable treatment).

In some embodiments, the liver cancer is CNLC stage III or BCLC stage C stage hepatocellular carcinoma. In some embodiments, the liver cancer is CNLC stage II or BCLC stage B hepatocellular carcinoma. In some embodiments, the liver cancer is a refractory hepatocellular carcinoma that is not amenable to topical treatment or topical treatment. In some embodiments, the liver cancer is a CNLC stage II hepatocellular carcinoma that is not amenable to topical treatment or refractory to topical treatment. In some embodiments, the liver cancer is BCLC stage B-stage hepatocellular carcinoma that is not amenable to topical treatment or refractory to topical treatment. In some embodiments, the subject of liver cancer has not previously received immunotherapy to treat hepatocellular carcinoma. In some embodiments, the topical treatment includes, but is not limited to, surgery, trans-hepatic arterial chemoembolization (TACE), hepatic arterial embolization (TAI), radiofrequency or microwave ablation, absolute alcohol injection, and radiation therapy.

In some embodiments, the hepatocellular carcinoma is a hepatocellular carcinoma with Child-Pugh liver function graded as grade A or grade B.

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 primary, 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, IIIC or IV non-small cell lung cancer.

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

In some embodiments, the non-small cell lung cancer is free of driver gene mutations, including but not limited to EGFR, ALK, ROS, BRAF, NTRK, MET, and/or KRAS. In some embodiments, the non-small cell lung cancer does not have EGFR mutations. In some embodiments, the non-small cell lung cancer is absent ALK fusion. In some embodiments, the non-small cell lung cancer is free of ROS1 mutations.

In some embodiments, the non-small cell lung cancer is PD-L1 expression positive non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer 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 positive for PD-L1 expression.

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 by surgery, radiation therapy, chemotherapy, and/or immunotherapy. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that has not been systematically treated. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer that has not been systematically treated. 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 systematically treated. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer that is positive for PD-L1 expression that is not systematically treated. In some embodiments, the non-small cell lung cancer is PD-L1 expression positive, non-systematically treated locally advanced, metastatic, and/or recurrent non-small cell lung cancer.

In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that is unsuitable for surgery and radical simultaneous chemoradiotherapy. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer that is not amenable to surgery and radical simultaneous chemoradiotherapy. In some embodiments, the non-small cell lung cancer is locally advanced, metastatic and/or recurrent non-small cell lung cancer that is not amenable to surgery and radical concurrent chemoradiotherapy. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer that is not systematically treated and is unsuitable for surgery and radical concurrent chemo-radiotherapy. In some embodiments, the non-small cell lung cancer is locally advanced, metastatic and/or recurrent non-small cell lung cancer that is not systematically treated and is unsuitable for surgery and radical concurrent chemo-radiation. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer that is positive for PD-L1 expression, that is not systematically treated, and that is not amenable to surgery and radical concurrent chemoradiotherapy. In some embodiments, the non-small cell lung cancer is locally advanced, metastatic and/or recurrent non-small cell lung cancer that is positive for PD-L1 expression, not systematically treated, and not amenable to surgery and radical concurrent chemo-radiation.

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 advanced non-small cell lung cancer that is not systematically treated and unresectable. In some embodiments, the non-small cell lung cancer is locally advanced, metastatic and/or recurrent non-small cell lung cancer that is not systematically treated and is unresectable. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer that is positive for PD-L1 expression, that is not systematically treated, and that is unresectable. In some embodiments, the non-small cell lung cancer is PD-L1 expression positive, non-systematically treated, and unresectable locally advanced, metastatic, and/or recurrent non-small cell lung cancer.

In some embodiments, the subject of non-small cell lung cancer has previously been treated with one or more different anti-tumor therapies (e.g., failed or inapplicable). In some specific embodiments, the subject of non-small cell lung cancer has previously received surgery, radiation therapy, induction chemotherapy, contemporaneous chemotherapy, and/or adjuvant chemotherapy to treat non-small cell lung cancer (e.g., failed or inapplicable). In some specific embodiments, the subject of non-small cell lung cancer has previously received a neoadjuvant or adjuvant therapy (e.g., chemotherapy or radiation therapy) to treat non-small cell lung cancer (e.g., failed or inapplicable). In some specific embodiments, the subject of non-small cell lung cancer has previously received systemic treatment to treat non-small cell lung cancer (e.g., failed or inapplicable).

In some embodiments, the solid tumor is a nasopharyngeal carcinoma. In some embodiments, the tumor is a nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is primary, unresectable, refractory, advanced, recurrent, and/or metastatic. In some embodiments, the nasopharyngeal carcinoma is a non-resectable nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is refractory nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is advanced nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is 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 refractory, metastatic, and/or recurrent. In some embodiments, the nasopharyngeal carcinoma is refractory and/or recurrent nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is metastatic and/or recurrent nasopharyngeal carcinoma.

In some embodiments, the nasopharyngeal carcinoma is untreated nasopharyngeal carcinoma (e.g., lacks an effective treatment regimen). In some embodiments, the nasopharyngeal carcinoma is a non-surgically, radiation, chemotherapy, and/or immunotherapy treated nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is a non-systematically treated nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is an advanced nasopharyngeal carcinoma without systemic treatment. In some embodiments, the nasopharyngeal carcinoma is a metastatic and/or recurrent nasopharyngeal carcinoma without systemic treatment. In some embodiments, the nasopharyngeal carcinoma is an advanced nasopharyngeal carcinoma that is not treated by an immunotherapy. In some embodiments, the nasopharyngeal carcinoma is a metastatic and/or recurrent nasopharyngeal carcinoma that is not treated by immunotherapy.

In some embodiments, the nasopharyngeal carcinoma is a nasopharyngeal carcinoma that is unsuitable for local treatment and radical concurrent chemoradiotherapy. In some embodiments, the nasopharyngeal carcinoma is a late stage nasopharyngeal carcinoma that is unsuitable for local treatment and radical concurrent chemoradiotherapy. In some embodiments, the nasopharyngeal carcinoma is a metastatic and/or recurrent nasopharyngeal carcinoma that is unsuitable for local treatment and radical concurrent chemoradiotherapy. In some embodiments, the nasopharyngeal carcinoma is a late stage nasopharyngeal carcinoma that has not been systematically treated and is unsuitable for local treatment and radical concurrent chemo-radiotherapy. In some embodiments, the nasopharyngeal carcinoma is a metastatic and/or recurrent nasopharyngeal carcinoma that is not systematically treated and is unsuitable for local treatment and radical concurrent chemo-radiotherapy. In some embodiments, the nasopharyngeal carcinoma is a late stage nasopharyngeal carcinoma which is not treated by immunotherapy and is unsuitable for local treatment and radical concurrent chemo-radiotherapy. In some embodiments, the nasopharyngeal carcinoma is a metastatic and/or recurrent nasopharyngeal carcinoma which is not treated by immunotherapy and is unsuitable for local treatment and radical concurrent chemo-radiotherapy. In some embodiments, the nasopharyngeal carcinoma is a late stage nasopharyngeal carcinoma that has not been treated by immunotherapy and systemic therapy, and is unsuitable for local treatment and radical concurrent chemo-radiotherapy. In some embodiments, the nasopharyngeal carcinoma is metastatic and/or recurrent nasopharyngeal carcinoma which is not treated by immunotherapy and systemic therapy, and is unsuitable for local treatment and radical concurrent chemo-radiotherapy.

In some embodiments, the nasopharyngeal carcinoma is a non-resectable advanced nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is unresectable metastatic and/or recurrent nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is an unresectable advanced nasopharyngeal carcinoma that is not treated systematically. In some embodiments, the nasopharyngeal carcinoma is a metastatic and/or recurrent nasopharyngeal carcinoma which is not systematically treated and is unresectable. In some embodiments, the nasopharyngeal carcinoma is an advanced nasopharyngeal carcinoma which is untreated by an immunotherapy and which is unresectable. In some embodiments, the nasopharyngeal carcinoma is a metastatic and/or recurrent nasopharyngeal carcinoma which is not treated by immunotherapy and which is unresectable. In some embodiments, the nasopharyngeal carcinoma is an advanced nasopharyngeal carcinoma which is not immunotherapy and systemic treatment and is unresectable. In some embodiments, the nasopharyngeal carcinoma is a non-resectable metastatic and/or recurrent nasopharyngeal carcinoma that is not immunotherapy and systemic treatment.

In some embodiments, the subject of the nasopharyngeal carcinoma has previously been treated (e.g., failed or inapplicable) with one or more different anti-tumor therapies. In some embodiments, the subject of the nasopharyngeal carcinoma has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy to treat the nasopharyngeal carcinoma (e.g., treatment failure or inapplicability). In some specific embodiments, the subject of nasopharyngeal carcinoma has previously received a novel adjuvant or adjuvant therapy (e.g., chemotherapy or radiation therapy) to treat the nasopharyngeal carcinoma (e.g., treatment failure or inapplicability). In some specific embodiments, the subject of nasopharyngeal carcinoma has previously received systemic treatment to treat the nasopharyngeal carcinoma (e.g., treatment failure or inapplicability).

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 checkpoint comprises 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 directed against an immune checkpoint (e.g., PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4, and/or CD 160), such as, for example, nal Wu Liyou mab (Nivolumab), palbociclizumab (Pembrolizumab), terep Li Shan mab (Toripalimab), singdi Li Shan mab (Sintilimab), carrilizumab (Camrelizumab), tirelimumab (Tislelizumab), batirimumab (Balstilimab), saparlizumab (Zimberelimab), atilizumab (Atezolizumab), divali You Shan mab (Durvalumab), aliskumumab (Avelumab), en Wo Lishan mab (Envafolimab), shu Geli mab (Sugemalimab), ipilimumab (Ipilimumab), or tizemumab (tremelimab).

Technical effects

In general, the use of the pharmaceutical combination of the application, or the 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 application in combination, will help:

(1) Producing a better therapeutic effect in reducing tumor growth or eliminating tumors than either drug administered alone in the combination;

(2) Providing a smaller amount of administration compared to either drug administered alone in the combination;

(3) Providing a treatment with good tolerance in the patient with fewer adverse reactions and/or complications than either drug administered alone;

(4) Providing better disease control rate among treated patients;

(5) Providing a longer survival (e.g., median survival, progression free survival, or total survival) in the treated patient;

(6) Providing a longer survival (e.g., median survival, progression free survival, or total survival) for the treated patient compared to standard chemotherapy;

(7) Provide longer duration of disease remission (DOR), and/or

(8) Compared with any one of the medicines singly administered in the combination, the composition has good anti-tumor activity and shows more excellent anti-tumor synergistic effect.

The medicine composition and the treatment scheme have better curative effect in treating solid tumors (including hepatocellular carcinoma, non-small cell lung cancer and nasopharyngeal carcinoma). Wherein at least one of ORR, DCR, DOR, PFS, OS, tolerance, and side effects has a beneficial effect.

Definition and description

The following terms used in the present application have the following meanings unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are present in the present application, it is intended to refer to their corresponding commercial products or active ingredients thereof.

As used herein, the term "pharmaceutical combination" refers to a combination of two or more active ingredients administered in any order, including as the respective active ingredients themselves, or as derivatives, prodrugs or compositions of their respective pharmaceutically acceptable salts or esters. The active ingredients may each be administered to the subject simultaneously as a single formulation, or each sequentially in any order as a single formulation, or simultaneously as a single formulation.

As used herein, the term "antibody" refers to an antigen binding protein having at least one antigen binding domain. The antibodies and fragments thereof of the present application may be whole antibodies or any fragment thereof. Thus, antibodies and fragments thereof of the application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof. Examples of antibodies and antigen-binding fragment fragments thereof 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 of the IgG1, igG2, igG3 or IgG4 isotype. The term "isotype" refers to the type of antibody 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 application may be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas, and humans. The anti-LAG-3 antibodies and antigen-binding fragments thereof of the application, and anti-PD-1 antibodies and antigen-binding fragments thereof, may be murine, chimeric, humanized or fully human. Unless otherwise indicated, "antibody" of the present application includes whole antibodies and any antigen-binding fragment or single chain thereof. Conventional "whole antibodies" are glycoproteins comprising two heavy (H) chains and two light (L) chains, the heavy and light chains being linked by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region consists of three domains, 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. VH and VL regions can also be divided into hypervariable regions, i.e., complementarity Determining Regions (CDRs), and Framework Regions (FR) that are more conserved in sequence. Each of VH and VL consists of three CDRs and four FRs, from amino to carboxy terminus, FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4, respectively. The variable regions of the heavy and light chains comprise binding domains that interact with antigens. The constant region of an antibody may mediate the binding of an immunoglobulin to host tissues or factors including various cells of the immune system (e.g., effector cells) and the first component of the classical complement system (C1 q). Meanwhile, as will be appreciated by those skilled in the art, a particular "whole antibody", such as a nanobody, has only heavy (H) chains and no light (L) chains.

An "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding 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 whole antibody. Examples of "antigen binding fragments" encompassed by the term antibody include (i) a Fab fragment, a monovalent fragment consisting of the V_L、V_H, CL and CH1 domains, (ii) a F (ab')₂ fragment, a bivalent fragment comprising two Fab fragments disulfide-bridged 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 an antibody single arm, (V) a dAb fragment consisting of the VH domain (see Ward et al, nature.341:544-546 (1989)), and (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. Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, the VH and VL can be joined, by recombinant methods, by a synthetic linker, into a single protein chain in which the VL and VH pair to form a monovalent molecule (known as a single chain Fv (scFv); see, e.g., bird et al, science 242:423-426 (1988); huston et al, proc. Natl. Acad. Sci.85:5879-5883 (1988)). These single chain antibodies are also encompassed by the term antigen binding fragments. In addition, recombinant polypeptides, fusion proteins, small modular immunopharmaceuticals (small modular immunopharmaceutical, SMIP) and immunoconjugates comprising the antigen binding fragments are also encompassed by the term antigen binding fragments.

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 murine variable regions and human constant regions.

A "humanized antibody" is an antibody that contains Complementarity Determining Regions (CDRs) derived from a non-human antibody and framework regions and constant regions derived from a human antibody. For example, anti-LAG-3 antibodies and anti-PD-1 antibodies may comprise CDRs derived from one or more murine antibodies as well as human framework regions and human constant regions. Exemplary humanized antibodies are provided herein. Additional anti-LAG-3 antibodies, or variants thereof, comprising HCDR and LCDR provided herein can be generated using any human framework sequences and are also included in the application. Additional anti-PD-1 antibodies or variants thereof comprising HCDR and LCDR provided herein can be generated using any human framework sequences and are also included in the application. In one embodiment, framework sequences suitable for use in the present application include those framework sequences that are similar in structure to the framework sequences provided herein. Additional modifications may be made in the framework regions to improve the properties of the antibodies provided herein. Such additional framework modifications may include chemical modifications, point mutations to reduce immunogenicity or remove T cell epitopes, or reversion of mutations to residues in the original germline sequence.

The term "identity", also known as consistency. "percent (%) identity" of amino acid sequences refers to the percentage of amino acid residues in an aligned sequence that are identical to the amino acid residues of a particular amino acid sequence shown herein, after aligning the aligned sequence to the particular amino acid sequence shown herein and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and without regard to any conservative substitutions as part of the sequence identity. Amino acid sequence alignment for identity can be performed in a variety of ways within the skill in the art, such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. One skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithm needed to obtain the maximum alignment over the entire length of the compared sequences.

The term "treatment" generally refers to an operation to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of preventing the disease, or symptoms thereof, in whole or in part, and/or may be therapeutic in terms of stabilizing or curing the disease, in part or in whole, and/or side effects resulting from the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including but not limited to preventing the occurrence or recurrence of the disease, alleviating symptoms of the disease, reducing any direct or indirect pathological consequences of the disease, preventing metastasis of the disease, slowing the progression of the disease, ameliorating or alleviating the status of the disease, extending the frequency and duration of the asymptomatic phase, and resolving or improving the prognosis of the disease.

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 a disease or promotes regression of a disease as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease-free symptomatic periods, or prevention of injury or disability caused by affliction of the disease. The ability of a therapeutic agent to promote disease regression can be assessed using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems that predict efficacy for humans, or by assaying the activity of the agent in an in vitro assay.

The term "administering" or "administering" means physically introducing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those of skill in the art.

Routes of administration of the antibody or antigen-binding fragment thereof (e.g., anti-LAG-3 antibody or antigen-binding fragment thereof or anti-PD-1 antibody or antigen-binding fragment thereof) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion. The phrase "parenteral administration" as used herein refers to modes of administration other than parenteral administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. Administration may also be performed, for example, one, multiple times, and/or over one or more extended periods of time.

The use of the term "flat dose" refers to the dose administered to a patient irrespective of the weight or Body Surface Area (BSA) of the patient. The uniform dose is therefore specified as an absolute amount of the agent (e.g., anti-PD-1 antibody or antigen-binding fragment thereof) rather than as a mg/kg dose. For example, 60kg of human and 100kg of human will receive the same dose of antibody (e.g., 200mg of anti-PD-1 antibody or antigen-binding fragment thereof).

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

The term "pharmaceutical composition" refers to a mixture of a compound of the application and a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the application to a subject. The terms "pharmaceutical composition" and "formulation" have the same meaning and are used interchangeably herein.

The terms "subject," "patient," or "subject" are used interchangeably herein. "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 term "subject," "patient," or "subject" is a mammal. In some embodiments, the subject, patient or subject is a mouse. In some embodiments, the subject, patient or subject is a human.

As used herein, "combination," "combined," or "combined" means that two or more compounds can each be administered to a subject simultaneously as a single formulation, or sequentially in any order, each as a single formulation. Or all of the active ingredients are formulated in a single formulation for simultaneous administration to a subject.

The term "single dose" refers to the smallest unit of packaging containing a quantity of a pharmaceutical product, e.g., a box of seven tablets, one tablet being a single dose, or a bottle of injectate being a single dose. The term "multi-dose" consists of a plurality of single doses. The term "unit dose" refers to the dosage of the active ingredient contained in the smallest packaging unit containing a quantity of pharmaceutical product, e.g., the dosage of the antibody contained in a bottle of antibody injection is a unit dose.

The words "comprise", "comprising" or "includes" and variations thereof such as include or comprise are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to".

The term "PD-L1 positive" or "PD-L1 positive" in relation to cell surface PD-L1 expression refers to the proportion of cells in a test tissue sample comprising tumor cells and tumor-infiltrating immune cells above which the sample is assessed as expressing cell surface PD-L1. For cell surface expression as determined by Immunohistochemistry (IHC), a PD-L1 positive tumor or a PD-L1 expression positive tumor means 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 may also be described herein as PD-L1 expressing tumors. In other embodiments, a PD-L1 positive tumor or a PD-L1 expressing 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 in the range of 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.

In this document, singular terms encompass plural referents and vice versa, unless the context clearly dictates otherwise.

All patents, patent applications, and other identified publications are expressly incorporated herein by reference for the purpose of description and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements as to the date or representation as to 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 or contents of these documents. Moreover, any reference to such 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.

The present application also provides the following specific embodiments, but is not limited thereto:

1. a pharmaceutical combination comprising an anti-LAG-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof, wherein,

The anti-LAG-3 antibody or antigen binding fragment thereof comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 5 and LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 6, or HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 21, HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 22, HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 23, LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 24, LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 25 and LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 26.

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.

2. The pharmaceutical 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 that is at least 95% identical to the amino acid sequence shown in SEQ ID No. 7, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID No. 8, or a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID No. 27, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID No. 28.

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 with at least 95% identity to the amino acid sequence shown in SEQ ID No. 9 and a light chain having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID No. 10, or a heavy chain having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID No. 29 and a light chain having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID No. 30.

4. The pharmaceutical combination according to any one of embodiments 1-3, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence set forth in SEQ ID NO. 17 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence set forth in SEQ ID NO. 18.

5. The pharmaceutical combination according to any one of embodiments 1-4, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence with at least 95% identity to the amino acid sequence set forth in SEQ ID NO. 19 and a light chain having an amino acid sequence with at least 95% identity to the amino acid sequence set forth in SEQ ID NO. 20.

6. The pharmaceutical combination according to any one of embodiments 1-5, 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 a formulation 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 formulation for intravenous, intramuscular or subcutaneous administration.

7. The pharmaceutical combination of any of embodiments 1-6, 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 of embodiments 1-7, wherein the pharmaceutical combination further comprises a chemotherapeutic agent, preferably the chemotherapeutic agent comprises a platinum-based anti-tumor agent and/or an anti-metabolite-based anti-tumor agent.

9. Use of the pharmaceutical combination according to any of embodiments 1-8 for the manufacture of a medicament for the treatment of a tumor.

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.

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 not treated by immunotherapy, optionally the liver cancer is advanced hepatocellular carcinoma not treated by immunotherapy.

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 not systematically treated, optionally the non-small cell lung cancer is locally advanced, metastatic and/or recurrent non-small cell lung cancer not systematically treated.

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 non-systematically treated metastatic and/or recurrent nasopharyngeal carcinoma.

14. The use of any one of embodiments 9-13, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered simultaneously, sequentially or alternately, or the anti-LAG-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent are administered simultaneously, sequentially or alternately.

15. The use of 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, at a dose of 80-1800mg, 120-1200mg, 140-1000mg, 160-800mg, or 400-800mg each time.

16. The use of 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, at a dose of 10-800mg, 50-500mg, or 100-200mg each time.

17. Use of an anti-LAG-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for the treatment of a tumor, wherein,

The anti-LAG-3 antibody or antigen binding fragment thereof comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 5 and LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 6, or HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 21, HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 22, HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 23, LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 24, LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 25 and LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 26.

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.

18. Use of an anti-LAG-3 antibody or antigen-binding fragment thereof in the manufacture of a medicament for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof in the treatment of a tumor,

The anti-LAG-3 antibody or antigen binding fragment thereof comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 5 and LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 6, or HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 21, HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 22, HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 23, LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 24, LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 25 and LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 26.

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.

19. The use of 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 that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 7, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 8, or a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 27, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 28.

20. The use of 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 that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 9 and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 10, or a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 29 and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 30.

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 having at least 95% identity to the amino acid sequence set forth in SEQ ID NO. 17 and a light chain variable region having an amino acid sequence having at least 95% identity to the amino acid sequence set forth in SEQ ID NO. 18.

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 with at least 95% identity to the amino acid sequence set forth in SEQ ID NO. 19 and a light chain having an amino acid sequence with at least 95% identity to the amino acid sequence set forth in SEQ ID NO. 20.

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

24. The use of any 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.

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.

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 not treated with immunotherapy, optionally the liver cancer is advanced hepatocellular carcinoma not treated with immunotherapy.

27. The use of 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 positive for PD-L1 expression, optionally the non-small cell lung cancer is non-small cell lung cancer not systematically treated, optionally the non-small cell lung cancer is locally advanced, metastatic and/or recurrent non-small cell lung cancer not systematically treated.

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 non-systematically treated metastatic and/or recurrent nasopharyngeal carcinoma.

29. The use of any one of embodiments 17-28, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered simultaneously, sequentially or alternately.

30. The use of 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, at a dose of 80-1800mg, 120-1200mg, 140-1000mg, 160-800mg, or 400-800mg each time.

31. The use of 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, at a dose of 10-800mg, 50-500mg, or 100-200mg each time.

32. Use of an anti-LAG-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent in the manufacture of a medicament for the treatment of a tumor, wherein,

The anti-LAG-3 antibody or antigen binding fragment thereof comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 5 and LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 6, or HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 21, HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 22, HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 23, LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 24, LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 25 and LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 26.

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.

33. Use of an anti-LAG-3 antibody or antigen-binding fragment thereof in the manufacture of a medicament for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof and a chemotherapeutic agent in the treatment of a tumor, wherein,

The anti-LAG-3 antibody or antigen binding fragment thereof comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 5 and LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 6, or HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 21, HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 22, HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 23, LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 24, LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 25 and LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 26.

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.

34. The use of 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 that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 7, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 8, or a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 27, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 28.

35. The use of 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 that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 9 and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 10, or a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 29 and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID No. 30.

36. The use of 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 set forth 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 set forth in SEQ ID No. 18.

37. The use of 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 set forth 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 set forth in SEQ ID No. 20.

38. The use of any of embodiments 32-37, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof and anti-PD-1 antibody or antigen-binding fragment thereof are formulated as a formulation for parenteral administration, preferably the anti-LAG-3 antibody or antigen-binding fragment thereof and anti-PD-1 antibody or antigen-binding fragment thereof are formulated as a formulation for intravenous, intramuscular, or subcutaneous administration.

39. The use of any 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.

40. The use according to any one of embodiments 32-39, wherein the chemotherapeutic agent comprises a platinum-based anti-tumor agent and/or an anti-metabolite-based anti-tumor agent.

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.

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 not treated by immunotherapy, optionally the liver cancer is advanced hepatocellular carcinoma not treated by immunotherapy.

43. The use of 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 positive for PD-L1 expression, optionally the non-small cell lung cancer is non-small cell lung cancer that has not been systematically treated, optionally the non-small cell lung cancer is locally advanced, metastatic and/or recurrent non-small cell lung cancer that has not been systematically treated.

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 non-systematically treated metastatic and/or recurrent nasopharyngeal carcinoma.

45. The use of any 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 agent are administered simultaneously, sequentially, or alternately.

46. The use of any 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, at a dose of 80-1800mg, 120-1200mg, 140-1000mg, 160-800mg, or 400-800mg each time.

47. The use of 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, at a dose of 10-800mg, 50-500mg, or 100-200mg each time.

Examples

The application is further illustrated by examples, which are not intended to limit the scope of the application, for clarity. All reagents used in the present application are commercially available and can be used without further purification.

The entire contents of WO2018069500a patent application 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.

The entire contents of CN106977602a patent application document are incorporated herein. The heavy chain amino acid sequence of the monoclonal antibody of pie An Puli in the following examples is shown as SEQ ID NO. 19 of the present application, and the light chain amino acid sequence is shown as SEQ ID NO. 20 of the present application.

Example 1 clinical trial for treating liver cancer

1. Criteria for inclusion

All of the following inclusion criteria were met to enter the group trial:

(1) Subjects voluntarily added to the study, signed an Informed Consent Form (ICF), and compliance was good;

(2) Age 18-75 years (when ICF was signed), ECOGPS score 0-1 score, expected lifetime exceeding 3 months;

(3) The subjects entered the group met the following criteria:

1) The liver cell cancer subjects confirmed by the pathological histology or cytology examination or the liver cell cancer subjects accord with clinical diagnosis standards of the American liver disease research institute (AASLD) or the primary liver cancer diagnosis and treatment guideline (2022 edition);

2) No immunotherapy (including immune checkpoint inhibitor, immune cell therapy, etc.) against advanced hepatocellular carcinoma has been accepted in the past (less than or equal to

2 Lines);

3) Subjects whose clinical stage of liver cancer in China (CNLC) is stage III or stage C of liver cancer in Barcelona (BCLC) or subjects whose stage CNLC-II or BCLC-B is unsuitable for local treatment (such as embolization by hepatic artery chemotherapy) and whose treatment or researcher judges that they cannot benefit from local treatment or surgical treatment;

4) The Child-Pugh liver function classification is grade A or B (less than or equal to 7);

5) HBsAg positive subjects should meet HBV DNA quantification < 1X 10⁴ IU/mL (or 5X 10⁴ copy/mL) or at least receive 1 week of anti-HBV treatment and have a 10-fold decrease in viral index (1 log value) and above before the study starts, while subjects would like to receive anti-HBV treatment all the way through the study;

6) Subjects following topical treatment (including, but not limited to, surgery, via hepatic arterial chemoembolization (TACE), hepatic arterial embolization (TAI), radiofrequency or microwave ablation, absolute alcohol injection, radiation therapy, etc.) should be enrolled at least 4 weeks after the topical treatment has ended and have been sufficiently recovered from treatment toxicity and/or complications;

7) Radiotherapy to bone metastases with clinical symptoms must be completed at least 2 weeks before the investigator begins;

(4) Confirm at least one measurable lesion according to RECIST 1.1 criteria;

(5) The major organs function normally, i.e. meet the following criteria:

1) Blood routine examination criteria (no blood transfusion or blood preparations, no granulocyte colony stimulating factor used, no drug correction used within 7 days prior to screening):

a. hemoglobin (HGB) is more than or equal to 90g/L;

b. The absolute value (NEUT) of the neutrophil is more than or equal to 1.5X10⁹/L;

c. Platelet count (PLT) is equal to or greater than 75×⁹/L;

2) The biochemical examination needs to meet the following criteria:

a. Albumin is more than or equal to 30g/L (albumin or blood products are not infused within 14 days);

b. Total bilirubin is less than or equal to 3 times the upper limit of normal value (ULN);

c. alanine Aminotransferase (ALT) and aspartic acid Aminotransferase (AST) <5.0 x ULN;

d. Serum Creatinine (CR) is less than or equal to 1.5 XULN or creatinine clearance (Ccr) is greater than 50mL/min (Cockcroft Gault formula: ccr= (140-age) x body weight (Kg)/72 XScr (mg/dL) or Ccr= (140-age) x body weight (Kg)/0.818 XScr (umol/L), female is calculated as result X0.85);

3) The prolongation of the Prothrombin Time (PT) is less than or equal to 6 seconds than the upper limit of a normal value;

(6) Female subjects of childbearing age should agree that contraceptive regimens (e.g., intrauterine devices, contraceptives or condoms) must be taken during and 6 months after the end of the study, that serum pregnancy/urinary pregnancy tests be negative and must be non-lactating subjects within 7 days prior to study entry, and that male subjects should agree that contraceptive regimens must be taken during and 6 months after the end of the study.

2. Test drug

The injection (specification: 100mg/10 mL/bottle) of the Pi An Puli mab is 1 treatment cycle in 3 weeks, and the Pi An Puli mab is administrated once at the 1 st day of each treatment cycle by intravenous infusion;

anti-LAG-3 antibody injection (specification: 160mg/8 mL/bottle) was administered once at 600mg of anti-LAG-3 antibody on day 1 of 3 weeks for 1 treatment cycle by intravenous infusion.

3. Treatment regimen

Infusion of the Pi An Puli mab injection was performed first, and anti-LAG-3 antibody injection was administered at least 30 minutes apart.

4. Dosing regimen adjustment

The An Puli monoclonal antibody injection is used for allowing delayed administration, but the longest delay administration time cannot exceed 12 weeks;

anti-LAG-3 antibody injection, which allows delayed administration, but the delayed administration time can not exceed 12 weeks at maximum.

5. Evaluation criteria

The efficacy evaluation standard is based on RECIST 1.1, and the iRECIST standard is used for confirming the efficacy;

the severity of adverse events was judged using the NCI-CTC AE 5.0 standard.

6. Endpoint index

Objective remission rate (orr=cr+pr), disease control rate (dcr=cr+pr+sd) mainly adopts descriptive analysis, and calculates ORR and DCR and 95% Clopper-pearson confidence intervals based on an accurate two-term method of F distribution;

Progression Free Survival (PFS), total survival (OS), duration of remission (DOR), the median and bilateral 95% confidence intervals thereof will be assessed using Kaplan-Meier method;

occurrence of all Adverse Events (AE), severe Adverse Events (SAE) and treatment-related adverse events (TRAEs), and abnormal laboratory test indicators;

pharmacokinetic/pharmacodynamic related indicators including Pharmacokinetic (PK) parameters, immunogenicity (ADA) incidence, receptor Occupancy (RO), etc.;

biomarkers associated with treatment, such as PD-L1, LAG-3 expression in tumor tissue, etc., are detected.

7. Results

The anti-LAG-3 antibody combined with the An Puli monoclonal antibody can safely and effectively treat advanced hepatocellular carcinoma, remarkably improve the clinical curative effect and survival benefit of hepatocellular carcinoma patients, ease and control the illness state of the patients, slow down the progress of the illness, prolong the progression-free survival time and the total survival time of the patients, and have low occurrence rate and severity of adverse events. By the day of data statistics, a total of 5 patients reached PR.

The specific results for an exemplary patient are shown below:

(1) Patient 1

Treatment effect and evaluation:

Screening period, namely 149mm of target focus;

2 treatment cycles, 113mm of target lesion;

Treatment for 4 cycles, 40mm of target lesion;

6 treatment cycles, 37mm of target focus;

8 treatment cycles, 34mm of target focus;

according to efficacy evaluation criteria, the best therapeutic effect for patients was PR (partial remission) until now.

(2) Patient 2

Treatment effect and evaluation:

Screening period, 122mm of target focus;

2 treatment cycles, 59mm of target focus;

treatment for 4 cycles, 59mm of target lesion;

according to efficacy evaluation criteria, the best therapeutic effect for patients was PR (partial remission) until now.

(3) Patient 3

Treatment effect and evaluation:

Screening period, namely 149mm of target focus;

2 treatment cycles, 25mm of target focus;

treatment for 4 cycles, 22mm of target lesion;

6 treatment cycles, 14mm of target focus;

according to efficacy evaluation criteria, the best therapeutic effect for patients was PR (partial remission) until now.

Example 2 clinical trials for the treatment of non-Small cell Lung cancer

1. Criteria for inclusion

All of the following inclusion criteria were met to enter the group trial:

(1) Subjects voluntarily added to the study, signed an Informed Consent Form (ICF), and compliance was good;

(2) Age 18-75 years (when ICF was signed), ECOGPS score 0-1 score, expected lifetime exceeding 3 months;

(3) The subjects entered the group met the following criteria:

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

2) PD-L1 expression is positive (TPS is more than or equal to 1%);

3) The subject has not received systemic anti-tumor therapy for advanced disease, allowing the subject to have previously received neoadjuvant/adjuvant chemotherapy or radiation therapy or concurrent radiation therapy, but the time for disease recurrence and/or metastasis must be at least 6 months from completion of the last treatment;

4) For non-squamous non-small cell lung cancer, detection demonstrated the absence of EGFR mutations, ALK fusions, ROS1 mutations (for squamous non-small cell lung cancer, patient exclusion for which the above gene mutations are known to be present, status unknowns do not mandate detection);

(4) Confirm at least one measurable lesion according to RECIST 1.1 criteria;

(5) The major organs function normally, i.e. meet the following criteria:

1) Blood routine examination criteria (no blood transfusion or blood products, no correction with hematopoietic stimulatory factor type drugs within 7 days prior to screening):

a. hemoglobin (HGB) is more than or equal to 90g/L;

b. The absolute value (NEUT) of the neutrophil is more than or equal to 1.5X10⁹/L;

c. Platelet count (PLT) is not less than 100X 10⁹/L;

2) The biochemical examination needs to meet the following criteria:

a. total bilirubin is less than or equal to 1.5 times the upper limit of normal value (ULN);

b. Alanine Aminotransferase (ALT) and aspartic acid Aminotransferase (AST) are less than or equal to 2.5 XULN, and if liver metastasis is accompanied, ALT and AST are less than or equal to 5 XULN;

c. creatinine clearance (Ccr) was 60mL/min (Cockcroft Gault equation: ccr= (140-age) x body weight (Kg)/72 XScr)

(Mg/dL) or ccr= (140-age) ×body weight (Kg)/0.818×scr (umol/L), female calculated result×0.85);

3) The coagulation function is required to meet the following criteria:

a. international Normalized Ratio (INR) is less than or equal to 1.5 x ULN (anticoagulation treatment not received);

4) Thyroid function examination should meet the following criteria:

a. Thyroid Stimulating Hormone (TSH) is less than or equal to ULN, and if the FT3 and FT4 levels are abnormal and should be examined, the FT3 and FT4 levels are normal, the thyroid stimulating hormone (FT 3 and FT4 cannot be detected, and T3 and T4 are the standard);

5) Heart color Doppler ultrasound assessment, namely, the Left Ventricular Ejection Fraction (LVEF) is more than or equal to 50%;

(6) Female subjects of childbearing age should agree that contraceptive regimens (e.g., intrauterine devices, contraceptives or condoms) must be taken during and 6 months after the end of the study, that serum pregnancy/urinary pregnancy tests be negative and must be non-lactating subjects within 7 days prior to study entry, and that male subjects should agree that contraceptive regimens must be taken during and 6 months after the end of the study.

2. Test drug

The injection (specification: 100mg/10 mL/bottle) of the Pi An Puli mab is 1 treatment cycle in 3 weeks, and the Pi An Puli mab is administrated once at the 1 st day of each treatment cycle by intravenous infusion;

anti-LAG-3 antibody injection (specification: 160mg/8 mL/bottle) was administered once at 600mg of anti-LAG-3 antibody on day 1 of 3 weeks for 1 treatment cycle by intravenous infusion.

3. Treatment regimen

Infusion of the Pi An Puli mab injection was performed first, and anti-LAG-3 antibody injection was administered at least 30 minutes apart.

4. Dosing regimen adjustment

The An Puli monoclonal antibody injection is used for allowing delayed administration, but the longest delay administration time cannot exceed 12 weeks;

anti-LAG-3 antibody injection, which allows delayed administration, but the delayed administration time can not exceed 12 weeks at maximum.

5. Evaluation criteria

The efficacy evaluation standard is based on RECIST 1.1, and the iRECIST standard is used for confirming the efficacy;

the severity of adverse events was judged using the NCI-CTC AE 5.0 standard.

6. Endpoint index

Objective remission rate (orr=cr+pr), disease control rate (dcr=cr+pr+sd), mainly using descriptive analysis, calculating ORR and DCR and 95% Clopper-pearson confidence intervals based on the exact two-term method of F distribution;

Progression Free Survival (PFS), total survival (OS), duration of remission (DOR), the median and bilateral 95% confidence intervals thereof will be assessed using Kaplan-Meier method;

occurrence of all Adverse Events (AE), severe Adverse Events (SAE) and treatment-related adverse events (TRAEs), and abnormal laboratory test indicators;

pharmacokinetic/pharmacodynamic related indicators including Pharmacokinetic (PK) parameters, immunogenicity (ADA) incidence, receptor Occupancy (RO), etc.;

biomarkers associated with treatment, such as PD-L1, LAG-3 expression in tumor tissue, etc., are detected.

7. Results

The anti-LAG-3 antibody combined with the An Puli monoclonal antibody can safely and effectively treat locally advanced, recurrent or metastatic non-small cell lung cancer, remarkably improves the clinical curative effect and survival benefit of a non-small cell lung cancer patient, relieves and controls the disease condition of the patient, slows down the progress of the disease, prolongs the progression-free survival time and the total survival time of the patient, and has low occurrence rate and severity of adverse events. By the day of data statistics, a total of 14 patients reached PR.

The specific results for an exemplary patient are shown below:

(1) Patient 1

The diagnosis result is that lung squamous carcinoma is diagnosed, and TPS score is 3%.

Treatment effect and evaluation:

Screening period, wherein the target focus is 90.04mm;

2 treatment cycles, target focus 63.81mm;

treatment for 4 cycles, 42.14mm of target lesion;

Treatment for 6 cycles, target focus 36.38mm;

treatment for 8 cycles, 31.73mm of target lesion;

according to efficacy evaluation criteria, the best therapeutic effect for patients was PR (partial remission) until now.

(2) Patient 2

The diagnosis result is that lung squamous carcinoma is diagnosed, and TPS score is 55%.

Treatment effect and evaluation:

Screening period, 74mm of target focus;

2 treatment cycles, 45mm of target focus;

Treatment for 4 cycles, 33mm of target lesion;

treatment for 6 cycles, 30mm of target focus;

8 treatment cycles, 25mm of target focus;

according to efficacy evaluation criteria, the best therapeutic effect for patients was PR (partial remission) until now.

(3) Patient 3

The diagnosis result is that lung squamous carcinoma is diagnosed, and TPS score is 90%.

Treatment effect and evaluation:

The screening period is 70mm of the target focus;

2 treatment cycles, 26mm of target focus;

Treatment for 4 cycles, 26mm of target lesion;

treatment for 6 cycles, 22mm of target lesion;

8 treatment cycles, 18mm of target focus;

according to efficacy evaluation criteria, the best therapeutic effect for patients was PR (partial remission) until now.

(4) Patient 4

The diagnosis result is that lung adenocarcinoma is diagnosed, and TPS score is 1%.

Treatment effect and evaluation:

screening stage, namely 65mm of target focus;

2 treatment cycles, 56mm of target focus;

Treatment for 4 cycles, 52mm of target lesion;

treatment for 6 cycles, 41mm of target focus;

8 treatment cycles, 35mm of target focus;

according to efficacy evaluation criteria, the best therapeutic effect for patients was PR (partial remission) until now.

(5) Patient 5

The diagnosis result is that lung adenocarcinoma is diagnosed, and TPS score is 60%.

Treatment effect and evaluation:

Screening period, 21mm of target focus;

2 treatment cycles, 12mm of target focus;

according to efficacy evaluation criteria, the best therapeutic effect for patients was PR (partial remission) until now.

(6) Patient 6

The diagnosis result is that lung adenocarcinoma is diagnosed, and TPS score is 90%.

Treatment effect and evaluation:

screening period, 139mm of target focus;

2 treatment cycles, 92.22mm of target focus;

Treatment for 4 cycles, target focus 87.29mm;

according to efficacy evaluation criteria, the best therapeutic effect for patients was PR (partial remission) until now.

(7) Patient 7

The diagnosis result shows that the lung lymphoepithelial tumor-like cancer is diagnosed, and the TPS score is 10%.

Treatment effect and evaluation:

The screening period is 35mm of the target focus;

2 treatment cycles, 21mm of target focus;

treatment for 4 cycles, 18mm of target lesion;

Treatment for 6 cycles, 18mm of target lesion;

8 treatment cycles, 18mm of target focus;

treatment for 10 cycles, 17mm of target lesion;

treatment for 12 cycles, 15mm of target focus;

according to efficacy evaluation criteria, the best therapeutic effect for patients was PR (partial remission) until now.

Example 3 clinical trial for treatment of nasopharyngeal carcinoma

1. Criteria for inclusion

All of the following inclusion criteria were met to enter the group trial:

(1) Subjects voluntarily added to the study, signed an Informed Consent Form (ICF), and compliance was good;

(2) Age 18-70 years (when ICF was signed), ECOGPS score 0-1 score, expected lifetime exceeding 3 months;

(3) The subjects entered the group met the following criteria:

1) Recurrent or metastatic nasopharyngeal carcinoma patients who are not suitable for receiving topical or curative treatments;

2) The recurrent or metastatic lesions must be treated systematically or have been treated with new adjuvant/adjuvant chemotherapy or radiotherapy or concurrent radiotherapy for the purpose of cure, but the time for the recurrence and/or metastasis of the disease must be at least 6 months apart from the completion of the last treatment;

3) The patient received no immune checkpoint inhibitor treatment;

(4) Confirm at least one measurable lesion according to RECIST 1.1 criteria;

(5) The major organs function normally, i.e. meet the following criteria:

1) Blood routine examination criteria (no blood transfusion or blood products, no correction with hematopoietic stimulatory factor type drugs within 7 days prior to screening):

a. hemoglobin (HGB) is more than or equal to 90g/L;

b. The absolute value (NEUT) of the neutrophil is more than or equal to 1.5X10⁹/L;

c. Platelet count (PLT) is not less than 100X 10⁹/L;

2) The biochemical examination needs to meet the following criteria:

a. total bilirubin is less than or equal to 1.5 times the upper limit of normal value (ULN);

b. Alanine Aminotransferase (ALT) and aspartic acid Aminotransferase (AST) are less than or equal to 2.5 XULN, and if liver metastasis is accompanied, ALT and AST are less than or equal to 5 XULN;

c. creatinine clearance (Ccr) was 60mL/min (Cockcroft Gault equation: ccr= (140-age) x body weight (Kg)/72 XScr)

(Mg/dL) or ccr= (140-age) ×body weight (Kg)/0.818×scr (umol/L), female calculated result×0.85);

3) The coagulation function is required to meet the following criteria:

a. international Normalized Ratio (INR) is less than or equal to 1.5 x ULN (anticoagulation treatment not received);

4) Thyroid function examination should meet the following criteria:

a. Thyroid Stimulating Hormone (TSH) is less than or equal to ULN, and if the FT3 and FT4 levels are abnormal and should be examined, the FT3 and FT4 levels are normal, the thyroid stimulating hormone (FT 3 and FT4 cannot be detected, and T3 and T4 are the standard);

5) Heart color Doppler ultrasound assessment, namely, the Left Ventricular Ejection Fraction (LVEF) is more than or equal to 50%;

(6) Female subjects of childbearing age should agree that contraceptive regimens (e.g., intrauterine devices, contraceptives or condoms) must be taken during and 6 months after the end of the study, that serum pregnancy/urinary pregnancy tests be negative and must be non-lactating subjects within 7 days prior to study entry, and that male subjects should agree that contraceptive regimens must be taken during and 6 months after the end of the study.

2. Test drug

The injection (specification: 100mg/10 mL/bottle) of the Pi An Puli mab is 1 treatment cycle in 3 weeks, and the Pi An Puli mab is administrated once at the 1 st day of each treatment cycle by intravenous infusion;

anti-LAG-3 antibody injection (specification: 160mg/8 mL/bottle) 1 treatment cycle for 3 weeks, with intravenous infusion, the dose of 600mg anti-LAG-3 antibody was administered once on day 1 of each treatment cycle;

Gemcitabine, 1 treatment cycle in 3 weeks, was administered by intravenous infusion at 1000mg/m² on days 1 and 8 of each treatment cycle, for a total of 4-6 treatment cycles;

Cisplatin was administered at a dose of 80mg/m² on day 1 of each treatment cycle by intravenous infusion for a total of 4-6 treatment cycles at week 3.

3. Treatment regimen

Infusion of the Pi An Puli mab injection was performed first, followed by administration of the anti-LAG-3 antibody injection at least 30 minutes apart, followed by administration of gemcitabine and cisplatin at least 10 minutes apart.

4. Dosing regimen adjustment

The An Puli monoclonal antibody injection is used for allowing delayed administration, but the longest delay administration time cannot exceed 12 weeks;

anti-LAG-3 antibody injection, which allows delayed administration, but the delayed administration time is not longer than 12 weeks at maximum;

Dose adjustment of chemotherapeutic agents reference the instructions.

5. Evaluation criteria

The efficacy evaluation standard is based on RECIST 1.1, and the iRECIST standard is used for confirming the efficacy;

the severity of adverse events was judged using the NCI-CTC AE 5.0 standard.

6. Endpoint index

Objective remission rate (orr=cr+pr), disease control rate (dcr=cr+pr+sd), mainly using descriptive analysis, calculating ORR and DCR and 95% Clopper-pearson confidence intervals based on the exact two-term method of F distribution;

Progression Free Survival (PFS), total survival (OS), duration of remission (DOR), the median and bilateral 95% confidence intervals thereof will be assessed using Kaplan-Meier method;

occurrence of all Adverse Events (AE), severe Adverse Events (SAE) and treatment-related adverse events (TRAEs), and abnormal laboratory test indicators;

pharmacokinetic/pharmacodynamic related indicators including Pharmacokinetic (PK) parameters, immunogenicity (ADA) incidence, receptor Occupancy (RO), etc.;

biomarkers associated with treatment, such as PD-L1, LAG-3 expression in tumor tissue, etc., are detected.

7. Results

The anti-LAG-3 antibody provided by the application can be used for safely and effectively treating recurrent or metastatic nasopharyngeal carcinoma by combining the An Puli monoclonal antibody and chemotherapy (gemcitabine and cisplatin), so that the clinical curative effect and survival benefit of a nasopharyngeal carcinoma patient are obviously improved, the disease condition of the patient is relieved and controlled, the disease progression is slowed down, the progression-free survival period and the total survival period of the patient are prolonged, and the occurrence rate and the severity of adverse events are low. By the day of data statistics, a total of 14 patients reached PR.

The specific results for an exemplary patient are shown below:

(1) Patient 1

Treatment effect and evaluation:

The screening period is 114mm of the target focus;

2 treatment cycles, 58mm of target focus;

treatment for 4 cycles, 48mm of target lesion;

according to efficacy evaluation criteria, the best therapeutic effect for patients was PR (partial remission) until now.

(2) Patient 2

Treatment effect and evaluation:

The screening period is 57mm of target focus;

2 treatment cycles, 40mm of target focus;

treatment for 4 cycles, 31mm of target lesion;

treatment for 6 cycles, 25mm of target lesion;

according to efficacy evaluation criteria, the best therapeutic effect for patients was PR (partial remission) until now.

(3) Patient 3

Treatment effect and evaluation:

screening period, 17mm of target focus;

2 treatment cycles, 10mm of target focus;

treatment for 4 cycles, 8mm of target focus;

6 treatment cycles, 7mm of target focus;

according to efficacy evaluation criteria, the best therapeutic effect for patients was PR (partial remission) until now.

Claims (10)

1. A pharmaceutical combination comprising an anti-LAG-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises:

HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 6, or

HCDR1 comprising the amino acid sequence shown in SEQ ID No. 21, HCDR2 comprising the amino acid sequence shown in SEQ ID No. 22, HCDR3 comprising the amino acid sequence shown in SEQ ID No. 23, LCDR1 comprising the amino acid sequence shown in SEQ ID No. 24, LCDR2 comprising the amino acid sequence shown in SEQ ID No. 25, and LCDR3 comprising the amino acid sequence shown in SEQ ID No. 26;

the anti-PD-1 antibody or antigen-binding fragment thereof comprises:

An HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 11, an HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 12, an HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 13, an LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 14, an LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 15, and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 16.

2. The pharmaceutical combination of 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 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 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 of claim 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 set forth in SEQ ID NO. 29, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO. 30.

4. The pharmaceutical combination of any one of claims 1-3, 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 set forth in SEQ ID NO. 17, 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. 18.

5. The pharmaceutical combination of any one of claims 1-4, 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 set forth in SEQ ID NO. 19, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO. 20.

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

7. The pharmaceutical combination of any one of claims 1-6, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof and anti-PD-1 antibody or antigen-binding fragment thereof are formulated separately, or the anti-LAG-3 antibody or antigen-binding fragment thereof and 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 1-7, wherein the pharmaceutical combination further comprises a chemotherapeutic drug, preferably the chemotherapeutic drug comprises a platinum-based anti-tumor drug and/or an anti-metabolite-based anti-tumor drug.

9. Use of a pharmaceutical combination according to any one of claims 1-8 for the manufacture of a medicament for the treatment of a tumor.

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.