CN119326879A

CN119326879A - Drug combinations for treating tumors

Info

Publication number: CN119326879A
Application number: CN202410959841.9A
Authority: CN
Inventors: 李�杰; 于鼎; 劳珊莉; 李许; 王训强; 张喜全; 王欢
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2023-07-18
Filing date: 2024-07-17
Publication date: 2025-01-21

Abstract

The application belongs to the field of biological medicine, and in particular provides a pharmaceutical composition for treating tumors, which comprises an anti-TIM-3 antibody or an antigen binding fragment thereof, an anti-PD-1 antibody or an antigen binding fragment thereof and An Luoti Ni or pharmaceutically acceptable salts thereof. Also provided is the use of the pharmaceutical combination in the manufacture of a medicament for the treatment of a tumour.

Description

Pharmaceutical composition for treating tumor

Technical Field

The application belongs to the field of biological medicine, and in particular relates to a pharmaceutical composition of an anti-TIM-3 antibody or an antigen binding fragment thereof, an anti-PD-1 antibody or an antigen binding fragment thereof and An Luoti Ni or pharmaceutically acceptable salt thereof and application of the pharmaceutical composition in tumor treatment.

Background

T cell immunoglobulin and mucin domain protein 3 (T cell immunoglobulin and mucin domain-containing protein 3, TIM-3), also known as hepatitis A Virus cell receptor 2 (HEPATITIS A Virus Cellular Receptor, HAVCR 2), is an immunomodulatory protein TIM family member (human TIM family includes TIM-1, 3, 4), TIM-3 is selectively expressed on the surface of activated Th1 cells, but also on myeloid, DC, NK, macrophages, and also on a variety of tumor cells. TIM-3 has a number of different ligands including Galectin9 (Galectin 9), phosphotidylserine (PtdSer), homomigratory group protein B1 (HMGB 1) and carcinoembryonic antigen cell adhesion molecule 1 (CEACAM 1). TIM-3 acts as an immune checkpoint whose physiological function is to negatively regulate the immune function of the body, avoiding damage to the body by excessive immune or autoimmune action. There is growing evidence that TIM-3 proteins and/or mRNA are up-regulated in expression on various tumor tissues and tumor-associated immune cells, involved in tumor immune escape and immune response, and promote tumor progression.

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.

An Luoti Ni (Anlotinib) is a quinoline derivative tyrosine kinase inhibitor which plays a role in influencing tumor angiogenesis and proliferation signaling as a multi-target tyrosine kinase inhibitor, and main targets include receptor tyrosine kinase VEGFR1 (FLT 1), VEGFR2 (KDR), VEGFR3 (FLT 4), EGFR, FGFR1-4, PDGFR alpha and beta, and Stem Cell Factor Receptors (SCFR) 7, 8 and 9.

Primary liver cancer is the seventh most common malignancy worldwide, with hepatocellular carcinoma (Hepatocellular Carcinoma, HCC) accounting for 80-85%. China is the region with the highest incidence of HCC and accounts for about 45% of global cases. Because the liver cancer patients have late initial diagnosis, about 70% of patients lose the opportunity of surgical treatment, have short life cycle and poor prognosis.

In 2020, the number of new cases of colorectal cancer in China reaches 55.5 ten thousand, the number of colorectal cancer death cases reaches 28.6 ten thousand, the incidence rate is second in malignant tumors, and the death rate is fifth in malignant tumors. About 21% of colorectal cancer patients have distant metastasis at the time of initial diagnosis, 50% -60% of patients will metastasize with disease progression, and patient survival is low.

Therefore, there is an urgent need to search for other drugs capable of treating hepatocellular carcinoma or colorectal cancer patients, and to improve the therapeutic effect.

Summary of The Invention

In one aspect, the application provides a pharmaceutical combination comprising an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is An Luoti ni or a pharmaceutically acceptable salt thereof, such as An Luoti ni hcl. For some embodiments, the pharmaceutical combination comprises an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination comprises an anti-TIM-3 antibody or antigen-binding fragment thereof in a unit dose of 60-1800mg, an anti-PD-1 antibody or antigen-binding fragment thereof in a unit dose of 10-500mg, and An Luoti ni or a pharmaceutically acceptable salt thereof in a unit dose of 6mg, 8mg, 10mg, and/or 12 mg.

In some embodiments, the pharmaceutical combination comprises 100-1800mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 10-800mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 6mg, 8mg, 10mg, or 12mg of An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 100-1800mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 10-800mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 84-168mg of An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination is for treating a tumor.

In another aspect, the application also provides the use of the pharmaceutical combination of the application for treating a tumor in a subject.

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 the first line treatment of 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 four-wire therapy or more for the treatment of a tumor in a subject.

In another 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 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 some specific embodiments, the application provides a method of first-line treatment of a tumor in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination of the application. In some specific embodiments, the application provides a method of four-line treatment or more for treating a tumor in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination of the application.

For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti Ni or a pharmaceutically acceptable salt thereof may be administered simultaneously, sequentially, and/or alternately.

For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100-1800mg, 600-1500mg, or 1200-1500mg per 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. 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 An Luoti ni, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, the An Luoti bits or pharmaceutically acceptable salt thereof are administered at a dose of 6mg, 8mg, 10mg, or 12mg at a time.

In another aspect, the application provides a kit for treating a tumor comprising the pharmaceutical combination of the application. For some embodiments, the kit comprises an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is An Luoti ni or a pharmaceutically acceptable salt thereof, such as An Luoti ni hcl. For some embodiments, the kit comprises an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof.

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

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-TIM-3 antibody or antigen-binding fragment thereof of the application and an anti-PD-1 antibody or antigen-binding fragment thereof. The application also provides the use of an anti-TIM-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 treating a tumor in a subject. The application also provides the use of an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof for the treatment of tumors.

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

Detailed Description

Pharmaceutical combination

In some embodiments, the pharmaceutical combination is packaged in the same kit, which further comprises instructions for the combined use of an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof to treat a tumor. In other embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof in the pharmaceutical combination are separately packaged in separate kits that further include instructions for the combined use of the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof to treat a tumor.

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

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

In some embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof in the non-immobilized combination is a liquid formulation or a solid formulation. For some embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof is an injectable solution. For some embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof is a lyophilized formulation.

In some embodiments, the pharmaceutical composition comprising the anti-PD-1 antibody or antigen-binding fragment thereof in the non-immobilized combination 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 non-immobilized combination, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation. In some embodiments, the non-immobilized combination, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof is a liquid formulation or a solid formulation. In some embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof is an injectable solution. For some embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized formulation.

In some embodiments, the pharmaceutical composition comprising An Luoti n or a pharmaceutically acceptable salt thereof in the non-fixed combination is a solid formulation. In some specific embodiments, the pharmaceutical composition comprising An Luoti n or a pharmaceutically acceptable salt thereof is in the form of a capsule.

For some embodiments, the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 60-1800mg, 100-1600mg, 120-1600mg, 180-1200mg, or 240-600mg. For some embodiments, the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 60mg、120mg、160mg、180mg、200mg、240mg、280mg、300mg、320mg、360mg、400mg、420mg、440mg、480mg、520mg、540mg、560mg、600mg、640mg、660mg、680mg、720mg、760mg、780mg、800mg、840mg、880mg、900mg、920mg、960mg、1000mg、1020mg、1040mg、1080mg、1120mg、1140mg、1160mg、1200mg、1240mg、1260mg、1280mg、1320mg、1360mg、1380mg、1400mg、1440mg、1480mg、1500mg、1520mg、1560mg、1600mg、1620mg、1640mg、1680mg、1720mg、1740mg、1760mg and/or 1800mg, or a range formed by any of the above values. For some embodiments, the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 240mg, 300mg, 360mg, and/or 600mg. For some embodiments, the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 240mg and/or 600mg. For some embodiments, the unit dose of the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 600mg.

In some embodiments, the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 10-500mg, 50-200mg, or 100-200mg. In some embodiments, the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 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 formed by any of the above values. In some embodiments, the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 100mg and/or 200mg. In some embodiments, the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is 100mg.

In some embodiments, the unit dose of An Luoti ni or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is 6mg, 8mg, 10mg, and/or 12mg.

In some embodiments, the pharmaceutical combination comprises an anti-TIM-3 antibody or antigen-binding fragment thereof in a unit dose of 60-1800mg, 100-1600mg, 120-1600mg, 180-1200mg, or 240-600mg, an anti-PD-1 antibody or antigen-binding fragment thereof in a unit dose of 10-500mg, 50-200mg, or 100-200mg, and An Luoti Ni or a pharmaceutically acceptable salt thereof in a unit dose of 6mg, 8mg, 10mg, and/or 12 mg. In some embodiments, the pharmaceutical combination comprises an anti-TIM-3 antibody or antigen-binding fragment thereof in a unit dose of 60mg、120mg、160mg、180mg、200mg、240mg、280mg、300mg、320mg、360mg、400mg、420mg、440mg、480mg、520mg、540mg、560mg、600mg、640mg、660mg、680mg、720mg、760mg、780mg、800mg、840mg、880mg、900mg、920mg、960mg、1000mg、1020mg、1040mg、1080mg、1120mg、1140mg、1160mg、1200mg、1240mg、1260mg、1280mg、1320mg、1360mg、1380mg、1400mg、1440mg、1480mg、1500mg、1520mg、1560mg、1600mg、1620mg、1640mg、1680mg、1720mg、1740mg、1760mg and/or 1800mg, or a range formed by any of the above, an anti-PD-1 antibody or antigen-binding fragment thereof in a unit dose of 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 formed by any of the above, and An Luoti ni or a pharmaceutically acceptable salt thereof in a unit dose of 6mg, 8mg, 10mg, and/or 12 mg. In some embodiments, the pharmaceutical combination comprises an anti-TIM-3 antibody or antigen-binding fragment thereof in a unit dose of 240mg, 300mg, 360mg and/or 600mg, an anti-PD-1 antibody or antigen-binding fragment thereof in a unit dose of 100mg and/or 200mg, and An Luoti ni or a pharmaceutically acceptable salt thereof in a unit dose of 6mg, 8mg, 10mg and/or 12 mg. In some embodiments, the pharmaceutical combination comprises an anti-TIM-3 antibody or antigen-binding fragment thereof in a unit dose of 240mg and/or 600mg, an anti-PD-1 antibody or antigen-binding fragment thereof in a unit dose of 100mg, and An Luoti ni or a pharmaceutically acceptable salt thereof in a unit dose of 6mg, 8mg, and/or 10 mg. In some embodiments, the pharmaceutical combination comprises an anti-TIM-3 antibody or antigen-binding fragment thereof in a unit dose of 240mg and/or 600mg, an anti-PD-1 antibody or antigen-binding fragment thereof in a unit dose of 100mg, and An Luoti ni or a pharmaceutically acceptable salt thereof in a unit dose of 6mg, 8mg, 10mg, and/or 12 mg.

For some embodiments, the pharmaceutical combination comprises 100-1800mg, 600-1500mg, or 1200-1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg or 1800mg, or a range formed by any of the above values, of an anti-TIM-3 antibody or antigen-binding fragment thereof. For some embodiments, the pharmaceutical combination comprises 1200mg or 1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof. For some embodiments, the pharmaceutical combination comprises 1200mg of an anti-TIM-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 or 800mg, or a range formed by any of the above values, of an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof.

In some embodiments, the pharmaceutical combination comprises An Luoti mg, 8mg, 10mg, or 12mg of An Luoti mg or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination comprises 6mg, 8mg, or 10mg An Luoti mg of An Luoti ni, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination comprises 8mg, 10mg, or 12mg An Luoti mg of An Luoti ni, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination comprises 10mg An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination comprises 12mg An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination comprises 100-1800mg, 600-1500mg, or 1200-1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 10-800mg, 50-500mg, or 100-200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 6mg, 8mg, 10mg, or 12mg of An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination comprises 100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg or 1800mg, or any of the above ranges of anti-TIM-3 antibodies or antigen-binding fragments thereof ,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 any of the above ranges of anti-PD-1 antibodies or antigen-binding fragments thereof, and 6mg, 8mg, 10mg, or 12mg of An Luoti ni, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination comprises 1200mg or 1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 6mg, 8mg or 10mg of An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination comprises 1200mg or 1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 8mg, 10mg or 12mg of An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination comprises 1200mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 10mg of An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination comprises 1200mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 12mg of An Luoti ni or a pharmaceutically acceptable salt thereof.

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

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

In some embodiments, the amount of anti-TIM-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 An Luoti n or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is one daily dose. In some embodiments, the amount of An Luoti n or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is one daily dose.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 100-1800mg, 600-1500mg, or 1200-1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg or 1800mg, or any range formed by any of the above values, of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 1200mg or 1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 1200mg of an anti-TIM-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 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 84-168mg An Luoti ni, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 84-140mg An Luoti ni, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 112-168mg An Luoti ni, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 140mg An Luoti ni, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 168mg An Luoti ni, or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 100-1800mg, 600-1500mg, or 1200-1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 10-800mg, 50-500mg, or 100-200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 84-168mg of An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg or 1800mg, or any of the above ranges of anti-TIM-3 antibody or antigen-binding fragment thereof ,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 any of the above ranges of anti-PD-1 antibody or antigen-binding fragment thereof, and 84-140mg of An Luoti ni or a pharmaceutically acceptable salt thereof. in some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 1200mg or 1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 84-140mg of An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 1200mg or 1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 112-168mg of An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 1200mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 84-140mg of An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 1200mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 112-168mg of An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 1200mg or 1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 140mg of An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 1200mg or 1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 168mg of An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 1200mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 140mg of An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 1200mg of an anti-TIM-3 antibody or antigen-binding fragment thereof, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof, and 168mg of An Luoti ni or a pharmaceutically acceptable salt thereof.

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

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

In some embodiments, the An Luoti ni or pharmaceutically acceptable salt thereof may be a pharmaceutical composition containing An Luoti ni or pharmaceutically acceptable salt thereof. Wherein the pharmaceutical composition containing An Luoti Ni or a pharmaceutically acceptable salt thereof is in single dose or multiple doses, preferably multiple doses. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing 6mg, 8mg, 10mg and/or 12mg An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing 6mg, 8mg, and/or 10mg An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the multiple doses may consist of a single dose of a pharmaceutical composition containing 8mg, 10mg, and/or 12mg An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises (0.1-180): 1, (0.2-50): 1, (0.5-9): 1, (3-7.5): 1, (4-7.5): 1 or (6-7.5): 1, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are packaged or packaged separately.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, an Luoti Ni or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical combination in a mass ratio of (0.1-50): 1, (1-30): 1, (3-20): 1, (6-18): 1, (8-12): 1 or (8-9): 1.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, an Luoti Ni or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical combination in a mass ratio of (0.1-50): 1, (1-30): 1, (3-20): 1, (7-15): 1, (7-11): 1 or (7-8): 1.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises An Luoti Ni or a pharmaceutically acceptable salt thereof in a mass ratio of (0.01-10): 1, (0.1-5): 1, (0.2-4): 1, (0.5-2): 1 or (1-2): 1.

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

In some specific embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for each administration of 100-1800mg, 600-1500mg, or 1200-1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof to a patient, 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 each administration of 10-800mg, 50-500mg, or 100-200mg of an anti-PD-1 antibody or antigen-binding fragment thereof to a patient, and the pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for each administration of 6mg, Single or multiple doses of 8mg, 10mg or 12mg An Luoti ni or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition comprising the anti-TIM-3 antibody or antigen-binding fragment thereof is prepared as a multi-dose suitable for each administration of 1200mg or 1500mg of the anti-TIM-3 antibody or antigen-binding fragment thereof to a patient, the pharmaceutical composition comprising the anti-PD-1 antibody or antigen-binding fragment thereof is prepared as a multi-dose suitable for each administration of 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof to a patient, and the pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof is prepared as a single dose suitable for each administration of 6mg, 8mg or 10mg An Luoti ni or a pharmaceutically acceptable salt thereof to a patient. In some specific embodiments, the pharmaceutical composition comprising the anti-TIM-3 antibody or antigen-binding fragment thereof is prepared as a multi-dose suitable for each administration of 1200mg or 1500mg of the anti-TIM-3 antibody or antigen-binding fragment thereof to a patient, the pharmaceutical composition comprising the anti-PD-1 antibody or antigen-binding fragment thereof is prepared as a multi-dose suitable for each administration of 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof to a patient, and the pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof is prepared as a single dose suitable for each administration of 8mg, 10mg or 12mg An Luoti ni or a pharmaceutically acceptable salt thereof to a patient. In some specific embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for each administration of 1200mg of an anti-TIM-3 antibody or antigen-binding fragment thereof to a patient, 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 each administration of 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof to a patient, and the pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof is prepared as a single dose suitable for each administration of 10mg An Luoti ni or a pharmaceutically acceptable salt thereof to a patient. In some specific embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for each administration of 1200mg of an anti-TIM-3 antibody or antigen-binding fragment thereof to a patient, 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 each administration of 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof to a patient, and the pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof is prepared as a single dose suitable for each administration of 12mg An Luoti ni or a pharmaceutically acceptable salt thereof to a patient.

In another aspect, the application provides a kit for treating a tumor, the kit comprising a pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof, a pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, and a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof, and instructions for using the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof, the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, and the pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof in combination to treat a tumor.

In another aspect, the application provides a kit for treating a tumor, the kit comprising a pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof, and a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof, and instructions for using a pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof in combination with a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof to treat a tumor.

The present application also provides a pharmaceutical pack comprising a single package of pharmaceutical compositions in separate containers, wherein the first container comprises a pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof, the second container comprises a pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof, and the third container comprises a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical pack is for treating a tumor.

The present application also provides a pharmaceutical pack comprising a single package of pharmaceutical compositions in separate containers, wherein the first container comprises a pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof, and the second container comprises a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical pack is for treating a tumor.

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

In some embodiments, the pharmaceutical composition comprising the anti-PD-1 antibody or antigen-binding fragment thereof in the kit or pack 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 pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof in the kit or package is a liquid formulation or a solid formulation. In some embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof is an injectable solution. For some embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized formulation.

In some embodiments, the kit or pack comprises a pharmaceutical composition comprising An Luoti n or a pharmaceutically acceptable salt thereof as a solid formulation. In some embodiments, the pharmaceutical composition comprising An Luoti n or a pharmaceutically acceptable salt thereof is in the form of a capsule.

Use of the same

The application also provides the use of the pharmaceutical combination of the application for treating a tumor in a subject. In some specific embodiments, the application also provides the use of a pharmaceutical combination of the application for the first line treatment of a tumor in a subject. In some specific embodiments, the application also provides the use of the pharmaceutical combination four-wire treatment or more posterior wire number treatment of a tumor in a subject 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 a pharmaceutical combination of the application. The application provides a method of first line treatment of a tumor in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination of the application. The application provides a method of four-line treatment or more for 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 the first line treatment of 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 four-wire therapy or more for the treatment of a tumor in a subject.

In some embodiments, in the methods or uses, the pharmaceutical combination comprises an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof.

The application also provides the use of an anti-TIM-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 An Luoti n or a pharmaceutically acceptable salt thereof. The application also provides the use of an anti-TIM-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for the first line treatment of 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 An Luoti n or a pharmaceutically acceptable salt thereof. The application also provides the use of an anti-TIM-3 antibody or antigen-binding fragment thereof of the application in the manufacture of a medicament for the four-wire treatment or more for the treatment of 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 An Luoti n or a pharmaceutically acceptable salt thereof.

The application also provides the use of an anti-TIM-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, wherein the medicament is for use in combination with An Luoti n or a pharmaceutically acceptable salt thereof. The application also provides the use of an anti-TIM-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 the first line treatment of a tumor in a subject, wherein the medicament is for use in combination with An Luoti ni or a pharmaceutically acceptable salt thereof. The application also provides the use of an anti-TIM-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 the four-wire treatment or more posterior wire number treatment of a tumor in a subject, wherein the medicament is for use in combination with An Luoti ni or a pharmaceutically acceptable salt thereof.

The application also provides the use of an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof of the application to treat a tumor in a subject. In some specific embodiments, the application also provides the use of an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof of the application for the first line treatment of a tumor in a subject. In some specific embodiments, the application also provides the use of an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti or a pharmaceutically acceptable salt thereof for four-wire therapy or later wire number treatment of a tumor in a subject.

The application also provides the use of an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt 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-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof of the application in the manufacture of a medicament for the first line treatment of a tumor in a subject. In some specific embodiments, the application also provides the use of an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof of the application in the manufacture of a medicament for four-wire therapy or more in the treatment of a tumor in a subject.

The application also provides a method of treating a tumor in a subject comprising administering to the subject an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof. 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-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof of the application. In some specific embodiments, the present application provides a method of first-line treatment of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof. In some specific embodiments, the application provides methods of four-wire treatment or more for treating a tumor in a subject comprising administering to the subject a therapeutically effective amount of an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof, may be administered simultaneously, sequentially, and/or alternately in the method or use. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition, which may be administered simultaneously, sequentially, and/or alternately. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof are administered sequentially in the method or use. In some embodiments, in the method or use, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition for administration sequentially. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation, which may be administered simultaneously, sequentially and/or alternately with An Luoti n or a pharmaceutically acceptable salt thereof. In some embodiments, in the method or use, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation, which is administered sequentially with An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation, which may be administered simultaneously, sequentially and/or alternately with a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, in the method or use, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation, which is administered sequentially with a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, in the method or use, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof are administered separately on the same or different dosing schedules. In some specific embodiments, in the method or use, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof are administered separately in different dosing regimens.

In some embodiments, in the methods or uses, the anti-TIM-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). For some specific embodiments, an anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100-1800mg, 600-1500mg, or 1200-1500mg per time. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg or 1800mg, or a range of any of the values set forth above, each time. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 1200mg or 1500mg each time. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 1200mg each time. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each at a dose of 100-1800mg, 600-1500mg, or 1200-1500mg of the anti-TIM-3 antibody or antigen-binding fragment thereof. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each at a dose of 1200-1500mg of anti-TIM-3 antibody or antigen-binding fragment thereof. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 1200mg or 1500mg of the anti-TIM-3 antibody or antigen-binding fragment thereof. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of 1200mg or 1500mg of the anti-TIM-3 antibody or antigen-binding fragment thereof. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 1200mg of the anti-TIM-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, every 2 weeks, every 3 weeks, or every 4 weeks. In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10-800mg, 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 of 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 formed by any of the values described above, each 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 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 An Luoti ni or pharmaceutically acceptable salt thereof is administered in a regimen of 2 weeks on a continuous basis, 1 week off. In some embodiments, the An Luoti ni, or a pharmaceutically acceptable salt thereof, is administered at a dose of 6mg, 8mg, 10mg, or 12mg per day. In some embodiments, the An Luoti ni, or a pharmaceutically acceptable salt thereof, is administered once daily at a dose of 6mg, 8mg, or 10mg per time. In some embodiments, the An Luoti ni or pharmaceutically acceptable salt thereof is administered at a dose of 8mg, 10mg, or 12mg per day. In some embodiments, the An Luoti ni or pharmaceutically acceptable salt thereof is administered once daily at a dose of 10mg each time. In some embodiments, the An Luoti ni or pharmaceutically acceptable salt thereof is administered once daily at a dose of 12mg each time. In some embodiments, the An Luoti ni or pharmaceutically acceptable salt thereof is administered in a dose of 6mg, 8mg, 10mg, or 12mg each time, once daily, 2 weeks after continuous administration, 1 week after discontinuation. In some embodiments, in the method or use, the An Luoti ni or pharmaceutically acceptable salt thereof is administered in a dose of 6mg, 8mg, or 10mg each time, once daily, 2 weeks of continuous administration, 1 week of withdrawal regimen. In some embodiments, in the method or use, the An Luoti ni or pharmaceutically acceptable salt thereof is administered at a dose of 8mg, 10mg, or 12mg each time, once daily, 2 weeks of continuous administration, 1 week of withdrawal. In some embodiments, in the method or use, the An Luoti ni or pharmaceutically acceptable salt thereof is administered in a dose of 10mg once daily, 2 weeks of continuous dosing, 1 week of withdrawal regimen. In some embodiments, in the method or use, the An Luoti ni or pharmaceutically acceptable salt thereof is administered in a regimen of 12mg dose each time, once daily, 2 weeks of continuous dosing, 1 week of withdrawal.

In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof each have the same or different treatment cycles. In some specific embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt 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-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof have the same treatment cycle, e.g., one treatment cycle every 3 weeks.

In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof are administered every 3 weeks for one treatment cycle. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered once every 3 weeks for a treatment cycle, and An Luoti ni or a pharmaceutically acceptable salt thereof is administered 14 times per treatment cycle, respectively. In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for one treatment cycle, on day 1 of each treatment cycle, the anti-PD-1 antibody or antigen-binding fragment thereof is administered every day 1 of each treatment cycle, and An Luoti ni or a pharmaceutically acceptable salt thereof is administered every 1-14 days of each treatment cycle. In some embodiments, in the methods or uses, the anti-TIM-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 daily on days 1-14 of each treatment cycle, an Luoti of ni or a pharmaceutically acceptable salt thereof.

In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation. In some embodiments, in the method or use, the single formulation and An Luoti ni, or a pharmaceutically acceptable salt thereof, are administered every 3 weeks for one treatment cycle. In some embodiments, in the method or use, the single formulation is administered once every 3 weeks for a treatment period, and An Luoti times, or a pharmaceutically acceptable salt thereof, is administered 14 times per treatment period. In some embodiments, in the method or use, the single formulation is administered every 3 weeks for a treatment period, on day 1 of each treatment period, and An Luoti ni, or a pharmaceutically acceptable salt thereof, is administered on days 1-14 of each treatment period. In some embodiments, in the method or use, the single formulation is administered once every 3 weeks for a treatment period, once on day 1 of each treatment period, and once daily on days 1-14 of each treatment period for An Luoti ni or a pharmaceutically acceptable salt thereof.

In some specific embodiments, in the methods or uses, 100-1800mg, 600-1500mg, or 1200-1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for one treatment cycle, 10-800mg, 50-500mg, or 100-200mg of an anti-PD-1 antibody or antigen-binding fragment thereof is administered every treatment cycle, and 84-168mg of An Luoti ni or a pharmaceutically acceptable salt thereof is administered every treatment cycle. In some specific embodiments, in the methods or uses, one treatment cycle is administered every 3 weeks, 1200mg or 1500mg of anti-TIM-3 antibody or antigen-binding fragment thereof is administered per treatment cycle, 200mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered per treatment cycle, and 84-140mg of An Luoti ni or a pharmaceutically acceptable salt thereof is administered per treatment cycle. In some specific embodiments, in the methods or uses, one treatment cycle is administered every 3 weeks, 1200mg or 1500mg of anti-TIM-3 antibody or antigen-binding fragment thereof is administered per treatment cycle, 200mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered per treatment cycle, and 112-168mg of An Luoti ni or pharmaceutically acceptable salt thereof is administered per treatment cycle. In some specific embodiments, in the methods or uses, 1200mg of the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof is administered every treatment cycle, and 84-140mg of An Luoti ni or a pharmaceutically acceptable salt thereof is administered every treatment cycle. In some specific embodiments, in the methods or uses, 1200mg of the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof is administered every treatment cycle, and 112-168mg of An Luoti ni or a pharmaceutically acceptable salt thereof is administered every treatment cycle. In some specific embodiments, in the methods or uses, 1200mg of the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof is administered every treatment cycle, and 140mg of An Luoti ni or a pharmaceutically acceptable salt thereof is administered every treatment cycle. in some specific embodiments, in the methods or uses, 1200mg of the anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, 200mg of the anti-PD-1 antibody or antigen-binding fragment thereof is administered every treatment cycle, and 168mg of An Luoti ni or pharmaceutically acceptable salt thereof is administered every treatment cycle. In some specific embodiments, in the methods or uses, 1200mg or 1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, and 84-140mg of An Luoti ni or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each treatment cycle for one treatment cycle every 3 weeks. In some specific embodiments, in the methods or uses, 1200mg or 1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, and 112-168mg of An Luoti ni or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each treatment cycle for one treatment cycle every 3 weeks. In some specific embodiments, in the methods or uses, 1200mg of anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, 200mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered every 1 day of a treatment cycle, and 84-140mg of An Luoti ni or pharmaceutically acceptable salt thereof is administered every 1-14 days of a treatment cycle. In some specific embodiments, in the methods or uses, 1200mg of anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, 200mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered every 1 day of a treatment cycle, and 112-168mg of An Luoti ni or pharmaceutically acceptable salt thereof is administered every 1-14 days of a treatment cycle. In some specific embodiments, in the methods or uses, 1200mg of anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, 200mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, and 140mg of An Luoti ni or pharmaceutically acceptable salt thereof is administered on days 1-14 of each treatment cycle. in some specific embodiments, in the methods or uses, 1200mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, and 168mg of An Luoti ni or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each treatment cycle. In some specific embodiments, in the methods or uses, 1200mg or 1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof is administered every 1 day for each treatment cycle, and 6mg, 8mg, 10mg or 12mg of An Luoti ni or pharmaceutically acceptable salt thereof is administered every 1-14 days for each treatment cycle. In some specific embodiments, in the methods or uses, 1200mg or 1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, on day 1 of each treatment cycle, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof is administered every 1 day of each treatment cycle, and 6mg, 8mg or 10mg of An Luoti ni or pharmaceutically acceptable salt thereof is administered every 1-14 days of each treatment cycle. In some specific embodiments, in the methods or uses, 1200mg or 1500mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, and 8mg, 10mg or 12mg of An Luoti ni or pharmaceutically acceptable salt thereof is administered daily on days 1-14 of each treatment cycle for one treatment cycle every 3 weeks. In some specific embodiments, in the methods or uses, 1200mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof is administered every 1 day for each treatment cycle, and 6mg, 8mg, or 10mg of An Luoti nii or a pharmaceutically acceptable salt thereof is administered every 1-14 days for each treatment cycle. In some specific embodiments, in the methods or uses, 1200mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof is administered every 1 day for each treatment cycle, and 8mg, 10mg, or 12mg of An Luoti nii or a pharmaceutically acceptable salt thereof is administered every 1-14 days for each treatment cycle. In some specific embodiments, in the methods or uses, 1200mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof is administered every 1 day for each treatment cycle, and 10mg of An Luoti ni or a pharmaceutically acceptable salt thereof is administered every 1 day to 14 days for each treatment cycle. In some specific embodiments, in the methods or uses, 1200mg of an anti-TIM-3 antibody or antigen-binding fragment thereof is administered every 3 weeks for a treatment cycle, 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof is administered every 1 day for each treatment cycle, and 12mg of An Luoti ni or a pharmaceutically acceptable salt thereof is administered every 1 day to 14 days for each treatment cycle.

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

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, is administered to the subject at a mass ratio of (0.1-50): 1, (1-30): 1, (3-20): 1, (6-18): 1, (8-12): 1 or (8-9): 1, an Luoti ni or a pharmaceutically acceptable salt thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof, and the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, is administered to the subject at a mass ratio of (0.1-50): 1, (1-30): 1, (3-20): 1, (7-15): 1, (7-11): 1 or (7-8): 1, an Luoti ni or a pharmaceutically acceptable salt thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof, and the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject and the anti-TIM-3 antibody or antigen-binding fragment thereof is administered to the subject at a mass ratio of (0.01-10): 1, (0.1-5): 1, (0.2-4): 1, (0.5-2): 1 or (1-2): 1 anti-PD-1 antibody or antigen-binding fragment thereof, an Luoti Ni or pharmaceutically acceptable salt thereof, and An Luoti Ni or pharmaceutically acceptable salt thereof, for each treatment cycle.

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof are administered in multiple doses or in a single dose during each treatment cycle. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti ni or a pharmaceutically acceptable salt thereof are administered in multiple doses during each treatment cycle.

In some embodiments, in the methods or uses, the anti-TIM-3 antibody or antigen-binding fragment thereof may be selected from 0.01 to 50mg/kg, 0.1 to 40mg/kg, 0.1 to 35mg/kg, 0.1 to 30mg/kg, 0.1 to 25mg/kg, 0.1 to 20mg/kg, 0.1 to 15mg/kg, 0.1 to 10mg/kg, 1 to 40mg/kg, 1 to 35mg/kg, 1 to 30mg/kg, 1 to 25mg/kg, 1 to 20mg/kg, 1 to 15mg/kg, 1 to 10mg/kg, 1 to 3mg/kg, 3 to 40mg/kg, 3 to 35mg/kg, 3 to 30mg/kg, 3 to 25mg/kg, 3 to 20mg/kg, 3 to 15mg/kg, 3 to 10mg/kg, 10 to 40mg/kg, 10 to 30mg/kg, 10 to 25mg/kg, 20mg/kg, or a uniform dose of 1800mg, 1000mg, 1400mg, 900mg or 1800mg administered to a subject.

In some embodiments, in the methods or uses, the anti-PD-1 antibody or antigen-binding fragment thereof may be administered at a dose selected from 0.01 to 50mg/kg, 0.1 to 40mg/kg, 0.1 to 35mg/kg, 0.1 to 30mg/kg, 0.1 to 25mg/kg, 0.1 to 20mg/kg, 0.1 to 15mg/kg, 0.1 to 10mg/kg, 1 to 30mg/kg, 1 to 25mg/kg, 1 to 20mg/kg, 1 to 15mg/kg, 1 to 10mg/kg, 1 to 8mg/kg, 1 to 5mg/kg, 1 to 3mg/kg, 3 to 30mg/kg, 3 to 25mg/kg, 3 to 20mg/kg, 3 to 15mg/kg, 3 to 10mg/kg, 3 to 8mg/kg, or 3 to 5mg/kg, or a subject, or at a uniform dose of 1-1000mg、10-1000mg、10-800mg、20-800mg、40-800mg、50-700mg、50-600mg、50-500mg、60-500mg、80-500mg、100-500mg、200-500mg、100-500mg、100-400mg、50-350mg、100-300mg、50-200mg、100-200mg、100mg or 200 mg.

In some embodiments, in the method or use An Luoti or a pharmaceutically acceptable salt thereof is administered in a divided dosing regimen, including a dosing period and a withdrawal period, which may be administered one or more times per day during the dosing period. In some embodiments, an Luoti or a pharmaceutically acceptable salt thereof is administered for 2 weeks, followed by 1 week of discontinuation. In some embodiments, an Luoti ni or a pharmaceutically acceptable salt thereof is orally administered at a dose of 6mg, 8mg, 10mg, or 12mg once daily, for 2 weeks, 1 week on-stream. In some embodiments, an Luoti ni or a pharmaceutically acceptable salt thereof is administered orally at a dose of 10mg once daily for 2 weeks, followed by 1 week of discontinuation. In some embodiments, an Luoti ni or a pharmaceutically acceptable salt thereof is administered orally at a dose of 12mg once daily for 2 weeks, followed by 1 week of discontinuation.

In some embodiments, in the methods or uses, the dosing regimen (e.g., dosing cycle, dosing time, dosing amount, and dose adjustment) of the anti-TIM-3 antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof, and/or An Luoti n or pharmaceutically acceptable salt thereof may 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-TIM-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. For example, the dosage of erlotinib or a pharmaceutically acceptable salt thereof can be adjusted from 10mg to 8mg, or further from 8mg to 6mg, and the dose adjustment of An Luoti ni or a pharmaceutically acceptable salt thereof can occur one or more times during a treatment cycle. For example, one treatment cycle of erlotinib or a pharmaceutically acceptable salt thereof can be adjusted to 5, 6 or 7 weeks. For another example, an Luoti or a pharmaceutically acceptable salt thereof may be administered with a delay of 1,2, 3,4, or 5 days during a treatment cycle.

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

In some embodiments, an anti-TIM-3 antibody or antigen-binding fragment thereof of the present application 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-TIM-3 antibody or antigen-binding fragment thereof of the application 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-TIM-3 antibody or antigen-binding fragment thereof of the application 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. CDR sequences of anti-TIM-3 antibodies or antigen binding fragments thereof are shown in table 1.

TABLE 1 CDR sequences of anti-TIM-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 Table 1 has shown CDR sequences (wherein the CDR regions shown in SEQ ID NOS: 1-6 are defined by the AbM numbering system), the scope of antibodies also encompasses antibodies defined by CDR sequences of any other numbering system definition (e.g., combinations of one or more of the Kabat, chothia, CCG, IMGT or Contact etc. definitions known in the art) when reference is made to antibodies defined by specific CDR sequences of the present application. For example, anti-TIM-3 antibodies or antigen-binding fragments thereof comprising the amino acid sequences shown in SEQ ID NO. 1, HCDR2 of the amino acid sequence shown in SEQ ID NO. 2, HCDR3 of the amino acid sequence shown in ARRYYGYDAMDY (SEQ ID NO: 31), LCDR1 of the amino acid sequence shown in SEQ ID NO. 4, LCDR2 of the amino acid sequence shown in SEQ ID NO. 5, and LCDR3 of the amino acid sequence shown in SEQ ID NO. 6 are also contemplated within the scope of the anti-TIM-3 antibodies or antigen-binding fragments thereof of the application.

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

In some embodiments, an anti-TIM-3 antibody or antigen-binding fragment thereof described herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO. 1, HCDR2 comprises the amino acid sequence set forth in SEQ ID NO. 2, HCDR3 comprises the amino acid sequence set forth in SEQ ID NO. 3, LCDR1 comprises the amino acid sequence set forth in SEQ ID NO. 4, LCDR2 comprises the amino acid sequence set forth in SEQ ID NO. 5, and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO. 6, and the heavy chain variable region comprises an amino acid sequence 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 SEQ ID NO. 7, and the light chain variable region comprises at least 80%, 81%, 82%, 83%, 84%, 90%, 91%, 92%, 93%, 96%, 98% or 100%.

QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYTINWVRQAPGQGLEWMGLFNPYNGGTTYAQKF QGRVTMTVDKSTSTVYMELSSLRSEDTAVYYCARRYYGYDAMDYWGQGTLVTVSS(SEQ ID NO:7);

DIQMTQSPSSLSASVGDRVTITCKSSQSVLYSSNQKNHLAWYQQKPGKAPKLLIYWASTRESGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCHQYLSSYTFGQGTKLEIK(SEQ ID NO:8);

EVQLQQSGAEVVRPGALVKLSCKASGFNIKDYYMHWVRQRPEQGLEWIGWIDPENDNTIYDPKFQ DRASITADTSSNTAYLQLSSLTSEDTAVYYCARDFGYVAWLVYWGQGTLVTVSA(SEQ ID NO:27);

DIVMTQSQEFMSTSVGDRVSITCKASQNVDTAVAWYQQKPGQSPKLLIYSASNRYTGVPDRFTGTGS GTDFTLTINNMQSEDLADYFCQQYSSYPTFGGRTKLEIK(SEQ ID NO:28).

For some embodiments, the anti-TIM-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 4. 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, 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-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO 9 or 29. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence 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. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises the heavy chain shown in SEQ ID NO. 9. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises the light chain shown in SEQ ID NO. 10. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence 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 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. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence shown in SEQ ID NO. 9 and a light chain of the amino acid sequence shown in SEQ ID NO. 10. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence shown in SEQ ID NO. 29 and a light chain of the amino acid sequence shown in SEQ ID NO. 30. In some specific embodiments, the heavy chain of the anti-TIM-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-TIM-3 antibody or antigen-binding fragment thereof has an amino acid sequence shown in SEQ ID NO. 29, and the light chain has an amino acid sequence 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.

QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYTINWVRQAPGQGLEWMGLFNPYNGGTTYAQKFQGRVTMTVDKSTSTVYMELSSLRSEDTAVYYCARRYYGYDAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:9);

DIQMTQSPSSLSASVGDRVTITCKSSQSVLYSSNQKNHLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYLSSYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:10);

EVQLQQSGAEVVRPGALVKLSCKASGFNIKDYYMHWVRQRPEQGLEWIGWIDPENDNTIYDPKFQDRASITADTSSNTAYLQLSSLTSEDTAVYYCARDFGYVAWLVYWGQGTLVTVSAASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:29);

DIVMTQSQEFMSTSVGDRVSITCKASQNVDTAVAWYQQKPGQSPKLLIYSASNRYTGVPDRFTGTGSGTDFTLTINNMQSEDLADYFCQQYSSYPTFGGRTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:30).

In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof of the application is mAb 50B5 or antigen-binding fragment thereof described in the patent application publication No. WO2020041520 or CN112566936, or a chimeric antibody of mAb 50B5 or antigen-binding fragment thereof, or a humanized antibody of mAb 50B5 or antigen-binding fragment thereof.

In other embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof of the application is mAb 15B4 or antigen-binding fragment thereof described in the patent application publication No. WO2020041520 or CN112566936, or a chimeric antibody of mAb 15B4 or antigen-binding fragment thereof, or a humanized antibody of mAb 15B4 or antigen-binding fragment thereof.

In other embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof of the application is selected from Lomvastomig (RG-7769) of Sabatolimab, cobolimab, surzebiclimab, roche, SHR-1702 of Henry, verzistobart (INCAGN-2390) of Agenus, BC-3402 of Lemonliving organisms, LBL-003 of Weilibbo, LNL-005 of Jian organisms, or BMS-986258 of BMS.

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 antibodies with specific CDR sequences of the application, the scope of the antibodies encompasses antibodies defined by CDR sequences of any numbering system definition (e.g., one or a combination of one or more of the AbM, kabat, chothia, CCG, IMGT or Contact etc. definitions as known in the art).

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 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.

In some embodiments, an anti-PD-1 antibody or antigen-binding fragment thereof of the application comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises the amino acid sequence set forth in SEQ ID NO. 11, HCDR2 comprises the amino acid sequence set forth in SEQ ID NO. 12, HCDR3 comprises the amino acid sequence set forth in SEQ ID NO. 13, LCDR1 comprises the amino acid sequence set forth in SEQ ID NO. 14, LCDR2 comprises the amino acid sequence set forth in SEQ ID NO. 15, and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO. 16, and the heavy chain variable region comprises an amino acid sequence 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 SEQ ID NO. 17, and the light chain variable region comprises at least 80%, 81%, 82%, 83%, 84%, 90%, 91%, 92%, 96%, 98% or 100%.

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, 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 nano Wu Liyou mab (Nivolumab), pamil mab (Pembrolizumab), terlipressin Li Shan mab (Toripalimab), singal Li Shan mab (Sintilimab), karellizumab (Camrelizumab), tirelizumab (Tislelizumab), sirolimus mab (Zimberelimab), baterimab (Balstilimab), jennuzumab (geptanolimab), lizhuzhuzhi Lipustobart (LZM-009), cimapril Li Shan mab (Cemiplimab), s Lu Lishan mab (Serplulimab), prolgolimab, puterimab (Pucotenlimab), nofazinlimab, finotonlimab, dostarlimab, cetrelimab, QL1604 of zilut, spartalizumab, retifanlimab, sasanlimab, rulonilimab (F520) of the new era pharmaceutical industry in the eastern, or Enlonstobart (SG 001) of yet healthy organisms.

Pharmaceutical compositions containing antibodies or antigen-binding fragments thereof

The anti-TIM-3 antibody or antigen-binding fragment thereof and/or the anti-PD-1 antibody or antigen-binding fragment 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. For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and/or the anti-PD-1 antibody or antigen-binding fragment thereof are formulated for parenteral administration. In some specific embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and/or the anti-PD-1 antibody or antigen-binding fragment thereof are formulated as a formulation for intravenous, intramuscular, subcutaneous, or other parenteral administration, e.g., for injection or infusion. For some specific embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and/or the anti-PD-1 antibody or antigen-binding fragment thereof are formulated for intravenous, intramuscular, or subcutaneous administration. For some specific embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and/or the anti-PD-1 antibody or antigen-binding fragment thereof may be formulated as an injection. For some specific embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and/or the anti-PD-1 antibody or antigen-binding fragment thereof are formulated as a formulation for intravenous injection or infusion.

For some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are formulated in a single formulation. For some embodiments, an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof is formulated with one or more pharmaceutically acceptable excipients to make a suitable pharmaceutical composition.

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

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

For some embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof is a water-soluble injection. In some embodiments, the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is a water-soluble injection. In some embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof is a water-soluble injection. The water-soluble injection includes, but is not limited to, a water-soluble preparation which is not freeze-dried or a water-soluble preparation which is reconstituted by freeze-dried powder.

In other embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof is a lyophilized formulation. In other embodiments, the pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized formulation. For some embodiments, the pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized formulation. The lyophilized preparation 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 concentration of the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical composition comprising the anti-PD-1 antibody or antigen-binding fragment thereof is 0.1-50mg/mL, 0.5-30mg/mL, 0.8-20mg/mL, 1-15mg/mL, 1-10mg/mL, 1-5mg/mL, 2-20mg/mL, 2-15mg/mL, 2-10mg/mL, or 2-5mg/mL. In some specific embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 0.8mg/mL, 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL, 6mg/mL, 7mg/mL, 8mg/mL, 9mg/mL, 10mg/mL, 15mg/mL, or 20mg/mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 1mg/mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 2mg/mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5mg/mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 10mg/mL.

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

An Luoti Ni or a pharmaceutically acceptable salt thereof

As used herein, the chemical name of An Luoti ni is 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine having the structural formula (I):

As used herein, erlotinib can be administered in its free base form or in the form of a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of An Luoti n are within the scope of the present application, which salts may be produced according to methods well known in the art from different organic and inorganic acids, for example the inorganic acid may be selected from hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, the organic acid may be selected from succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic or methanesulfonic acid. In some embodiments, the pharmaceutically acceptable salt of An Luoti n may be the hydrochloride salt of An Luoti n (i.e., an Luoti n of hydrochloric acid). In some embodiments, the pharmaceutically acceptable salt of An Luoti n is the dihydrochloride salt of An Luoti n.

In some embodiments of the application, an Luoti n is administered in the form of its hydrochloride salt. In some embodiments of the application, an Luoti ni is administered in the form of its dihydrochloride salt.

The dosages of An Luoti of the present application, or a pharmaceutically acceptable salt thereof, are based on the molecular weight of the compound of formula (I), unless otherwise indicated.

Pharmaceutical composition containing An Luoti Ni or pharmaceutically acceptable salt thereof

In some embodiments of the application, the pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof has a unit dose of 6mg, 8mg, 10mg, or 12mg of An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical composition includes, but is not limited to, a formulation suitable for oral, parenteral, topical administration, in some embodiments the pharmaceutical composition is a formulation suitable for oral, in some embodiments the pharmaceutical composition is a solid formulation suitable for oral, in some embodiments the pharmaceutical composition includes, but is not limited to, a tablet, a capsule.

Tyrosine kinase inhibitors

As used herein, a Tyrosine Kinase Inhibitor (TKI) refers to a substance or agent that inhibits (e.g., blocks, breaks, or inactivates) a tyrosine kinase or downstream signaling from a tyrosine kinase. Tyrosine kinases are enzymes responsible for the addition of phosphate groups (phosphorylation) to the tyrosine of proteins, a step in which TKIs are directly or indirectly inhibited. Tyrosine phosphorylation leads to activation of intracellular signaling cascades. Many TKIs are useful in cancer treatment. In one embodiment, the tyrosine kinase inhibitor refers to a substance or agent that specifically inhibits the protein phosphorylation activity of a tyrosine kinase.

In some embodiments, the tyrosine kinase inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some specific embodiments, the tyrosine kinase inhibitor is An Luoti n's hydrochloride. In some specific embodiments, the tyrosine kinase inhibitor is An Luoti n dihydrochloride.

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 oral, 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, by injection, such as intravenous or subcutaneous injection. 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, orally.

The components of the pharmaceutical combinations of the present application may each independently, or some or all of them may be co-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, such as 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 embodiments, the components of the pharmaceutical combination of the present application may each be formulated independently, or some or all of them together, into an injection. In some embodiments, the components of the pharmaceutical combination of the present application may each be formulated into a capsule independently, or together with some or all of them.

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)

In certain aspects, the neoplasm of the application is a malignancy (i.e., cancer), which refers to any malignant and/or invasive growth resulting from 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 tumor is a solid tumor that is recurrent and/or metastatic. In some embodiments, the tumor is a refractory solid tumor. In some embodiments, the tumor is a solid tumor that is unresectable. In some embodiments, the tumor is an advanced solid tumor. In some embodiments, the tumor is a locally advanced solid tumor. In some embodiments, the tumor is a primary advanced solid tumor.

In some embodiments, the tumor is liver cancer. In some embodiments, the tumor is a primary, unresectable, refractory, advanced, recurrent, and/or metastatic liver cancer. In some embodiments, the tumor is a recurrent and/or metastatic liver cancer. In some embodiments, the tumor is refractory liver cancer. In some embodiments, the tumor is a non-resectable liver cancer. In some embodiments, the tumor is advanced liver cancer. In some embodiments, the tumor is locally advanced liver cancer. In some embodiments, the tumor is a primary advanced liver cancer.

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

In some embodiments, the tumor is a hepatocellular carcinoma of stage III or II in clinical (CNLC) stage of chinese liver cancer. In some embodiments, the tumor is a hepatocellular carcinoma of chinese liver cancer clinically staged as stage III. In some embodiments, the tumor is a hepatocellular carcinoma that is stage II in clinical stages of chinese liver cancer and is not suitable for surgery and/or topical treatment.

In some embodiments, the tumor is a hepatocellular carcinoma of the Bazerana Clinical Liver Cancer (BCLC) stage B-stage or C-stage. In some embodiments, the tumor is hepatocellular carcinoma with BCLC stage C. In some embodiments, the tumor is hepatocellular carcinoma that is BCLC staged as stage B and is not amenable to surgery and/or topical treatment.

In some embodiments, the subject of liver cancer has not previously been treated for liver cancer (e.g., lacks an effective treatment regimen). In some embodiments, the subject of liver cancer has not previously received systemic treatment to treat liver cancer.

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 systemic treatment to treat hepatocellular carcinoma. In some embodiments, the subject of hepatocellular carcinoma has not previously received an immune checkpoint (e.g., PD-1, PD-L1, TIM-3) inhibitor to treat hepatocellular carcinoma. In some embodiments, the subject of hepatocellular carcinoma has not previously been immunized with cells to treat hepatocellular carcinoma. In some embodiments, the subject of hepatocellular carcinoma has not previously received surgical treatment and/or topical treatment (e.g., topical chemotherapy) to treat hepatocellular carcinoma.

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

In some embodiments, the subject of the chinese liver cancer with stage III hepatocellular carcinoma has not previously been treated for advanced or locally advanced hepatocellular carcinoma (e.g., lacks an effective treatment regimen). In some embodiments, the subject of the chinese liver cancer stage III hepatocellular carcinoma has not previously received systemic treatment to treat advanced or locally advanced hepatocellular carcinoma.

In some embodiments, the subject of the chinese liver cancer is stage II and is not suitable for surgery and/or local treatment of hepatocellular carcinoma that has not previously been treated for advanced or locally advanced hepatocellular carcinoma (e.g., lacks an effective treatment regimen). In some embodiments, the subject of the chinese liver cancer that is clinically stage II and is not suitable for surgery and/or local treatment has not previously received systemic treatment to treat advanced or locally advanced hepatocellular carcinoma.

In some embodiments, the BCLC stage is stage C hepatocellular carcinoma in which the subject was previously untreated with advanced or locally advanced hepatocellular carcinoma (e.g., lacking an effective treatment regimen). In some embodiments, the subject who is BCLC staged as stage C hepatocellular carcinoma has not previously received systemic treatment to treat advanced or locally advanced hepatocellular carcinoma.

In some embodiments, the BCLC stage is stage B and the subject of hepatocellular carcinoma unsuitable for surgery and/or local treatment has not previously been treated for advanced or locally advanced hepatocellular carcinoma (e.g., lacks an effective treatment regimen). In some embodiments, the BCLC stage is stage B and the subject of hepatocellular carcinoma not suitable for surgery and/or topical treatment has not previously received systemic treatment to treat advanced or locally advanced hepatocellular carcinoma.

In some embodiments, patients that are "unsuitable for surgery and/or topical treatment" include patients that do not benefit from surgery and/or topical treatment.

In some embodiments, the topical treatment includes, but is not limited to, surgery, hepatic arterial chemoembolization (TACE), hepatic Arterial Infusion Chemotherapy (HAIC), transcatheter arterial infusion chemotherapy (TAI), radiofrequency or microwave ablation, and absolute alcohol injection.

In some embodiments, the tumor is colorectal cancer. In some embodiments, the tumor is primary, unresectable, refractory, advanced, recurrent, and/or metastatic colorectal cancer. In some embodiments, the tumor is recurrent colorectal cancer. In some embodiments, the tumor is metastatic colorectal cancer. In some embodiments, the tumor is recurrent and/or metastatic colorectal cancer. In some embodiments, the tumor is refractory colorectal cancer. In some embodiments, the tumor is unresectable colorectal cancer. In some embodiments, the tumor is advanced colorectal cancer. In some embodiments, the tumor is locally advanced colorectal cancer. In some embodiments, the tumor is recurrent and/or metastatic advanced colorectal cancer.

In some embodiments, the subject of colorectal cancer has not previously been treated for colorectal cancer (e.g., lacks an effective treatment regimen). In some embodiments, the subject has not previously received systemic treatment for colorectal cancer.

In some embodiments, the subject of colorectal cancer has previously been treated for colorectal cancer (e.g., failed or intolerant treatment). In some embodiments, the subject of colorectal cancer has previously received one or more different anti-tumor treatment methods to treat colorectal cancer (e.g., failed or intolerant treatment).

In some embodiments, the subject of colorectal cancer has previously been treated for colorectal cancer (e.g., failed or intolerant treatment) with one or more of surgical treatment, radiation therapy, chemotherapy, and immunotherapy. In some embodiments, the subject of colorectal cancer has previously received systemic treatment to treat colorectal cancer (e.g., failed or intolerant treatment). In some embodiments, the subject of colorectal cancer has previously received treatment of colorectal cancer with an immune checkpoint inhibitor (e.g., failed or intolerant treatment). In some embodiments, the subject of colorectal cancer has previously received an EGFR-targeted drug to treat colorectal cancer (e.g., failed or intolerant treatment). In some embodiments, the subject of colorectal cancer has previously received treatment of colorectal cancer with a BRAF inhibitor (e.g., failed or intolerant treatment).

In some embodiments, the subject of colorectal cancer has previously received at least one first-line therapeutic drug to treat colorectal cancer (e.g., failed or intolerant treatment). In some embodiments, the subject of colorectal cancer has previously received at least two line treatment medications to treat colorectal cancer (e.g., failed or intolerant treatment). In some embodiments, the subject of colorectal cancer has previously received at least three-line treatment of colorectal cancer (e.g., failed or intolerant treatment). In some specific embodiments, the subject of colorectal cancer has previously received at least three-line standard therapeutic drugs to treat colorectal cancer (e.g., failed or intolerant treatment). In some embodiments, the colorectal cancer is recurrent and/or metastatic colorectal cancer. In some embodiments, the colorectal cancer is advanced colorectal cancer. In some embodiments, the colorectal cancer is recurrent and/or metastatic advanced colorectal cancer. In some embodiments, the subject of recurrent and/or metastatic colorectal cancer has previously received at least three-line treatment medication to treat colorectal cancer (e.g., failed or intolerant treatment). In some embodiments, the subject of advanced colorectal cancer has previously received at least three-line treatment of colorectal cancer (e.g., failed or intolerant treatment). In some embodiments, the subject of recurrent and/or metastatic advanced colorectal cancer has previously received at least three-line treatment medication to treat colorectal cancer (e.g., failed or intolerant treatment).

In some embodiments, the colorectal cancer is recurrent and/or metastatic colorectal cancer that fails or is intolerant of trilinear therapeutic drug treatment. In some embodiments, the colorectal cancer is advanced colorectal cancer that fails or is intolerant of trilinear treatment with a therapeutic drug. In some embodiments, the colorectal cancer is recurrent and/or metastatic advanced colorectal cancer that fails or is intolerant of trilinear therapeutic drug treatment.

In some embodiments, the therapeutic agent comprises one or a combination of several of fluorouracil, irinotecan, oxaliplatin, folinic acid, capecitabine, a drug targeting VEGF (e.g., bevacizumab), a drug targeting EGFR (e.g., cetuximab), regorafenib, furquitinib, and/or TAS-102. In some embodiments, the therapeutic agent comprises fluorouracil, irinotecan, and oxaliplatin, optionally, bevacizumab. In some embodiments, the therapeutic agent comprises fluorouracil, irinotecan, and oxaliplatin, optionally, further comprising cetuximab. In some embodiments, the therapeutic agent comprises regorafenib, furquitinib, and/or TAS-102. In some embodiments, the therapeutic agents include fluorouracil, folinic acid and irinotecan, optionally, further including cetuximab. In some embodiments, the therapeutic agent comprises fluorouracil, folinic acid and oxaliplatin, optionally, further comprising cetuximab. In some embodiments, the therapeutic agents include fluorouracil, folinic acid and irinotecan, optionally, bevacizumab. In some embodiments, the therapeutic agent comprises capecitabine and oxaliplatin, and optionally, bevacizumab. In some embodiments, the therapeutic agent comprises fluorouracil, folinic acid and oxaliplatin, optionally, bevacizumab. In some embodiments, the therapeutic agent comprises fluorouracil, folinic acid, oxaliplatin and irinotecan, optionally, bevacizumab.

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

In some embodiments, the colorectal cancer is a mismatch repair defect (dMMR) or highly microsatellite unstable (MSI-H type) colorectal cancer. In some embodiments, the colorectal cancer is a dMMR/MSI-H type recurrent or/and metastatic colorectal cancer. In some embodiments, the colorectal cancer is advanced colorectal cancer of dMMR/MSI-H type. In some embodiments, the colorectal cancer is recurrent and/or metastatic advanced colorectal cancer of dMMR/MSI-H type. In some embodiments, the subject of dMMR/MSI-H type of colorectal cancer receives an immune checkpoint inhibitor to treat colorectal cancer (e.g., treatment failed or inapplicable). In some embodiments, the subject of dMMR/MSI-H type of recurrent and/or metastatic colorectal cancer has received treatment of colorectal cancer (e.g., failed or inapplicable) with an immune checkpoint inhibitor. In some embodiments, the subject of dMMR/MSI-H type of advanced colorectal cancer receives treatment of colorectal cancer (e.g., treatment failure or inapplicability) with an immune checkpoint inhibitor. In some embodiments, the subject of dMMR/MSI-H type of recurrent and/or metastatic advanced colorectal cancer has received treatment of colorectal cancer (e.g., failed or inapplicable) with an immune checkpoint inhibitor.

In some embodiments, the colorectal cancer is RAS/BRAF wild-type colorectal cancer. In some embodiments, the colorectal cancer is recurrent and/or metastatic colorectal cancer of the RAS/BRAF wild-type. In some embodiments, the colorectal cancer is advanced colorectal cancer of RAS/BRAF wild-type. In some embodiments, the colorectal cancer is recurrent and/or metastatic advanced colorectal cancer of the RAS/BRAF wild-type. In some embodiments, the subject of RAS/BRAF wild-type colorectal cancer receives treatment of colorectal cancer (e.g., failed or inapplicable) with an EGFR-targeted drug. In some embodiments, the subject of recurrent and/or metastatic colorectal cancer of the RAS/BRAF wild-type receives treatment of colorectal cancer (e.g., failed or inapplicable) with EGFR-targeted drugs. In some embodiments, the subject of RAS/BRAF wild-type advanced colorectal cancer receives treatment of colorectal cancer (e.g., failed or inapplicable) with an EGFR-targeted drug. In some embodiments, the subject of recurrent and/or metastatic advanced colorectal cancer of the RAS/BRAF wild-type receives treatment of colorectal cancer (e.g., failed or inapplicable) with an EGFR-targeted drug.

In some embodiments, the colorectal cancer is a BRAF V600E mutant colorectal cancer. In some embodiments, the colorectal cancer is recurrent and/or metastatic colorectal cancer of the BRAF V600E mutant. In some embodiments, the colorectal cancer is advanced colorectal cancer of BRAF V600E mutant. In some embodiments, the colorectal cancer is recurrent and/or metastatic advanced colorectal cancer of BRAF V600E mutant. In some embodiments, the subject of the BRAF V600E mutant colorectal cancer receives a BRAF inhibitor to treat colorectal cancer (e.g., failed or inapplicable). In some embodiments, the subject of recurrent and/or metastatic colorectal cancer of the BRAF V600E mutant has received a BRAF inhibitor to treat colorectal cancer (e.g., failed or inapplicable). In some embodiments, the subject of advanced colorectal cancer of BRAF V600E mutant receives a BRAF inhibitor to treat colorectal cancer (e.g., failed or inapplicable). In some embodiments, the subject of recurrent and/or metastatic advanced colorectal cancer of the BRAF V600E mutant has received treatment of colorectal cancer (e.g., failed or inapplicable) with a BRAF inhibitor.

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

In some embodiments, the immune checkpoint inhibitor comprises an antibody or antigen-binding fragment thereof directed against an immune checkpoint, e.g., an anti-PD-1 antibody or antigen-binding fragment thereof, an anti-PD-L1 antibody or antigen-binding fragment thereof, and an anti-CTLA-4 antibody or antigen-binding fragment thereof.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises nal Wu Liyou mab (Nivolumab), pamil mab (Pembrolizumab), terlipressin Li Shan mab (Toripalimab), singdi Li Shan mab (Sintilimab), karellizumab (Camrelizumab), tirelizumab (Tislelizumab), sirolimus mab (Zimberelimab), baterimab (Balstilimab), jennumab (Geptanolimab), lizhuzhu medicine Lipustobart (LZM 009), cimipn Li Shan mab (Cemiplimab), s Lu Lishan mab (Serplulimab), puterimab (Pucotenlimab), prolgolimab, nofazinlimab, finotonlimab, dostarlimab, cetrelimab, zilut pharmaceutical QL1604, spartalizumab, retifanlimab, sasanlimab, mountain eastern new era pharmaceutical industry Rulonilimab, or further biotechnology Enlonstobart (SG 001).

In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises atilizumab (Atezolizumab), dulcis You Shan antibody (Durvalumab), avilamab (Avelumab), en Wo Lishan antibody (Envafolimab), shu Geli mab (Sugemalimab), adebelimab (Adebrelimab), first gram-seclizumab (Socazolimab), sudubrilimab, betifisolimab, le Pu biological LP002, monatin JS003, or tetracos KL-a167.

In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment thereof comprises Ipilimumab and Tremelimumab.

In some embodiments, the drug targeting VEGF comprises an anti-VEGF antibody or antigen-binding fragment thereof and a small molecule inhibitor of VEGF, such as bevacizumab.

In some embodiments, the EGFR-targeting drug comprises an anti-EGFR antibody or antigen-binding fragment thereof and an EGFR small molecule inhibitor, such as cetuximab and panitumumab.

In some embodiments, the BRAF inhibitor refers to a substance capable of inhibiting (e.g., blocking, disrupting, or inactivating) BRAF kinase or mutant BRAF kinase (one or more mutant forms of serine-threonine protein kinase B-RAF (BRAF)) activity or signal transduction downstream thereof, e.g., vemurafenib, regorafenib, dasatinib, dabrafenib and Encorafenib.

The present disclosure also provides some specific embodiments below, but the scope of protection of the present disclosure is not limited thereto:

Embodiment 1. A pharmaceutical combination comprising an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises:

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

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

Embodiment 2. The pharmaceutical combination according to embodiment 1, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO. 7 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO. 8, or a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO. 27 and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO. 28.

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

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

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

Embodiment 5. The pharmaceutical combination according to any of embodiments 1 to 4, 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 shown 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 shown in SEQ ID NO. 18.

Embodiment 6. The pharmaceutical combination according to any of embodiments 1 to 5, 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 shown in SEQ ID NO. 19 and a light chain having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO. 20.

Embodiment 7 the pharmaceutical combination according to any one of embodiments 1-6, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and/or the anti-PD-1 antibody or antigen-binding fragment thereof is formulated as a formulation for parenteral administration, preferably the anti-TIM-3 antibody or antigen-binding fragment thereof and/or the anti-PD-1 antibody or antigen-binding fragment thereof is formulated as a formulation for intravenous, intramuscular or subcutaneous administration.

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

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

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

Embodiment 11. The pharmaceutical combination according to any of embodiments 1 to 10, wherein the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 10-500mg, 50-200mg, or 100-200mg, preferably the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 100mg and/or 200mg.

Embodiment 12. The pharmaceutical combination according to any of embodiments 1-11, wherein the unit dose of An Luoti n or a pharmaceutically acceptable salt thereof is 6mg, 8mg, 10mg and/or 12mg.

Embodiment 13. The pharmaceutical combination according to any one of embodiments 1 to 12, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof, is present in a mass ratio of (0.1 to 180): 1, (0.2 to 50): 1, (0.5 to 9): 1, (3 to 7.5): 1, (4 to 7.5): 1 or (6 to 7.5): 1.

Embodiment 14. The pharmaceutical combination according to any one of embodiments 1 to 13, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof is An Luoti Ni or a pharmaceutically acceptable salt thereof in a mass ratio of (0.1 to 50): 1 (1 to 30): 1 (3 to 20): 1 (6 to 18): 1 (7 to 15): 1 (8 to 12): 1 (7 to 11): 1 (7 to 8): 1 or (8 to 9): 1.

Embodiment 15. The pharmaceutical combination according to any of embodiments 1 to 14, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises An Luoti Ni or a pharmaceutically acceptable salt thereof in a mass ratio of (0.01-10): 1, (0.1-5): 1, (0.2-4): 1, (0.5-2): 1 or (1-2): 1.

Embodiment 16. The pharmaceutical combination according to any one of embodiments 1-15, wherein the pharmaceutical combination is suitable for administration over a single treatment cycle, comprising 100-1800mg, 600-1500mg, or 1200-1500mg of the anti-TIM-3 antibody or antigen-binding fragment thereof, 10-800mg, 50-500mg, or 100-200mg of the anti-PD-1 antibody or antigen-binding fragment thereof, and 84-168mg, or 84-140mg, or 112-168mg of An Luoti ni or a pharmaceutically acceptable salt thereof.

Embodiment 17 the use of the pharmaceutical combination of any one of embodiments 1-16 in the manufacture of a medicament for treating a tumor in a subject.

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

Embodiment 19. The use according to embodiment 18, wherein the hepatocellular carcinoma is an advanced hepatocellular carcinoma.

Embodiment 20. The use according to embodiment 18 or 19, wherein the subject of hepatocellular carcinoma has not previously been treated for hepatocellular carcinoma, preferably wherein the subject of hepatocellular carcinoma has not previously been treated systematically for the treatment of hepatocellular carcinoma.

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

Embodiment 22. The use according to any of embodiments 17 to 21, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof, the anti-PD-1 antibody or antigen-binding fragment thereof and An Luoti n or a pharmaceutically acceptable salt thereof, are administered simultaneously, sequentially and/or alternately.

The use according to any one of embodiments 17-22, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, preferably once every 3 weeks, alternatively the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100-1800mg, 600-1500mg, or 1200-1500mg each time, preferably the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 1200mg each time.

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

Embodiment 25 the use according to any one of embodiments 17-24, wherein said An Luoti ni or pharmaceutically acceptable salt thereof is administered in a regimen of 2 weeks consecutive, 1 week off, optionally said An Luoti ni or pharmaceutically acceptable salt thereof is administered once daily at a dose of 6mg, 8mg, 10mg or 12mg each time, preferably said An Luoti ni or pharmaceutically acceptable salt thereof is administered once daily at a dose of 10mg or 12mg each time.

Embodiment 26 a kit for treating a tumor comprising the pharmaceutical combination of any one of embodiments 1-25.

Embodiment 27 use of an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a tumor, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises:

Embodiment 28. The use according to embodiment 27, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence 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.

Embodiment 29. The use according to embodiment 27 or 28, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence 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.

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

Embodiment 31. The use of any of embodiments 27-30, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence of 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 of at least 95% identity to the amino acid sequence set forth in SEQ ID NO. 18.

Embodiment 32. The use according to any one of embodiments 27 to 31, 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.

Embodiment 33. The use according to any of embodiments 27-32, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof and/or anti-PD-1 antibody or antigen-binding fragment thereof is formulated as a formulation for parenteral administration, preferably the anti-TIM-3 antibody or antigen-binding fragment thereof and/or anti-PD-1 antibody or antigen-binding fragment thereof is formulated as a formulation for intravenous, intramuscular or subcutaneous administration.

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

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

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

Embodiment 37 the use of any one of embodiments 27-36, wherein the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 10-500mg, 50-200mg, or 100-200mg, preferably the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 100mg and/or 200mg.

Embodiment 38 the use according to any one of embodiments 27-37, wherein the unit dose of An Luoti n or a pharmaceutically acceptable salt thereof is 6mg, 8mg, 10mg and/or 12mg.

Embodiment 39 the use according to any of embodiments 27-38, wherein the tumor is a solid tumor, preferably the solid tumor is liver cancer or colorectal cancer, more preferably the solid tumor is hepatocellular carcinoma.

Embodiment 40. The use according to embodiment 39, wherein the hepatocellular carcinoma is an advanced hepatocellular carcinoma.

Embodiment 41 the use according to embodiment 39 or 40, wherein the subject of hepatocellular carcinoma has not previously been treated with hepatocellular carcinoma, preferably wherein the subject of hepatocellular carcinoma has not previously been treated with a systemic treatment to treat hepatocellular carcinoma.

Embodiment 42 the use according to claim 39, wherein said colorectal cancer is advanced colorectal cancer or metastatic colorectal cancer.

Embodiment 43 the use according to any one of embodiments 27-42, wherein said anti-TIM-3 antibody or antigen-binding fragment thereof, anti-PD-1 antibody or antigen-binding fragment thereof and An Luoti n or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially and/or alternately.

Embodiment 44. The use according to any one of embodiments 27-43, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, preferably once every 3 weeks, alternatively the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 100-1800mg, 600-1500mg, or 1200-1500mg each time, preferably the anti-TIM-3 antibody or antigen-binding fragment thereof is administered at a dose of 1200mg each time.

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

Embodiment 46. The use of any of embodiments 27-45, wherein the An Luoti ni or pharmaceutically acceptable salt thereof is administered in a regimen of 2 weeks consecutive, 1 week off, optionally the An Luoti ni or pharmaceutically acceptable salt thereof is administered once daily at a dose of 6mg, 8mg, 10mg or 12mg each time, preferably the An Luoti ni or pharmaceutically acceptable salt thereof is administered once daily at a dose of 10mg or 12mg each time.

Technical effects

Generally, the use of the pharmaceutical combination of the application 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 (DCR) among treated patients;

(5) Providing a longer survival (e.g., median survival, progression Free Survival (PFS), or total survival (OS)) 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 liver cancer, especially hepatocellular carcinoma. The pharmaceutical composition and the treatment scheme have better curative effect in treating colorectal cancer, especially recurrent and/or metastatic advanced colorectal cancer. Wherein the beneficial effect is at least in one aspect of Objective Remission Rate (ORR), DCR, DOR, PFS, OS, tolerability, and side effects.

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 simultaneously or sequentially (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 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. Or a portion of the active ingredient is formulated in a single formulation and the other portions of the active ingredient are each administered to the subject as a single formulation, either simultaneously or sequentially in any order.

The term "fixed combination" refers to the simultaneous administration of the active ingredients in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation, to a subject.

The term "non-fixed combination" refers to the simultaneous, concurrent or sequential administration of two or more active ingredients as separate entities (e.g., pharmaceutical compositions, formulations) to a subject, wherein the administration of the active ingredients to the subject achieves a therapeutically effective amount level. An example of a non-fixed combination is a cocktail therapy, e.g., administration of 3 or more active ingredients. In a non-fixed combination, the individual active ingredients may be packaged, marketed or administered as a fully independent pharmaceutical composition. The term "non-immobilized combination" also includes the use of "immobilized combinations" between, or in combination with, separate entities of any one or more of the active ingredients.

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, fab fragments, fab 'fragments, F (ab)' ₂ fragments, fv fragments, isolated CDR regions, single chain Fv molecules (scFv), and other antibody fragments known in the art. The anti-TIM-3 antibodies and anti-PD-1 antibodies and antigen-binding fragments thereof disclosed herein may be 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-TIM-3 antibodies and antigen-binding fragments thereof and anti-PD-1 antibodies and antigen-binding fragments thereof of the present application may be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas, and humans. The anti-TIM-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 region of an antibody comprises a binding domain that interacts with an antigen. 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. 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 a single arm of the antibody, (V) a dAb fragment consisting of the VH domain (see Ward et al, nature.341:544-546 (1989)), (vi) an isolated Complementarity Determining Region (CDR), and (vii) a nanobody, a heavy chain variable region comprising a single variable domain and two constant domains. 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, 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, as well as framework and constant regions derived from a human antibody. For example, anti-TIM-3 antibodies as well as anti-PD-1 antibodies may comprise CDRs derived from one or more murine antibodies as well as human framework regions and human constant regions. Additional anti-TIM-3 antibodies, or variants thereof, comprising HCDR and LCDR provided herein may be generated using any human framework sequences and are also encompassed by 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. In some embodiments, such modifications include those corresponding to the mutations exemplified herein, including back mutations to germline sequences. For example, in one embodiment, one or more amino acids in the human framework regions of VH and/or VL of a humanized antibody provided herein are back mutated to corresponding amino acids in a parent murine antibody.

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," "administration," 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-TIM-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 term "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.

An Luoti Ni or a pharmaceutically acceptable salt thereof can be administered by a variety of routes including, but not limited to, oral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, vaginal, intraocular, subcutaneous, intrafat, intra-articular, intraperitoneal, and intrathecal administration. In some particular embodiments, an Luoti ni or a pharmaceutically acceptable salt thereof is administered orally.

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 unified dose is therefore specified as an absolute amount of the agent (e.g., antibody or antigen binding fragment thereof) rather than as a mg/kg dose. For example, 60kg of humans and 100kg of humans will receive the same dose of antibody.

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 "pharmaceutically acceptable salts" includes salts of a base ion with a free acid or salts of a acid ion with a free base, including for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzoate, benzenesulfonate or p-toluenesulfonate salts, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-toluenesulfonate, sodium, potassium, ammonium, amino acid salts and the like.

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

The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present application with pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the active ingredient of the present 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, "combined" or "combined" means that two or more active substances can each be administered to a subject simultaneously as a single formulation, or each as a single formulation sequentially in any order. Or all of the active ingredients are formulated in a single formulation for simultaneous administration to a subject. Or a portion of the active ingredient is formulated in a single formulation and the other portions of the active ingredient are each administered to the subject as a single formulation, either simultaneously or sequentially in any order.

The term "single dose" refers to the smallest unit of packaging containing a quantity of a pharmaceutical product, e.g., a kit of seven capsules, one capsule 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 term "recurrent" cancer is a cancer that regenerates at an initial site or a distant site after responding to an initial treatment (e.g., surgery). The term "metastatic" cancer refers to cancer that spreads from one part of the body (e.g., liver) to another part of the body.

The term "refractory" refers to the situation in which a subject or mammal has residual cancer cells in its body even after intensive treatment.

The term "first line therapy" refers to treatment with a drug that may be selected first or as a function of the patient's condition.

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".

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

As used herein, "about" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" may mean within 1 or more than 1 standard deviation per the practice of the art. Or "about" may mean a range of up to + -5%, e.g., fluctuating within + -2%, within + -1%, or within + -0.5% of a given specific numerical range. When a particular value is given in the application or in the claims, unless otherwise indicated, the meaning of "about" is to be considered within the acceptable error range for that particular value. In this context, the values of the dose, time, step parameters or conditions of all drugs are by default modified by "about" unless otherwise indicated.

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.

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 WO2020041520 or CN112566936 patent application are incorporated herein by reference. The heavy chain amino acid sequence of the anti-TIM-3 antibody in the following examples is shown in SEQ ID NO. 9 of the present 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 anti-PD-1 antibody 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 trials of hepatocellular carcinoma (HCC)

1. Criteria for inclusion

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

(1) Age 18-75 years, ECOGPS score 0-1 score, expected survival over 3 months;

(2) HCC patients diagnosed by histopathological or cytological examination or according with clinical diagnostic criteria of hepatocellular carcinoma in the american society of liver disease research (AASLD) or "guidelines for diagnosis and treatment of primary liver cancer (2022 edition);

(3) No systemic treatment for advanced HCC has been accepted in the past;

(4) Subjects with stage III (or BCLC C) in chinese liver cancer clinic (CNLC) or subjects with stage II (BCLC B) who are unsuitable for topical treatment (e.g. TACE) and surgical treatment or who are judged by researchers to be unable to benefit from topical treatment and surgical treatment;

(5) The Child-Pugh liver function classification is A or B (less than or equal to 7 points), and the MELD score is less than or equal to 18 points;

(6) HBsAg positive patients should meet HBV DNA quantification < 1X 10 ⁴ IU/mL (or 5X 10 ⁴ 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 patients would like to receive anti-HBV treatment all the way through the study period;

(7) Patients following topical treatment (including but not limited to surgery, arterial Transfer Arterial Chemoembolization (TACE), arterial infusion chemotherapy (HAIC), ductal arterial infusion chemotherapy (TAI), radiofrequency or microwave ablation, absolute alcohol injection) should be at least 4 weeks after topical treatment is completed, and

The group can be entered after sufficient recovery from treatment of toxicity and/or complications;

(8) Radiotherapy to bone metastases with clinical symptoms must be completed at least 2 weeks before the study begins;

(9) Having at least one measurable lesion (RECIST 1.1);

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

1) The standard of blood routine examination is required to be met, namely a) the hemoglobin is more than or equal to 90g/L, b) the absolute count of neutrophils is more than or equal to 1.5X10 ⁹/L, c) the count of platelets is more than or equal to 75X 10 ⁹/L, (no blood transfusion or blood products are needed in 7 days, no granulocyte colony stimulating factor is used, and no medicine correction is needed);

2) The biochemical examination is in accordance with the following standards that a) albumin is more than or equal to 30g/L (albumin or blood products are not infused within 14 days), b) alanine Aminotransferase (ALT) and aspartic acid Aminotransferase (AST) are less than 5.0 times the upper limit of the normal range (ULN), and total bilirubin is less than or equal to 3 times ULN;

c) Serum creatinine +.1.5XULN or creatinine clearance (Ccr) >50mL/min (calculated using the Cockcroft-Gault formula:

Or alternatively Or alternatively);

3) The Prolease Time (PT) is prolonged by less than or equal to 6 seconds compared with the upper limit of a normal value;

(11) Women of childbearing age should agree that contraceptive measures (e.g., intrauterine device, contraceptive or condom) must be taken during and 6 months after study completion, that serum HCG tests be negative and must be non-lactating patients within 7 days prior to study entry, and that men should agree during study

And contraceptive measures must be taken within 6 months after the end of the study period;

(12) Patients voluntarily added the study, signed informed consent, and compliance was good.

2. Test drug

2.1 Anti-PD-1 antibody injection, 100mg/10 mL/bottle, available from the company Limited of the pharmaceutical industry group;

2.2 anti-TIM-3 antibody injection, 240mg/4 mL/bottle, or 600mg/10 mL/bottle, available from the pharmaceutical company, inc., of the pharmaceutical company, inc.;

2.3 Hydroxy An Luoti Nile Capsule (active ingredient is An Luoti Nile dihydrochloride) with a specification of 12 mg/granule, 10 mg/granule, 8 mg/granule, or 6mg +.

The granules are provided by the pharmaceutical company, inc. of the pharmaceutical industry group.

3. Treatment regimen

Anti-PD-1 antibody injection for 1 treatment period of 3 weeks, and by intravenous infusion, the 1 st day (administration time window: + -3 days) of each treatment period is administered once at a dose of 200mg anti-PD-1 antibody;

anti-TIM-3 antibody injection for 1 treatment cycle at 3 weeks, with intravenous infusion, once at day1 of each treatment cycle (dosing time window: + -3 days) at a dose of 1200mg anti-TIM-3 antibody;

an Luoti Nile hydrochloride capsule for 3 weeks 1 treatment period (2 weeks of continuous administration, 1 week of discontinuation), and the administration period was orally administered at a dose of 10mg An Luoti Nile each time once daily.

The administration sequence is An Luoti Ni hydrochloride capsule, anti-PD-1 antibody injection and anti-TIM-3 antibody injection

4. Dosing regimen adjustment

4.1 Anti-PD-1 antibody injection, delay administration is allowed, but the delay administration time is not longer than 12 weeks at maximum.

4.2 Anti-TIM-3 antibody injections, delayed administration is allowed, but the delayed administration time is not longer than 12 weeks at maximum.

4.3 Hydrochloric acid An Luoti Nile Capsule, wherein in each treatment period, the hydrochloric acid An Luoti Nile capsule is allowed to delay administration in the administration period (namely, 1-14 days), the delay time is not longer than 5 days at maximum, and the delay time is not longer than 4 weeks at maximum until the administration of the next treatment period begins. The dispensing amount was allowed to be set at 10mg to 8mg to 6mg, and after a period of time, the dispensing amount was allowed to be set up once from the next cycle.

5. Evaluation criteria

The efficacy evaluation criteria were based on RECIST 1.1, while the iRECIST criteria were used to confirm efficacy. The severity of adverse events was judged using the NCI-CTC AE 5.0 standard.

6. Endpoint index

Objective Remission Rate (ORR), total survival (OS), progression Free Survival (PFS), disease Control Rate (DCR), duration of remission (DOR), etc.;

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

Incidence and severity of Adverse Events (AEs) and Severe Adverse Events (SAE).

7. Results

Preliminary research results show that the anti-TIM-3 antibody, the anti-PD-1 antibody and An Luoti Ni hydrochloride can be used in combination to safely and effectively treat advanced hepatocellular carcinoma. After the combined treatment of the anti-TIM-3 antibody, the anti-PD-1 antibody and the hydrochloric acid An Luoti, the clinical curative effect and the survival benefit of the patients with advanced hepatocellular carcinoma are obviously improved, the illness state of the patients is relieved and controlled, the progression-free survival period and the total survival period of the patients are prolonged, and partial patients can achieve Complete Remission (CR) or Partial Remission (PR), and the exemplary results are shown in the following table 3:

TABLE 3 information of curative effect

Example 2 clinical trials for colorectal cancer

1. Criteria for inclusion

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

(1) Age 18-75 years (calculated by date of informed consent), ECOGPS score 0-1 score, expected survival period exceeding 3 months, and (2) histologically/cytologically confirmed metastatic colorectal cancer with clear RAS/BRAF status.

(3) Subjects must provide satisfactory fresh or archived tumor tissue (formalin fixed, paraffin embedded (FFPE) tissue blocks or unstained FFPE slides) for mismatch repair (MMR) protein detection and the result of the detection is a complete mismatch repair function (pMMR). Acceptable MSI/MMR detection results meeting the previous requirements of patients, wherein the previous detection results are pMMR/MSI-L/MSS type, if the previous detection results are

DMMR/MSI-H type requires prior progression to treatment with PD-1/PD-L1 inhibitors.

(4) The subject was able to provide satisfactory tumor tissue for PD-L1 expression level detection (tumor tissue specimens require co-selection criterion 3). The subject was approved for a past satisfactory PD-L1 expression level detection report.

(5) Advanced colorectal cancer that progressed or was intolerant after ≡3 standard treatments, based on fluorouracil, irinotecan and oxaliplatin chemotherapy and bevacizumab treatment, patients with RAS/BRAF wild-type in the left half colon had to be treated with anti-EGFR and patients with BRAF V600E mutations had to be treated with RAF inhibitors. Patients who received oxaliplatin in adjuvant therapy and who developed metastasis within 6 months of completion of adjuvant therapy were considered to have received a first line of oxaliplatin therapy, exceeding after completion of adjuvant therapy with oxaliplatin

Patients with metastatic disease occurring for 6 months must receive oxaliplatin-containing therapy for the metastatic disease to be enrolled.

(6) At least one of the drugs failed to treat (TAS-102, regorafenib, furquitinib).

(7) The method is characterized in that the method has at least one measurable focus according to RECIST 1.1 standard, and the measurable focus is not subjected to local treatment such as radiotherapy (focus in a previous radiotherapy target area can be selected as target focus if progress is confirmed).

(8) Weight is more than or equal to 40kg and BMI more than or equal to 18.5kg/m ².

(9) The main organs function well, i.e. meet the following criteria:

1) The blood routine examination criteria need to be met (no transfusion, no correction with hematopoietic stimulatory factor type drugs within 14 days prior to examination):

a) The hemoglobin content (HB) is more than or equal to 90g/L;

b) Absolute Neutrophil Count (ANC) 1.5X10 ⁹/L;

c) Platelet count (PLT) was ≡100× ⁹/L.

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

a) Serum Total Bilirubin (TBIL) is less than or equal to 1.5 times the upper limit of normal value (ULN) (Gilbert syndrome patient is less than or equal to 3 XULN);

b) ALT and AST are less than or equal to 2.5 XULN, if liver metastasis is accompanied, ALT and AST are less than or equal to 5 XULN;

c) Serum creatinine (Cr) is less than or equal to 1.5 XULN or creatinine clearance (CCr) is less than or equal to 50mL/min (calculated by using a Cockcroft-Gault formula);

d) Urine routine examination standard is that urine routine prompts urine protein < ++, if urine protein is more than or equal to++, the urine protein ration is less than or equal to 1.0g after 24 hours.

3) The blood coagulation function is sufficient and is defined as Prothrombin Time (PT), activated Partial Thromboplastin Time (APTT) and international standardized ratio (INR) less than or equal to 1.5 XULN (anticoagulation treatment is not received).

4) Thyroid function examination should meet the following criteria that Thyroid Stimulating Hormone (TSH) is less than or equal to ULN, and if abnormal levels of triiodothyronine (T3) and tetraiodothyronine (T4) should be examined, T3 and T4 levels are normal, then selection can be made.

5) Heart color Doppler ultrasound evaluation, the Left Ventricular Ejection Fraction (LVEF) is more than or equal to 50 percent.

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

(11) The subjects voluntarily added the study, signed informed consent, and were well-compliant.

2. Test drug

2.1 Anti-PD-1 antibody injection, 100mg/10 mL/bottle, offered by the pharmaceutical company, inc., datenqing, inc., 1 treatment cycle over 3 weeks, was administered once at 200mg of anti-PD-1 antibody on day 1 (dosing time window: + -3 days) of each treatment cycle by intravenous infusion.

2.2 Anti-TIM-3 antibody injections, 240mg/4 mL/bottle, or 600mg/10 mL/bottle, offered by the pharmaceutical company, inc., on day 3 for 1 treatment cycle, were administered once on day 1 (dosing time window: + -3 days) of each treatment cycle by intravenous infusion.

The granule is provided by the pharmaceutical company Limited of the pharmaceutical industry, the day of the day, and 1 treatment period (2 weeks of continuous administration and 1 week of drug withdrawal) is 3 weeks, and the granule is orally administered at a dose of 12mg An Luoti Ni once daily during administration.

3. Treatment regimen

Test group A, anti-TIM-3 antibody injection, anti-PD-1 antibody injection and An Luoti Ni hydrochloride capsules;

test group B, anti-TIM-3 antibody injection+anti-PD-1 antibody injection;

test C anti-TIM-3 antibody injection;

Wherein, in test group A and test group B, anti-PD-1 antibody injection is firstly applied, and then anti-TIM-3 antibody injection is applied.

4. Dosing regimen adjustment

4.3 Hydrochloric acid An Luoti Nile Capsule, wherein in each treatment period, the hydrochloric acid An Luoti Nile capsule is allowed to delay administration in the administration period (namely, 1-14 days), the delay time is not longer than 5 days at maximum, and the delay time is not longer than 4 weeks at maximum until the administration of the next treatment period begins. The dispensing amount was allowed to be set at 12mg to 10mg to 8mg, and after a period of time, the dispensing amount was allowed to be set up once from the next cycle.

5. Evaluation criteria

6. Endpoint index

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

Incidence and severity of Adverse Events (AEs) and Severe Adverse Events (SAE).

7. Results

Preliminary studies have shown that the combination of an anti-TIM-3 antibody and an anti-PD-1 antibody, or the combination of an anti-TIM-3 antibody, an anti-PD-1 antibody and An Luoti Ni HCl, can safely and effectively treat advanced colorectal cancer.

Claims

1. A pharmaceutical combination comprising an anti-TIM-3 antibody or antigen-binding fragment thereof, an anti-PD-1 antibody or antigen-binding fragment thereof, and An Luoti n or a pharmaceutically acceptable salt thereof, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises:

2. The pharmaceutical combination of claim 1, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises:

A heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence 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 according to claim 1 or 2, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises:

A heavy chain having an amino acid sequence 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 according to any one of claims 1 to 3, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises HCDR1 of the amino acid sequence shown in SEQ ID NO. 11, HCDR2 of the amino acid sequence shown in SEQ ID NO. 12, HCDR3 of the amino acid sequence shown in SEQ ID NO. 13, LCDR1 of the amino acid sequence shown in SEQ ID NO. 14, LCDR2 of the amino acid sequence shown in SEQ ID NO. 15, and LCDR3 of the amino acid sequence shown in SEQ ID NO. 16.

5. The pharmaceutical combination according to any one of claims 1 to 4, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region 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.

6. The pharmaceutical combination according to any one of claims 1-5, 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.

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

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

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

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